Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection.

To globally profile circRNAs, we employ RNA-Sequencing paired with chimeric junction analysis for alpha-, beta-, and gamma-herpesvirus infection. We find circRNAs are, as a population, resistant to host shutoff. We validate this observation using ectopic expression assays of human and murine herpesvirus endoribonucleases. During lytic infection, four circRNAs are commonly induced across all subfamilies of human herpesviruses, suggesting a shared mechanism of regulation. We test one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs are upregulated by either interferon-ß or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we find an interferon-stimulated circRNA, circRELL1, inhibits lytic Herpes Simplex Virus-1 infection. We previously reported circRELL1 inhibits lytic Kaposi sarcoma-associated herpesvirus infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape.

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

Effectiveness and toxicity of five-fraction prone accelerated partial breast irradiation.

PURPOSE: Our institution was an early adopter of 5-fraction accelerated partial breast irradiation (ABPI) to treat women with early-stage breast cancer. This study reports long-term oncologic and cosmetic outcomes. METHODS: We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Logistic regression models were used to identify factors associated with development of late toxicities, clinician, and patient-rated cosmesis. Kaplan-Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free survival (LR-RFS). RESULTS: 442 patients received APBI either daily (56%) or every other day (44%) in the prone position (92%). At a median follow-up of 48 months (range: 5.96-155 months), 12 (2.7%) patients developed a local recurrence (LR). Out of 258 patients with > 3-month toxicity data available, the most common late grade ≥ 2 adverse event was breast fibrosis (6.2%). On multivariate analysis, daily APBI treatment (vs every other day) did not correlate with an increased risk of any late grade ≥ 2 toxicity though it did correlate with a lower risk of any late grade ≥ 2 fibrosis. Overall, at a median follow-up of 80 months, the rates of good-excellent physician and patient-rated cosmesis were 95% and 85%, respectively, with no difference between patients treated on consecutive vs. every other day. On multivariate analysis, patients who did not receive any adjuvant therapy were at increased risk of developing a LR. Five-year OS, LRFS, and DFS were 97.2%, 97.7%, and 89.5%, respectively. CONCLUSIONS: Five-fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity, and excellent cosmesis at long-term follow-up.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Early effectiveness and toxicity outcomes of reirradiation after breast conserving surgery for recurrent or new primary breast cancer.

PURPOSE: Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT. METHODS AND MATERIALS: Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). RESULTS: Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. CONCLUSION: In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required.

Breast Cancer Screening in Survivors of Childhood Cancer.

Women who survived childhood cancers or cancers at a young age are at high risk for breast cancer later in life. The accentuated risk is notable among those treated at a young age with a high radiation dose but also extends to survivors treated with therapies other than or in addition to radiation therapy. The predisposing risk factors are complex. Advances in radiation therapy continue to curtail exposure, yet the risk of a second cancer has no dose threshold and a long latency period, and concurrent use of chemotherapy may have an additive effect on long-term risk of cancer. Early screening with annual mammography and MRI is recommended for chest radiation exposure of 10 Gy or greater, beginning 8 years after treatment or at age 25 years, whichever is later. However, there is a lack of recommendations for those at high risk without a history of radiation therapy. Because mortality after breast cancer among survivors is higher than in women with de novo breast cancer, and because there is a higher incidence of a second asynchronous breast cancer in survivors than that in the general population, regular screening is essential and is expected to improve mortality. However, awareness and continuity of care may be lacking in these young patients and is reflected in their poor screening attendance. The transition of care from childhood to adulthood for survivors requires age-targeted and lifelong strategies of education and risk prevention that are needed to improve long-term outcomes for these patients. © RSNA, 2023 See the invited commentary by Chikarmane in this issue. Quiz questions for this article are available through the Online Learning Center.

Expanding the Phenotypic Spectrum of Alazami Syndrome: Two Unrelated Spanish Families.

Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome.

The neonatal DAV-expert algorithm: a GAVeCeLT/GAVePed consensus for the choice of the most appropriate venous access in newborns.

In most NICUs, the choice of the venous access device currently relies upon the operator's experience and preferences. However, considering the high failure rate of vascular devices in the neonatal population, such clinical choice has a critical relevance and should preferably be based on the best available evidence. Though some algorithms have been published over the last 5 years, none of them seems in line with the current scientific evidence. Thus, the GAVePed-which is the pediatric interest group of the most important Italian group on venous access, GAVeCeLT-has developed a national consensus about the choice of the venous access device in the neonatal population. After a systematic review of the available evidence, the panel of the consensus (which included Italian neonatologists specifically experts in this area) has provided structured recommendations answering four sets of questions regarding (1) umbilical venous catheters, (2) peripheral cannulas, (3) epicutaneo-cava catheters, and (4) ultrasound-guided centrally and femorally inserted central catheters. Only statements reaching a complete agreement were included in the final recommendations. All recommendations were also structured as a simple visual algorithm, so as to be easily translated into clinical practice.  Conclusion: The goal of the present consensus is to offer a systematic set of recommendations on the choice of the most appropriate vascular access device in Neonatal Intensive Care Unit.

Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Effect of Instant Controlled Pressure Drop (DIC) on Polyphenols, Flavonoids and Antioxidant Capacity of Green Lentils (Lens culinaris).

Instant controlled pressure drop (DIC) is one of the emerging technologies in food processing; it can be used for drying, freezing and the extraction of bioactive molecules without damaging their properties. Legumes, such as lentils, are one of the most consumed foods in the world; however, they are mainly cooked by boiling, which causes the loss of antioxidant compounds. This work evaluated the effect of 13 different DIC treatments (with pressure ranges of 0.1-0.7 MPa and times of 30-240 s) on the content of polyphenols (Folin-Ciocalteu and High Performance Liquid Chromatography HPLC) and flavonoids (2-aminoethyl diphenylborinate) as well as the antioxidant activity (DPPH and TEAC) of green lentils. The DIC 11 treatment (0.1 MPa, 135 s) obtained the best release of polyphenols, which in turn are related to antioxidant capacity. The abiotic stress generated by DIC could lead to the breakdown of the cell wall structure, which favors the availability of antioxidant compounds. Finally, the most efficient conditions for DIC to promote the release of phenolic compounds and maintain antioxidant capacity were found under low pressures (<0.1 MPa) and short times (<160 s).

Antioxidant Activity and GC-MS Profile of Cardamom (Elettaria cardamomum) Essential Oil Obtained by a Combined Extraction Method-Instant Controlled Pressure Drop Technology Coupled with Sonication.

Cardamom Essential oils are highly demanded because of their antimicrobial, anti-inflammatory, and antioxidant activities. Nonetheless, retrieving quality extracts quickly with efficient energy savings has been challenging. Therefore, green technologies are emerging as possible alternatives. Thus, this study evaluates the yield and quality of the instant controlled pressure drop (DIC) process coupled with ultrasound-assisted extraction (UAE) of cardamom essential oil (CEO). Likewise, the antioxidant activity, chemical profile of CEO, and microstructure of seeds were analyzed. This study analyzed 13 different treatments with varying saturated steam processing temperatures (SSPT), thermal processing times (TPT), and 1 control. The results showed that CEO yield increased significantly by DIC (140 °C and 30 s) and UAE compared to the control (22.53% vs. 15.6%). DIC 2 (165 °C, 30 s) showed the highest DPPH inhibition (79.48%) and the best Trolox equivalent antioxidant capacity (TEAC) by the control with 0.60 uMTE/g. The GC/MS analysis showed 28 volatile constituents, withα-Terpinyl acetate, geranyl oleate, and oleic acid being the most abundant. DIC (140 °C and 30 s) and UAE showed the best yield and chemical profile. The SEM microscopy of untreated seeds revealed collapsed structures before the oil cell layer, which reduced the extraction yield, contrary to DIC-treated seeds, with more porous structures. Therefore, combining innovative extraction methods could solve the drawbacks of traditional extraction methods.

WHO Ordinal Scale and Inflammation Risk Categories in COVID-19. Comparative Study of the Severity Scales.

BACKGROUND: The WHO ordinal severity scale has been used to predict mortality and guide trials in COVID-19. However, it has its limitations. OBJECTIVE: The present study aims to compare three classificatory and predictive models: the WHO ordinal severity scale, the model based on inflammation grades, and the hybrid model. DESIGN: Retrospective cohort study with patient data collected and followed up from March 1, 2020, to May 1, 2021, from the nationwide SEMI-COVID-19 Registry. The primary study outcome was in-hospital mortality. As this was a hospital-based study, the patients included corresponded to categories 3 to 7 of the WHO ordinal scale. Categories 6 and 7 were grouped in the same category. KEY RESULTS: A total of 17,225 patients were included in the study. Patients classified as high risk in each of the WHO categories according to the degree of inflammation were as follows: 63.8% vs. 79.9% vs. 90.2% vs. 95.1% (p<0.001). In-hospital mortality for WHO ordinal scale categories 3 to 6/7 was as follows: 0.8% vs. 24.3% vs. 45.3% vs. 34% (p<0.001). In-hospital mortality for the combined categories of ordinal scale 3a to 5b was as follows: 0.4% vs. 1.1% vs. 11.2% vs. 27.5% vs. 35.5% vs. 41.1% (p<0.001). The predictive regression model for in-hospital mortality with our proposed combined ordinal scale reached an AUC=0.871, superior to the two models separately. CONCLUSIONS: The present study proposes a new severity grading scale for COVID-19 hospitalized patients. In our opinion, it is the most informative, representative, and predictive scale in COVID-19 patients to date.

The Use of Corticosteroids or Tocilizumab in COVID-19 Based on Inflammatory Markers.

BACKGROUND: The inflammatory cascade is the main cause of death in COVID-19 patients. Corticosteroids (CS) and tocilizumab (TCZ) are available to treat this escalation but which patients to administer it remains undefined. OBJECTIVE: We aimed to evaluate the efficacy of immunosuppressive/anti-inflammatory therapy in COVID-19, based on the degree of inflammation. DESIGN: A retrospective cohort study with data on patients collected and followed up from March 1st, 2020, to May 1st, 2021, from the nationwide Spanish SEMI-COVID-19 Registry. Patients under treatment with CS vs. those under CS plus TCZ were compared. Effectiveness was explored in 3 risk categories (low, intermediate, high) based on lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and D-dimer values. PATIENTS: A total of 21,962 patients were included in the Registry by May 2021. Of these, 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). MAIN MEASURES: The primary outcome of the study was in-hospital mortality. Secondary outcomes were the composite variable of in-hospital mortality, requirement for high-flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission. KEY RESULTS: A total of 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). No significant differences were observed in either the low/intermediate-risk category (1.5% vs. 7.4%, p=0.175) or the high-risk category (23.1% vs. 20%, p=0.223) after propensity score matching. A statistically significant lower mortality was observed in the very high-risk category (31.9% vs. 23.9%, p=0.049). CONCLUSIONS: The prescription of CS alone or in combination with TCZ should be based on the degrees of inflammation and reserve the CS plus TCZ combination for patients at high and especially very high risk.

Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

Effect of the Instant Controlled Pressure Drop Technology in Cardamom (Elettaria cardamomum) Essential Oil Extraction and Antioxidant Activity.

Green cardamom (Elettaria cardamomum) is an outspread spice native to Asia, which is well appreciated for its sensory characteristics, delicate aroma, and unique taste. Currently, the main cardamom extracts are essential oils (EOs), and regarding current market tendencies, this market is in high growth. For this reason, technologies such as the instant controlled pressure drop (DIC) have been applied to reach higher yields and better quality of EO. Then, this study explores the impact of DIC as a pretreatment before hydrodistillation (HD) on the EO yield and their antioxidant activity. Obtained results showed that the coupling of DIC-HD increased the yield of essential oil and also had a positive impact on their antioxidant capacity. The EO yield of DIC-HD (140 °C and 30 s) was 4.43% vs. 2.52% for control; the AOX of DIC-HD (165 °C and 30 s) was 86% inhibition vs. 57.02% for control, and the TEAC of DIC-HD (140 °C and 30 s) was 1.44 uMTE/g EO vs. 13.66 uMTE/g EO.

Assessment of risk from lead intake in mining areas: proposal of indicators.

This study discusses an estimate of the risk associated with the intake of soil contaminated by lead, based on the nature of the source, through a detailed study of the parameters that can influence the bioaccessibility of the element from soil intake. Statistical variables that are related to the solubility and bioavailability of lead are used for this purpose. This includes considering the values of pH, electrical conductivity, particle size, mineralogical composition and the bioaccessibility/bioasimilability of lead. Obtaining an algorithm, represented by different probability distributions of the parameters considered, needs a thorough knowledge of the source materials, which may allow estimating/evaluating the intake health risk provided by the concentration of the metal present. The selected materials are from sites affected by mining activities in the Region of Murcia (SE of Spain) and soils in nearby areas, using a total of 186 samples. Soil samples, once screened and homogenized, were parameterized by determining pH, electrical conductivity, granulometry, both total and water-extractable Pb content. Oral bioaccessibility tests were also performed, and a detailed mineralogical analysis by X-ray diffraction was carried out.

Uptake of potentially toxic elements by edible plants in experimental mining Technosols: preliminary assessment.

A study was carried out to evaluate the absorption of potentially toxic elements from mining Technosols by three types of vegetable plants (broccoli (Brassica oleracea var. italica), lettuce (Lactuca sativa) and onion (Allium cepa)), the different parts of which are intended for human and farm animal consumption (leaves, roots, edible parts). The preliminary results obtained highlight the importance of the design of the mining Technosols used for agricultural purposes, obtained from soils and sediments of mining origin and amended with residues of high calcium carbonate concentrations (limestone filler and construction and demolition wastes). The experiment was carried out in a greenhouse, and the total metal(loid)s concentration (As, Pb, Cd, Cu, Fe, Mn and Zn) of the soil, rhizosphere, aqueous leachates and plant samples was monitored, the translocation and bioconcentration factors (TF and BCF, respectively) being calculated. The characterization of the soils included a mobilization study in media simulating different environmental conditions that can affect these soils and predicting the differences in behavior of each Technosol. The results obtained showed that the levels of potentially toxic elements present in the cultivated species are within the range of values mentioned in the literature when they were cultivated in soils with calcareous amendments. However, when the plants were grown in contaminated soils, the potentially toxic elements levels varied greatly according to the species, being higher in onions than in lettuce. Experiments with the use of lime filler or construction and demolition wastes for soil remediation result in crops that, in principle, do not present health risks and are similar in development to those grown on non-contaminated soil.

Sedation level with midazolam: A pediatric surgery approach.

Midazolam (MDZ) is a short-acting benzodiazepine that is widely used to induce and maintain general anesthesia during diagnostic and therapeutic procedures in pediatric patients due to its sedative properties. The aim of this study was to perform a systematic review without a meta-analysis to identify scientific articles and clinical assays concerning MDZ-induced sedation for a pediatric surgery approach. One hundred and twenty-eight results were obtained. After critical reading, 37 articles were eliminated, yielding 91 publications. Additional items were identified, and the final review was performed with a total of 106 publications. In conclusion, to use MDZ accurately, individual patient characteristics, the base disease state, comorbidities, the treatment burden and other drugs with possible pharmacological interactions or adverse reactions must be considered to avoid direct alterations in the pharmacokinetics and pharmacodynamics of MDZ to obtain the desired effects and avoid overdosing in the pediatric population.