Mesenchymal stromal cells in the treatment of pediatric hematopoietic cell transplantation-related complications (graft vs. host disease, hemorrhagic cystitis, graft failure and poor graft function): a single center experience.

Objectives: To describe mesenchymal stromal cells (MSCs) in the treatment of hematopoietic stem cell transplantation (HSCT) complications and to assess its safety and efficacy. Methods: Single-center retrospective study (2016-2023). Patients under 20 years who received MSCs for the treatment of HSCT-related complications were included. Results: Thirty patients (53.7% boys), median age at transplant 11 years (range 2-19) were included. MSCs indications were: graft-vs.-host disease (GVHD) in 18 patients (60%), of them 13 had acute GVHD (43.3%) and 5 chronic GVHD (16.7%); Grade 3-4 hemorrhagic cystitis (HC) in 4 (13.3%); poor graft function (PGF) in 6 (20%), 5 of them receiving MSCs with a CD34 stem cell-boost coinfusion; graft failure (GF) in 2 (6.7%), to enhance engraftment after a subsequent HSCT. Infusion-related-adverse-events were not reported. Overall response (OR) was 83% (25/30); 44% of responders (11/25) showed complete response (CR). OR for GVHD, HC, PGF and GF was 83.3%, 100%, 66.7% and 100% respectively. Response rate was 40% (95% CI: 20-55) and 79% (95% CI: 57-89) at 15 and 30 days. With a median follow-up of 21 months (IQR11-52.5), overall survival (OS) was 86% (95% CI: 74-100) and 79% (95% CI: 65-95) at 6 and 12 months post-MSCs infusion. Conclusion: In our study, the most frequent indication of MSCs was refractory aGVHD (43.3%). Response rates were high (OR 83%) and safety profile was good.

Drug Cost Avoidance Resulting from Participation in Clinical Trials: A 10-Year Retrospective Analysis of Cancer Patients with Solid Tumors.

The objective of this single-center retrospective study was to describe the clinical characteristics of adult patients with solid tumors enrolled in cancer clinical trials over a 10-year period (2010-2019) and to assess drug cost avoidance (DCA) associated with sponsors' contributions. The sponsors' contribution to pharmaceutical expenditure was calculated according to the actual price (for each year) of pharmaceutical specialties that the Vall d'Hebron University Hospital (HUVH) would have had to bear in the absence of sponsorship. A total of 2930 clinical trials were conducted with 10,488 participants. There were 140 trials in 2010 and 459 in 2019 (228% increase). Clinical trials of high complexity phase I and basket trials accounted for 34.3% of all trials. There has been a large variation in the pattern of clinical research over the study period, whereas, in 2010, targeted therapy accounted for 79.4% of expenditure and cytotoxic drugs for 20.6%; in 2019, immunotherapy accounted for 68.4%, targeted therapy for 24.4%, and cytotoxic drugs for only 7.1%. A total of four hundred twenty-one different antineoplastic agents were used, the variability of which increased from forty-seven agents in 2010, with only seven of them accounting for 92.8% of the overall pharmaceutical expenditure) to three hundred seventeen different antineoplastic agents in 2019, with thirty-three of them accounting for 90.6% of the overall expenditure. The overall expenditure on antineoplastic drugs in clinical care patients not included in clinical trials was EUR 120,396,096. The total cost of antineoplastic drugs supplied by sponsors in a clinical trial setting was EUR 107,306,084, with a potential DCA of EUR 92,662,609. Overall, clinical trials provide not only the best context for the progress of clinical research and healthcare but also create opportunities for reducing cancer care costs.

Reducing the demand for magnetic resonance imaging scans and prostate biopsies during the early detection of clinically significant prostate cancer: Applying the Barcelona risk-stratified pathway in Catalonia.

PURPOSE: To analyze the reduction in multiparametric magnetic resonance imaging (mpMRI) demand and prostate biopsies after the hypothetical implementation of the Barcelona risk-stratified pathway (BCN-RSP) in a population of the clinically significant prostate cancer (csCaP) early detection program in Catalonia. MATERIALS AND METHODS: A retrospective comparation between the hypothetical application of the BCN-RSP and the current pathway, which relied on pre-biopsy mpMRI and targeted and/or systematic biopsies, was conducted. The BCN-RSP stratify men with suspected CaP based on a prostate specific antigen (PSA) level >10 ng/ml and a suspicious rectal examination (DRE), and the Barcelona-risk calculator 1 (BCN-RC1) to avoid mpMRI scans. Subsequently, candidates for prostate biopsy following mpMRI are selected based on the BCN-RC2. This comparison involved 3,557 men with serum PSA levels > 3.0 ng/ml and/or suspicious DRE. The population was recruited prospectively in 10 centers from January 2021 and December 2022. CsCaP was defined when grade group ≥ 2. RESULTS: CsCaP was detected in 1,249 men (35.1%) and insignificant CaP was overdeteced in 498 (14%). The BCN-RSP would have avoid 705 mpMRI scans (19.8%), and 697 prostate biopsies (19.6%), while 61 csCaP (4.9%) would have been undetected. The overdetection of insignificant CaP would have decrease in 130 cases (26.1%), and the performance of prostate biopsy for csCaP detection would have increase to 41.5%. CONCLUSION: The application of the BCN-RSP would reduce the demand for mpMRI scans and prostate biopsies by one fifth while less than 5% of csCaP would remain undetected. The overdetection of insignificant CaP would decrease by more than one quarter and the performance of prostate biopsy for csCaP detection would increase to higher than 40%.

Effect of 5-Alpha Reductase Inhibitors on Magnetic Resonance Imaging and Prostate Cancer Detection.

Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our objective is to analyze the effect of 5-ARI on the prostate imaging-reporting and data system (PI-RADS) distribution and csPCa and insignificant PCa (iPCa) detection. Among 2212 men with serum prostate-specific antigen levels of >3.0 ng/mL and/or suspicious digital rectal examinations who underwent mpMRI and targeted and/or systematic biopsies, 120 individuals exposed to 5-ARI treatment for over a year were identified. CsPCa was defined when the grade group (GG) was >2. The overall csPCa and iPCa detection rates were 44.6% and 18.8%, respectively. Since logistic regression revealed independent predictors of PCa, a randomized matched group of 236 individuals was selected for analysis. The PI-RADS distribution was comparable with 5-ARI exposure (p 0.685). The CsPCa detection rates in 5-ARI-naïve men and 5-ARI-exposed men were 52.6% and 47.4%, respectively (p 0.596). IPCa was detected in 37.6 and 62.5%, respectively (p 0.089). The tumor GG distribution based on 5-ARI exposure was similar (p 0.149) to the rates of csPCa and iPCa across the PI-RADS categories. We conclude that exposure to 5-ARI in suspected PCa men did not change the PI-RADS distribution and the csPCa and iPCa detection rates.

Investigating Efficient Risk-Stratified Pathways for the Early Detection of Clinically Significant Prostate Cancer.

Risk-stratified pathways (RSPs) are recommended by the European Association of Uro-logy (EAU) to improve the early detection of clinically significant prostate cancer (csPCa). RSPs can reduce magnetic resonance imaging (MRI) demand, prostate biopsies, and the over-detection of insignificant PCa (iPCa). Our goal is to analyze the efficacy and cost-effectiveness of several RSPs by using sequential stratifications from the serum prostate-specific antigen level and digital rectal examination, the Barcelona risk calculators (BCN-RCs), MRI, and Proclarix™. In a cohort of 567 men with a serum PSA level above 3.0 ng/mL who underwent multiparametric MRI (mpMRI) and targeted and/or systematic biopsies, the risk of csPCa was retrospectively assessed using Proclarix™ and BCN-RCs 1 and 2. Six RSPs were compared with those recommended by the EAU that, stratifying men from MRI, avoided 16.7% of prostate biopsies with a prostate imaging-reporting and data system score of <3, with 2.6% of csPCa cases remaining undetected. The most effective RSP avoided mpMRI exams in men with a serum PSA level of >10 ng/mL and suspicious DRE, following stratifications from BCN-RC 1, mpMRI, and Proclarix™. The demand for mpMRI decreased by 19.9%, prostate biopsies by 19.8%, and over-detection of iPCa by 22.7%, while 2.6% of csPCa remained undetected as in the recommended RSP. Cost-effectiveness remained when the Proclarix™ price was assumed to be below EUR 200.

The Role of Digital Rectal Examination Prostate Volume Category in the Early Detection of Prostate Cancer: Its Correlation with the Magnetic Resonance Imaging Prostate Volume.

PURPOSE: To relate the prostate volume category (PVC) assessed with digital rectal examination (DRE)-small, median, and large-and the prostate volumes (PVs) assessed with magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS). To compare the clinically significant prostate cancer (csPCa) discrimination ability of two predictive models based on DRE-PVC and MRI-PV. MATERIALS AND METHODS: A prospective trial of 2,090 men with prostate-specific antigen >3 ng/mL and/or PCa suspicious DRE were prospectively recruited in 10 centers from Catalonia (Spain), between 2021 and 2022, in whom DRE-PVC was assessed. Pre-biopsy MRI, and 12-core TRUS-random biopsy was always performed after 2- to 6-core TRUS-fusion targeted biopsy of prostate imaging-report and data system >3 lesions. In 370 men (17.7%) the DRE-PVC was unconclusive. Among the 1,720 men finally analyzed the csPCa (grade group >2) detection was 42.4%. RESULTS: The median (interquartile range) of TRUS and MRI-PVs of small prostates were 33 mL (19-37 mL) and 35 mL (23-30 mL), p=0.410; in median prostates they were 51 mL (38-58 mL) and 55 mL (48-63 mL) respectively, p<0.001; in large prostates 80 mL (60-100 mL) and 95 mL (75-118 mL) respectively, p<0.001. The predictive models sharing the MRI-PV and DRE-PVC showed areas under the curves of 0.832 (95% confidence interval [CI], 0.813-0.851) and 0.828 (95% CI, 0.809-0.848) respectively, p=0.632, as well as similar net benefit and clinical utility. CONCLUSIONS: PVC was unconclusive in 17% of DREs. MRI-PV overestimated the TRUS-PV in median and large prostates. The predictive models based on MRI-PV and DRE-PVC showed similar efficacy to predict csPCa. PVC assessed with DRE is helpful to predict the csPCa risk before MRI.

Association of magnetic resonance imaging phenotypes and serum biomarker levels with treatment response and long-term disease outcomes in multiple sclerosis patients.

BACKGROUND AND PURPOSE: The aim was to evaluate whether magnetic resonance imaging (MRI) phenotypes defined by inflammation and neurodegeneration markers correlate with serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relapsing-remitting multiple sclerosis (RRMS) patients; and to explore the role of radiological phenotypes and biomarker levels on treatment response and long-term prognostic outcomes. METHODS: Magnetic resonance imaging scans from 80 RRMS patients were classified at baseline of interferon-beta (IFNß) treatment into radiological phenotypes defined by high and low inflammation and high and low neurodegeneration, based on the number of contrast-enhancing lesions, brain parenchymal fraction and the relative volume of non-enhancing black holes on T1-weighted images. Serum levels of NfL and GFAP were measured at baseline with single molecule array (Simoa) assays. MRI phenotypes and serum biomarker levels were investigated for their association with IFNß response, and times to second-line therapies, secondary-progressive MS (SPMS) conversion and Expanded Disability Status Scale (EDSS) 6.0. RESULTS: Mean (SD) follow-up was 17 (2.9) years. Serum NfL levels and GFAP were higher in the high inflammation (p = 0.04) and high neurodegeneration phenotypes (p = 0.03), respectively. The high inflammation phenotype was associated with poor response to IFNß treatment (p = 0.04) and with shorter time to second-line therapies (p = 0.04). In contrast, the high neurodegeneration phenotype was associated with shorter time to SPMS (p = 0.006) and a trend towards shorter time to EDSS 6.0 (p = 0.09). High serum NfL levels were associated with poor response to IFNß treatment (p = 0.004). CONCLUSIONS: Magnetic resonance imaging phenotypes defined by inflammation and neurodegeneration correlate with serum biomarker levels, and both have prognostic implications in treatment response and long-term disease outcomes.

Isavuconazole use and TDM in real-world pediatric practice.

Isavuconazole (ISA) is approved for treating invasive aspergillosis and mucormycosis in adults, but its use in children remains off-label. We report on the use of ISA in real-world pediatric practice with 15 patients receiving ISA for treatment of invasive fungal infections. Therapeutic drug monitoring (TDM) was performed in all patients, with 52/111 (46.8%) Ctrough determinations out of range, thus supporting the need for TDM in children, especially those receiving extracorporeal membrane oxygenation (ECMO).

Plasma metabolomic profiles of plant-based dietary indices reveal potential pathways for metabolic syndrome associations.

BACKGROUND AND AIMS: Plant-based dietary patterns have been associated with improved health outcomes. This study aims to describe the metabolomic fingerprints of plant-based diet indices (PDI) and examine their association with metabolic syndrome (MetS) and its components in a Danish population. METHODS: The MAX study comprised 676 participants (55% women, aged 18-67 y) from Copenhagen. Sociodemographic and dietary data were collected using questionnaires and three 24-h dietary recalls over one year (at baseline, and at 6 and 12 months). Mean dietary intakes were computed, as well as overall PDI, healthful (hPDI) and unhealthful (uPDI) scores, according to food groups for each plant-based index. Clinical variables were also collected at the same time points in a health examination that included complete blood tests. MetS was defined according to the International Diabetes Federation criteria. Plasma metabolites were measured using a targeted metabolomics approach. Metabolites associated with PDI were selected using random forest models and their relationships with PDIs and MetS were analyzed using generalized linear mixed models. RESULTS: The mean prevalence of MetS was 10.8%. High, compared to low, hPDI and uPDI scores were associated with a lower and higher odd of MetS, respectively [odds ratio (95%CI); hPDI: 0.56 (0.43-0.74); uPDI: 1.61 (1.26-2.05)]. Out of 411 quantified plasma metabolites, machine-learning metabolomics fingerprinting revealed 13 metabolites, including food and food-related microbial metabolites, like hypaphorine, indolepropionic acid and lignan-derived enterolactones. These metabolites were associated with all PDIs and were inversely correlated with MetS components (p < 0.05). Furthermore, they had an explainable contribution of 12% and 14% for the association between hPDI or uPDI, respectively, and MetS only among participants with overweight/obesity. CONCLUSIONS: Metabolites associated with PDIs were inversely associated with MetS and its components, and may partially explain the effects of plant-based diets on cardiometabolic risk factors.

Use of Drugs in Clinical Practice and the Associated Cost of Cancer Treatment in Adult Patients with Solid Tumors: A 10-Year Retrospective Cohort Study.

BACKGROUND: Cancer is one of the leading causes of morbidity and mortality in the world. Its growing incidence and prevalence, as well as the advances in diagnostic and treatment tools, motivate an open debate about the economic burden it may place on health systems and have raised concerns about access to this technological innovation. There is a lack of information on the detailed costs of pharmacological treatment of cancer in our health setting. In this context, it is necessary to know the use of drugs in cancer treatment in conditions of real clinical practice. A real-word, evidence-based retrospective cohort study was conducted at Vall d'Hebron University Hospital (VHUH), the largest hospital complex in Catalonia, Spain, in order to determine the use of drugs and the associated cost in real clinical practice for the treatment of solid tumors in adult patients attended at this institution over 10 years (2010-2019). METHODS: This was a single-center retrospective cohort study of adult cancer patients attended in clinical practice at the Medical Oncology Department of VHUH between 1 January 2010 and 31 December 2019. Data of prescription, preparation, and cost of antineoplastic treatments were analyzed by pharmacological class (cytotoxic drugs, immunotherapy, targeted therapy, radiopharmaceuticals, and others), by antineoplastic agent, and by type of tumor. The number of patients and the pharmaceutical expenditure corresponding to all these subgroups were recorded. The cost per patient in each tumor location was also calculated. RESULTS: The study population included 13,209 patients with an overall pharmaceutical antineoplastic expenditure of EUR 120,396,097, increasing from 7.67% in relation to the total HUVH pharmaceutical expenditure in 2010 to 12.82% in 2019. By pharmacological class, the specific weight of the cost of targeted therapy is relevant (75.22% of pharmaceutical antineoplastic expenditure, 21.3% of patients) compared to the group of conventional cytotoxics (17.25% of pharmaceutical antineoplastic expenditure, 76.37% of patients), while immunotherapy has represented the largest relative increase, from 5% in 2014 to 12% in 2019. Eight targeted therapy drugs represented 50% of the costs of the targeted therapy drug class (palbociclib, trastuzumab, pertuzumab, bevacizumab, nivolumab, cetuximab, pembrolizumab, and trastuzumab emtansine). Eleven tumor sites accounted for 90% of the expenditure in 71% of all patients. Breast cancer had the highest expenditure during the study period (EUR 34,332,210) and at each individual year. Melanoma showed the highest increase, with 9.7% of total pharmaceutical antineoplastic expenditure in 2019 (2% of patients), representing a paradigm of the rising costs of cancer treatment due to the incorporation of new high-cost therapies. The average annual cost per patient was highly variable depending on the pathology. There was a growing increase in costs per patient in most tumor locations, particularly in patients with melanoma (from EUR 1922 in 2010 to EUR 37,020 in 2019), prostate cancer (from EUR 2992 in 2010 to EUR 14,118 in 2019), and non-small cell lung cancer (from EUR 3545 in 2010 to EUR 8371 in 2019). The relevance of the difference in monthly cost per patient that has been identified for the different intrinsic subtypes in breast cancer patients during 2019 (HER2+ EUR 2661/month, Luminal EUR 881/month, Triple negative EUR 386/month) makes us consider suggesting differentiated reimbursement rates for certain clinical conditions. Finally, support treatment with antiemetic drugs, erythropoietin stimulating agents, granulocyte-colony stimulating factor (G-CSF), and bone resorption inhibitors has involved a cost of EUR 5,751,910, which represents 4.6% of the overall pharmacological cost of cancer treatment. CONCLUSION: This study provides detailed insights on the oncological pharmaceutical expenditure for the treatment for solid tumors in the VHUH, based on real cost information from our hospital practice and for all antineoplastic therapies and types of solid tumors. This type of information on all the different types of cancer can be useful to better understand the economic burden of the disease and can be decisive for allocating public resources and funds for research, especially in those areas where information is scarce and therefore where further studies are needed. The contribution to knowledge of the cost of oncology therapy is of great value due to its realism and scope.

Sustainable intensification for a larger global rice bowl.

Future rice systems must produce more grain while minimizing the negative environmental impacts. A key question is how to orient agricultural research & development (R&D) programs at national to global scales to maximize the return on investment. Here we assess yield gap and resource-use efficiency (including water, pesticides, nitrogen, labor, energy, and associated global warming potential) across 32 rice cropping systems covering half of global rice harvested area. We show that achieving high yields and high resource-use efficiencies are not conflicting goals. Most cropping systems have room for increasing yield, resource-use efficiency, or both. In aggregate, current total rice production could be increased by 32%, and excess nitrogen almost eliminated, by focusing on a relatively small number of cropping systems with either large yield gaps or poor resource-use efficiencies. This study provides essential strategic insight on yield gap and resource-use efficiency for prioritizing national and global agricultural R&D investments to ensure adequate rice supply while minimizing negative environmental impact in coming decades.

Use of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy.

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA.

Voriconazole Use in Children: Therapeutic Drug Monitoring and Control of Inflammation as Key Points for Optimal Treatment.

Voriconazole plasma concentrations (PC) are highly variable, particularly in children. Dose recommendations in 2-12-year-old patients changed in 2012. Little data on therapeutic drug monitoring (TDM) after these new recommendations are available. We aimed to evaluate voriconazole monitoring in children with invasive fungal infection (IFI) after implementation of new dosages and its relationship with safety and effectiveness. A prospective, observational study, including children aged 2-12 years, was conducted. TDM was performed weekly and doses were changed according to an in-house protocol. Effectiveness, adverse events, and factors influencing PC were analysed. A total of 229 PC from 28 IFI episodes were obtained. New dosing led to a higher rate of adequate PC compared to previous studies; still, 35.8% were outside the therapeutic range. In patients aged < 8 years, doses to achieve therapeutic levels were higher than recommended. Severe hypoalbuminemia and markedly elevated C-reactive protein were related to inadequate PC. Therapeutic PC were associated with drug effectiveness and safety. Higher doses in younger patients and a dose adjustment protocol based on TDM should be considered. Voriconazole PC variability has decreased with current updated recommendations, but it remains high and is influenced by inflammatory status. Additional efforts to control inflammation in children with IFI should be encouraged.

A drought-responsive rice amidohydrolase is the elusive plant guanine deaminase with the potential to modulate the epigenome.

Drought stress in plants causes differential expression of numerous genes. One of these differentially expressed genes in rice is a specific amidohydrolase. We characterized this amidohydrolase gene on the rice chromosome 12 as the first plant guanine deaminase (OsGDA1). The biochemical activity of GDA is known from tea and coffee plants where its catalytic product, xanthine, is the precursor for theine and caffeine. However, no plant gene that is coding for GDA is known so far. Recombinant OsGDA1 converted guanine to xanthine in vitro. Measurement of guanine and xanthine contents in the OsGDA1 knockout (KO) line and in the wild type Tainung 67 rice plants also suggested GDA activity in vivo. The content of cellular xanthine is important because of its catabolic products allantoin, ureides, and urea which play roles in water and nitrogen stress tolerance among others. The identification of OsGDA1 fills a critical gap in the S-adenosyl-methionine (SAM) to xanthine pathway. SAM is converted to S-adenosyl-homocysteine (SAH) and finally to xanthine. SAH is a potent inhibitor of DNA methyltransferases, the reduction of which leads to increased DNA methylation and gene silencing in Arabidopsis. We report that the OsGDA1 KO line exhibited a decrease in SAM, SAH and adenosine and an increase in rice genome methylation. The OsGDA1 protein phylogeny combined with mutational protein destabilization analysis suggested artificial selection for null mutants, which could affect genome methylation as in the KO line. Limited information on genes that may affect epigenetics indirectly requires deeper insights into such a role and effect of purine catabolism and related genetic networks.

CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS.

OBJECTIVE: To identify biomarkers associated with progressive phases of MS and with neuroprotective potential. METHODS: Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs). RESULTS: Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01). CONCLUSION: These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.

Antifungal stewardship in a tertiary care paediatric hospital: the PROAFUNGI study.

BACKGROUND: The increasing use of antifungal drugs (AF) in children and the concern for related adverse events and costs has led to the development of specific AF stewardship programmes (AFS). Studies in adult patients have shown improvements in AF prescription and usage after implementation, but paediatric data are scant. The aim of this PROAFUNGI study was to describe the use and appropriateness of AF in a high complexity paediatric centre. METHODS: Observational, prospective, single-centre, modified point-prevalence study (11 surveys, July-October 2018), including paediatric (< 18 years) patients receiving at least one systemic AF. Prescriptions were evaluated by the AFS team. RESULTS: The study included 119 prescriptions in 55 patients (53% males, median age 8.7 years [IQR 2.4-13.8]). The main underlying condition was cancer (45.5% of patients; HSCT in 60% of them); and the first indication for AF was prophylaxis (75 prescriptions, 63.2%). Liposomal amphotericin B was used most commonly (46% prescriptions), mainly as prophylaxis (75%). Among the 219 evaluations, 195 (89%) were considered optimal. The reason for non-optimal prescriptions was mostly lack of indication (14/24), especially in critical patients with ventricular assist devices. The use of AF without paediatric approval accounted for 8/24 inappropriate prescriptions. CONCLUSIONS: A high rate of AF appropriateness was found for the children's hospital as a whole, in relation with a well-established AFS. Nonetheless, the identification of specific areas of improvement should guide future actions of the AFS team, which will focus mainly on prophylaxis in critically ill patients receiving circulatory assistance and the use of non-approved drugs in children.

The Ontologies Community of Practice: A CGIAR Initiative for Big Data in Agrifood Systems.

Heterogeneous and multidisciplinary data generated by research on sustainable global agriculture and agrifood systems requires quality data labeling or annotation in order to be interoperable. As recommended by the FAIR principles, data, labels, and metadata must use controlled vocabularies and ontologies that are popular in the knowledge domain and commonly used by the community. Despite the existence of robust ontologies in the Life Sciences, there is currently no comprehensive full set of ontologies recommended for data annotation across agricultural research disciplines. In this paper, we discuss the added value of the Ontologies Community of Practice (CoP) of the CGIAR Platform for Big Data in Agriculture for harnessing relevant expertise in ontology development and identifying innovative solutions that support quality data annotation. The Ontologies CoP stimulates knowledge sharing among stakeholders, such as researchers, data managers, domain experts, experts in ontology design, and platform development teams.

Photosynthesis research: a model to bridge fundamental science, translational products, and socio-economic considerations in agriculture.

Despite impressive success in molecular physiological understanding of photosynthesis, and preliminary evidence on its potential for quantum shifts in agricultural productivity, the question remains of whether increased photosynthesis, without parallel fine-tuning of the associated processes, is enough. There is a distinct lack of formal socio-economic impact studies that address the critical questions of product profiling, cost-benefit analysis, environmental trade-offs, and technological and market forces in product acceptability. When a relatively well understood process gains enough traction for translational value, its broader scientific and technical gap assessment, in conjunction with its socio-economic impact assessment for success, should be a prerequisite. The successes in the upstream basic understanding of photosynthesis should be integrated with a gap analysis for downstream translational applications to impact the farmers' and customers' lifestyles and livelihoods. The purpose of this review is to assess how the laboratory, the field, and the societal demands from photosynthesis could generate a transformative product. Two crucial recommendations from the analysis of the state of knowledge and potential ways forward are (i) the formulation of integrative mega-projects, which span the multistakeholder spectrum, to ensure rapid success in harnessing the transformative power of photosynthesis; and (ii) stipulating spatiotemporal, labour, and economic criteria to stage-gate deliverables.

Rice Seed Germination Underwater: Morpho-Physiological Responses and the Bases of Differential Expression of Alcoholic Fermentation Enzymes.

The water-, energy-, and labor-intensive system of transplanted puddled rice (Oryza sativa) is steadily being replaced by direct seeding due to the progressive scarcity of these resources. However, the alternate dry direct seeding leads to competition with weeds and poor establishment when soils are flooded. Direct seeded rice capable of anaerobic germination (germination in flooded soil, AG) is ideal, which under rainfed ecosystems would also overcome waterlogging during germination. AG tolerance is associated with faster germination and faster elongation of coleoptiles, with the activities of alcoholic fermentation enzymes replacing aerobic respiration as a source of energy. To better understand the variability in the morpho-physiological responses and in the nature of the alcoholic fermentation enzymes during AG, 21 rice genotypes were studied. The genotypes Khao Hlan On (KHO) and IR42 were used as the tolerant and susceptible checks, respectively. KHO exhibited faster germination, with 82.5% of the coleoptiles emerging out of 10 cm of water within 8 days, whereas IR42 exhibited 20% germination and limited coleoptile growth. Among the test genotypes, four performed well, including two that are drought tolerant. Increased content and activity of the alcoholic fermentation enzymes, alcohol dehydrogenase (ADH1) and acetaldehyde dehydrogenase (ALDH2a and ALDH2b), was noted in KHO under anaerobic than under aerobic conditions and also in comparison with IR42 under AG. Gene transcripts for these enzymes were also more in KHO undergoing AG. However, no major differences were observed between KHO and IR42 in the critical cis-acting regulatory elements, such as the auxin, light, and sugar response elements, in the promoters of ADH1, ALDH2a, and ALDH2b genes. Post-transcriptional and post-translational regulatory mechanisms were implicated for the increased transcript and protein content/activity of the enzymes in KHO by observing four different transcripts of ALDH2a and a unique non-glycosylated form of ADH1 under AG. IR42 lacked the non-glycosylated ADH1 and contained only a truncated form of ALDH2a, which lacked the active site. Additionally, KHO exhibited increased activity and more isoforms for reactive oxygen species detoxifying enzymes under AG compared to IR42. These results highlight the need for a deeper functional understanding of the critical enzymes involved in AG.

Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy.

OBJECTIVE: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). METHODS: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively. RESULTS: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment. INTERPRETATION: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195.