Articles de revues sur le sujet « LC-DS »

AbstractWe aimed to configure impaired/altered metabolomic profiles of pregnant women carrying Down syndrome (DS) fetuses. The study involved 21 and 32 pregnant women with DS and euploid fetuses, respectively, as determined by prenatal screening and diagnosis as part of an antenatal care program. Metabolomic analyses were carried out using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) methods. A total of 95 metabolites were identified. GC-MS analysis indicated that levels of 2-hydroxybutyric acid, benzoic acid, nonanoic acid, 3-hydroxybutyric acid, and 2-ketoisocaproic acid were increased in the DS group, where beta-alanine, threonic acid, oxalic acid, alpha-tocopherol, uracil, 2-piperidone, and creatinine were decreased. However, LC-qTOF-MS analysis showed that lipid-related metabolites were decreased in women carrying DS fetuses, whereas creatine, N4-phosphoagmatine, citrate, 2,5-dioxopentanoate, 2-furoate, pyruvate, and fructose levels were increased. Pathway analysis was also performed using metabolites whose levels were significantly altered (p<0.05) between the groups, and the findings indicated that the biosynthesis pathways of aminoacyl-tRNA and “valine-leucine-isoleucine”, and metabolism pathways of “glycine-serine-threonine”, nitrogen, “alanine-aspartate-glutamate”, propanoate, glycerophospholipid, cysteine, methionine, and phenylalanine were significantly altered. Our findings indicate a special type of metabolic status/syndrome in pregnant women with Down syndrome fetuses. It could be speculated that altered metabolic status might influence both gametogenesis and embryogenesis. Down syndrome is a complex genetic disorder that is important to detect prenatally, but may also be prevented by taking necessary precautions prior to pregnancy.

The objective of this study is to clone and charecterize the expression of dammarenediol synthase gene and then to determine the relationship between the expression of dammarenediol synthase gene that is involved in the ginsenoside biosynthetic pathway and the ginsenoside content. A cDNA phage library was constructed from a five-year-old ginseng root. The cDNA library was screened for the dammarenediol synthase gene by using its specific primers. It was further cloned and expressed in pET-30a vector. The recombinant plasmid pET-30a-DS was expressed in RosettaE. coli. The recombinant DS protein was purified by affinity chromatography. The production of dammarenediol was detected by liquid chromatography-mass spectrometry (LC-MS). Results showed that dammarenediol synthase gene was cloned from the cDNA library and was expressed in RosettaE. coliand the SDS-PAGE analysis showed the presence of purified DS protein. LS-MS showed the activity of DS protein, as the protein content increases the dammarenediol increases. Our results indicate that the recombinant dammarenediol synthase protein could increase the production of dammarenediol and the expression of DS played a vital role in the biosynthesis of ginsenosides inP. ginseng.

From a cost point of view SNECMA has found DS columnar grain manufacturing technology to be highly attractive compared to single crystal. CM 186 LC alloy exhibits enhanced mechanical and environmental properties and temperature capability compared to MAR M 200 Hf alloy; these properties are close to first-generation single crystal alloys up to 982°C (1800°F). The alloy is shown to be amenable to various coating and brazing high-temperature processes. The longer term creeprupture/phase stability data base on the alloy has now been extended out to 8300 hours at 1038°C (1900°F). Castings for engine test have been produced using CM 186 LC alloy.

Neuroinflammation plays a critical role in the pathogenesis of most neurological and neurodegenerative diseases and therefore represents a potential therapeutic target. In this regard, accelerating the resolution process in chronic neuroinflammation may be an effective strategy to deal with the cognitive consequences of neuropathology and generalized inflammatory processes. N-acylethanolamine (NAE) derivatives of fatty acids, being highly active lipid mediators, possess pro-resolving activity in inflammatory processes and are promising agents for the suppression of neuroinflammation and its consequences. This paper is devoted to a study of the effects played by dietary supplement (DS), containing a composition of fatty acid-derived NAEs, obtained from squid Berryteuthis magister, on the hippocampal neuroinflammatory and memory processes. By detecting the production of pro-inflammatory cytokines and glial markers, a pronounced anti-inflammatory activity of DS was demonstrated both in vitro and in vivo. DS administration reversed the LPS-induced reduction in hippocampal neurogenesis and memory deterioration. LC-MS analysis revealed an increase in the production of a range of NAEs with well-documented anti-inflammatory activity in response to the administered lipid composition. To conclude, we found that tested DS suppresses the neuroinflammatory response by reducing glial activation, positively regulates neural progenitor proliferation, and attenuates hippocampal-dependent memory impairment.

AbstractObjectivesMucopolysaccharidosis type I (MPS I) was added to our expanded screening panel in 2015. Since then, 127,869 newborns were screened by measuring α-L-iduronidase (IDUA) enzyme activity with liquid chromatography tandem mass spectrometry (LC-MS/MS). High false positives due to frequent pseudodeficiency alleles prompted us to develop a second-tier test to quantify glycosaminoglycan (GAG) levels in dried blood spot (DBS).MethodsHeparan-sulfate (HS) and dermatan-sulfate (DS) were measured with LC-MS/MS after methanolysis. DBSs were incubated with methanolic-HCl 3 N at 65 °C for 45 min. Chromatographic separation used an amide column with a gradient of acetonitrile and water with 10 mM ammonium acetate in a 9-min run. The method was validated for specificity, linearity, lower limit of quantification (LOQ), accuracy and precision.ResultsIntra- and inter-day coefficients of variation were <15% for both metabolites. Reference values in 40 healthy newborns were: HS mean 1.0 mg/L, 0–3.2; DS mean 1.5 mg/L, 0.5–2.7). The two confirmed newborn MPS I patients had elevated HS (4.9–10.4 mg/L, n.v. <3.2) and DS (7.4–8.8 mg/L, n.v. <2.7). Since its introduction in February 2019, the second-tier test reduced the recall rate from 0.046% to 0.006%. Among 127,869 specimens screened, the incidence was 1:63,935 live births. Both patients started enzyme replacement therapy (ERT) within 15 days of birth and one of them received allogenic hematopoietic stem cell transplantation (HSCT) at ht age of 6 months.ConclusionsGAGs in DBS increased the specificity of newborn screening for MPS I by reducing false-positives due to heterozygosity or pseudodeficiency. Early diagnosis and therapeutical approach has improved the outcome of our patients with MPS I.

Isoprene is a small lipophilic molecule synthesized in plastids and abundantly released into the atmosphere. Isoprene-emitting plants are better protected against abiotic stresses, but the mechanism of action of isoprene is still under debate. In this study, we compared the physiological responses and proteomic profiles of Arabidopsis which express the isoprene synthase (ISPS) gene and emit isoprene with those of non-emitting plants under both drought-stress (DS) and well-watered (WW) conditions. We aimed to investigate whether isoprene-emitting plants displayed a different proteomic profile that is consistent with the metabolic changes already reported. Only ISPS DS plants were able to maintain the same photosynthesis and fresh weight of WW plants. LC–MS/MS-based proteomic analysis revealed changes in protein abundance that were dependent on the capacity for emitting isoprene in addition to those caused by the DS. The majority of the proteins changed in response to the interaction between DS and isoprene emission. These include proteins that are associated with the activation of secondary metabolisms leading to ABA, trehalose, and proline accumulations. Overall, our proteomic data suggest that isoprene exerts its protective mechanism at different levels: under drought stress, isoprene affects the abundance of chloroplast proteins, confirming a strong direct or indirect antioxidant action and also modulates signaling and hormone pathways, especially those controlling ABA synthesis. Unexpectedly, isoprene also alters membrane trafficking.

El objetivo de este trabajo fue determinar el efecto de sistemas de labranza y densidades de siembra en la calidad de las raíces tuberosas de batata (Ipomoea batata (L) Lamb.). El estudio se realizó en la Universidad Central de Venezuela, en el año 2014. Se determinaron los grados de severidad de la degradación del suelo y su correspondencia con las escalas de preferencia basadas en el peso unitario y dimensiones de la raíz tuberosa. Se usó un arreglo en franjas, donde los sistemas de labranza (SL) fueron asignados a las parcelas, y las densidades de siembra (Ds) a las franjas. Los SL consistieron en labranza vertical con cincel (LC), con arado de disco (LA), convencional con tres pases de rastra de disco (LCo) y mínima con un pase de rastra de disco (LM). Las Ds fueron de 0,25 cm (D1) y 0,15 cm (D2) en la hilera. La calidad física del suelo fue superior en los tratamientos de LA. De estos, la combinación con la distancia de siembra más larga (LA-D1) favoreció la mayor calidad postcosecha del cultivo. Al contrario, en los tratamientos con cincel se promovió la menor aceptación del consumidor. La ligera a moderada severidad de la degradación del suelo no explicó la variación de la calidad postcosecha. Se in ere sobre la menor tasa de movimiento de agua en LC, que promovió un exceso de humedad y la más baja calidad de la raíz tuberosa.

Cyanobacterial biomass is important for biofuel and biofertilizer, however, biomass production requires expensive chemical growth nutrients. To address this issue, we explored the use of inexpensive growth nutrient media from an integrated manure-seawater system for cyanobacterial biomass production. Salt-tolerant cyanobacterial strain HSaC and salt-sensitive cyanobacterial strain LC were tested to evaluate the potential of integrated manure-seawater media for sustainable cyanobacterial biomass production. As a prerequisite for seawater experiments, strain HSaC was grown at different NaCl concentrations (0 mM, 60 mM, 120 mM, 180 mM, 240 mM and 300 mM) to identify the optimum salt concentration. The highest biomass yield and photosynthetic pigment contents were obtained at 120 mM NaCl concentration. The highest exo-polysaccharide (EPS) content was obtained at 180 mM NaCl concentration. The treatments for the manure-seawater media were cow manure, pig manure, chicken manure and BG11, each with distilled water, diluted seawater and non-diluted seawater. The highest biomass and photosynthetic pigment yield for cyanobacterial strains LC and HSaC were obtained from 0.5 dS/m and 10 dS/m diluted seawater integrated with cow manure, respectively, but pig and chicken manure performed poorly. Overall, the biomass production and photosynthetic pigment results from cow manure-seawater were relatively better than those from the reference media (BG11). Based on the current findings, it is concluded that the growth nutrients from integrated cow manure-seawater can wholly substitute for the BG11 without affecting cyanobacterial growth, thereby reducing the usage of expensive chemical growth media. Thus, the results of study help to enhance the biomass production of both salt-sensitive and salt-tolerant cyanobacteria for sustainable biofuel and biofertilizer production.

Abstract. The development of cytosterile maize hybrids in Russia is a necessary condition for their wide implementation into production. To develop such hybrids, it’s greatly relevant to be aware how the lines react to sterile cytoplasm. The study was carried out at the Agricultural Research Center “Donskoy” (“ARC “Donskoy”) in 2010–2021. The purpose of the current study was to classify the new self-pollinated maize lines according to the composition of the fertility-restoring genes of the Paraguay (C) type of CMS, to optimize the number of analyzing test-crosses. Methods. As initial material there have been used 45 new self-pollinated maize lines and 8 sources of sterility with different genetic structure. The method of complete top-crosses there have been identified 360 maize hybrids, used for estimation of the new lines’ reaction. Results. According to the study results, the sterility-fixing lines KV 204, SP 286, DS 255, SP 207, DS 180, which had no fertility-restoring genes in the dominant state, belonged to the I class. As the natural complete constant fertility-restorers there has been recommended to use the lines of the VIII class KV 498, KV 272, KV 7/07, SP 357, RD 261, DS 295, SP 210, SP 197, DS 177, DS 188, having all three dominant genes Rf4, Rf5, Rf6 in the genotype. The incomplete sterility-fixing lines included the lines of the II–IV classes (KV 3, RD 245, SP 198, etc.). The incomplete fertility-restoring lines were the lines of the V–VII classes (KV 469, RD 331, KV 276, etc.). There has been found out that the most common lines were the lines of the V (24.4%) and VIII (22.3 %) classes. The scientific novelty of the study was an optimal number and genetic structure of the analyzers WF 9c of the V class, Lc of the VI class and W 401c of the VII class, which are necessary for crossings and allow identifying lines according to the fertility-restoring genes.

Most multidrug-resistant tuberculosis (MDR-TB) patients fail to receive a timely diagnosis and treatment. Therefore, we explored the differentially expressed peptides in MDR-TB compared with drug-susceptible tuberculosis (DS-TB) patients using LC-MS/MS and Ingenuity Pathway Analysis (IPA) to analyse the potential significance of these differentially expressed peptides. A total of 301 peptides were differentially expressed between MDR-TB and DS-TB groups. Of these, 24 and 16 peptides exhibited presented high (fold change ≥ 2.0, P < 0.05) and low (fold change ≤ −2.0, P < 0.05) levels in MDR-TB. Significant canonical pathways included the prothrombin activation system, coagulation system, and complement system. In the network of differentially expressed precursor proteins, lipopolysaccharide (LPS) regulates many precursor proteins, including four proteins correlated with organism survival. These four important differentially expressed proteins are prothrombin (F2), complement receptor type 2 (CR2), collagen alpha-2(V) chain (COL5A2), and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). After addition of CR2 peptide, IL-6 mRNA expression in THP-1 cells decreased significantly in dose- and time-dependent manners. Cumulatively, our study proposes potential biomarkers for MDR-TB diagnosis and enables a better understanding of the pathogenesis of MDR-TB. The functions of differentially expressed peptides, especially CR2, in MDR-TB require further investigation.

Abstract BACKGROUND Anti-PD-1+CTLA-4 therapy has revolutionized melanoma brain metastases (MBM) treatment. Prospective trials show higher response in asymptomatic versus symptomatic patients. We evaluated clinical outcomes in MBM treated with stereotactic radiosurgery (SRS) and anti-PD-1+CTLA-4. METHODS Patients were included if MBM were diagnosed and treated with SRS within 3 months of anti-PD-1+CTLA-4, and this was their last course of systemic treatment. Endpoints of this study were distant MBM control, MBM local control (LC) defined as less than 20% volume increase on follow-up MRI, and overall survival (OS) from SRS. Adverse advents were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS 29 patients with 122 MBM treated over 40 SRS sessions between 2015-2020 were identified. Median SRS dose: 24 Gy (range: 15-24). Median MBM diameter: 0.6 cm (range: 0.3-2.9). Median follow-up using reverse Kaplan-Meier (KM) method: 19.3 months (interquartile range: 14.6-38.4).Six-, twelve-, and eighteen-month KM distant MBM control rates were 51%, 42%, 42%, respectively. LC rates: 90%, 86%, 85%. OS rates: 76%, 68%, 56%. 17 patients (59%) were asymptomatic and 12 (41%) symptomatic. KM distant MBM control and OS for asymptomatic and symptomatic patients were not significant; p=0.61 and p=0.67, respectively.On univariate analysis (UVA), Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) 0-1 was associated with increased risk of distant MBM failure versus DS-GPA 3.5-4 (hazard ratio (HR): 9.8, 95% confidence interval (CI) 1.9-51.5, p=0.007). UVA showed decreased OS with increased number of organs with metastases at diagnosis (HR:12, 95% CI 2.0-83.1, p=0.0075).2 lesions (1.6%) developed symptomatic radiation necrosis requiring steroids; 10 lesions developed grade 3 edema (8%); 13 patients experienced grade 1-2 fatigue and/or headache (45%); no patients experienced grade &gt;3 events. CONCLUSION Combination SRS and anti-PD-1+CTLA-4 in MBM shows durable intracranial control with similar outcomes between asymptomatic and symptomatic patients with acceptable toxicity. Further study is warranted.

Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform between medical geneticists and other medical specialists based on at-risk criteria to allow for an earlier confirmative diagnosis of MPS. Methods: Children (<19 years of age) with clinical signs and symptoms compatible with MPS were prospectively enrolled from pediatric clinics between July 2013 and June 2018. Urine samples were collected for a non-specific total GAG analysis using the dimethylmethylene blue (DMB) spectrophotometric method, and the quantitation of three urinary GAGs (dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)) was performed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The subjects with elevated urinary GAG levels were recalled for leukocyte enzyme activity assay and genetic testing for confirmation. Results: Among 153 subjects enrolled in this study, 13 had a confirmative diagnosis of MPS (age range, 0.6 to 10.9 years—three with MPS I, four with MPS II, five with MPS IIIB, and one with MPS IVA). The major signs and symptoms with regards to different systems recorded by pediatricians at the time of the decision to test for MPS were the musculoskeletal system (55%), followed by the neurological system (45%) and coarse facial features (39%). For these 13 patients, the median age at the diagnosis of MPS was 2.9 years. The false negative rate of urinary DMB ratio using the dye-based method for these 13 patients was 31%, including one MPS I, two MPS IIIB, and one MPS IVA. However, there were no false negative results with urinary DS, HS and KS using the MS/MS-based method. Conclusions: We established an at-risk population screening program for MPS by measuring urinary GAG fractionation biomarkers using the LC-MS/MS method. The program included medical geneticists and other medical specialists to increase awareness and enable an early diagnosis by detecting MPS at the initial onset of clinical symptoms.

AbstractLGD-4033 (ligandrol) is a selective androgen receptor modulator (SARM), which is prohibited in sports by the World Anti-Doping Agency (WADA) and led to 62 adverse analytical findings (AAFs) in 2019. But not only deliberate doping with LGD-4033 constitutes a problem. In the past years, some AAFs that concerned SARMs can be attributed to contaminated dietary supplements (DS). Thus, the urgency to develop methods to differentiate between inadvertent doping and abuse of SARMs to benefit from the performance-enhancing effect of the compound in sports is growing. To gain a better understanding of the metabolism and excretion patterns of LGD-4033, human micro-dose excretion studies at 1, 10, and 50 µg LGD-4033 were conducted. Collected urine samples were prepared for analysis using enzymatic hydrolysis followed by solid-phase extraction and analyzed via LC-HRMS/MS. Including isomers, a total of 15 phase I metabolites were detected in the urine samples. The LC-HRMS/MS method was validated for qualitative detection of LGD-4033, allowing for a limit of detection (LOD) of 8 pg/mL. The metabolite M1, representing the epimer of LGD-4033, was synthesized and the structure elucidated by NMR spectroscopy. As the M1/LGD-4033 ratio changes over time, the ratio and the approximate LGD-4033 concentration can contribute to estimating the time point of drug intake and dose of LGD-4033 in doping control urine samples, which is particularly relevant in anti-doping result management. Graphical abstract

Exocellular (1→6)-β-d-glucan (lasiodiplodan) produced by the fungus Lasiodiplodia theobromae MMPI was derivatized by carboxymethylation using different concentrations of a derivatizing agent. Lasiodiplodan was derivatized by carboxymethylation in an attempt to increase its solubility and enhance its biological activities. Carboxymethylglucans with degrees of substitution (DS) of 0.32, 0.47, 0.51, 0.58, and 0.68 were produced and characterized. FTIR analysis showed a band of strong intensity at 1600 cm−1 and an absorption band at 1421 cm−1, resulting from asymmetric and symmetrical stretching vibrations, respectively, of the carboxymethyl group COO- in the carboxymethylated samples. Thermal analysis showed that native lasiodiplodan (LN) and carboxymethylated derivatives (LC) exhibited thermal stability up to 200–210 °C. X-ray diffractometry demonstrated that both native and carboxymethylated lasiodiplodan presented predominantly an amorphous nature. Scanning electron microscopy revealed that carboxymethylation promoted morphological changes in the biopolymer and increased porosity, and alveolar structures were observed along the surface. The introduction of carboxymethyl groups in the macromolecule promoted increased solubility and potentiated the hydroxyl radical-scavenging activity, suggesting a correlation between degree of substitution and antioxidant activity.

72 Background: Clonality testing is an integral part of the initial assessment of B and T cell malignancies. The further use of conventional clonality assays for monitoring of disease post treatment is limited by low assay sensitivity and inability to track clones based on their unique sequences. Clonality assessment by next generation sequencing (NGS) provides increased diagnostic capabilities, allowing the tracking of disease specific clones as well as the full spectrum of clonal sequences that arise in response to therapy. Here we describe our initial experience using an NGS based assay for monitoring and our comparison to conventional clonality assays and flow cytometry. Methods: DNA was extracted from hematologic samples received for routine clonality assessment including diagnostic (DS) and follow-up post therapy (PT) samples. Clonality testing was performed by conventional PCR-based assays using biomed II primers and by NGS utilizing Lymphotrack IGH FR1 and TRG kits (Invivoscribe). The amplified products were sequenced on Illumina MiSeq. For MRD assessment, we created dedicated laboratory protocols as well as in-house developed software, MSK-LymphoClone (LC), containing a data analysis pipeline, analytical tools for clonality assessment and a signout portal for easy search and retrieval of pertinent clones. Results: Samples from 48 patients were included (48 DS and 60 PT) encompassing 12 plasma cell neoplasms, 11 acute lymphoblastic leukemias, 16 mature B-cell and 9 T-cell lymphomas. All diagnostic samples showed clonal rearrangement with 100% concordance between conventional and NGS assays. Residual disease was detected in 27/60 (45%) PT samples using conventional fragment size based assays, 27/57 (47%) using flow and 38/60 (63%) using NGS. Diagnostic clonal sequences were detected in as low as 0.0019% of total reads in PT samples tested by NGS. 18/60 (30.0%) PT samples (17 patients) were disease negative by all assays; 16 patients remained disease-free (median follow-up - 2.4 months). Conclusions: NGS clonality testing is a valuable tool for monitoring patients with B and T cell neoplasms showing higher sensitivity and specificity than conventional assays.

Abstract Background:Racial disparities in multiple myeloma (MM) outcomes are well established. Clinical characteristics and cytogenetic abnormalities dictate outcomes in MM but historically they have been mostly defined in White patients with paucity of information regarding racial-ethnic minorities. Hispanics are the fastest growing racial-ethnic subgroup in United States and have the worst overall survival (OS) in MM but differences in disease presentation among Hispanics compared to Whites, the historical control, are undefined. Methods: MM patients seen at Mayo Clinic in Florida (MCF) and Arizona (MCA) between 1/1/2000-06/15/2017 were included. Patient and disease characteristics including gender, age at diagnosis, bone marrow (BM) plasmacytosis, laboratory data [M spike, creatinine (Cr), beta-2-microglobulin (B2M), Hemoglobin (Hb), calcium (Ca)], MM subtype [IgG, IgA, light chain (LC), other], LC subtype (κ, λ, biclonal), presence of lytic bone lesions, disease stage (DS, ISS, R-ISS), mSMRT cytogenetic risk category, presence of individual cytogenetic mutations (deletions, translocations, gains, trisomy/hyperdiploidy) was collected. Comparisons between Hispanic study cohort characteristics and historical control were made by Chi-square, Fischer's exact and Signed rank tests, where applicable, using data from previous publications [Kyle et al, 2003 (n=1027) and Fonseca et al, 2003 (n=351)]. Patients with missing data on a certain clinical or disease feature were not included in the statistical analysis of that specific characteristic. Results: A total of 1705 MM patients were screened and 266 Hispanic patients seen at either site between the specified dates were identified for the analysis. These included equal number of males and females (n=133 each) with a median age of 58 years (range 25-87). IgG disease was seen in 52% with IgA and LC subtypes in 23% each. LC subtype was κ in 67%, λ in 31% and biclonal in 2% cases. Lytic and extramedullary disease were noted in 71% and 44% patients, respectively. DS and R-ISS stage at the time of MM diagnosis was not available in most patients while ISS stage among 150 patients showed stage 1, 2 and 3 in 48%, 28% and 24% patients, respectively. mSMART risk categories were present in 226 patients and included high, intermediate and standard risk in 12%, 11% and 77% patients, respectively. Of these 226 patients, cytogenetic disease prior to starting any MM treatment was available in 153 patients with similar risk category distribution. Median follow up for the whole Hispanic cohort was 38.6 months with a median OS 10.7 years (Figure 1). Comparison with historical control datasets which were 97% or greater comprised of White patients showed some significant differences for the Hispanic cohort including gender distribution, median age, BM plasmacytosis at the time of diagnosis, median Hb, Cr or M spike at presentation, light chain subtype, presence of lytic bone disease and certain cytogenetic alterations including t(4;14) and del13q/monosomy (Table 1). We did not note differences in high-risk cytogenetics between Hispanics and historical White controls. Conclusions: We report the first description of clinical and cytogenetic characteristics of Hispanic MM patients. The current and historical datasets that we have used are all from Mayo Clinic experience, thus making reasonable comparisons possible. We were able to confirm previous reports of demographic differences in Hispanics e.g., younger age at diagnosis. While some characteristics were significantly different, the clinical and cytogenetic differences we note do not clearly explain the inferior OS noted for Hispanics in population-based studies. Significant differences that we report warrant continued exploration in larger institutional and public databases in addition to a continued look into healthcare access and utilization. An ongoing collaborative analysis with data from Mayo Clinic, University of Miami and University of Southern California, Los Angeles is ongoing. Disclosures Fonseca: AMGEN: Consultancy; Jansen: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Celgene Corporation: Consultancy, Research Funding; Merck: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy. Kelly: Pharmacyclics: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Sher: LAM Therapeutics, Inc: Research Funding. Ailawadhi: Pharmacyclics: Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

The aminocoumarin antibiotic clorobiocin contains a 5-methylpyrrole-2-carboxylic acid unit, attached via an ester bond to the 3-OH group of the deoxysugar moiety. To investigate candidate genes responsible for the formation of this ester bond, a gene inactivation experiment was carried out in the clorobiocin producer Streptomyces roseochromogenes var. oscitans DS 12.976. An in-frame deletion was created in the coding sequence of the gene cloN2. The production of secondary metabolites in the wild-type and in the cloN2 mutant was analysed. The wild-type showed clorobiocin as the main product, whereas the cloN2 mutant accumulated a new aminocoumarin derivative, novclobiocin 104, lacking the pyrrole moiety at the 3-OH of the deoxysugar. In addition, free pyrrole-2-carboxylic acid accumulated in the culture extract of the cloN2 mutant. The structures of the metabolites were confirmed by NMR and LC-MS analysis. Clorobiocin production was successfully restored in the cloN2 mutant by introducing a replicative plasmid containing the cloN2 sequence. These results prove an involvement of cloN2 in the formation of the ester bond between the pyrrole moiety and the deoxysugar in clorobiocin biosynthesis. Furthermore, they indicate that the C-methylation at position 5 of the pyrrole moiety occurs after the attachment of pyrrole-2-carboxylic acid unit to the deoxysugar moiety.

Objectives: The prognosis of brain metastatic colorectal cancer patients (BMCRC) is poor. Several local treatments have been used, but the optimal treatment choice remains an unresolved issue. We evaluated the clinical outcomes of a large series of BMCRC patients treated in several Italian centers using stereotactic radiosurgery (SRS). Methods: 185 BMCRC patients for a total of 262 lesions treated were evaluated. Treatments included surgery followed by post-operative SRS to the resection cavity, and SRS, either single-fraction, then hypofractionated SRS (HSRS). Outcomes was measured in terms of local control (LC), toxicities, brain distant failure (BDF), and overall survival (OS). Prognostic factors influencing survival were assed too. Results: The median follow-up time was 33 months (range 3–183 months). Surgery plus SRS have been performed in 28 (10.7%) cases, SRS in 141 (53.8%), and HSRS in 93 (35.5%). 77 (41.6%) patients received systemic therapy. The main total dose and fractionation used were 24 Gy in single fraction or 24 Gy in three daily fractions. Local recurrence occurred in 32 (17.3%) patients. Median, 6 months,1-year-LC were 86 months (95%CI 36-86), 87.2% ± 2.8, 77.8% ± 4.1. Median,6 months,1-year-BDF were 23 months (95%CI 9-44), 66.4% ± 3.9, 55.3% ± 4.5. Median,6 months,1-year-OS were 7 months (95% CI 6–9), 52.7% ± 3.6, 33% ± 3.5. No severe neurological toxicity occurred. Stage at diagnosis, Karnofsky Performance Status (KPS), presence and number of extracranial metastases, and disease-specific-graded-prognostic-assessment (DS-GPA) score were observed as conditioning survival. Conclusion: SRS/HSRS have proven to be an effective local treatment for BMCRC. A careful evaluation of prognostic factors as well as a multidisciplinary evaluation is a valid aid to manage the optimal therapeutic strategy for CTC patients with BMs. Advances in knowledge: The prognosis of BMCRC is poor. Several local treatments was used, but optimal treatment choice remains undefined. Radiosurgery has proven to be an effective local treatment for BMCRC. A careful evaluation of prognostic factors and a multidisciplinary evaluation needed.

Abstrak: Pemendekan komunikasi dalam pemainan DoTA 2 menarik untuk diteliti. Hal tersebut disebabkan kecepatan dan fokus pemain menjadi kunci utama dalam memenangkan permainan. Oleh karena itu, tentunya bentuk pemendekan dalam mempercepat proses komunikasi yang dilakukan oleh pemainnya. Penelitian ini bertujuan untuk mendeskripsikan bentuk pemendekan kata dalam komunikasi pada permainan DoTA 2. Metode penelitian ini adalah kualitatif dengan pendekatan deskriptif. Sumber data diperoleh dari pemain DoTA 2. Objek kajian berupa tuturan dalam permainan yang menggunakan pemendekan. Pengumpulan data menggunakan metode simak dan cakap. Analisis data menggunakan metode agih dan teknik bagi unsur langsung. Hasil penelitian berupa singkatan yang terbagi menjadi (i) singkatan dua huruf sebanyak 30 data, yakni AA, AM, CK, BS, CM, DS, DK, DR, ES, LC, LS, OD, PA, PL, SK, SF, TA, TB, WR, BB, HP, NM, TI, MT, PT, BM, SB, TP, DC, GG. (ii) singkatan tiga huruf sebanyak 6 data, yakni BKB, MKB, MMR, DPS, BRB, AFK (iii) singkatan empat huruf sebanyak 1 kata, yakni GGWP; akronim sebanyak 4 data, yakni QOP, MOM, DoTA, OL; kontraksi sebanyak 4 data, yakni Dipier, Upbrack, Lowbrack, Mismid; penggalan sebanyak 5 data penggalan tiga huruf pertama kata, yakni Bat, Sky, Sup, Agi, Pro; 8 penggalan empat huruf pertama kata, yakni Brew, Gyro, Morp, Omni, Tide, Agha, Deff, Ulti, dan 10 pelepasan sebagian kata atau suku kata, yakni Alche, Centa, Invis, Jugger, Pango, Necro, Silen, Timber, Venge, Tarras; serta lambang huruf sebanyak 3 data, yakni P, B, G. Abstract: The abbreviation of communication in the DoTA 2 game is interesting to study. This is because the speed and focus of the players are the main keys in the game. Therefore, of course abbreviation in accelerating the communication process carried out by the players. This study aims to describe the abbreviation of words communication in the DoTA 2 game. This research method is qualitative with a descriptive approach. Sources of data were obtained from DoTA 2 players. The object of the study of speech in games that use abbreviation. Data collection used the listening and proficient method. Data analysis used separate methods and techniques for direct elements. The results of the study are abbreviations divided into (i) two-letter abbreviations of 30 data, i.e. AA, AM, CK, BS, CM, DS, DK, DR, ES, LC, LS, OD, PA, PL, SK, SF, TA, TB, WR, BB, HP, NM, TI, MT, PT, BM, SB, TP, DC, GG; (ii) three-letter abbreviations of 6 data, i.e. BKB, MKB, MMR, DPS, BRB, AFK; (iii) four-letter abbreviations of 1 data, i.e. GGWP; acronyms for 4 data, i.e. QOP, MOM, DoTA, OL; contraction of 4 data, i.e. Dipier, Upbrack, Lowbrack, Mismid; fragments of 5 pieces of the first three letters of the word, i.e. Bat, Sky, Sup, Agi, Pro; 8 fragments of the first four letters of the words, i.e. Brew, Gyro, Morp, Omni, Tide, Agha, Deff, Ulti; and 10 partial releases of words or syllables, i.e. Alche, Centa, Invis, Jugger, Pango, Necro, Silen, Timber, Venge, Tarras; and symbol letters as much as 3 data, i.e. P, B, G.

Agrifood by-products and microalgae represent a low-cost and valuable source of bioactive compounds with neuroprotective properties. However, the neuroprotective effectiveness of therapeutic molecules can be limited by their capacity to cross the blood–brain barrier (BBB) and reach the brain. In this research, various green extracts from Robinia pseudoacacia (ASFE), Cyphomandra betacea (T33), Coffea arabica (PPC1), Olea europaea L., (OL-SS), Citrus sinensis (PLE100) by-products and from the microalgae Dunaliella salina (DS) that have demonstrated in vitro neuroprotective potential were submitted to an in vitro BBB permeability and transport assay based on an immortalized human brain microvascular endothelial cells (HBMEC) model. Toxicity and BBB integrity tests were performed, and the transport of target bioactive molecules across the BBB were evaluated after 2 and 4 h of incubation using gas and liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (GC/LC-Q-TOF-MS). The HBMEC-BBB transport assay revealed a high permeability of representative neuroprotective compounds, such as mono- and sesquiterpenoids, phytosterols and some phenolic compounds. The obtained results from the proposed in vitro BBB cellular model provide further evidence of the neuroprotective potential of the target natural extracts, which represent a promising source of functional ingredients to be transferred into food supplements, food additives, or nutraceuticals with scientifically supported neuroprotective claims.

Background. Asphodelus tenuifolius Cav. (Asphodelaceae) is widely used in Pakistan traditional medicine as a hypotensive and diuretic agent. Despite the cardioprotective effects described for A. tenuifolius, the mechanisms involved in its probable hypotensive and diuretic effects have never been evaluated. Firstly, different extracts from A. tenuifolius seeds were obtained, and their antioxidant profiles and chemical constituents by LC-DAD-were determined, including molecular networking by the GNPS platform. Then, to evaluate changes in blood pressure, different groups of anesthetized normotensive rats were intravenously treated with the crude extract (AT-Cr, 1–50 mg/kg), aqueous (AS-AT, 1–25 mg/kg), n-butanol (BS-AT, 1–50 mg/kg), and dichloromethane fraction (DS-AT, 1–80 mg/kg). The diuretic effects of AT-Cr, AS-AT, BS-AT, and DS-AT at 100, 200, and 300 mg/kg, p.o. doses, were also evaluated in comparison with hydrochlorothiazide (HCTZ, 10 mg/kg, p.o). The urinary volume, sodium, potassium, and pH were estimated in the sample collected for 6 h from saline-loaded rats. Using pharmacological antagonists or inhibitors, we determine the involvement of acetylcholine, prostaglandins, and nitric oxide in A. tenuifolius-induced hypotensive and diuresis action. In addition, the activities of angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase were evaluated in vitro. Acute treatment with crude extract and fractions of A. tenuifolius exhibited significant hypotensive and diuretic potential in normotensive rats. However, AS-AT produced the most potent and significant dose-dependent hypotension and diuretic effects in normotensive rats. Previous treatment with atropine significantly reduced the hypotensive and diuretic action of AS-AT, but pretreatment with indomethacin or L-NAME did not affect these effects. Moreover, the 7-day treatment with AS-AT did not reduce activities of serum angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase. AS-AT showed four major compound node clusters, which included sugars, alkaloids, nucleoside, amino acid, and glycosylated flavonoids. This research supports and extends the traditional use of A. tenuifolius as a hypotensive and diuretic agent. The results showed that AS-AT from A. tenuifolius could present compounds responsible for hypotensive and diuretic activities through the activation of muscarinic receptors.

Mucopolysaccharidoses (MPS) and mucolipidosis (ML II/III) are a group of lysosomal storage disorders (LSDs) that occur due to a dysfunction of the lysosomal hydrolases responsible for the catabolism of glycosaminoglycans (GAGs). However, ML is caused by a deficiency of the enzyme uridine-diphosphate N-acetylglucosamine:lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. A timely diagnosis of MPS and ML can lead to appropriate therapeutic options for patients. To improve the accuracy of diagnosis for MPS and ML in a high-risk population, we propose a combination method based on known biomarkers, enzyme activities, and specific GAGs. We measured five lysosomal enzymes (α-L-iduronidase (MPS I), iduronate-2-sulfatase (MPS II), α-N-acetylglucosaminidase (MPS IIIB), N-acetylglucosamine-6-sulfatase (MPS IVA), and N-acetylglucosamine-4-sulfatase (MPS VI)) and five GAGs (two kinds of heparan sulfate (HS), dermatan sulfate (DS), and two kinds of keratan sulfate (KS)) in dried blood samples (DBS) to diagnose suspected MPS patients by five-plex enzyme and simultaneous five GAGs assays. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) for both assays. These combined assays were tested for 43 patients with suspected MPS and 103 normal control subjects. We diagnosed two MPS I, thirteen MPS II, one MPS IIIB, three MPS IVA, two MPS VI, and six ML patients with this combined method, where enzymes, GAGs, and clinical manifestations were compatible. The remaining 16 patients were not diagnosed with MPS or ML. The five-plex enzyme assay successfully identified MPS patients from controls. Patients with MPS I, MPS II, and MPS IIIB had significantly elevated HS and DS levels in DBS. Compared to age-matched controls, patients with ML and MPS had significantly elevated mono-sulfated KS and di-sulfated KS levels. The results indicated that the combination method could distinguish these affected patients with MPS or ML from healthy controls. Overall, this study has shown that this combined method is effective and can be implemented in larger populations, including newborn screening.

Purpose: To determine the safety and outcome profile of five-fraction stereotactic radiotherapy (FSRT) for brain metastases (BM), either as a definitive or adjuvant treatment. Methods: We assessed clinical data of patients receiving five fractions of 7 Gy each (cumulative physical dose of 35 Gy) to BM or surgical cavities. The primary endpoints were toxicity and radiation necrosis (RN) rates. Secondary endpoints were 1-year cumulative local control rate (LCR) and estimated overall survival (OS). Results: A total of 36 eligible patients receiving FSRT to a total of 49 targets were identified and included. The median follow up was 9 (1.1–56.2) months. The median age was 64.5 (34–92) years, the median ECOG score was 1, and the median Diagnostic-Specific Graded Prognostic Assessment (DS-GPA) score was 2. Treatment was well tolerated and there were no grade 3 adverse events or higher. The overall RN rate was 14.3% and the median time to RN was 12.9 (1.8–23.8) months. RN occurrence was associated with immunotherapy, young age (≤45 years), and large PTV. The cumulative 1-year local control rate was 83.1% and the estimated median local progression free-survival was 18.8 months. The estimated median overall survival was 11 (1.1–56.2) months and significantly superior in those patients presenting with RN. Conclusions: FSRT with 5 × 7 Gy represents a feasible, safe, and efficient fast track approach of intensified FSRT with acceptable LC and comparable RN rates for both the adjuvant and definitive RT settings.

Background. Naolingsu capsule (NLSC) is a well-known traditional Chinese medicine (TCM) prescription in China. It is widely used to treat neurasthenia, insomnia, cardiovascular and cerebrovascular disease, and other diseases. However, its inalienable chemical groups have not been carried out. Methods. We first established the nontargeted investigation based on fingerprinting coupled with UHPLC-Q/TOF-MS/MS. Second, the quantitative methods based on HPLC-DAD and LC-MS/MS were connected to the synchronous quantitative assurance of eleven and fourteen marker compounds. Finally, the quantitative information was processed with SIMCA-P for differentiating the distinctive bunches of samples to screen the foremost appropriate chemical markers. Results. The similarity of HPLC fingerprints of 24 batches of NLSC samples was 0.645–0.992. In total, 37 flavonoids, 21 organic acids, 22 lignans, 13 saponins, and 20 other compounds were recognized in NLSC by the UHPLC-Q/TOF-MS/MS method. The quantitative determination was approved for linearity, discovery limits, accuracy, repeatability, soundness, and precision. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models accomplished the great classification of the samples from the five enterprises, respectively. Rehmannioside D (RD), methylophiopogonanone A (MPA), 3,6′-disinapoyl sucrose (DS), schisandrin B (SSB), epimedin C (EC), icariin (ICA), and jujuboside B (JB) were considered as the potential chemical markers for NLSC quality control. Conclusion. The experimental results illustrated that the combinative strategy was valuable for quick pharmaceutical quality assessment, which can potentially differentiate the origin, decide the realness, and assess the overall quality of the formulation.

The ADP-ribosylation factor (Arf) GTPases are important regulators of vesicular transport in eukaryotic cells. Like other GTPases, the Arfs require guanine nucleotide exchange factors to facilitate GTP loading and GTPase-activating proteins (GAPs) to promote GTP hydrolysis. Whereas there are only six mammalian Arfs, the human genome encodes over 20 proteins containing Arf GAP domains. A subset of these, referred to as AZAPs (Randazzo PA, Hirsch DS. Cell Signal 16: 401–413, 2004), are characterized by the presence of at least one NH2-terminal pleckstrin homology domain and two or more ankyrin repeats following the GAP domain. The substrate specificities of these proteins have been previously characterized by using in vitro assay systems. However, a limitation of such assays is that they may not accurately represent intracellular conditions, including posttranslational modifications, or subcellular compartmentalization. Here we present a systematic analysis of the GAP activity of seven AZAPs in vivo, using an assay for measurement of cellular Arf-GTP (Santy LC, Casanova JE. J Cell Biol 154: 599–610, 2001). In agreement with previous in vitro results, we found that ACAP1 and ACAP2 have robust, constitutive Arf6 GAP activity in vivo, with little activity toward Arf1. In contrast, although ARAP1 was initially reported to be an Arf1 GAP, we found that it acts primarily on Arf6 in vivo. Moreover, this activity appears to be regulated through a mechanism involving the NH2-terminal sterile-α motif. AGAP1 is unique among the AZAPs in its specificity for Arf1, and this activity is dependent on its NH2-terminal GTPase-like domain. Finally, we found that expression of AGAP1 induces a surprising reciprocal activation of Arf6, which suggests that regulatory cross talk exists among Arf isoforms.

In this paper, production of charmonium state [Formula: see text] in exclusive [Formula: see text] decays is analyzed in the framework of both leading order Non-relativistic Quantum Chromodynamics (NRQCD) and light-cone (LC) expansion models. Analytical and numerical predictions for the branching fractions of these decays in both the approaches are given. The typical value of the branching fractions is [Formula: see text][Formula: see text][Formula: see text] and it turns out that the LC results are significantly larger than NRQCD ones (approximately two or four times increase depending on the quantum numbers of the final particles), so the effect of internal quark motion should be taken into account. Some rough estimates of color-octet contributions are presented and it is shown that these contributions could be comparable with color-singlet results.

In the present study, the role of a novel protein involved in neurite development and endoplasmic reticulum (ER) stress, canopy homolog 2 (CNPY2), was investigated in mouse and human hepatocarcinogenesis. Firstly, a sensitive quantitative and qualitative detection of protein expression using QSTAR Elite LC-Ms/Ms was performed for the analysis of lysates of microdissected hepatocellular altered foci (AF), adenomas (HCAs), carcinomas (HCCs) and peri-tumoral livers from C57Bl/6J mice treated with diethylnitrosamine (DEN) and then maintained for 27 or 38 weeks on basal diet. Significant overexpression of 18.5 kDa CNPY2 processed form was demonstrated in AF, HCAs and HCCs, while low expression was observed in the livers of DEN-treated and control mice. Furthermore, CNPY2 elevation in AF and tumors was coordinated with accumulation of numerous cytoskeletal proteins, including cytokeratins 8 and 18, actin, non-muscle myosin and septin 9 and those involved in ER and mitochondrial stresses such as calreticulin, prohibitins 1 and 2 and YME1-like-1. Knockdown of CNPY2 in Huh7 and HepG2 human liver cancer cells resulted in significant suppression of cell survival and invasive potential, inhibition of cyclin D1, induction of p21Waf1/Cip1 and suppression of the apoptosis inhibitor Bcl2. In contrast, transfection of a mouse CNPY2 (mCNPY2-Ds-Red) vector plasmid in Huh7 and HepG2 cancer cells, with subsequent accumulation of CNPY2 in the ER, resulted in significant increase in cancer cells survival. Clinicopathological analysis in 90 HCV-positive HCC patients, revealed significant association of CNPY2 overexpression with poor overall (p = 0.041) survival. Furthermore, CNPY2 increase was associated with vessel invasion (p = 0.038), poor histological differentiation (p = 0.035) and advanced clinical stage (p = 0.016). In conclusion, CNPY2 is a promising molecular target elevated early in hepatocarcinogenesis and prognostic marker for human HCV-associated HCC. CNPY2 is involved in the processes of ER stress, cell cycle progression, proliferation, survival and invasion of liver tumor cells.

Por meio do ensaio de compressibilidade, foram estudados os efeitos do manejo e da umidade na pressão de preconsolidação (σp) de três solos: Latossolo Vermelho-Amarelo, Latossolo Roxo e Latossolo Vermelho-Escuro sob cultura anual, mata natural e pastagem, na região de Lavras (MG), em duas profundidades (0-0,03 e 0,27-0,30 m). Para cada condição, foram coletadas cinco amostras indeformadas e uma deformada, com três repetições. As amostras, indeformadas e com diferentes umidades, foram utilizadas no ensaio de compressão uniaxial, obtendo-se as curvas de compressão, das quais foram extraídas as respectivas pressões de preconsolidação. Com as amostras deformadas, determinaram-se os limites de plasticidade e de contração, textura e matéria orgânica. Os modelos de compactação testados foram baseados na pressão de preconsolidação e na umidade do solo. Para uma mesma condição e profundidade, houve diferença significativa entre os valores dos teores de argila e areia nos três solos. Os valores da densidade do solo inicial (Ds i) foram estatisticamente diferentes para todas as condições na mesma profundidade, exceto na camada de 0-0,03 m para a cultura anual. À medida que a umidade do solo aumentou, a pressão de preconsolidação decresceu exponencialmente, indicando uma redução na capacidade de suporte de carga do solo. O LR apresentou, em geral, maior capacidade de suporte de carga do que o LE e LV. Essa maior capacidade de suporte de carga pode estar associada com o seu maior teor de argila e menor teor de areia. A capacidade de suporte de carga na zona de friabilidade variou de 154 a 167 kPa, para o LV; de 77 a 183 kPa, para o LR, e de 77 a 132 kPa, para o LE. As umidades 0,33 a 0,30 kg kg-1, 0,42 a 0,27 kg kg-1, e 0,35 a 0,33 kg kg-1 correspondem à faixa de friabilidade (LP - LC) do LV, LR e LE, respectivamente. O modelo baseado na história de tensão do solo evidenciou o efeito da compactação causada pelas máquinas de preparo do solo na camada de 0,27-0,30 m, para a cultura anual, enquanto, para a pastagem, ocorreu o efeito do pisoteio do gado na camada de 0-0,03 m.

Background:Recently, immunometabolism has gathered attention of many immunologists. It has been widely recognized that metabolic reprogramming in each immune cell brings different effects on different cells and is important for regulating their functions. Along with the progress of statistical genetics, serum metabolites were shown to be under genetic regulations1). Metabolic changes are now considered not only to be mere phenotypes of cells but also to be key factors for controlling immune cell differentiation, proliferation and function through regulating gene expressions eventually. Although genome-wide association studies have brought deep insights into SLE pathogenesis, the precise pathway from genome to metabolome has been largely unknown, and vice versa.Objectives:The aim of this study is to investigate metabolomic regulation in SLE in relation to gene expressions by integrating plasma metabolome data and transcriptome data.Methods:We collected plasma samples from patients with SLE (n=57) who met the 1997 American College of Rheumatology criteria for SLE. Gender- and age-matched healthy controls (HCs) (n=56) were recruited. Metabolic profiles focusing on 39 amino acids were analyzed with liquid chromatography (LC)-mass spectrometry. Transcriptome data of SLE patients were obtained from our RNA-sequencing data of each immune cell subset (total 19 subsets). Whole-genome sequencing was also performed.Results:Our previous experiment showed that about 160 peaks were detected from comprehensive LC-TOFMS and amino acids were useful for distinguishing SLE patients from HCs. Both partial least squares discriminant analysis (PLS-DA) and random forest, a machine learning algorithm, revealed the importance of histidine (His), one of the essential amino acids, to classify SLE patients from HCs, whose plasma level was lower in SLE patients. In addition, inverse correlation between His level and titer of ds-DNA as well as damage index (SDI) was detected. His level was correlated neither with PSL dosage nor with type I interferon (IFN) signature. Receiver operating characteristic (ROC) analysis showed the best predictability for SLE with the combination of specific amino acids including His. Our transcriptome analysis has revealed the significance of oxidative phosphorylation (OXPHOS) in B cells for SLE pathogenesis. Interestingly, OXPHOS signature was inversely correlated with His level in SLE B cells.Conclusion:His may be an important factor for SLE pathogenesis especially in B cells independently from IFN signal. SLC15A4, a transporter of His on lysosome, is one of the SLE GWAS SNPs and has been reported to play an important role in IFN production in B cells through regulation of TLR7/9 activation 2). We also identified that SLE patients with risk allele of SLC15A4 had tendency to show higher plasma His level, indicating His homeostasis could become a novel treatment target for SLE. Moreover, the inverse correlation of His level to SDI as well as OXPHOS signature suggests that His might play a key role for promoting organ damages in SLE.References:[1]Nat Genet.2017;49:568. 2)Immunity. 2014;41:375. 3)Semin Arthritis Rheum.2019;48:1142Disclosure of Interests: :Yukiko Iwasaki: None declared, Yusuke Takeshima: None declared, Masahiro Nakano: None declared, Mineto Ota: None declared, Yasuo Nagafuchi: None declared, Akari Suzuki: None declared, Yuta Kochi: None declared, Tomohisa Okamura: None declared, Takaho Endo: None declared, Ichiro Miki: None declared, Kazuhiro Sakurada: None declared, Kazuhiko Yamamoto Grant/research support from: Astellas, BMS, MitsubishiTanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, and ImmunoFuture, Keishi Fujio Grant/research support from: Astellas, BMS, MitsubishiTanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, Eli Lilly, Sanofi, and UCB

Os sistemas de manejo que promovem adição de resíduos de cana-de-açúcar ao solo podem provocar alterações nos parâmetros de compressibilidade. O objetivo deste trabalho foi investigar o comportamento da compressibilidade de um Latossolo Amarelo distrocoeso dos Tabuleiros Costeiros de Alagoas, considerando a adição de resíduos orgânicos em três diferentes sistemas de manejo com cana-de-açúcar. O trabalho experimental foi realizado na Usina Santa Clotilde, localizada no Estado de Alagoas. Foram escolhidas três áreas em talhões com cana-de-açúcar, sendo investigadas: uma área cultivada sob sistema de manejo irrigado (SMI), uma área sob sistema de manejo de fertirrigação com vinhaça (SMV) e uma área sob sistema de manejo com aplicação de vinhaça + torta de filtro (SMVT). Esses sistemas de manejo foram comparados entre si e em relação a uma testemunha-padrão, representada por uma mata nativa (MN). Os três sistemas de manejo sob cultivo da cana-de-açúcar foram implantados quatro anos antes do início da coleta das amostras de solo. Para o ensaio de compressão uniaxial foram coletadas amostras indeformadas, nas profundidades de 0-0,20 e 0,20-0,40 m, com a intervenção de um amostrador metálico. As amostras preparadas foram ensaiadas por compressão uniaxial, nas seguintes umidades gravimétricas: 0,10; 0,14; 0,18; e 0,22 kg kg-1. No ensaio de compressão foram aplicados carregamentos verticais, correspondentes a tensões de 12,5, 25, 50, 100, 200, 400, 800 e 1.600 kPa, e realizadas leituras aos 30 s. Após o ensaio, as amostras foram levadas à estufa, para determinação da umidade gravimétrica. Os resultados foram submetidos à análise de variância e análise de regressão múltipla da tensão de pré-compactação, considerando as seguintes variáveis independentes: densidade do solo (Ds), umidade gravimétrica (Ug), diâmetro médio ponderado de agregados via úmida (DMPu) e energia dissipada (Ed). O solo sob mata nativa apresenta menor capacidade de suporte de cargas nas duas profundidades estudadas, em relação aos três sistemas de manejo sob cultivo com cana-de-açúcar; os sistemas de manejo sob cultivo da cana-de-açúcar aos quais foram adicionados resíduos orgânicos (SMVT e SMV) apresentam menores históricos de tensões; as curvas-limite (SI e LC) podem ser empregadas no planejamento da execução das operações mecanizadas; e a tensão de pré-compactação pode ser predita a partir de propriedades físicas.

Methyl cellulose and its derivatives are widely used in the food industry, cosmetics, and as construction materials. The properties of methyl celluloses (MC) strongly depend on their degrees and positions of substitution. In order to generate MCs with uncommon blocky substitution, we apply fully protected O-benzyl-O-methyl celluloses (BnMC). Such complex polysaccharide derivatives could not be deprotected completely and without shift of the composition by methods usually applied to mono- and oligosaccharides. Therefore, a facile debenzylation method was developed based on photo-initiated free-radical bromination in the presence of hydrobromic acid scavengers followed by alkaline treatment. The reaction proceeds under homogeneous conditions and without the aid of any catalyst. There is no need for expensive equipment, materials, anhydrous reagents, or running the reaction under anhydrous conditions. Reaction parameters were investigated and optimized for successful debenzylation of completely protected BnMC with degrees of methyl substitution (DSMe) around 1.9 (and DSBn around 1.1). Side-product-free and almost complete debenzylation was achieved when 1,2-epoxybutane (0.5 eq./eq. N-bromosuccinimide) and 2,6-di-tert-butylpyridine (0.5 eq./eq. N-bromosuccinimide) were used in the reaction. Furthermore, ATR-IR and 1H NMR spectroscopy confirmed the successful removal of benzyl ether groups. The method was developed to monitor the transglycosylation reaction of the BnMC with permethylated cellulose, for which the deprotection of many small samples in parallel is required. This comprises the determination of the methyl pattern in the glucosyl units by gas-liquid chromatography (GLC), as well as oligosaccharide analysis by liquid chromatography mass spectrometry (LC-MS) after perdeuteromethylation and partial hydrolysis to determine the methyl pattern in the chains. The unavoidable partial chain degradation during debenzylation does not interfere with this analytical application, but, most importantly, the DS and the methyl pattern were almost congruent for the debenzylated product and the original MC, indicating the full success of this approach The presented method provides an unprecedented opportunity for high throughput and parallel debenzylation of complicated glucans, such as BnMC (as a model compound), for analytical purposes. For comparison, debenzylation using Na/NH3 was applied to BnMC and resulted in a completely debenzylated product with a remarkably high recovery yield of 99 mol% and is, thus, the method of choice for synthetic applications, e.g., for the transglycosylation product prepared under the selected conditions in a preparative scale.

Abstract The zinc finger transcription factor GATA-1 is required for proliferative inhibition and terminal maturation of megakaryocytes, and is mutated in Down Syndrome Transient Myeloproliferative Disorder (TMD) and Acute Megakaryoblastic Leukemia (DS-AMKL). Yet the molecular mechanisms that regulate GATA-1 activity in megakaryopoiesis remain incompletely understood. Many transcription factors, in addition to binding DNA, make important protein-protein interactions that modulate their activity. In order to further understand GATA-1’s function, and possibly identify new factors involved in megakaryopoiesis, we purified GATA-1 containing multiprotein complexes from the murine L8057 megakaryocytic cell line. We generated stable L8057 cell lines expressing metabolically biotinylated and FLAG epitope tagged GATA-1, and then performed a tandem anti-FLAG immunoaffinity and streptavidin affinity purification. Using mass spectrometry (LC/MS/MS), we identified the known GATA-1 associated proteins Friend of GATA-1 (FOG-1), SCL, Ldb1, Runx-1/Cbf-β. SP1 and all components of the NuRD complex (which binds FOG-1) as co-purifying proteins. In addition, we reproducibly obtained several novel proteins. We previously reported the identification of the kruppel-type zinc finger transcription factor zfp148 (also called ZBP-89), and showed that it plays an essential role in megakaryopoiesis and definitive erythropoiesis. Here we report the identification of Kindlin 3 (also called URP2 for UNC-112 related protein 2), a member of a family of PH and FERM domain containing proteins that are thought to play a role in integrin-mediated processes. Expression of Kindlin 3 is restricted to hematopoietic cells, principally megakaryocytes and lymphocytes. It is first expressed at ~E9.5 during murine embryogenesis, and is abundant in fetal liver megakaryocytes by day E14.5. In order to begin to assess the role of Kindlin 3 in megakaryopoiesis in vivo, we performed morpholino-mediated knockdown of Kindlin 3 expression in CD41-GFP transgenic zebrafish embryos. In contrast to control embryos, embryos injected with Kindlin 3 specific morpholinos exhibited nearly complete loss of GFP+ thrombocytes (equivalent to mammalian megakaryocyte/platelets). Erythroid development (equivalent to mammalian primitive erythropoiesis at this stage of development) was not significantly affected, similar to embryos injected with zfp148-specific morpholinos. Given the role of integrin outside-to-inside signaling in megakaryopoiesis, we propose that Kindlin 3 may play a role linking extracellular signals to megakaryocyte maturation and growth control via GATA-1 transcription complexes. Further analysis in murine systems is underway to test this hypothesis.

The phthalate and semi-volatile organic compounds (SVOCs) are modern chemical substances and extensively existing in the indoor environment. The European Commission stipulated the “European Unified Test Criteria”, since 2011, for the declared specifications of building products (CEN/TS 16516), based on the “lowest concentrations of interest (LCI)”, the index pollutants, test method, and emission standard of “phthalate” and “SVOC” were specified in detail. The purpose of this study is to use six common indoor floor construction products in Taiwan (regenerated pseudoplastic rubber flooring, healthy pseudoplastic imitation wood floor, regenerated pseudoplastic rubber flooring, PVC floor tile/floor, plastic click floor, composite floor covered with carpet) to detect the changes in the concentration of phthalate emitted to the air. The ISO 16000-25 Indoor air—Part 25: Determination of the emission of semi-volatile organic compounds by building products—micro-chamber method is used to build a DS-BMEMC (glass micro-chamber: volume 630 mL), the SVOC, including phthalate, is collected in two stages, in the stable conditions of temperature 25 °C, relative humidity 50% and air change rate 2 times/h, the Stage 1 emission detection experiment (24 h) is performed, and then the Stage 2 heating-up desorption emission detection experiment (40 min air sampling) is performed, the temperature rises to 200–220 °C, the phthalate and SVOC adsorbed on the glass micro-chamber is desorbed at a high temperature to catch the air substances, the air is caught by Tenax®—TA and Florisil® adsorption tube, and then the GC/MS and LC/MSMS analysis methods are used for qualitative and emission concentration analyses of SVOC of two-stage emission, respectively. The findings show that the floor construction materials emit nine phthalate SVOCs: DEHP, DINP, DNOP, DIDP, BBP, DBP, DIBP, DEP, and DMP, the two-stage emission concentrations are different, Stage 1 (normal temperature) emission concentration of six floor construction materials is 0.01–1.2% of Stage 2 (high temperature) emission concentration, meaning the phthalate SVOC of floor construction materials is unlikely to be volatilized or emitted at normal temperature. An interesting finding is that only S3 was detected DINP 72.6 (μg/m3) in stage 1. Others were detected DINP in stage 2. This might be because S3 has carpet on the surface. This implies that floor material with carpet may have an emission of DINP at normal temperature. The result of this study refers to the limited value evaluation of EU structural material standard emission TSVOC ≤ 0.1 ug/m3, the floor building material emissions are much higher than the evaluation criteria, increasing the health risk of users. The detection method and baseline can be used as the standard for controlling the emission of phthalate SVOC of Taiwan’s green building material labeling system in the future.

Abstract Abstract 2827 Poster Board II-803 Centrosome amplification (CA) has been previously detected in hematological malignancies including multiple myeloma (MM) and is usually associated with disease progression. CA leads to the formation of multipolar mitotic spindles that may lead to chromosome segregation errors and genomic instability. In this pilot study, we have evaluated the occurrence of CA in two populations of B-lineage cells including B-lymphocytes and plasma cells (PCs) of MM patients. We have analyzed possible associations of CA with established prognostic factors including the most common chromosomal abnormalities in malignant PCs. Immunofluorescence labeling was used for the evaluation of centrosome amplification (CA) in B-cells (CD19+) and PCs (CD138+) of MM patients. The centrin (centrosome protein) copy numbers were used to define three cellular subpopulations: (1) no centrin signal (Non-CS), (2) 1-4 centrin signals (1-4CS) or (3) more than 4 signals of centrin (CA). Samples with ≥11% of B-cells or ≥10% of PCs with >4 fluorescence signals of centrin were considered CA positive. A total of 70 patients were evaluated for CA in PCs and/or B-cells, including 18 patients who had analysis of both cell types. The patient population characteristics were as follows: males/females 34/36, median age of 65 years (range, 40-84 years). Most patients had advanced stage of MM (DS II/III n = 48; ISS II/III; n = 21). Peripheral blood samples from 20 healthy donors were used as controls and for the estimation of CA positivity threshold for B-cells (Mean + 3SD). There was a statistically significant difference between the percentage of B-cells subpopulations with centrosome amplification in MM patients and that in healthy donors ([Mean ± SD] 9.9 ± 7.9% versus 3.2 ± 2.5%; P<0.0001). The frequency of MM cases positive for CA was 34% (17/50) and 37% (14/38) based the analysis of PC samples and B-cell samples, respectively. Overall, 22% (4/18) MM patients were double-positive. No significant correlation was detected between B-cells and PCs (r=0.387; P=0.113) obtained from patients with both available samples. No significant associations were identified between CA status and the following common cytogenetic abnormalities in PCs: del(13)(q14) (p= 1.000); del(17)(p13) (p=0.132); gain(1)(q21) (p= 1.000), hyperdiploidy (p= 1.000). In summary, we have confirmed the presence of centrosome amplification in B-cells of MM patients. Immunofluorescence staining is a sensitive method for the detection of abnormal subpopulations of B-cells that probably represent a reservoir of clonogenic cells in MM. This study was supported by grants NR 8945-4/2006, MSM 0021622434, MZ LC 06027 and IGA NR 9317 from the Departments of Education and Health of the Czech Republic. Disclosures: No relevant conflicts of interest to declare.

Background:Osteonecrosis of the femoral head (ONFH) is a common disease caused by many trauma factors and un-trauma factors. Among those un-trauma factors, steroid-induced osteonecrosis of the femoral head (SNFH) accounted for a large proportion and mainly concentrated in young people. SNFH has been reported as an irreversible disease and associated with the damage of blood vessels and the loss balance of bone homeostasis. Circulating endothelial progenitor cells (CEPCs), one part of circulating endothelial cells (CECs), are immature precursor cells with proliferative potential. The damage of vascular endothelial cells in SNFH has been confirmed by many studies, but the changes of CECs and CEPCs in the peripheral blood of patients with SNFH have not been studied yet.Objectives:The objective of the study is to explore the number of CECs and CEPCs in SNFH patients and normal people and then investigate whether EC-secreted exosomes (EC-exos) could prevent the progression of SNFH in rat model and its mechanism of action.Methods:We collect peripheral blood of 3 SNFH patients and 3 heathy people and detected the levels of CECs and CEPCs by Flow cytometer. TEM, NTA and western blot was used to characterize the isolated EC-exos. Annexin V-FITC/PI double staining with flow cytometric analysis and western blot were used to evaluate MC3T3-E1 cells apoptosis. CCK-8, scratching experiment and transwell were used to evaluate MC3T3-E1 cells viability and migration ability. Micro-CT and morphological staining were used to evaluate the progress of SNFH in rat model.Results:Firstly, we found that the number of CECs and CEPCs in the peripheral blood was decreased in SNFH patients than normal people. Then our results indicated that EC-exos could improve the migration, viability and prevent apoptosis of osteoblasts under dexamethasone by activating the PI3K/AKT/Bcl-2 signal pathway in vitro. Finally, our Micro-CT and morphological staining results in SNFH rat model revealed that EC-exos prevented the progression of SNFH.Conclusion:EC-exos could enhance the cell viability and migration ability of osteoblasts under dexamethasone and play an anti-apoptosis role against steroids-induced osteoblast apoptosis by activating the PI3K/AKT/Bcl-2 signal pathway. EC-exos prevented the progression of SNFH in rat model.References:[1]Zalavras CG, Lieberman JR. Osteonecrosis of the femoral head: evaluation and treatment. J Am Acad Orthop Surg. 2014;22(7):455-64.[2]Microsurgery Department of the Orthopedics Branch of the Chinese Medical Doctor A, Group from the O, Bone Defect Branch of the Chinese Association of R, Reconstructive S, Microsurgery, Reconstructive Surgery Group of the Orthopedics Branch of the Chinese Medical A. Chinese Guideline for the Diagnosis and Treatment of Osteonecrosis of the Femoral Head in Adults. Orthop Surg. 2017;9(1):3-12.[3]Mont MA, Jones LC, Hungerford DS. Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am. 2006;88(5):1117-32.[4]Yuan HF, Zhang J, Guo CA, Yan ZQ. Clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation: a meta-analysis of seven case-control studies. Clinics (Sao Paulo). 2016;71(2):110-3.[5]Houdek MT, Wyles CC, Packard BD, Terzic A, Behfar A, Sierra RJ. Decreased Osteogenic Activity of Mesenchymal Stem Cells in Patients With Corticosteroid-Induced Osteonecrosis of the Femoral Head. J Arthroplasty. 2016;31(4):893-8.Disclosure of Interests:None declared.

Nanopatterned or roughed metallic structures have received considerable attention due to the effective light absorption capability via optical effects of light confinement or photonic excitation of surface plasmon polaritons.1, 2, 3, 4, 5 However, individual metallic structures have limited light capture. To augment the solar light utilization, coupling of different absorption modes was developed within three-dimensional architectures.6, 7 Among these, the absorbers using dielectric-nanostructures interactions showed effective light harvesting, which exhibited enhanced photocatalysis and water splitting activities. Here, we present a solid visible light absorber made of proper sub-oxidation of metal Ti through a facial approach. First, surface nanostructures were prepared using a chemical etching process on cleaned metal Ti foils. Then, a thermal sub-oxidation was employed to diffuse oxygen into the sub-surface region of the metal Ti, forming titanium-oxides nanocomposites. The titanium-oxides are composed of titanium suboxides on the sub-surface of metal Ti nanostructures. The surface sharpness of nanostructures was checked by atomic force microscopy (AFM) and scanning electron microscopy (SEM) (Figure 1), showing favorable surface nanostructures. The nanostructures of quasi-prisms with sharp nano-curvatures allow light concentration in a more vigorous intensity. The affluent sharp edges of nanostructures could behave as “hot spots”. In Figure 2, the UV-vis absorption spectra of the as-prepared specimen disclose a strong resonant light absorption in the visible region with an almost four times enhancement. The resonant absorption band position and intensity are adjustable by controlling thermal diffusion parameters and surface structures. Our observation is quite distinctive from the absorption spectra of single phases, anatase or rutile phase TiO2, and the cases of mixed-phase TiO2-x nanoparticles. To our best knowledge, this is the first demonstration of uniquely strong resonant visible absorption band by sub-oxidized metal Ti nanostructures. The absorber is of particular interest in a wide range of extensive photo-responsive applications, such as optoelectronic devices, photovoltaics, and photocatalysis. The approach represents a new pathway to enable photonic absorption within nanostructures, not only for metal Ti but also for other related metallic structures. Acknowledgments: The authors acknowledge the research grants from EEA (European Economic Area)-Norway-Romania project# GRAFTID, RO-NO-2019-0616, EEA-Poland-NOR/POLNORCCS/PhotoRed/0007/2019-00, and the Research Council of Norway projects #314012 and #245963/F50. References Montoya JH, Seitz LC, Chakthranont P, Vojvodic A, Jaramillo TF, Norskov JK. Materials for solar fuels and chemicals. Nat Mater 16, 70-81 (2016). Chen X, Liu L, Huang F. Black titanium dioxide (TiO2) nanomaterials. Chem Soc Rev 44, 1861-1885 (2015). Robatjazi H, Zhao H, Swearer DF, Hogan NJ, Zhou L, Alabastri A, McClain MJ, Nordlander P, Halas NJ. Plasmon-induced selective carbon dioxide conversion on earth-abundant aluminum-cuprous oxide antenna-reactor nanoparticles. Nat Commun 8, 27 (2017). Atwater HA, Polman A. Plasmonics for improved photovoltaic devices. Nat Mater 9, 205-213 (2010). Maier SA, Brongersma ML, Kik PG, Meltzer S, Requicha AAG, Atwater HA. Plasmonics-a route to nanoscale optical devices. Adv Mater 13, 1501-1505 (2001). Shi X, Ueno K, Oshikiri T, Sun Q, Sasaki K, Misawa H. Enhanced water splitting under modal strong coupling conditions. Nat Nanotechnol 13, 953-958 (2018). Choi D, Shin CK, Yoon D, Chung DS, Jin YW, Lee LP. Plasmonic optical interference. Nano Lett 14, 3374-3381 (2014). Figure 1

Abstract Background: Multiple myeloma (MM) is a lymphoproliferative disease characterized by the clonal expansion of neoplastic plasma cells within the bone marrow. The genome of the malignant plasma cells is extremely unstable characterized by a complex combination of structure and numerical abnormalities. DNA copy number variants (CNV) affects target gene expression but such affectation is not compulsory and target gene expression can be modulated. We supposed that this modulation serves as a compensatory mechanism to keep genomic homeostasis. Further compensation mechanisms exhausting leads disease aggressiveness. Aims: The objective of our study was to define and describe influence of DNA copy number variants on gene expression level in multiple myeloma. Material and methods: 66 newly diagnosed patients with MM were evaluated for this study. The patients' baseline characteristics were as follows: males/females: 34/32 (52% /48%); median age of 68 years (range 49-83 years). Type of M protein IgG/IgA/LC/other (total n=58); 36/11/10/1 (62%/19%/17%/2%); most of the patients had advanced stage of MM DS II+III (total n=58) n =58 (100%); ISS II+III (total n=53) n=42 (79%). CD138+ plasma cells separated by MACS. Gene expression profiling was performed using Affymetrix GeneChip Human Gene ST 1.0 array (Affymetrix). DNA copy number variations was evaluated using Agilent Human Genome CGH Microarray (4x44K), Agilent SurePrint G3 Human Genome CGH+SNP Microarray Kit (4x180K), OGT CytoSure Haematological Cancer +SNP (8x60K), Agilent SurePrint G3 Human CGH Microarray (8x60K) with proper platforms aggregation (Agilent technologies). Results: Each patient had at least one CNV, the most often changes were at the level of entire chromosomes. Hyperdiploid/non-hyperdiploid patients (H-MM/NH-MM) represent 53 % (31/66) and 47 % (35/66), resp. CNV considered as uncompensated, if the value of target gene expression is lower than the 25th percentile of norm (gene expression of genes without loss or gain of DNA) for gene loss, or greater than the 75th percentile of norm for gene gain. Figure 1A shows that level of CNV modulation is determined by the number of changes that occur in a given patient. Further, ROC analysis was done to determine whether certain level of compensation is related to the overall survival and CNV compensation limit 20% (p=0.026) was established. Patients with ≥20% of decompensated CNV had significantly worse OS (survival median 5.2 month) compared to patients with <20% of decompensated CNV (survival median 23.5 month). Kaplan-Meier curves for given patients' subgroups are presented in Figure 1B. Conclusion: Copy number variants in MM can be compensated on gene expression level. Compensatory capacity of genome is associated with total number of CNV. Patients with ≥20% of decompensated CNV had significantly worse OS. Acknowledgment: This study was supported by grants no. MSK 02680/2014/RRC and MSK 02692/2014/RRC; MH CZ-DRO-FNOs/2014; SGS01/LF/2014-2015, SGS02/LF/2014-2015, SGS03/LF/2015-2016, NT14575, AZV 15-29508A and AZV 15-29667A Figure 1. Copy number variants (CNV) modulation and their clinical impact in multiple myeloma A. The overall rate of CNV occurrence in proportion to the gene expression affectation (loss of CNV compensation) B. Overall survival in newly diagnosed MM patients with different level of CNV compensation. Figure 1. Copy number variants (CNV) modulation and their clinical impact in multiple myeloma A. The overall rate of CNV occurrence in proportion to the gene expression affectation (loss of CNV compensation) B. Overall survival in newly diagnosed MM patients with different level of CNV compensation. Disclosures Hajek: Janssen-Cilag: Honoraria; Celgene, Amgen: Consultancy, Honoraria.

Background:Psoriatic arthritis (PsA) is a heterogeneous disease with variability of response to different therapeutic modalities.1 Identifying potential demographic and disease characteristics as predictors of treatment response may define personalised treatment optimisation strategies.2–3Objectives:This post-hoc exploratory analysis of the MAXIMISE trial4 investigated the differential treatment effect of demographics and baseline characteristics as predictive factors in biologic naïve patients with active PsA and symptoms of active spinal disease.Methods:The full analysis set (FAS) comprised of all patients from the randomised set assigned to study treatment, fulfilling the predefined clinical criteria for active axial disease and for whom Assessment of SpondyloArthritis International Society (ASAS) 20 data were available at Week 12. The research hypothesis was that the odds ratio associated with the effect of treatment on ASAS20 responder status at Week 12 would be different depending on 12 pre-specified predictor variables. A logistic regression model was initially fitted to the FAS that included 12 pre-specified covariates. A second logistic regression model was then fitted to the FAS that allowed for all 12 pre-specified variables to interact with treatment.5 The log-likelihood of the two fitted models were compared using a likelihood ratio test at a pre-specified significance level of 20% (i.e. P-value ≤0.20) to test whether any of the predefined variables interacted with treatment. If the above test was statistically significant at the 20% level of statistical significance the variables of the second model were formally examined to determine whether the overall effect of treatment is not applicable. Three forest plots were produced, one for each treatment group. Hypothesis tests were employed to determine the strength of evidence for each individual variable.Results:The likelihood ratio test provided evidence against the assumption that the overall effect of treatment is applicable to all patients (P-value = 0.08). Notably, the odds of being an ASAS20 responder if nail dystrophy is present at baseline were 3 times greater in the secukinumab 150 mg group and 5 times greater in the 300 mg group compared with placebo (interaction P-value = 0.029). Although males fare worse than females in the placebo group, in the secukinumab 150 mg and 300 mg treatment groups the odds of being a responder were similar to females (interaction P-value = 0.039). Current smokers were less likely to be ASAS20 responders compared to never smokers regardless of treatment group (interaction P-value = 0.589) (Figure 1). Age, CRP level, Berlin MRI spine/SIJ score, time since first axial signs, number of swollen joints, new bone formation and BMI did not show a differential treatment effect on ASAS20 responses.Conclusion:Of the 12 baseline variables of a unique population of 473 PsA patients with active axial disease diagnosed by clinical criteria, our analyses showed evidence of a differential treatment effect most notably for nail dystrophy suggesting that the presence of nail dystrophy may predict a better response to secukinumab in PsA patients with axial manifestations.References:[1]Coates LC, Helliwell PS. Clin Med (Lond). 2017;17(1):65–70.[2]Watson DS, et al. BMJ. 2019;364:l886.[3]Hügle M, et al. Rheumatol Adv Pract. 2020;4(1):rkaa005.[4]Baraliakos X, et al. Ann Rheum Dis. Published Online First: 17 Dec 2020. doi:10.1136/annrheumdis-2020-218808.[5]Peto R, et al. Br J Cancer. 1977;35(1):1–39.Figure 1.Forest plots of the adjusted odds ratio by treatment using interaction modelDisclosure of Interests:Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, MSD, Novartis, Pfizer, and UCB., Consultant of: AbbVie, BMS, Celgene, Chugai, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB., Grant/research support from: AbbVie, and Novartis., Effie Pournara Shareholder of: Novartis, Employee of: Novartis, Laure Gossec Consultant of: AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB., Grant/research support from: Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi, and Galapagos., Helena Marzo-Ortega Consultant of: Janssen, Novartis, AbbVie, Celgene, Lilly, Pfizer, Takeda and UCB., Grant/research support from: Janssen, Novartis, AbbVie, Celgene, Lilly, Pfizer, Takeda and UCB., Philip J Mease Speakers bureau: AbbVie, Amgen, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB., Consultant of: AbbVie, Amgen, BMS, Boehringer Ingelheim, Galapagos, Celgene, Genentech, Gilead, Janssen, Lilly, Novartis, Pfizer, SUN Pharma, and UCB., Grant/research support from: AbbVie, Amgen, BMS, Celgene, Galapagos, Genentech, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, SUN, and UCB., Roisin White Shareholder of: Novartis, Employee of: Novartis, Eamonn O’Brien Shareholder of: Novartis, Employee of: Novartis, Barbara Schulz Employee of: Novartis, Laura C Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Gilead, Eli Lilly, Janssen, Medac, Novartis, Pfizer, and UCB., Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB., Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Pfizer, and Novartis.

A higiene bucal, parte integrante dos cuidados corporais, é realizada com o auxílio de dispositivos, em especial, a escova dental. Com a evolução tecnológica, as escovas dentais passaram a ser fabricadas com diferentes materiais. Objetivou-se investigar as marcas e modelos de escovas dentárias disponíveis no mercado brasileiro; analisar a legislação vigente sobre a produção e verificar as informações fornecidas pelo fabricante ao consumidor final. Trata-se de um estudo transversal, descritivo, qualitativo, de análise documental. Foi realizado levantamento nas páginas eletrônicas da Agencia Nacional de Vigilância Sanitária e do Instituto Nacional de Metrologia, Qualidade e Tecnologia sobre a legislação vigente, que estabelece as características exigidas para produção e comercialização de escovas dentárias. Foram pesquisadas marcas e modelos disponíveis no mercado brasileiro, nas páginas eletrônicas das empresas, fabricantes ou importadoras e em pontos de vendas para o consumidor final para verificar as informações disponíveis nas embalagens. A Resolução N° 54/17 da Diretoria Colegiada da ANVISA, estabelece algumas características físicas, tais como: largura máxima da cabeça e comprimento mínimo da escova dentária. Foram incluídos nesta pesquisa 20 marcas comerciais, as quais distribuem 108 modelos no mercado brasileiro. Apenas 2 modelos (1,85%) apresentaram todas as informações exigidas pela resolução da ANVISA, sendo a “supervisão do adulto” e “orientação do dentista” os itens menos contemplados. Não apresentaram indicação para uso adulto ou infantil 44,4% do total. Conclui-se, que existem muitas marcas e modelos no mercado brasileiro, porém faltam informações importantes para o profissional realizar a indicação apropriada e o paciente, a aquisição consciente. Descritores: Escovação Dentária; Higiene Bucal; Saúde Bucal. Referências Jardim JJ, Alves LS, Maltz M. The history and global market of oral home-care products. Braz Oral Res. 2009;23(Suppl 1):17-22. Fischman SL. The history of oral hygiene products: how far have we come in 6000 years? Periodontol 2000. 1997;15:7-14. Borghi WMMC, Moimaz SAS, Saliba NA. Métodos alternativos para higienização bucal e terapêutica odontológica. Rev Inst Ciênc Saúde. 2005;23(4):309-14. McCauley HB. Toothbrushes, toothbrush materials and design. J Am Dent Assoc. 1946;33(5):283-93. Garfin LA. Tooth picks and tooth brushes. Dent Survery. 1964;40:102-8. Garbin CAS, Rovida TAS, Garbin AJÍ, Arcieri RM. Saúde bucal e educação infantil: avaliação do desgaste e do acondicionamento de escovas dentárias utilizadas por pré-escolares. Rev Odontol UNESP. 2012;41:148. Conforti NJ, Cordero RE, Liebman J, Bowman JP, Putt MS, Kuebler DS, et al. An investigation into the effect of three months’ clinical wear on toothbrush efficacy: results from two independent studies. J Clin Dent. 2003;14(2):29-33. Kaiser E, Meyners M, Markgraf D, Stoerkel U, von Koppenfels R, Adam R, et al. Brush head composition, wear profile, and cleaning efficacy: an assessment of three electric brush heads using in vitro methods. J Clin Dent. 2014;25(2):19–25. R aiyani CM, Arora R, Bhayya DP, Dogra S, Katageri AA, Singh V. Assessment of microbial contamination on twice a day used toothbrush head after 1-month and 3 months: an in vitro study. J Nat Sci Biol Med. 2015;6(Suppl 1):S44-8. Hamal JD, Hensley DM, Maller SC, Palazzolo DJ, Vandewalle KS. An in vitro comparison of antimicrobial toothbrushes. Gen Dent. 2014;62(6):e24-7. Slot DE, Wiggelinkhuizen L, Rosema NA, Van der Weijden GA. The efficacy of manual toothbrushes following a brushing exercise: a systematic review. Int J Dent Hyg. 2012;10(3):187–97. Niazi F, Naseem M, Khurshid Z, Zafar MS, Almas K. Role of Salvadora persica chewing stick (miswak): A natural toothbrush for holistic oral health. Eur J Dent. 2016;10(2):301-8. Ministério da Saúde. Resolução - RDC nº 142, de 17 de março de 2017. Dispõe sobre a regularização de produtos de higiene pessoal descartáveis destinados ao asseio corporal, que compreendem escovas e hastes para higiene bucal, fios e fitas dentais, absorventes higiênicos descartáveis, coletores menstruais e hastes flexíveis. Diário Oficial União. 2017 mar20. Ministério da Saúde. Portaria no 97, de 26 de junho de 1996. Dispõe sobre as Normas e Requisitos Técnicos, a que ficam sujeitos as escovas dentais, com ou sem pigmentos ou corantes nas cerdas. Diário Oficial União. 1996 jun 27. International Organization for Standardization. ISO 8627:1987: dentistry: stiffness of the tufted area of tooth-brushes. Disponível em: https://www.iso.org/standard/15961.html. Ministério do Desenvolvimento, Indústria e Comércio Exterior. Programa de análise de produtos: relatório da análise em escovas dentais para uso adulto e infantil. Disponível em: http://estaticog1.globo.com/2013/06/10/rel_escovas_dentais_final.pdf. Pontes TE, Costa TF, Marum ABRF, Brasil ALD, Taddei JAAC. Orientação nutricional de crianças e adolescentes e os novos padrões de consumo: propagandas, embalagens e rótulos. Rev Paul Pediatr. 2009;27(1):99-105. Associação Brasileira de Embalagem. Valor do design. Disponível em: http://www.abre.org.br/comitesdetrabalho/design/valor-do-design/ Bottan ER, Campos L, Odebrecht CMLR, Silveira EG, Schmitt P, Araújo SM. Critérios adotados para a escolha da escova dental: estudo com consumidores de Florianópolis, Santa Catarina (Brasil). RSBO Rev Sul-Bras Odontol. 2010;7(2):173-81. Yaacob M, Worthington HV, Deacon SA, Deery C, Walmsley AD, Robinson PG, et al. Powered versus manual toothbrushing for oral health. Cochrane Database Syst Rev. 2014;(6):CD002281. Vorwerk L, Ghassemi A, Hooper W, Patel V, Milleman J, Milleman K. Comparative plaque removal efficacy of a new powered toothbrush and a manual toothbrush. J Clin Dent. 2016;27(3):76–9. Li Z, He T, Li C, Sun L, Chang J, He Y, et al. A randomized 3-month clinical comparison of a power toothbrush to a manual toothbrush in the reduction of gingivitis. Am J Dent. 2016;29(4):193–6 Costa CC, Costa Filho LC, Sória ML, Mainardi APR. Plaque removal by manual and electric toothbrushing among children. Pesqui Odontol Bras. 2001;15(4):296–301. Oliveira LB, Zardetto CGDC, Rocha RO, Rodrigues CRMD, Wanderley MT. Eficácia da escova dental convencional e de cabeça tripla na remoção do biofilme dental em crianças. RGO, Rev Gaúch Odontol. 2011;59(2):259–63. Kalf‐Scholte SM, Van der Weijden GA, Bakker EWP, Slot DE. Plaque removal with triple-headed vs single-headed manual toothbrushes: a systematic review. Int J Dent Hyg. 2018;16(1):13-23 Aass AM, Gjermo P. Comparison of oral hygiene efficacy of one manual and two electric toothbrushes. Acta Odontol Scand. 2000;58(4):166-70. Laher A, Kroon J, Booyens SJ. Effectiveness of four manual toothbrushes in a cohort of patients undergoing fixed orthodontic treatment in an academic training hospital. SADJ. 2003;58(6):231-37. Gomes LK, Sarmento CF, Seabra FRG, Santos PBD, Pinheiro FHSL. Randomized clinical controlled trial on the effectiveness of conventional and orthodontic manual toothbrushes. Braz Oral Res. 2012;26(4):360-65. Hogan LME, Daly CG, Curtis BH. Comparison of new and 3-month-old brush heads in the removal of plaque using a powered toothbrush. J Clin Periodontol. 2007;34(2):130-36. Rosema NA, Hennequin-Hoenderdos NL, Versteeg PA, van Palenstein Helderman WH, van der Velden U, et al. Plaque-removing efficacy of new and used manual toothbrushes: a professional brushing study. Int J Dent Hyg. 2013;11(4):237-43.

Background: Although sleep has been identified as an important modifiable risk factor for sports injury, the effect of decreased sleep on sports injuries in adolescents is poorly studied. Purpose: To systematically review published literature to examine if a lack of sleep is associated with sports injuries in adolescents and to delineate the effects of chronic versus acute lack of sleep. Methods: PubMed and EMBASE databases were systematically searched for studies reporting statistics regarding the relationship between sleep and sports injury in adolescents aged <19 years published between 1/1/1997 and 12/21/2017. From included studies, the following information was extracted: bibliographic and demographic information, reported outcomes related to injury and sleep, and definitions of injury and decreased sleep. Additionally, a NOS (Newcastle-Ottawa Scale) assessment and an evaluation of the OCEM (Oxford Center for Evidence-Based Medicine) level of evidence for each study was conducted to assess each study’s individual risk of bias, and the risk of bias across all studies. Results: Of 907 identified articles, 7 met inclusion criteria. Five studies reported that adolescents who chronically slept poorly were at a significantly increased likelihood of experiencing a sports or musculoskeletal injury. Two studies reported on acute sleep behaviors. One reported a significant positive correlation between acutely poor sleep and injury, while the other study reported no significant correlation. In our random effects model, adolescents who chronically slept poorly were more likely to be injured than those who slept well (OR 1.58, 95% CI 1.05 to 2.37, p = 0.03). OCEM criteria assessment showed that all but one study (a case-series) were of 2b level of evidence—which is the highest level of evidence possible for studies which were not randomized control trials or systematic reviews. NOS assessment was conducted for all six cohort studies to investigate each study’s individual risk of bias. Five out of six of these studies received between 4 to 6 stars, categorizing them as having a moderate risk of bias. One study received 7 stars, categorizing it as having a low risk of bias. NOS assessment revealed that the most consistent source of bias was in ascertainment of exposure: all studies relied on self-reported data regarding sleep hours rather than a medical or lab record of sleep hours. Conclusions: Chronic lack of sleep in adolescents is associated with greater risk of sports and musculoskeletal injuries. Current evidence cannot yet definitively determine the effect of acute lack of sleep on injury rates. Our results thus suggest that adolescents who either chronically sleep less than 8 hours per night, or have frequent night time awakenings, are more likely to experience sports or musculoskeletal injuries. [Figure: see text][Figure: see text][Table: see text][Table: see text][Table: see text] References used in tables and full manuscript Barber Foss KD, Myer GD, Hewett TE. Epidemiology of basketball, soccer, and volleyball injuries in middle-school female athletes. Phys Sportsmed. 2014;42(2):146-153. Adirim TA, Cheng TL. Overview of injuries in the young athlete. Sports Med. 2003;33(1):75-81. Valovich McLeod TC, Decoster LC, Loud KJ, et al. National Athletic Trainers’ Association position statement: prevention of pediatric overuse injuries. J Athl Train. 2011;46(2):206-220. Milewski MD, Skaggs DL, Bishop GA, et al. Chronic lack of sleep is associated with increased sports injuries in adolescent athletes. J Pediatr Orthop. 2014;34(2):129-133. Wheaton AG, Olsen EO, Miller GF, Croft JB. Sleep Duration and Injury-Related Risk Behaviors Among High School Students--United States, 2007-2013. MMWR Morb Mortal Wkly Rep. 2016;65(13):337-341. Paruthi S, Brooks LJ, D’Ambrosio C, et al. Consensus Statement of the American Academy of Sleep Medicine on the Recommended Amount of Sleep for Healthy Children: Methodology and Discussion. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine. 2016;12(11):1549-1561. Watson NF, Badr MS, Belenky G, et al. Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Sleep. 2015;38(8):1161-1183. Juliff LE, Halson SL, Hebert JJ, Forsyth PL, Peiffer JJ. Longer Sleep Durations Are Positively Associated With Finishing Place During a National Multiday Netball Competition. J Strength Cond Res. 2018;32(1):189-194. Beedie CJ, Terry PC, Lane AM. The profile of mood states and athletic performance: Two meta- analyses. Journal of Applied Sport Psychology. 2000;12(1):49-68. Panic N, Leoncini E, de Belvis G, Ricciardi W, Boccia S. Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One. 2013;8(12): e83138. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine. 2009;6(7): e1000100. Watson A, Brickson S, Brooks A, Dunn W. Subjective well-being and training load predict in- season injury and illness risk in female youth soccer players. Br J Sports Med. 2016. Alricsson M, Domalewski D, Romild U, Asplund R. Physical activity, health, body mass index, sleeping habits and body complaints in Australian senior high school students. Int J Adolesc Med Health. 2008;20(4):501-512. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Luke A, Lazaro RM, Bergeron MF, et al. Sports-related injuries in youth athletes: is overscheduling a risk factor? Clin J Sport Med. 2011;21(4):307-314. University of Oxford Center for Evidence-Based Medicine. Oxford Centre for Evidence-based Medicine – Levels of Evidence. 2009; https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/ . von Rosen P, Frohm A, Kottorp A, Friden C, Heijne A. Too little sleep and an unhealthy diet could increase the risk of sustaining a new injury in adolescent elite athletes. Scand J Med Sci Sports. 2017;27(11):1364-1371. von Rosen P, Frohm A, Kottorp A, Friden C, Heijne A. Multiple factors explain injury risk in adolescent elite athletes: Applying a biopsychosocial perspective. Scand J Med Sci Sports. 2017;27(12):2059-2069. Picavet HS, Berentzen N, Scheuer N, et al. Musculoskeletal complaints while growing up from age 11 to age 14: the PIAMA birth cohort study. Pain. 2016;157(12):2826-2833. Kim SY, Sim S, Kim SG, Choi HG. Sleep Deprivation Is Associated with Bicycle Accidents and Slip and Fall Injuries in Korean Adolescents. PLoS One. 2015;10(8): e0135753. Stare J, Maucort-Boulch D. Odds Ratio, Hazard Ratio and Relative Risk. Metodoloski Zvezki. 2016;13(1):59-67. Watson AM. Sleep and Athletic Performance. Curr Sports Med Rep. 2017;16(6):413-418. Stracciolini A, Stein CJ, Kinney S, McCrystal T, Pepin MJ, Meehan Iii WP. Associations Between Sedentary Behaviors, Sleep Patterns, and BMI in Young Dancers Attending a Summer Intensive Dance Training Program. J Dance Med Sci. 2017;21(3):102-108. Stracciolini A, Shore BJ, Pepin MJ, Eisenberg K, Meehan WP, 3 rd. Television or unrestricted, unmonitored internet access in the bedroom and body mass index in youth athletes. Acta Paediatr. 2017;106(8):1331-1335. Snyder Valier AR, Welch Bacon CE, Bay RC, Molzen E, Lam KC, Valovich McLeod TC. Reference Values for the Pediatric Quality of Life Inventory and the Multidimensional Fatigue Scale in Adolescent Athletes by Sport and Sex. Am J Sports Med. 2017;45(12):2723-2729. Simpson NS, Gibbs EL, Matheson GO. Optimizing sleep to maximize performance: implications and recommendations for elite athletes. Scand J Med Sci Sports. 2017;27(3):266-274. Liiv H, Jurimae T, Klonova A, Cicchella A. Performance and recovery: stress profiles in professional ballroom dancers. Med Probl Perform Art. 2013;28(2):65-69. Van Der Werf YD, Van Der Helm E, Schoonheim MM, Ridderikhoff A, Van Someren EJ. Learning by observation requires an early sleep window. Proc Natl Acad Sci U S A. 2009;106(45):18926- 18930. Lee AJ, Lin WH. Association between sleep quality and physical fitness in female young adults. J Sports Med Phys Fitness. 2007;47(4):462-467. Mejri MA, Yousfi N, Hammouda O, et al. One night of partial sleep deprivation increased biomarkers of muscle and cardiac injuries during acute intermittent exercise. J Sports Med Phys Fitness. 2017;57(5):643-651. Mejri MA, Yousfi N, Mhenni T, et al. Does one night of partial sleep deprivation affect the evening performance during intermittent exercise in Taekwondo players? Journal of exercise rehabilitation. 2016;12(1):47-53. Hirshkowitz M, Whiton K, Albert SM, et al. National Sleep Foundation’s updated sleep duration recommendations: final report. Sleep health. 2015;1(4):233-243. Dennis J, Dawson B, Heasman J, Rogalski B, Robey E. Sleep patterns and injury occurrence in elite Australian footballers. J Sci Med Sport. 2016;19(2):113-116. Bergeron MF, Mountjoy M, Armstrong N, et al. International Olympic Committee consensus statement on youth athletic development. Br J Sports Med. 2015;49(13):843-851. Riley M, Locke AB, Skye EP. Health maintenance in school-aged children: Part II. Counseling recommendations. Am Fam Physician. 2011;83(6):689-694. Spector ND, Kelly SF. Sleep disorders, immunizations, sports injuries, autism. Curr Opin Pediatr. 2005;17(6):773-786. Asarnow LD, McGlinchey E, Harvey AG. The effects of bedtime and sleep duration on academic and emotional outcomes in a nationally representative sample of adolescents. J Adolesc Health. 2014;54(3):350-356. Dahl RE, Lewin DS. Pathways to adolescent health sleep regulation and behavior. J Adolesc Health. 2002;31(6 Suppl):175-184. School start times for adolescents. Pediatrics. 2014;134(3):642-649. Bland JM, Altman DG. The odds ratio. BMJ. 2000;320(7247):1468.

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. Available at: https://covid19.who.int/ [Accessed on 23 August 2020] Sim K, Chua HC. The psychological impact of SARS: a matter of heart and mind. CMAJ. 2004; 170:811e2. https://doi.org/10.1503/cmaj.1032003. Wu P, Fang Y, Guan Z, Fan B, Kong J, Yao Z, et al. The psychological impact of the SARS epidemic on hospital employees in China: exposure, risk perception, and altruistic acceptance of risk. Can J Psychiatr. 2009; 54:302e11. https://doi.org/10.1177/070674370905400504. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020; 395:912e20. https://doi.org/10.1016/S0140-6736(20)30460-8. Robertson E, Hershenfield K, Grace SL, Stewart DE. The psychosocial effects of being quarantined following exposure to SARS: a qualitative study of Toronto health care workers. Can J Psychiatr. 2004; 49:403e7. https://doi.org/10.1177/070674370404900612. Barbisch D, Koenig KL, Shih FY. Is there a case for quarantine? Perspectives from SARS to Ebola. Disaster Med Public Health Prep. 2015; 9:547e53. https://doi.org/10.1017/dmp.2015.38. Jeong H, Yim HW, Song YJ, Ki M, Min JA, Cho J, et al. Mental health status of people isolated due to Middle East Respiratory Syndrome. Epidemiol Health. 2016;38: e2016048. https://doi.org/10.4178/epih.e2016048. Liu X, Kakade M, Fuller CJ, Fan B, Fang Y, Kong J, et al. Depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic. Compr Psychiatr. 2012; 53:15e23. https://doi.org/10.1016/j.comppsych.2011.02.003 Chadda RK, Deb KS. Indian family systems, collectivistic society and psychotherapy. Indian J Psychiatry. 2013;55: S299‑ https://dx.doi.org/10.4103%2F0019-5545.105555. Grover S, Sahoo S, Mehra A, Avasthi A, Tripathi A, Subramanyan A, et al. Psychological impact of COVID‑19 lockdown: An online survey from India. Indian J Psychiatry. 2020; 62:354-62. https://doi.org/ 10.4103/psychiatry.IndianJPsychiatry _427_20. Hawkley LC, Cacioppo JT. Loneliness matters: a theoretical and empirical review of consequences and mechanisms. Ann Behav Med. 2010; 40: 218–27. https://dx.doi.org/10.1007%2Fs12160-010-9210-8. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. https://doi.org/10.1016/S0140-6736(20)30211-7. Bhandari S, Sharma R, Singh Shaktawat A, Banerjee S, Patel B, Tak A, et al. COVID-19 related mortality profile at a tertiary care centre: a descriptive study. Scr Med. 2020;51(2):69-73. https://doi.org/10.5937/scriptamed51-27126. Baumeister RF, Leary MR. The need to belong: desire for interpersonal attachments as a fundamental human motivation. Psychol Bull. 1995; 117: 497–529. https://doi.org/10.1037/0033-2909.117.3.497. Caspi A, Harrington H, Moffitt TE, Milne BJ, Poulton R. Socially isolated children 20 years later: risk of cardiovascular disease. Arch Pediatr Adolesc Med. 2006; 160(8):805-11. https://doi.org/10.1001/archpedi.160.8.805. Eaker ED, Pinsky J, Castelli WP. Myocardial infarction and coronary death among women: psychosocial predictors from a 20-year follow-up of women in the Framingham Study. Am J Epidemiol. 1992; 135(8):854-64. https://doi.org/10.1093/oxfordjournals.aje.a116381. Luo Y, Hawkley LC, Waite LJ, Cacioppo JT. Loneliness, health, and mortality in old age: a national longitudinal study. Soc Sci Med. 2012 Mar; 74(6):907-14. https://dx.doi.org/10.1016%2Fj.socscimed.2011.11.028. Olsen RB, Olsen J, Gunner-Svensson F, Waldstrøm B. Social networks and longevity. A 14-year follow-up study among elderly in Denmark. Soc Sci Med. 1991; 33(10):1189-95. https://doi.org/10.1016/0277-9536(91)90235-5. Patterson AC, Veenstra G. Loneliness and risk of mortality: a longitudinal investigation in Alameda County, California. Soc Sci Med. 2010; 71(1):181-6. https://doi.org/10.1016/j.socscimed.2010.03.024. Savikko N, Routassalo P, Tilvis RS, Strandberg TE, Pitkalla KH. Predictors and subjective causes of loneliness in an aged population. Arch Gerontol Geriatrics. 2005; 41:3;223-33. https://doi.org/10.1016/j.archger.2005.03.002. Health Advisory for Elderly Population of India during COVID19. Available at: https://www.mohfw.gov.in/pdf/AdvisoryforElderlyPopulation.pdf [Accessed on 13 August 2020]. Dicks D, Myers R, Kling A. Uncus and amygdala lesions: effects on social behavior in the free-ranging rhesus monkey. Science. 1969; 165:69–71. https://doi.org/10.1126/science.165.3888.69. Kanai R, Bahrami B, Duchaine B, Janik A, Banissy MJ, Rees G. Brain structure links loneliness to social perception. Curr Biol. 2012; 22(20):1975-9. https://dx.doi.org/10.1016%2Fj.cub.2012.08.045. Bender AR, Daugherty A, Raz N. Vascular risk moderates associations between hippocampal subfield volumes and memory. J Cogn Neurosci. 2013; 25:1851–62. https://doi.org/10.1162/jocn_a_00435. Raz N. Diabetes: brain, mind, insulin–what is normal and do we need to know? Nat Rev Endocrinol. 2011; 7:636–7. https://doi.org/10.1038/nrendo.2011.149. Colcombe SJ, Erickson KI, Naftali R, Andrew GW, Cohen NJ, McAuley E, et al. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci. 2003; 58:176–80. https://doi.org/10.1093/gerona/58.2.m176. Maass A, Düzel S, Goerke M, Becke A, Sobieray U, Neumann K, et al. Vascular hippocampal plasticity after aerobic exercise in older adults. Mol Psychiatry. 2015; 20, 585–93. https://doi.org/10.1038/mp.2014.114. Wilson RS, Krueger KR, Arnold SE, Schneider JA, Kelly JF, Barnes LL, et al. Loneliness and Risk of Alzheimer Disease. Arch Gen Psychiatry. 2007;64(2):234–240. https://doi.org/10.1001/archpsyc.64.2.234. Kogan JH, Frankland PW, Silva AJ. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus. 2000;10(1):47-56. https://doi.org/10.1002/(sici)1098-1063(2000)10:1%3C47::aid-hipo5%3E3.0.co;2-6. Yorgason JT, España RA, Konstantopoulos JK, Weiner JL, Jones SR. Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats. Eur J Neurosci. 2013;37(6):1022-31. https://doi.org/10.1111/ejn.12113. Bledsoe AC, Oliver KM, Scholl JL, Forster GL. Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus. Brain Res Bull. 2011;85(3-4):117-22. https://dx.doi.org/10.1016%2Fj.brainresbull.2011.03.003. Lukkes JL, Engelman GH, Zelin NS, Hale MW, Lowry CA. Post-weaning social isolation of female rats, anxiety-related behavior, and serotonergic systems. Brain Res. 2012; 1443:1-17. https://dx.doi.org/10.1016%2Fj.brainres.2012.01.005. Ago Y, Araki R, Tanaka T, Sasaga A, Nishiyama S, Takuma K, et al. Role of social encounter-induced activation of prefrontal serotonergic systems in the abnormal behaviors of isolation-reared mice. Neuropsychopharmacology. 2013; 38(8):1535-47. https://doi.org/10.1038/npp.2013.52. Veenema AH. Early life stress, the development of aggression and neuroendocrine and neurobiological correlates: what can we learn from animal models? Front Neuroendocrinol. 2009;30(4):497-518. https://doi.org/10.1016/j.yfrne.2009.03.003. Zhao X, Sun L, Jia H, Meng Q, Wu S, Li N, et al. Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1173-1177. https://doi.org/10.1016/j.pnpbp.2009.06.016. Sciolino NR, Bortolato M, Eisenstein SA, Fu J, Oveisi F, Hohmann AG, et al. Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats. Neuroscience. 2010;168(2):371-86. https://dx.doi.org/10.1016%2Fj.neuroscience.2010.04.007. Ghasemi M, Phillips C, Trillo L, De Miguel Z, Das D, Salehi A. The role of NMDA receptors in the pathophysiology and treatment of mood disorders. Neurosci Biobehav Rev. 2014; 47:336-358. https://doi.org/10.1016/j.neubiorev.2014.08.017. Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Fernández AP, Rodrigo J, et al. Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex. J Neurochem. 2000;74(2):785-791. https://doi.org/10.1046/j.1471-4159.2000.740785.x. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63(4):349-352. https://doi.org/10.1016/j.biopsych.2007.05.028. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 2008;7(8):742-755. https://dx.doi.org/10.1016%2FS1474-4422(08)70165-0. Waxman EA, Lynch DR. N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease. The Neuroscientist. 2005; 11(1), 37–49. https://doi.org/10.1177/1073858404269012. Hermes G, Li N, Duman C, Duman R. Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats. Physiol Behav. 2011;104(2):354-9. https://dx.doi.org/10.1016%2Fj.physbeh.2010.12.019. Sestito RS, Trindade LB, de Souza RG, Kerbauy LN, Iyomasa MM, Rosa ML. Effect of isolation rearing on the expression of AMPA glutamate receptors in the hippocampal formation. J Psychopharmacol. 2011;25(12):1720-1729. https://doi.org/10.1177/0269881110385595. Toua C, Brand L, Möller M, Emsley RA, Harvey BH. The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl-D-aspartate and D1 receptor binding in rats. Neuroscience. 2010;165(2):492-499. https://doi.org/10.1016/j.neuroscience.2009.10.039. Alò R, Avolio E, Mele M, Storino F, Canonaco A, Carelli A et al. Excitatory/inhibitory equilibrium of the central amygdala nucleus gates anti-depressive and anxiolytic states in the hamster. Pharmacol Biochem Behav. 2014; 118:79-86. https://doi.org/10.1016/j.pbb.2014.01.007. St JP, Petkov VV. Changes in 5-HT1 receptors in different brain structures of rats with isolation syndrome. General pharmacology. 1990;21(2):223-5. https://doi.org/10.1016/0306-3623(90)90905-2. Miachon S, Rochet T, Mathian B, Barbagli B, Claustrat B. Long-term isolation of Wistar rats alters brain monoamine turnover, blood corticosterone, and ACTH. Brain Res Bull. 1993;32(6):611-614. https://doi.org/10.1016/0361-9230(93)90162-5. Van den Berg CL, Van Ree JM, Spruijt BM, Kitchen I. Effects of juvenile isolation and morphine treatment on social interactions and opioid receptors in adult rats: behavioural and autoradiographic studies. Eur J Neurosci. 1999;11(9):3023-3032. https://doi.org/10.1046/j.1460-9568.1999.00717.x. Vanderschuren LJ, Stein EA, Wiegant VM, Van Ree JM. Social play alters regional brain opioid receptor binding in juvenile rats. Brain Res. 1995;680(1-2):148-156. https://doi.org/10.1016/0006-8993(95)00256-p. Moles A, Kieffer BL, D'Amato FR. Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science. 2004;304(5679):1983-1986. https://doi.org/10.1126/science.1095943. Panksepp J, Herman BH, Vilberg T, Bishop P, DeEskinazi FG. Endogenous opioids and social behavior. Neurosci Biobehav Rev. 1980;4(4):473-487. https://doi.org/10.1016/0149-7634(80)90036-6. Gong JP, Onaivi ES, Ishiguro H, Liu Q, Tagliaferro PA, Brusco A, et al. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071(1):10-23. https://doi.org/10.1016/j.brainres.2005.11.035. Breivogel CS, Sim-Selley LJ. Basic neuroanatomy and neuropharmacology of cannabinoids. Int Rev Psychiatry 2009; 21:2:113-121. https://doi.org/10.1080/09540260902782760. Haj-Mirzaian A, Amini-Khoei H, Haj-Mirzaian A, Amiri S, Ghesmati M, Zahir M, et al. Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress. Brain Res Bull. 2017; 130:200-210. https://doi.org/10.1016/j.brainresbull.2017.01.018. Banach M, Piskorska B, Czuczwar SJ, Borowicz KK. Nitric Oxide, Epileptic Seizures, and Action of Antiepileptic Drugs. CNS & Neurological Disorders - Drug Targets 2011;10: 808. https://doi.org/10.2174/187152711798072347. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-37, 837a-837d. https://dx.doi.org/10.1093%2Feurheartj%2Fehr304. Hu Y, Wu D, Luo C, Zhu L, Zhang J, Wu H, et al. Hippocampal nitric oxide contributes to sex difference in affective behaviors. PNAS. 2012, 109 (35) 14224-14229. https://doi.org/10.1073/pnas.1207461109. Khan MI, Ostadhadi S, Zolfaghari S, Mehr SE, Hassanzadeh G, Dehpour, A et al. The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test. Neuroscience Letters. 2016; 612:52-61. https://doi.org/10.1016/j.neulet.2015.12.006. Matsumoto K, Puia G, Dong E, Pinna G. GABAA receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: Possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress. 2007; 10:1:3-12. https://doi.org/10.1080/10253890701200997. Zlatković J, Filipović D. Chronic social isolation induces NF-κB activation and upregulation of iNOS protein expression in rat prefrontal cortex. Neurochem Int. 2013;63(3):172-179. https://doi.org/10.1016/j.neuint.2013.06.002. Haj-Mirzaian A, Amiri S, Kordjazy N, Momeny M, Razmi A, Balaei MR, et al. Lithium attenuated the depressant and anxiogenic effect of juvenile social stress through mitigating the negative impact of interlukin-1β and nitric oxide on hypothalamic-pituitary-adrenal axis function. Neuroscience. 2016; 315:271-285. https://doi.org/10.1016/j.neuroscience.2015.12.024. Larson HJ. The biggest pandemic risk? Viral misinformation. Nature 2018; 562:309. https://doi.org/10.1038/d41586-018-07034-4. Zarocostas J. How to fight an infodemic. Lancet 2020; 395:676. https://doi.org/10.1016/S0140-6736(20)30461-X. World Health Organization, 2019. Ebola Virus Disease – Democratic Republic of the Congo. Geneva, Switzerland: WHO. Available at: https://www.who.int/csr/don/28-november-2019-ebola-drc/en/ [Accessed on August 8, 2020] Times of India. Covid-19: doctors gone to collect samples attacked in Indore. Available at: https://timesofindia.indiatimes.com/videos/news/covid-19-doctors-goneto- collect-samples-attacked-in-indore/videoshow/74942153.cms; 2020 [Accessed on August 8, 2020]. Withnall A. Coronavirus: why India has had to pass new law against attacks on healthcare workers. The Independent. April 23, 2020. Semple K. “Afraid to be a nurse”: health workers under attack. The New York Times. 2020 Apr 27. The Economist. Health workers become unexpected targets during COVID-19. The Economist. May 11, 2020. Turan B, Budhwani H, Fazeli PL, Browning WR, Raper JL, Mugavero MJ, et al. How does stigma affect people living with HIV? The mediating roles of internalized and anticipated HIV stigma in the effects of perceived community stigma on health and psychosocial outcomes. AIDS Behav. 2017; 21: 283–291. https://doi.org/10.1007/s10461-016-1451-5. James PB, Wardle J, Steel A, Adams J. An assessment of Ebola-related stigma and its association with informal healthcare utilisation among Ebola survivors in Sierra Leone: a cross sectional study. BMC Public Health. 2020; 20: 182. https://doi.org/10.1186/s12889-020-8279-7. Aljazeera, 2020. Iran: Over 700 Dead after Drinking Alcohol to Cure Coronavirus. Aljazeera. Available at: https://www.aljazeera.com/ news/2020/04/iran-700-dead-drinking-alcohol-cure-coronavirus200427163529629.html. (Accessed June 4, 2020) Delirrad M, Mohammadi AB, 2020. New methanol poisoning outbreaks in Iran following COVID-19 pandemic. Alcohol Alcohol. 55: 347–348. https://doi.org/10.1093/alcalc/agaa036. Hassanian-Moghaddam H, Zamani N, Kolahi A-A, McDonald R, Hovda KE. Double trouble: methanol outbreak in the wake of the COVID-19 pandemic in Iran-a cross-sectional assessment. Crit Care. 2020; 24: 402. https://doi.org/10.1186/s13054-020-03140-w. Soltaninejad K. Methanol Mass Poisoning Outbreak: A Consequence of COVID-19 Pandemic and Misleading Messages on Social Media. Int J Occup Environ Med. 2020;11(3):148-150. https://dx.doi.org/10.34172%2Fijoem.2020.1983. Islam MS, Sarkar T, Khan SH, Kamal AM, Hasan SMM, Kabir A, et al. COVID-19–Related Infodemic and Its Impact on Public Health: A Global Social Media Analysis. Am J Trop Med Hyg. 2020; 00(0):1–9. https://doi.org/10.4269/ajtmh.20-0812. Hawryluck L, Gold W, Robinson S, Pogorski S, Galea S, Styra R. SARS control and psychological effects of quarantine, Toronto, Canada. Emerg Infect Dis. 2004;10(7):1206–1212. https://dx.doi.org/10.3201%2Feid1007.030703. Lee S, Chan LYY, Chau AAM, Kwok KPS, Kleinman A. The experience of SARS-related stigma at Amoy Gardens. Soc Sci Med. 2005; 61(9): 2038-2046. https://doi.org/10.1016/j.socscimed.2005.04.010. Yoon MK Kim SY Ko HS Lee MS. System effectiveness of detection, brief intervention and refer to treatment for the people with post-traumatic emotional distress by MERS: a case report of community-based proactive intervention in South Korea. Int J Ment Health Syst. 2016; 10: 51. https://doi.org/10.1186/s13033-016-0083-5. Reynolds DL, Garay JR, Deamond SL, Moran MK, Gold W, Styra R. Understanding, compliance and psychological impact of the SARS quarantine experience. Epidemiol Infect. 2008; 136: 997-1007. https://dx.doi.org/10.1017%2FS0950268807009156. Marjanovic Z, Greenglass ER, Coffey S. The relevance of psychosocial variables and working conditions in predicting nurses' coping strategies during the SARS crisis: an online questionnaire survey. Int J Nurs Stud. 2007; 44(6): 991-998. https://doi.org/10.1016/j.ijnurstu.2006.02.012. Bai Y, Lin C-C, Lin C-Y, Chen J-Y, Chue C-M, Chou P. Survey of stress reactions among health care workers involved with the SARS outbreak. Psychiatr Serv. 2004; 55: 1055-1057. https://doi.org/10.1176/appi.ps.55.9.1055. Ministry of Health and Family Welfare. Available at: https://www.mohfw.gov.in/pdf/Guidelinesforhomequarantine.pdf [Accessed on 25 August 2020]. Ministry of Health and Family Welfare. Available at: https://www.mohfw.gov.in/pdf/RevisedguidelinesforHomeIsolationofverymildpresymptomaticCOVID19cases10May2020.pdf [Accessed on 25 August 2020]. Ministry of Health and Family Welfare. Available at: https://www.mohfw.gov.in/pdf/AdvisoryformanagingHealthcareworkersworkinginCOVIDandNonCOVIDareasofthehospital.pdf (Accessed on 25 August 2020). Ministry of Health and Family Welfare. Available at: https://www.mohfw.gov.in/pdf/RevisedguidelinesforInternationalArrivals02082020.pdf [Accessed on 25 August 2020]. Cost of the lockdown? Over 10% of GDP loss for 18 states. Available at: https://timesofindia.indiatimes.com/india/cost-of-the-lockdown-over-10-of-gdp-loss-for-18-states/articleshow/76028826.cms [Accessed on 21 August 2020]. Jorda O, Singh SR, Taylor AM. Longer-Run Economic Consequences of Pandemics. Federal Reserve Bank of San Francisco Working Paper. 2020-09. https://doi.org/10.24148/wp2020-09. Firdaus G. Mental well‑being of migrants in urban center of India: Analyzing the role of social environment. Indian J Psychiatry. 2017; 59:164‑ https://doi.org/10.4103/psychiatry.indianjpsychiatry_272_15. National Crime Record Bureau. Annual Crime in India Report. New Delhi, India: Ministry of Home Affairs; 2018. 198 migrant workers killed in road accidents during lockdown: Report. Available at: https://www.hindustantimes.com/india-news/198-migrant-workers-killed-in-road-accidents-during-lockdown-report/story-hTWzAWMYn0kyycKw1dyKqL.html [Accessed on 25 August 2020]. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis. 2020; 20:689-96. https://doi.org/10.1016/S1473-3099(20)30198-5. Dalton L, Rapa E, Stein A. Protecting the psychological health of through effective communication about COVID-19. Lancet Child Adolesc Health. 2020;4(5):346-347. https://doi.org/10.1016/S2352-4642(20)30097-3. Centre for Disease Control. Helping Children Cope with Emergencies. Available at: https://www.cdc.gov/childrenindisasters/helping-children-cope.html [Accessed on 25 August 2020]. Liu JJ, Bao Y, Huang X, Shi J, Lu L. Mental health considerations for children quarantined because of COVID-19. Lancet Child & Adolesc Health. 2020; 4(5):347-349. https://doi.org/10.1016/S2352-4642(20)30096-1. Sprang G, Silman M. Posttraumatic Stress Disorder in Parents and Youth After Health-Related Disasters. Disaster Med Public Health Prep. 2013;7(1):105-110. https://doi.org/10.1017/dmp.2013.22. Rehman U, Shahnawaz MG, Khan NH, Kharshiing KD, Khursheed M, Gupta K, et al. Depression, Anxiety and Stress Among Indians in Times of Covid-19 Lockdown. Community Ment Health J. 2020:1-7. https://doi.org/10.1007/s10597-020-00664-x. Cao W, Fang Z, Hou, Han M, Xu X, Dong J, et al. The psychological impact of the COVID-19 epidemic on college students in China. Psychiatry Research. 2020; 287:112934. https://doi.org/10.1016/j.psychres.2020.112934. Wang C, Zhao H. The Impact of COVID-19 on Anxiety in Chinese University Students. Front Psychol. 2020; 11:1168. https://dx.doi.org/10.3389%2Ffpsyg.2020.01168. Kang L, Li Y, Hu S, Chen M, Yang C, Yang BX, et al. The mental health of medical workers in Wuhan, China dealing with the 2019 novel coronavirus. Lancet Psychiatry 2020;7(3): e14. https://doi.org/10.1016/s2215-0366(20)30047-x. Lai J, Ma S, Wang Y, Cai Z, Hu J, Wei N, et al. Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019. JAMA Netw Open 2020;3(3): e203976. https://doi.org/10.1001/jamanetworkopen.2020.3976. Lancee WJ, Maunder RG, Goldbloom DS, Coauthors for the Impact of SARS Study. Prevalence of psychiatric disorders among Toronto hospital workers one to two years after the SARS outbreak. Psychiatr Serv. 2008;59(1):91-95. https://dx.doi.org/10.1176%2Fps.2008.59.1.91. Tam CWC, Pang EPF, Lam LCW, Chiu HFK. Severe acute respiratory syndrome (SARS) in Hongkong in 2003: Stress and psychological impact among frontline healthcare workers. Psychol Med. 2004;34 (7):1197-1204. https://doi.org/10.1017/s0033291704002247. Lee SM, Kang WS, Cho A-R, Kim T, Park JK. Psychological impact of the 2015 MERS outbreak on hospital workers and quarantined hemodialysis patients. Compr Psychiatry. 2018; 87:123-127. https://dx.doi.org/10.1016%2Fj.comppsych.2018.10.003. Koh D, Meng KL, Chia SE, Ko SM, Qian F, Ng V, et al. Risk perception and impact of severe acute respiratory syndrome (SARS) on work and personal lives of healthcare workers in Singapore: What can we learn? Med Care. 2005;43(7):676-682. https://doi.org/10.1097/01.mlr.0000167181.36730.cc. Verma S, Mythily S, Chan YH, Deslypere JP, Teo EK, Chong SA. Post-SARS psychological morbidity and stigma among general practitioners and traditional Chinese medicine practitioners in Singapore. Ann Acad Med Singap. 2004; 33(6):743e8. Yeung J, Gupta S. Doctors evicted from their homes in India as fear spreads amid coronavirus lockdown. CNN World. 2020. Available at: https://edition.cnn.com/2020/03/25/asia/india-coronavirus-doctors-discrimination-intl-hnk/index.html. [Accessed on 24 August 2020] Violence Against Women and Girls: the Shadow Pandemic. UN Women. 2020. May 3, 2020. Available at: https://www.unwomen.org/en/news/stories/2020/4/statement-ed-phumzile-violence-against-women-during-pandemic. [Accessed on 24 August 2020]. Gearhart S, Patron MP, Hammond TA, Goldberg DW, Klein A, Horney JA. The impact of natural disasters on domestic violence: an analysis of reports of simple assault in Florida (1999–2007). Violence Gend. 2018;5(2):87–92. https://doi.org/10.1089/vio.2017.0077. Sahoo S, Rani S, Parveen S, Pal Singh A, Mehra A, Chakrabarti S, et al. Self-harm and COVID-19 pandemic: An emerging concern – A report of 2 cases from India. Asian J Psychiatr 2020; 51:102104. https://dx.doi.org/10.1016%2Fj.ajp.2020.102104. Ghosh A, Khitiz MT, Pandiyan S, Roub F, Grover S. Multiple suicide attempts in an individual with opioid dependence: Unintended harm of lockdown during the COVID-19 outbreak? Indian J Psychiatry 2020; [In Press]. The Economic Times. 11 Coronavirus suspects flee from a hospital in Maharashtra. March 16 2020. Available at: https://economictimes.indiatimes.com/news/politics-and-nation/11-coronavirus-suspects-flee-from-a-hospital-in-maharashtra/videoshow/74644936.cms?from=mdr. [Accessed on 23 August 2020]. Xiang Y, Yang Y, Li W, Zhang L, Zhang Q, Cheung T, et al. Timely mental health care for the 2019 novel coronavirus outbreak is urgently needed. The Lancet Psychiatry 2020;(3):228–229. https://doi.org/10.1016/S2215-0366(20)30046-8. Van Bortel T, Basnayake A, Wurie F, Jambai M, Koroma A, Muana A, et al. Psychosocial effects of an Ebola outbreak at individual, community and international levels. Bull World Health Organ. 2016;94(3):210–214. https://dx.doi.org/10.2471%2FBLT.15.158543. Kumar A, Nayar KR. COVID 19 and its mental health consequences. Journal of Mental Health. 2020; ahead of print:1-2. https://doi.org/10.1080/09638237.2020.1757052. Gupta R, Grover S, Basu A, Krishnan V, Tripathi A, Subramanyam A, et al. Changes in sleep pattern and sleep quality during COVID-19 lockdown. Indian J Psychiatry. 2020; 62(4):370-8. https://doi.org/10.4103/psychiatry.indianjpsychiatry_523_20. Duan L, Zhu G. Psychological interventions for people affected by the COVID-19 epidemic. Lancet Psychiatry. 2020;7(4): P300-302. https://doi.org/10.1016/S2215-0366(20)30073-0. Dubey S, Biswas P, Ghosh R, Chatterjee S, Dubey MJ, Chatterjee S et al. Psychosocial impact of COVID-19. Diabetes Metab Syndr. 2020; 14(5): 779–788. https://dx.doi.org/10.1016%2Fj.dsx.2020.05.035. Wright R. The world's largest coronavirus lockdown is having a dramatic impact on pollution in India. CNN World; 2020. Available at: https://edition.cnn.com/2020/03/31/asia/coronavirus-lockdown-impact-pollution-india-intl-hnk/index.html. [Accessed on 23 August 2020] Foster O. ‘Lockdown made me Realise What’s Important’: Meet the Families Reconnecting Remotely. The Guardian; 2020. Available at: https://www.theguardian.com/keep-connected/2020/apr/23/lockdown-made-me-realise-whats-important-meet-the-families-reconnecting-remotely. (Accessed on 23 August 2020) Bilefsky D, Yeginsu C. Of ‘Covidivorces’ and ‘Coronababies’: Life During a Lockdown. N. Y. Times; 2020. Available at: https://www.nytimes.com/2020/03/27/world/coronavirus-lockdown-relationships.html [Accessed on 23 August 2020]

Introducción: La preeclampsia-eclampsia es un trastorno sistémico del embarazo prevalente caracterizado por hipertensión y proteinuria, un signo de disfunción renal. Se sabe relativamente poco sobre sus efectos a largo plazo en el riñón ya sea en términos de daño físico medido por albuminuria o proteinuria, desarrollo de hipertensión arterial crónica, deterioro funcional medido por la reducción de tasa de filtración glomerular o insuficiencia renal crónica (ERC). Métodos: En el presente estudio analítico y retrospectivo se tomaron los datos de las historias clínicas de pacientes con antecedente de preeclampsia- eclampsia atendidas en el servicio de ginecología y obstetricia del Hospital de Especialidades Carlos Andrade Marín diagnosticadas desde enero 2008 hasta diciembre 2018 (grupo expuestas), y embarazadas sanas durante el mismo período de tiempo (grupo no expuestas), una vez aleatorizadas se realiza el seguimiento para establecer la prevalencia de algún grado de enfermedad renal crónica en los grupos. Resultados: Se incluyeron 201 casos en el grupo de preeclampsia (GPE) y 201 al grupo control (GC). Edad de 29.5 ± 6.8 años en GPE y 31.4 ± 6.5 en GC, P=0.30. Etnia hispánica 191 (95.0%) en GPE y 196 (97.5%) en GC, P=0.90.Escolaridad superior en 93 (46.3%) en GPE y 94 (46.8%) en GC. ERC (Estadio 1-5) OR=3.725 (IC95% 1.935 – 8.381), P=0.0002. ERC (Estadio 5) OR=1.764 (0.75 – 239.5), P=0.077. Etnia mestiza OR= 3.911, (IC95% 2.21 – 10.91) P=0.0001. Desarrollo de Hipertensión arterial 2.041 (IC95% 1.038 – 6.317) P=0.0413. Desarrollo de proteinuria OR= 2.193 (IC95% 1.164 – 15.083) P=0.0283. Conclusiones: Las mujeres con antecedente de preeclampsia-eclampsia en cualquiera de sus embarazos presentaron mayor riesgo de desarrollar cualquier grado de ERC. Introdución De las diferentes patologías asociadas a embarazo, los trastornos hipertensivos son los más prevalentes siendo la preeclampsia la forma más común de ellos. La tasa de preeclampsia (PE) varía entre un 5% y un 10% en los países desarrollados, esta cifra podría verse incrementada hasta alcanzar un 18% en algunos países en vías de desarrollo [1]. Esta patología se presenta concomitantemente con alteraciones renales reversibles como la insuficiencia renal aguda cuya recuperación ocurre habitualmente dentro de las seis semanas posteriores al parto; sin embargo, se sabe relativamente poco sobre los efectos a largo plazo en el riñón ya sea en términos de daño físico medido por albuminuria o proteinuria, deterioro de la función medido por reducción en tasa de filtración glomerular (TFG) o insuficiencia renal en etapa terminal [2]. La causa más frecuente de injuria renal aguda en el embarazo es la asociada a la preeclampsia-eclampsia, pese a que en Latinoamérica existen escasos datos, reportes establecen que aproximadamente el 57% de las gestantes con IRA correspondían a aquellas que presentaron desórdenes hipertensivos como la preeclampsia, con una mortalidad materna de menos del 2% [3, 4]. El desarrollo de un episodio de IRA se asocia a un fuerte y significativo riesgo de desarrollo y progresión de enfermedad renal crónica termina (ERCT) e incluso a diálisis crónica [5]. Otra de las posibles implicaciones de la preeclampsia-eclampsia a nivel renal y a largo plazo es la de presentar daño crónico per se al antecedente de preeclampsia así; la ERC se define como el “daño renal por al menos tres meses, definido por anormalidades estructurales o funcionales del riñón con o sin descenso del filtrado glomerular” [6]. A pesar de la normalización después del parto de todas las alteraciones maternas desarrolladas por la preeclampsia, dichas alteraciones no han sido suficientemente estudiadas por el paradigma ampliamente extendido de que la “cura” de la preeclampsia-eclampsia es el parto, sin embargo, estudios muestran consistentemente que las mujeres antes preeclámpticas experimentan un riesgo aproximadamente doble de eventos cardiovasculares que ocurren principalmente en la quinta y sexta década de la vida [7]. Además, se ha visto que estas mujeres desarrollan hipertensión crónica de 6 a 8 años antes en comparación con las mujeres con antecedentes de embarazo normotenso, en lo que respecta a la función renal existe evidencia que podría aumentar el riesgo de desarrollar daño renal crónico [8], si embargo hay estudios no concluyentes como el estudio de “Mannist o et al” demostró una relación de riesgo (HR) para el desarrollo de ERC después de la hipertensión inducida por el embarazo de (HR 1.91) pero no después de la preeclampsia (HR 0.75) [4]: otro estudio demostró lo contrario en una corte retrospectiva de mujeres con antecedente de preeclampsia con un riesgo relativo (RR) de 4.7 para el desarrollo de ERCT después de la corrección para los factores de riesgo tradicionales. Este riesgo se ha visto que se podría triplicar cuando las mujeres tienen más de un embarazo con preeclampsia [9]. El objetivo del presente estudio fue determinar el riesgo de desarrollo de ERCT en un grupo de mujeres embarazadas con pre y eclampsia, comparadas con un grupo control con 11 años de seguimiento. Materiales y métodos Diseño del estudio El presente estudio es observacional, de casos y controles, de tipo retrospectivo. Escenario El estudio se realizó en el departamento de Estadística, Gineco-obstetricia y nefrología del Hospital de Especialidades “Carlos Andrade Marín”, del Instituto Ecuatoriano de Seguridad Social en Quito-Ecuador, durante el periodo de 1ro de enero del 2021 al 30 de septiembre del 2021. El período de análisis retrospectivo correspondió a 11 años: Desde el 1 de enero del 208 al 31 de diciembre del 2018. Participantes Se incluyeron mujeres con embarazo. En el grupo de casos se registraron pacientes con del diagnóstico de pre-eclampsia y eclampsia. En el grupo control se registraron mujeres embarazadas en el mismo período, sin patologías. Se excluyeron casos con antecedentes de enfermedad renal crónica y/o aguda, pacientes con antecedente de hipertensión crónica y/o pre gestacional, pacientes con antecedente de diabetes mellitus tipo 1 y 2, pacientes con antecedente de cardiopatía preexistente y pacientes con diagnóstico de cualquier enfermedad crónica que predisponga a desarrollo de enfermedad renal (como diabetes). Se eliminaron casos con datos incompletos para el análisis, con historias clínicas incompletas o sin seguimiento posterior al parto por al menos 1 año. Variables Las variables fueron: demográficas como edad, etnia, escolaridad, paridad. Variables clínicas: tasa de filtrado glomerular estimado por CKD-EPI, proteinuria, hematuria. Fuentes de datos/mediciones La fuente fue indirecta, se revisó el expediente electrónico institucional, el registro de los servicios de gineco-obstetricia. Los resultados de laboratorio fueron obtenidos del registro electrónico del laboratorio. El diagnóstico de preeclampsia se estableció con los criterios clínicos de: hipertensión presente >140/90 mmHg, proteinuria >300 mg/24 h, Trombocitopenia <150.000/u, alteración hepática con LDH > 600 UI/L, AST o ALT > 70 UI/L. Síntomas Vasomotores presentes: cefalea, epigastralgia, tinitus o escotomas. La eclampsia se estableció con Criterios clínicos de convulsiones en pacientes con preeclampsia. La enfermedad renal se clasificó en 5 estadios según la tasa de filtrado glomerular. La proteinuria se declarada positiva cuando la concentración fue mayor a 150 mg/24 horas o a la tirilla reactiva dio 1+. Sesgos Con el fin de evitar posibles sesgos de entrevistador, de información y de memoria, los datos fueron custodiados durante todo el tiempo por el investigador principal con una guía y registros aprobados en el protocolo de investigación. El sesgo de observación y selección fueron evitados con la aplicación de los criterios de selección de los participantes. Se consignaron todas las variables clínicas y paraclínicas del periodo ya comentado. Dos investigadores de manera independiente analizaron cada uno de los registros por duplicado y se consignaron las variables en la base de datos una vez verificada su concordancia. Tamaño del estudio La muestra fue probabilística, se usó la fórmula: n=2p*q(zα+zβ)2/(p1-p0)2, con un error alfa de 0.05, nivel de confianza del 95%, zα= 1.96, zβ= 0.842, p0 = 0.10, p1 = 0,2, el tamaño muestral fue de 200 casos y 200 controles. Variables cuantitativas Se utilizó estadística descriptiva. Se expresaron los resultados en escala en medias y desviación estándar. Los datos categóricos como el sexo se presentan en proporciones. Análisis estadístico Se utiliza estadística inferencial. Se utilizó la Prueba de Chi cuadrado para demostrar si existe relación entre las variables; para conocer el grado de asociación se usó el Riesgo Relativo (RR) con el intervalo de confianza del 95% y el valor P. El paquete estadístico utilizado fue SPSS 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Resultados Participantes Ingresaron al estudio 402 pacientes, 201 casos y 201 controles. Características basales de la población de estudio Las características de la población se presentan en la tabla 1. No hubo diferencias poblacionales con respecto a la edad, etnia, escolaridad o paridad al inicio del estudio. Desarrollo de enfermedad renal En las consultas de seguimiento se registró la presencia de enfermedad renal crónica en 35/201 casos (17.41%) versus 10/201 controles (4.98%) P<0.001. El tiempo transcurrido entre el diagnóstico de pre-eclampsia / eclampsia y el desarrollo de ERC fue de 3.95 años, el tiempo mínimo fue de 3.21 años y el máximo de 4.7 años (IC 95%). Se analizó el desarrollo de ERC en la etnia mestiza (hispánica) siendo un factor de riesgo (Tabla 2). Análisis secundarios Determinación mediante regresión logística de probabilidad de que ocurra ERC en función de variables con significancia estadística analizadas previamente en donde, se ratifica al antecedente de preeclampsia con un valor B de 1.27; P=0.001 (IC 95% 1.689 – 7.55) como factor predictor de ERC (Tabla 3). Discusión El antecedente de PE se ha estudiado como factor de riesgo para desarrollo de ERC, en este contexto los principales resultados en nuestro estudio fueron los siguientes: La incidencia de la preeclampsia se identifica entre 5 y 10%, cifras que pueden considerarse relativamente bajas, sin embargo, en algunos países constituye la primera causa de muerte materno-fetal y perinatal, no obstante estar identificada como una atención prioritaria [1, 10]. La asociación entre la preeclampsia y ERC es alta, así lo revela la razón de momios estimada no obstante exista esta asociación, no se puede afirmar que la preeclampsia es un factor de riesgo para ERC con el peso señalado por la imposibilidad de muchos estudios de controlar todas las variables que pudieran intervenir en el desarrollo a futuro de ERC [10 - 12]. Buscamos responder la interrogante sobre la relación de riesgo que existe entre el antecedente de preeclampsia y el desarrollo de ERC Esta asociación se ha investigado desde hace algunos años en pacientes con ERC y fuente de continuo trabajo [10, 13]. En estudios recientes el antecedente de PE ha sido asociado como factor de riesgo para el desarrollo de ERC [14], actualmente esta asociación es considerada objeto de observación para el seguimiento personalizado y determinación de factores de riesgo potencialmente controlables en el desarrollo de ERC. En el presente estudio la prevalencia de ERC atribuible a antecedente de preeclampsia fue de 17.41%, similar a los resultados obtenidos previamente [10 - 12]. El objetivo principal del estudio es demostrar la asociación entre el antecedente de PE y el desarrollo de ERC, además se incorporó una definición más amplia de ERC utilizando la proteinuria, hematuria y TFGe como determinantes de ERC, similar al estudio publicado previamente [15]. La existencia del antecedente de preeclampsia supone un riesgo relativo (RR) de 3.30 (IC 95%: 1.672 – 6.513), P< 0.05 para el desarrollo de ERC, valor muy parecido a los encontrados en un estudio previo con un RR 4.77 (IC 95%: 3.88 - 5.86) [15]. Estos resultados sugieren que debe prestarse atención al antecedente de preeclampsia para brindar un seguimiento nefrológico oportuno a esta población. El presente estudio describió que el tiempo promedio para presentar ERC en pacientes con preeclampsia fue de 3.95 años con un límite inferior de 3.21 años y uno superior de 4.7 años, estos datos difieren discretamente de los encontrados en Villarreal [6]. Con el objetivo de fortalecer el hallazgo de riesgo del antecedente de PE en el desarrollo de ERC se hizo el análisis de regresión logística multivariada, donde se incluyeron todas aquellas variables que resultaron tener significancia estadística encontrándose a la PE como único factor predictor de riesgo en el desarrollo de ERC con un valor B de 1.27; P=0.001 (IC 95% 1.689 – 7.55) como factor predictor de ERC, hallazgo que, ratifica el análisis estadístico previo. Conclusiones La preeclampsia es un factor asociado a ERC, conocimiento que puede ser utilizado para recordar al personal de salud la implicación de la preeclampsia en la salud de la mujer en edad fértil a corto y largo plazo, y la necesidad de implementar estrategias de prevención y control de ERC. La prevalencia de ERC en pacientes con antecedente de PE es del 17.41% valor comparable a la prevalencia en otros estudios. La población estudiada que desarrolló ERC corresponde a una población joven, al respecto la literatura identifica 40 años como edad promedio, grupo considerado como adulto joven, escenario que se puede considerar crítico por las repercusiones sociales si se asume que la mujer representa el 50% de la población mundial. El tiempo promedio para aparición de ERC entre el antecedente de PE y la aparición de cualquier forma de ERC fue de 3,95 años, con este estudio se sugiere que al menos un subconjunto de mujeres con datos previos de preeclampsia necesita seguimiento clínico para tamizaje de enfermedad renal en los años inmediatamente posteriores el embarazo. Abreviaturas ERC: enfermedad renal crónica. PE: pre-eclampsia. RR: riesgo relativo. OR: Odds ratio. Información suplementaria: Materiales suplementarios no han sido declarados. Agradecimientos: No aplica. Contribución de los autores: Norlys Margoth Fontalvo Díaz: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Boris Marcelo Torres Zavala: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Jorge Washing-ton Vélez Páez: Metodología, validación, supervisión, redacción: Revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Finaciamiento: Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales: Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar Este estudio fue aprobado por el comité de bioética (CEISH) del Hospital Carlos Andrade Marín. Consentimiento para publiación: No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés: Los autores reportan no tener conflictos de interés. Referencias Khashan AS, Evans M, Kublickas M, McCarthy FP, Kenny LC, Stenvinkel P, et al. Erratum: Preeclampsia and risk of end stage kidney disease: A Swedish nationwide cohort study (PLoS Med (2019) 16(7): e1002875. doi. 10.1371/journal.pmed.1002875). PLoS Med. 2019;16(10):1–18. PMID: 31361741; PMCID: PMC6667103. Heida KY, Franx A, van Rijn BB, Eijkemans MJ, Boer JM, Verschuren MW, Oudijk MA, Bots ML, van der Schouw YT. Earlier Age of Onset of Chronic Hypertension and Type 2 Diabetes Mellitus After a Hypertensive Disorder of Pregnancy or Gestational Diabetes Mellitus. 2015 Dec;66(6):1116-22. DOI: 10.1161/HYPERTENSIONAHA.115.06005. Epub 2015 Oct 12. PMID: 26459420. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008 Aug 21;359(8):800-9. DOI: 10.1056/NEJMoa0706790. PMID: 18716297. Männistö T, Mendola P, Vääräsmäki M, Järvelin MR, Hartikainen AL, Pouta A, Suvanto E. Elevated blood pressure in pregnancy and subsequent chronic disease risk. 2013 Feb 12;127(6):681-90. DOI: 10.1161/CIRCULATIONAHA.112.128751. PMID: 23401113; PMCID: PMC4151554. Grandi SM, Filion KB, Yoon S, Ayele HT, Doyle CM, Hutcheon JA, et al. Cardiovascular Disease-Related Morbidity and Mortality in Women with a History of Pregnancy Complications: Systematic Review and Meta-Analysis. Circulation. 2019;139(8):1069–79. DOI: 10.1161/CIRCULATIONAHA.118.036748. Erratum in: Circulation. 2019 Aug 27;140(9):e544. PMID: 30779636. Villarreal Ríos E, López Bejarano P, Rodríguez L. Artículo Original Asociación Entre Preeclampsia Y Enfermedad Renal. Rev Nefrol Dial Traspl 2019; 39 184-92 ISSN: 0326-3428. 2019;39(3). Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015 May;11(5):264-76. DOI: 10.1038/nrneph.2015.3. Epub 2015 Feb 3. PMID: 25643664; PMCID: PMC4412815. McDonald SD, Han Z, Walsh MW, Gerstein HC, Devereaux PJ. Kidney disease after preeclampsia: a systematic review and meta-analysis. Am J Kidney Dis. 2010 Jun;55(6):1026-39. DOI: 10.1053/j.ajkd.2009.12.036. Epub 2010 Mar 25. PMID: 20346562. Cunningham MW, LaMarca B. Risk of cardiovascular disease, end-stage renal disease, and stroke in postpartum women and their fetuses after a hypertensive pregnancy. Am J Physiol Regul Integr Comp Physiol. 2018;315(3):R521–8. DOI: 10.1152/ajpregu.00218.2017 PMID: 29897824; PMCID: PMC6172627. Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-33. DOI: 10.1016/S2214-109X(14)70227-X. Epub 2014 May 5. PMID: 25103301. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, Hobss FD. Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis. Remuzzi G, editor. PLoS One 2016 Jul 6;11(7):e0158765. DOI: 10.1371/journal.pone.0158765. PMID: 27383068. PMCID: PMC4934905. Peraçoli JC, Borges VTM, Ramos JGL, Cavalli RDC, Costa SHDAM, Oliveira LGD, et al. Pre-eclampsia/Eclampsia. Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics. 2019 05;41(05):318-332. DOI: https://doi.org/10.1055/s-0039-1687859 PMID: 31181585. Simpson LL, Rochelson B, Ananth CV, Bernstein PS, D'Alton M, Chazotte C, Lavery JA, Zielinski K; Safe Motherhood Initiative Severe Hypertension in Pregnancy Work Group. Safe Motherhood Initiative: Early Impact of Severe Hypertension in Pregnancy Bundle Implementation. AJP Rep. 2018 Oct;8(4):e212-e218. doi: 10.1055/s-0038-1673632. Epub 2018 Oct 11. PMID: 30319925; PMCID: PMC6181646. Covella B, Vinturache AE, Cabiddu G, Attini R, Gesualdo L, Versino E, Piccoli GB. A systematic review and meta-analysis indicates long-term risk of chronic and end-stage kidney disease after preeclampsia. Kidney Int. 2019 Sep;96(3):711-727. DOI: 10.1016/j.kint.2019.03.033. Epub 2019 May 14. PMID: 31352975. Zhang S, Wu QJ, Liu SX. A methodologic survey on use of the GRADE approach in evidence syntheses published in high-impact factor urology and nephrology journals. BMC Med Res Methodol. 2022 Aug 10;22(1):220. DOI: 10.1186/s12874-022-01701-x. PMID: 35948868; PMCID: PMC9367121.

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style="letter-spacing: -0.05pt;">c</span>hicoslos quem<span style="letter-spacing: 0.1pt;">a</span><span style="letter-spacing: -0.25pt;">y</span>o<span style="letter-spacing: 0.05pt;">r</span><span style="letter-spacing: -0.05pt;">e</span>s puntua<span style="letter-spacing: -0.05pt;">c</span>iones<span style="letter-spacing: -0.05pt;">a</span>lc<span style="letter-spacing: -0.05pt;">a</span>n<span style="letter-spacing: 0.05pt;">z</span><span style="letter-spacing: -0.05pt;">a</span>ron<span style="letter-spacing: -0.05pt;">e</span>nuso<span style="letter-spacing: -0.05pt;">c</span>ompu<span style="letter-spacing: 0.05pt;">l</span>sivoy<span style="letter-spacing: 0.05pt;">c</span>ons<span style="letter-spacing: -0.05pt;">ec</span>u<span style="letter-spacing: -0.05pt;">e</span>n<span style="letter-spacing: -0.05pt;">c</span><span style="letter-spacing: 0.15pt;">i</span><span style="letter-spacing: -0.05pt;">a</span>sn<span style="letter-spacing: -0.05pt;">e</span>g<span style="letter-spacing: -0.05pt;">a</span>t<span style="letter-spacing: 0.05pt;">i</span>v<span style="letter-spacing: -0.05pt;">a</span>s.<span style="letter-spacing: 0.05pt;">S</span>e<span style="letter-spacing: -0.05pt;">c</span>onfi<span style="letter-spacing: -0.05pt;">r</span>mó una<span style="letter-spacing: -0.05pt;"> c</span><span style="letter-spacing: 0.1pt;">o</span>r<span style="letter-spacing: -0.05pt;">re</span>l<span style="letter-spacing: 0.1pt;">a</span><span style="letter-spacing: -0.05pt;">c</span>ión s<span style="letter-spacing: 0.15pt;">i</span><span style="letter-spacing: -0.1pt;">g</span>nifi<span style="letter-spacing: -0.05pt;">ca</span><span style="letter-spacing: 0.15pt;">t</span>ivaydi<span style="letter-spacing: 0.1pt;">r</span><span style="letter-spacing: -0.05pt;">ec</span>ta<span style="letter-spacing: -0.05pt;">e</span>nt<span style="letter-spacing: 0.1pt;">r</span>euso <span style="letter-spacing: 0.1pt;">p</span><span style="letter-spacing: 0.05pt;">r</span>oblem<span style="letter-spacing: -0.05pt;">á</span>t<span style="letter-spacing: 0.05pt;">i</span><span style="letter-spacing: -0.05pt;">c</span>o de<span style="letter-spacing: -0.15pt;">I</span>nte<span style="letter-spacing: -0.05pt;">r</span><span style="letter-spacing: 0.1pt;">n</span><span style="letter-spacing: -0.05pt;">e</span>ty r<span style="letter-spacing: -0.1pt;">e</span>spu<span style="letter-spacing: -0.05pt;">e</span>stasde <span style="letter-spacing: -0.05pt;">a</span>nsied<span style="letter-spacing: -0.05pt;">a</span>ds<span style="letter-spacing: 0.1pt;">o</span><span style="letter-spacing: -0.05pt;">c</span>ialy ob<span style="letter-spacing: 0.2pt;">s</span><span style="letter-spacing: 0.05pt;">e</span>siv<span style="letter-spacing: 0.05pt;">o</span><span style="letter-spacing: -0.05pt;">-c</span>ompu<span style="letter-spacing: 0.05pt;">l</span>sivas.<span style="letter-spacing: -0.25pt;">L</span>ospr<span style="letter-spacing: -0.1pt;">e</span>dicto<span style="letter-spacing: -0.05pt;">re</span>smási<span style="letter-spacing: 0.05pt;">m</span>por<span style="letter-spacing: 0.1pt;">t</span><span style="letter-spacing: -0.05pt;">a</span>nted<span style="letter-spacing: -0.05pt;">e</span>luso probl<span style="letter-spacing: -0.05pt;">e</span>mático de <span style="letter-spacing: -0.15pt;">I</span>nte<span style="letter-spacing: -0.05pt;">r</span><span style="letter-spacing: 0.1pt;">n</span><span style="letter-spacing: 0.05pt;">e</span>t fu<span style="letter-spacing: -0.1pt;">e</span>ron <span style="letter-spacing: -0.05pt;">e</span>l dom<span style="letter-spacing: 0.05pt;">i</span>nio d<span style="letter-spacing: -0.05pt;">e</span>l <span style="letter-spacing: -0.05pt;">e</span>ntorno,la <span style="letter-spacing: -0.05pt;">a</span>nsied<span style="letter-spacing: -0.05pt;">a</span>d so<span style="letter-spacing: -0.05pt;">c</span>ial y los sín<span style="letter-spacing: 0.05pt;">t</span>omasobs<span style="letter-spacing: -0.05pt;">e</span>siv<span style="letter-spacing: 0.1pt;">o</span><span style="letter-spacing: -0.05pt;">-c</span>ompu<span style="letter-spacing: 0.05pt;">l</span>sivo<span style="letter-spacing: 0.05pt;">s</span>.<span style="letter-spacing: 0.05pt;">S</span>epodría <span style="letter-spacing: -0.05pt;">c</span>o<span style="letter-spacing: 0.1pt;">n</span><span style="letter-spacing: -0.05pt;">c</span>lu<span style="letter-spacing: 0.05pt;">i</span>r,<span style="letter-spacing: -0.05pt;">a</span>unque<span style="letter-spacing: -0.05pt;">c</span>on<span style="letter-spacing: -0.05pt;">ca</span>utel<span style="letter-spacing: -0.05pt;">a</span>,quem<span style="letter-spacing: 0.05pt;">i</span><span style="letter-spacing: -0.05pt;">e</span>ntr<span style="letter-spacing: 0.05pt;">a</span>s que losjóven<span style="letter-spacing: -0.05pt;">e</span>s<span style="letter-spacing: -0.05pt;">c</span>on<span style="letter-spacing: -0.05pt;">a</span>nsied<span style="letter-spacing: -0.05pt;">a</span>dso<span style="letter-spacing: -0.05pt;">c</span><span style="letter-spacing: 0.1pt;">i</span><span style="letter-spacing: -0.05pt;">a</span>lpodr<span style="letter-spacing: 0.1pt;">í</span><span style="letter-spacing: -0.05pt;">a</span>nbus<span style="letter-spacing: 0.05pt;">c</span><span style="letter-spacing: -0.05pt;">a</span>r <span style="letter-spacing: -0.05pt;">e</span>lusode in<span style="letter-spacing: 0.05pt;">te</span>rn<span style="letter-spacing: -0.1pt;">e</span>t<span style="letter-spacing: -0.05pt;">c</span>o<span style="letter-spacing: 0.15pt;">m</span>ounmediode in<span style="letter-spacing: 0.05pt;">t</span><span style="letter-spacing: -0.05pt;">e</span>r<span style="letter-spacing: -0.1pt;">a</span><span style="letter-spacing: -0.05pt;">cc</span>iónpl<span style="letter-spacing: 0.1pt;">a</span><span style="letter-spacing: -0.05pt;">ce</span>nt<span style="letter-spacing: 0.1pt;">e</span>ro, losjóven<span style="letter-spacing: -0.05pt;">e</span>s<span style="letter-spacing: -0.05pt;">c</span>onsín<span style="letter-spacing: 0.05pt;">t</span>omasobs<span style="letter-spacing: -0.05pt;">e</span>siv<span style="letter-spacing: 0.2pt;">o</span><span style="letter-spacing: -0.05pt;">-c</span>ompu<span style="letter-spacing: 0.05pt;">l</span>sivospodrí<span style="letter-spacing: -0.05pt;">a</span>nl<span style="letter-spacing: 0.05pt;">l</span><span style="letter-spacing: -0.05pt;">e</span>g<span style="letter-spacing: -0.05pt;">a</span>r a un uso <span style="letter-spacing: -0.05pt;">e</span><span style="letter-spacing: 0.1pt;">x</span><span style="letter-spacing: -0.05pt;">ce</span>sivo como m<span style="letter-spacing: -0.05pt;">e</span>dio de <span style="letter-spacing: -0.05pt;">e</span>l<span style="letter-spacing: 0.05pt;">i</span>m<span style="letter-spacing: 0.05pt;">i</span>n<span style="letter-spacing: -0.05pt;">a</span>r la<span style="letter-spacing: -0.05pt;"> a</span>nsi<span style="letter-spacing: 0.1pt;">e</span>d<span style="letter-spacing: -0.05pt;">a</span>d <span style="letter-spacing: -0.05pt;">c</span>ompu<span style="letter-spacing: 0.05pt;">l</span>siva.</span>

Abstract CM 186 LC is a rhenium-containing, directionally solidified (DS) superalloy. It has excellent DS castability and above average resistance to grain boundary cracking in complex cored, thin wall turbine airfoils. This datasheet provides information on composition and physical properties as well as creep. It also includes information on casting and heat treating. Filing Code: Ni-450. Producer or source: Cannon-Muskegon Corporation.

Abstract CM 247 LC alloy is a derivative of the MAR M 247 composition, specifically designed for directionally solidified (DS) turbine blade and vane applications. This datasheet provides information on composition and physical properties. It also includes information on casting and heat treating. Filing Code: Ni-415. Producer or source: Cannon-Muskegon Corporation.