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Abstract Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research.

Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given the widespread deployment of the COVID-19 vaccines, the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components. In this study, we investigated a series of polysarcosine (pSar) lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems. We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.

Abstract Background Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. Results Seal and human endothelial cells exposed to 1% O2 for up to 6 h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. Conclusions We found that the glutathione antioxidant system is upregulated in seal endothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal.

Background. In modern linguistics the phenomena of oral speech are actively studied, in particular the functioning of the discourse markers (units that play a crucial role in organizing the narrative and structuring the generated by the speaker discourse) in it. The purpose of this work is to describe the forming of new functions of discourse marker znachit to identify contextual and prosodic features that allow to classify the uses of the word znachit in natural oral speech. Materials and methods. The material of an analysis was taken from the oral and multimedia corpora of the National Corpus of the Russian Language. The total amount of material selected for the study consists of approximately 8500 words, 200 uses of the discourse marker znachit were analyzed. The method of the discourse analysis, the comparative method and quantitative method were used during the research. Results. The results of the study show the development of the functions of the discourse marker znachit in the natural oral speech: znachit fulfills the «starting function», the speech error marking function, and the quotation marking function. Via the Praat program the prosodic features of the discourse marker znachit were analyzed in the above-mentioned functions. In the course of the analysis of the prosodic features znachit in the different groups we managed to reveal that in the 3rd group contexts (in the situation of quoting) znachit is pronounced shorter than in the examples from the 1st, 2nd and 4th groups. The uses of znachit in the examples of the 2nd (the situation of the speech error) and 4th (the beginning of a new part of discourse) groups have an approximately equal duration range, but differ in the tone movement and pause locations in relation to the discourse marker. In the 2nd group of examples znachit is pronounced longer than in the other groups. Practical implications. The results of the study can be used to specify the definition of this unit.

Summary: This scoping review assessed the surgical backlog in Latin America and the Caribbean (LAC) due to COVID-19 and identified mitigation strategies. We searched seven databases for citations from December 2019 to December 2022, focusing on LAC patients with cancelled or postponed procedures. We registered our protocol at Open Science Framework (https://osf.io/x2nd8) and adhered to PRISMA-ScR guidelines. We included 83 citations covering 23 LAC countries and 19 surgical specialities, with Brazil (67%, 56/83) and transplant surgery (24%, 20/83) being the most documented. Surgical backlogs were mainly reported at the hospital (44%, 37/83) and national levels (38%, 32/83). We identified 58 citations that reported a total of 42 strategies to mitigate the backlog, the most cited being establishing prioritisation criteria for surgical cases (41%, 24/58). Our findings highlight challenges across differing healthcare systems in LAC, including disparities in data availability, surgical capacity, and resource allocation. For instance, while countries like Brazil had extensive data on national surgical backlogs, others lacked comprehensive national-level data. Our review can help inform policymakers and healthcare stakeholders to implement targeted interventions to prepare LAC-based surgical systems for future health emergencies.

Two series of novel Cu (II) (4a–e) and Ni (II) (5a–e) complexes bearing 1-(N-phenylthiocarbamoyl)-pyrazoline ligands (3a–e) were synthesized and characterized. The structures of Ni (II) complexes 5a, c were confirmed by X-ray crystallography; both complexes have a distorted octahedral coordination environment of the Ni (II); metal atoms are coordinated by pyridyl and pyrazoline nitrogen atoms and thiocarbonyl sulfur of two ligand moiety, with two chloride anions in the outer sphere. The Cu (II) complex 4a derived from ligand 3a demonstrate a non-typical electrochemical behavior indicating Cu (I) complex formation which can be explained either by pyrazoline ligand ring opening in DMF solution or by a non-innocent nature of 3a. All of the synthesized complexes were cytotoxic against HCT116 and К562 cell lines; the most cytotoxic ligand was 3d, which is structurally related to combretastatin A4.

Abstract Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies.

Obesity and related comorbidities heighten risks for complications in kidney transplant settings. While pre-transplant patients often have access to nutrition counseling and health support, literature is limited on patients' perceptions of weight and motivation to lose weight prior to transplantation. We conducted a survey among ≥18-year-old patients on the kidney transplant waitlist at a single center. Questions addressed weight perception, motivation for weight loss, available resources, and engagement in physical activity. Medical records provided demographic and clinical data. Statistical tests analyzed quantitative data, while free-text responses were thematically grouped and described. Of 1055 patients, 291 responded and were matched with demographic data. Perceived weight changes correlated with actual changes in body mass index (BMI) (

Purpose: Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone because of its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Methods and Materials: In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at Brigham and Women's Hospital/Dana Farber Cancer Center and Beth Israel Deaconess Medical Center between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol mandated. Local progression-free survival, progression-free survival, prostatic specific antigen progression, and overall survival were reported. Treatment-related toxicity was also reported. Results: A total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume and higher dose to the gross tumor volume. Four patients (4.1%, 4/98) experienced local progression at 1 site for each patient (3.2%, 4/126). Among the entire cohort, 2-year local progression-free survival (including death without local progression) was 84.8%, 2-year progression-free survival (including deaths as well as local, distant, and prostatic specific antigen progression) was 47.5%, and 2-year overall survival was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. Conclusions: Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

A transparent Er3+,Yb3+:GdMgB5O10 single crystal with dimensions up to 24 × 15 × 12 mm was grown successfully by the high-temperature solution growth on dipped seeds technique from K2Mo3O10-based solvent. The grown crystal was characterized using PXRD, DSC and ATR techniques. Differential scanning calorimetry measurements and SEM analysis of the heat-treated solids revealed Er,Yb:GdMgB5O10 to be an incongruent melting compound with an onset point of 1087 °C. The absorption edge of the Er,Yb:GMBO sample is located in the region of 245 nm, which approximates a value of 4.8 eV. Absorption and emission spectra, and luminescence kinetics, were studied. The energy transfer efficiency from ytterbium to erbium ions was determined. The laser operation in continuous-wave mode was realized and output characteristics were measured. The maximal output power of 0.15 W with a slope efficiency of 11% was obtained at 1568 nm.

Abstract The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3–33 antibodies and highlight key features underlying the potent protection of this antibody family.

Background: Despite the assurance of universal health coverage, large disparities exist in access to surgery in the state of Chiapas. The purpose of this study was to determine the effectiveness of the surgical referral system at hospitals operated by the Ministry of Health in Chiapas. Methods: 13 variables were extracted from surgical referrals data from three public hospitals in Chiapas over a three-year period. Interviews were performed of health care workers involved in the referral system and surgical patients. The quantitative and qualitative data was analyzed convergently and reported using a narrative approach. Findings: In total, only 47.4% of referred patients requiring surgery received an operation. Requiring an elective, gynecological, or orthopedic surgery and each additional surgery cancellation were significantly associated with lower rates of receiving surgery. The impact of gender and surgical specialty, economic fragility of farmers, dependence upon economic resources to access care, pain leading people to seek care, and futility leading patients to abandon the public system were identified as main themes from the mixed methods analysis. Interpretation: Surgical referral patients in Chiapas struggle to navigate an inefficient and expensive system, leading to delayed care and forcing many patients to turn to the private health system. These mixed methods findings provide a detailed view of often overlooked limitations to universal health coverage in Chiapas. Moving forward, this knowledge must be applied to improve referral system coordination and provide hospitals with the necessary workforce, equipment, and protocols to ensure access to guaranteed care. Funding: Harvard University and the Abundance Fund provided funding for this project. Funding sources had no role in the writing of the manuscript or decision to submit it for publication.

Abstract Background The prevalence of depression has increased among adolescents in western countries. Prevention is needed to reduce the number of adolescents who experience depression and to avoid negative consequences, including suicide. Several preventive interventions are found to be promising, especially multi-modal approaches, for example combining screening and preventive intervention. However, an important bottleneck arises during the implementation of preventive intervention. Only a small percentage of adolescents who are eligible for participation actually participate in the intervention. To ensure that more adolescents can benefit from prevention, we need to close the gap between detection and preventive intervention. We investigated the barriers and facilitators from the perspective of public health professionals in screening for depressive and suicidal symptoms and depression prevention referral in a school-based setting. Methods We conducted 13 semi-structured interviews with public health professionals, who execute screening and depression prevention referral within the Strong Teens and Resilient Minds (STORM) approach. The interviews were recorded, transcribed verbatim, and coded in several cycles using ATLAS.ti Web. Results Three main themes of barriers and facilitators emerged from the interviews, namely “professional capabilities,” “organization and collaboration,” and “beliefs about depressive and suicidal symptoms and participation in prevention”. The interviews revealed that professionals do not always feel sufficiently equipped in terms of knowledge, skills and supporting networks. Consequently, they do not always feel well able to execute the process of screening and prevention referral. In addition, a lack of knowledge and support in schools and other cooperating organizationorganizations was seen to hinder the process. Last, the beliefs of public health professionals, school staff, adolescents, and parents —especially stigma and taboo—were found to make the screening and prevention referral process more challenging. Conclusions To further improve the process of screening and prevention referral in a school-based setting, enhancing professional competence and a holding work environment for professionals, a strong collaboration and a joint approach with schools and other cooperating organizations and society wide education about depressive and suicidal symptoms and preventive intervention are suggested. Future research should determine whether these recommendations actually lead to closing the gap between detection and prevention.

Summary: Background: Accessibility to surgical services can impact earthquake preparedness and response. We aimed to estimate the population with timely access to surgical care in Guerrero, a Mexican state with high tectonic activity, and identify populations at risk in the event of an earthquake. Methods: We conducted an ecological study using open government data. We extracted data from Guerrero municipalities regarding their earthquake risk, social vulnerability, social inequality, marginalisation, and resilience indices. The latest combines municipalities’ resistance to unexpected events and capacity to maintain optimal functionality without immediate federal or international support. Geographical coordinates of active public and private surgical facilities in Guerrero were combined with ancillary spatial data on roads and municipalities' population density to estimate population coverage within 30-min and 1-h driving time to surgical facilities in Redivis. We built an ordered beta regression model for each driving time estimate. Findings: We identified 25 public and 16 private facilities capable of providing surgical care in Guerrero. The population with access to facilities with surgical capacity within 30 min and 1-h driving times were 48.4% and 69.1%, respectively. We found that municipalities with very high levels of earthquake risk, social vulnerability, social inequality, and marginalisation, and very low levels of resilience had decreased coverage. In the multivariable analysis, the resilience index was statistically significant only for the 30-min model, with an effect size of 0.524 (95% CI 0.082, 1.089). Interpretation: Access to surgical care remains unequally distributed in Guerrero municipalities at the highest risk for earthquakes. Municipalities' resilience was the most significant predictor of higher surgical care coverage in 30-min driving time. Our study provides insights on how surgical system strengthening can enhance earthquake emergency disaster planning. Funding: No funding.

Abstract Cell therapy has revolutionized the treatment of various diseases, such as cancers, genetic disorders, and autoimmune diseases. Currently, most cell therapy products rely on ex vivo cell engineering, which requires sophisticated manufacturing processes and poses safety concerns. The implementation of in situ cell therapy holds the potential to overcome the current limitations of cell therapy and provides a broad range of applications and clinical feasibility in the future. A variety of biomaterials have been developed to improve the function and target delivery to specific cell types due to their excellent biocompatibility, tunable properties, and other functionalities, which provide a reliable method to achieve in vivo modulation of cell reprogramming. In this article, we summarize recent advances in biomaterials for in situ cell therapy including T cells, macrophages, dendritic cells, and stem cells reprogramming leveraging lipid nanoparticles, polymers, inorganic materials, and other biomaterials. Finally, we discuss the current challenges and future perspectives of biomaterials for in situ cell therapy.

Dear Colleagues!We are glad to present the 10th Edition (revised) of the Standards of Specialized Diabetes Care. These evidence-based guidelines were designed to standardize and facilitate diabetes care in all regions of the Russian Federation.The Standards are updated on the regular basis to incorporate new data and relevant recommendations from national and international clinical societies, including World Health Organization Guidelines (WHO, 2011, 2013), International Diabetes Federation (IDF, 2011, 2012, 2013), European Association for the Study of Diabetes (EASD 2018, 2019), American Diabetes Association (ADA, 2018, 2019, 2021), American Association of Clinical Endocrinologists (AACE, 2020, 2021), International Society for Pediatric and Adolescent Diabetes (ISPAD, 2018) and Russian Association of Endocrinologists (RAE, 2019). Current edition of the “Standards” also integrates results of completed randomized clinical trials (ADVANCE, ACCORD, VADT, UKPDS, SAVOR, TECOS, LEADER, EXAMINE, ELIXA, SUSTAIN, DEVOTE, EMPA-REG OUTCOME, CANVAS, DECLARE, CARMELINA, REWIND, CREDENCE, CAROLINA, DAPA-CKD, DAPA-HF, EMPEROR-Reduced trial, VERIFY, VERTIS CV, PIONEER, etc.), as well as findings from the national studies of diabetes mellitus (DM), conducted in close partnership with a number of Russian hospitals.Latest data indicates that prevalence of DM in the world increased during the last decade more than two-fold, reaching some 537 million patients by the end of 2021. According to the current estimation by the International Diabetes Federation, 643 million patients will be suffering from DM by 2030 and 784 million by 2045.Like many other countries, Russian Federation experiences a sharp rise in the prevalence of DM. According to Russian Federal Diabetes Register, there are at least 4 871 863 patients with DM in this country on 01.01.2021 (3,34% of population) with 92,3% (4 498 826)–Type 2 DM, 5,6% (271 468)–Type 1 DM and 2,1% (101 569)–other types of DM, including 9 729 women with gestational DM. However, these results underestimates real quantity of patients, because they consider only registered cases. Results of Russian epidemiological study (NATION) confirmed that only 54% of Type 2 DM are diagnosed. So real number of patients with DM in Russia is 10 million patients (about 7% of population). This is a great long-term problem, because a lot of patients are not diagnosed, so they don’t receive any treatment and have high risk of vascular complications.Severe consequences of the global pandemic of DM include its vascular complications: nephropathy, retinopathy, coronary, cerebral and peripheral vascular disease. These conditions are responsible for the majority of cases of diabetes-related disability and death.In сurrent edition of the “Standards”:New goals of glycemic control for continuous glucose monitoring (time in range, below range and above range, glucose variability) are given.It also features updated guidelines on stratification of treatment in newly diagnosed Type 2 diabetes.In the recommendations for the personalization of the choice of antidiabetic agents, it is taken into account that in certain clinical situations (the presence of atherosclerotic cardiovascular diseases and their risk factors, chronic heart failure, chronic kidney disease, obesity, the risk of hypoglycemia) certain classes of hypoglycemic agents (or individual drugs) have proven advantages.Indications for the use of antidiabetic agents in chronic kidney disease are expanded.Information about insulin pump therapy is added.Recommendations on vaccination are added.An algorithm for replacing some insulin preparations with others is given.This text represents a consensus by the absolute majority of national experts, achieved through a number of fruitful discussions held at national meetings and forums. These guidelines are intended for endocrinologists, primary care physicians, pediatricians and other medical professionals involved in the treatment of DM.Compared with previous edition of the Standards of Specialized Diabetes Care edited by Dedov I.I., Shestakova M.V., ­Mayorov A.Yu., 10th edition, Moscow, 2021 (signed for printing on 10.09.2021) a number of changes have been made.On behalf of the Working Group

Summary: Background: Laparoscopic surgery remains limited in low-resource settings. We aimed to examine its use in Mexico and determine associated factors. Methods: By querying open-source databases, we conducted a nationwide retrospective analysis of three common surgical procedures (i.e., cholecystectomies, appendectomies, and inguinal hernia repairs) performed in Mexican public hospitals in 2021. Procedures were classified as laparoscopic based on ICD-9 codes. We extracted patient (e.g., insurance status), clinical (e.g., anaesthesia technique), and geographic data (e.g., region) from procedures performed in hospitals and ambulatories. Multivariable analysis with random forest modelling was performed to identify associated factors and their importance in adopting laparoscopic approach. Findings: We included 97,234 surgical procedures across 676 public hospitals. In total, 16,061 (16.5%) were performed using laparoscopic approaches, which were less common across all procedure categories. The proportion of laparoscopic procedures per 100,000 inhabitants was highest in the northwest (22.2%, 16/72) while the southeast had the lowest (8.3%, 13/155). Significant factors associated with a laparoscopic approach were female sex, number of municipality inhabitants, region, anaesthesia technique, and type of procedure. The number of municipality inhabitants had the highest contribution to the multivariable model. Interpretation: Laparoscopic procedures were more commonly performed in highly populated, urban, and wealthy northern areas. Access to laparoscopic techniques was mostly influenced by the conditions of the settings where procedures are performed, rather than patients' non-modifiable characteristics. These findings call for tailored interventions to sustainably address equitable access to minimally invasive surgery in Mexico. Funding: None.

Summary: Lower-grade gliomas exhibit a high prevalence of isocitrate dehydrogenase 1 (IDH1) mutations, but faithful models for studying these tumors are lacking. Here, we present a protocol to establish a genetically engineered mouse (GEM) model of grade 3 astrocytoma driven by the Idh1R132H oncogene. We describe steps for breeding compound transgenic mice and intracranially delivering adeno-associated virus particles, followed by post-surgical surveillance via magnetic resonance imaging. This protocol enables the generation and use of a GEM to study lower-grade IDH-mutant gliomas.For complete details on the use and execution of this protocol, please refer to Shi et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract This article describes the context, development, objectives, and content of three instruments. They stem from two questionnaires, used in the ERiK-Surveys 2020 and the Corona-KiTa-Study (CKS), two multi-perspective surveys which were developed by the German Youth Institute, to measure quality as well as challenges and solutions of the Corona pandemic in early childhood education and care (ECEC). The three instruments focus on (1) childcare center directors’ subjective level of information about pandemic-related regulations in the ERiK questionnaire and the extent of implementation of (2) hygiene and (3) protective measures in ECEC in the CKS questionnaire. First analyses suggest good performance and quality of the instruments. Further analyses (e.g., regarding validity and reliability) will be carried out. The instruments seem to be promising for future research, for example regarding medical questions in the field of ECEC.

TmMgB5O10 spontaneous crystals were synthesized via the flux-growth technique from a K2Mo3O10-based solvent. The crystal structure of the compound was solved and refined within the space group P21/n. The first principles calculations of the electronic structure reveal that TmMg-pentaborate with an ideal not defected crystal structure is an insulator with an indirect energy band gap of approximately 6.37 eV. Differential scanning calorimetry measurements and powder X-ray diffraction studies of heat-treated solids show that TmMgB5O10 is an incongruent melting compound. A characteristic band of the Tm3+ cation corresponding to the 3H6 → 1D2 transition is observed in the photoluminescence excitation spectra of TmMg-borate. The as-obtained crystals exhibit intense blue emission with the emission peaks centered at 455, 479, 667, and 753 nm. The most intensive band corresponds to the 1D2 → 3F4 transition. TmMgB5O10 solids demonstrate the thermal stability of photoluminescence.

El siguiente texto presenta una experiencia pedagógica acontecida en la institución educativa distrital Eduardo Umaña Luna IED (EUL) - Bogotá Colombia, en el escenario de la educación remota no presencial causada por la pandemia del coronavirus (SARS-CoV-2); teniendo como fondo teórico la tensión originada en el hecho de transitar y habitar la escuela desde una materialidad hacia una virtualidad; generando por un lado, un reparto de lo sensible (Rancière, 2009) al producirse en los actores de la comunidad educativa otras prácticas de socialización mediadas por las herramientas tecnológicas; y por el otro un marco pedagógico para la comprensión de subjetividades mediadas por la interacción y la socialización online, esto último y siguiendo la conceptualización trazada por Zemelman (2005) desde la producción y comprensión de las subjetividades en la modernidad, en clave de conceptos como el agenciamiento, las resistencias y las potencias identificadas en la trayectoria de la experiencia pedagógica, que vincula y da voz a la comunidad educativa.

Antibodies targeting OX40 or CD137, two T cell costimulatory receptors, have been shown to improve antitumor immunity. Here the authors design a phospholipid-derived nanoparticle to deliver OX40 or CD137 mRNA to T cells in vivo, improving efficacy of anti-OX40 and anti-CD137 antibody therapy in preclinical tumor models.

Objectives: To assess the natural history for development of carpal tunnel syndrome (CTS) in persons with acute spinal cord injury (SCI) at 1 year postdischarge from initial rehabilitation and to assess baseline median nerve (MN) cross-sectional area (CSA) above/below 10 mm2 correlates with any longitudinal changes in quantitative ultrasound (US) of the MN. Design: A prospective cohort study of persons with acute SCI evaluated for CTS using quantitative US and compared to a group without SCI (non-SCI). Setting: Academic medical center. Participants: N=69 total (N=34 SCI, N=35 non-SCI). The average age in both groups was 28 and the SCI group included 30 males and 2 females and the non-SCI group included 30 males and 3 females. Interventions: Not applicable. Main Outcome Measures: The primary outcome was the change in quantitative US parameters of the MN, including CSA and grayscale, from baseline to 1-year follow-up in those with SCI and those without SCI. CTS symptomatology and physical exam sum score and US measures for dominant and nondominant arms were considered secondary outcomes. Results: The SCI had darker nerves at baseline (P=.036, nondominant), greater CTS symptoms at follow-up (P≤.036, bilateral), and no differences in all change scores (all P≥.056). Individuals with smaller nerves at baseline had larger increases in nerve size (P=.029, nondominant) vs those with larger nerves. Change in CTS symptoms CSA (nondominant) and nerve echogenicity (dominant) were inversely associated with their respective baseline values (all P≤.045). Conclusions: We observed few differences between the SCI group and the non-SCI control group and between those with smaller vs larger MN. In general, MN pathology changes (CTS symptoms and US variables) over 1 year were more common in the nondominant arm and appear to be a function of MN pathology at enrollment. Individuals with SCI may experience increased CTS symptoms as soon as 1 year after injury.

Background: Kidney transplant (KT) is the optimal treatment for kidney failure (KF), and although completion of KT evaluation is an essential step in gaining access to transplantation, the process is lengthy, time consuming, and burdensome. Furthermore, despite similar referral rates to non-Hispanic Whites, both Hispanic/Latinos and American Indians are less likely to be wait-listed or to undergo KT. Methods: The Access to Kidney Transplantation in Minority Populations (AKT-MP) Trial compares two patient-centered methods to facilitate KT evaluation: kidney transplant fast track (KTFT), a streamlined KT evaluation process; and peer navigators (PN), a peer-assisted evaluation program that incorporates motivational interviewing. This pragmatic randomized trial will use a comparative effectiveness approach to assess whether KTFT or PN can help patients overcome barriers to transplant listing. We will randomly assign patients to the two conditions. We will track participants’ medical records and conduct surveys prior to their initial evaluation clinic visit and again after they complete or discontinue evaluation. Conclusion: Our aims are to (1) compare KTFT and PN to assess improvements in kidney transplant (KT) related outcomes and cost effectiveness; (2) examine how each approach effects changes in cultural/contextual factors, KT concerns, KT knowledge, and KT ambivalence; and (3) develop a framework for widespread implementation of either approach. The results of this trial will provide key information for facilitating the evaluation process, improving patient care, and decreasing disparities in KT.

Abstract Background Neuroinflammation has been proved to play a role in dopaminergic neuronal death in Parkinson’s disease (PD). This link highlights the relevance of the immune response in the progression of the disease. However, little is known about the impact of peripheral immune response on the disease. This study is aimed to evaluate how immune cell populations change in untreated PD patients followed-up for 2 years. Methods Thirty-two patients with no previous treatment (PD-0 yr) and twenty-two healthy subjects (controls) were included in the study. PD patients were sampled 1 and 2 years after the start of the treatment. CD4 T cells (naïve/central memory, effector, and activated), CD8 T cells (activated, central memory, effector memory, NKT, Tc1, Tc2, and Tc17), and B cells (activated, plasma, and Lip-AP) were characterized by flow cytometry. Results We observed decreased levels of naïve/central memory CD4 and CD8 T cells, Tc1, Tc2, NKT, and plasma cells, and increased levels of effector T cells, activated T cells, and Tc17. Conclusions PD patients treated for 2 years showed an imbalance in the naive/effector immune response. Naïve and effector cell levels were associated with clinical deterioration. These populations are also correlated to aging. On the other hand, higher Tc17 levels suggest an increased inflammatory response, which may impact the progression of the disease. Our results highlight the relevant effect of treatment on the immune response, which could improve our management of the disease.

Cancer patients (CPs) have been identified as particularly vulnerable to SARS-CoV-2 infection, and therefore are a priority group for receiving COVID-19 vaccination. From the patients with advanced solid tumors, about 20% respond very efficiently to immunotherapy with anti-PD1/PD-L1 antibodies and achieve long lasting cancer responses. It is unclear whether an efficient cancer-specific immune response may also correlate with an efficient response upon COVID-19 vaccination. Here, we explored the antiviral immune response to the mRNA-based COVID-19 vaccine BNT162b2 in a group of 11 long-lasting cancer immunotherapy responders. We analysed the development of SARS-CoV-2-specific IgG serum antibodies, virus neutralizing capacities and T cell responses. Control groups included patients treated with adjuvant cancer immunotherapy (IMT, cohort B), CPs not treated with immunotherapy (no-IMT, cohort C) and healthy controls (cohort A). The median ELISA IgG titers significantly increased after the prime-boost COVID vaccine regimen in all cohorts (Cohort A: pre-vaccine = 900 (100-2700), 3 weeks (w) post-boost = 24300 (2700-72900); Cohort B: pre-vaccine = 300 (100-2700), 3 w post-boost = 8100 (300-72900); Cohort C: pre-vaccine = 500 (100-2700), 3 w post-boost = 24300 (300-72900)). However, at the 3 w post-prime time-point, only the healthy control group showed a statistically significant increase in antibody levels (Cohort A = 8100 (900-8100); Cohort B = 900 (300-8100); Cohort C = 900 (300-8100)) (P

ABSTRACT Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC24) of 40 to 50 μg·h/mL. Full-length UL54 and UL97 were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of

Objective Disagreement exists between rheumatology and primary care societies regarding gout management. This paper describes a formal process for gathering input from stakeholders in the planning of a trial to compare gout management strategies. Methods We recruited patients, nurses, physician assistants, primary care clinicians, and rheumatologists to participate in a modified Delphi panel (mDP) to provide input on design of a trial focused on optimal management for primary care patients with gout. The 16 panelists received a plain‐language briefing document that discussed the rationale for the trial, key clinical issues in gout, and aspects of trial design. The panelists also received information and considerations on nine voting questions (VQs), judged to be the key design questions. Cognitive interviews with panelists ensured that the VQs were understood by the range of panelists involved in the mDP. Panelists were asked to score all VQs from 1 (definitely no) to 9 (definitely yes). Two voting rounds were conducted—round 1 by email and round 2 by video conference. Results The VQs were modified through the cognitive interviews. The round 1 voting resulted in consensus on eight items, with consensus defined as median voting score in the same tercile (1‐3, 4‐6 or 7‐9). Re‐voting at the meeting (round 2) reached consensus on the remaining item. Conclusion An mDP with various stakeholders facilitated consensus on the design of a trial of different management strategies for chronic gout. This method may be useful for designing trials of clinical questions with substantial disagreement across stakeholders.

Introducción: La producción de biodiesel enzimático, tiene como principal inconveniente, altos precios del biocatalizador. La utilización de sólidos fermentados con actividad lipasa, mitigan los costos, pero al ser un conjunto de enzimas lipasas se desconoce las mejores condiciones de reacción. Objetivo: Determinar las mejores condiciones de tamaño de partícula, velocidad de agitación y relación molar etanol/aceite, para la reacción de producción de etil-ésteres, utilizando como sustratos: aceite de Jatropha curcas y etanol y, como biocatalizador, un sólido fermentado con actividad lipasa. Materiales y Métodos: Se contrastaron inicialmente dos biocatalizadores. Se estudiaron la velocidad de agitación, el tamaño de partícula y la relación molar alcohol/aceite, en la reacción de transesterificación. Los productos de la reacción se midieron, mediante cromatografía de capa fina de alta resolución. Resultados y Discusión: Se seleccionó como biocatalizador el sólido de Rhizopus homothallicus, con una actividad de 75,39 UI gMS-1 y una alta productividad de 4,19 UI gMS-1 h-1. Se estableció que las resistencias a la transferencia de masa difusional se minimizan, al utilizar 200 rpm y un intervalo de tamaños de partícula de 0,149 a 0,297 mm. Se comprobó que para la relación molar 3:1 y 4:1, no hay diferencias significativas en el porciento de conversión, obteniéndose valores de 77,69 %. Sin embargo, para la relación 6:1, se afectó la conversión, debido a los procesos de inhibición de la enzima. Conclusiones: Se estima que el biocatalizador utilizado en las condiciones de reacción establecidas tiene un buen potencial para ser usado en la síntesis de biodiesel.

Strains of the genus Delftia are poorly studied microorganisms. In this work, the complete genome of the naphthalene-degrading Delftia tsuruhatensis strain ULwDis3 isolated from seawater of the Gulf of Finland of the Baltic Sea was assembled. For the first time, genes encoding naphthalene cleavage pathways via salicylate and gentisate were identified in a strain of the genus Delftia. The genes are part of one operon (nag genes). Three open reading frames (ORFs) were found in the genome of D. tsuruhatensis strain ULwDis3 that encode gentisate 1.2-dioxygenase. One of the ORFs is part of the nag operon. The physiological and biochemical characteristics of the strain ULwDis3 when cultured in mineral medium with naphthalene as the sole source of carbon and energy were also studied. It was found that after 22 h of growth, the strain stopped consuming naphthalene, and at the same time, naphthalene 1.2-dioxygenase and salicylate 5-hydroxylase activities were not detected. Later, a decrease in the number of living cells and the death of the culture were observed. Gentisate 1.2-dioxygenase activity was detected from the time of gentisate formation until culture death.

Recent studies of persons with spinal cord injury (SCI) report higher conversion rates of the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grades, especially for complete injuries. We examined the rate of conversion over time after complete SCI, accounting for demographic and injury characteristics. Subjects were 16 years of age and older with a complete SCI injury between 1995 and 2015, enrolled in the National SCI Database as day-1 admissions. We grouped subjects into 3-year intervals and assessed trends in conversion for the total sample and by tetraplegia (Tetra), high paraplegia (levels T1?9, HPara), and low paraplegia (levels T10?12, LPara).We used logistic regression to identify factors related to conversion such as age, sex, etiology, and level of injury. Of 2036 subjects, 1876 subjects had a follow-up examination between 30 and 730 days post-injury. Average age at injury was 34.2???14.6 years; 79.8% were male, 44.6% Tetra, 35.3% HPara, and 20.1% LPara. There was a strong trend toward increased rates of conversion over time (p?LPara >HPara), non-violent etiology, and age (older is better). We found similar factors for conversion to motor incomplete, except sex was significant and etiology was not. Conversion rates from complete to incomplete and motor incomplete injury have been increasing, particularly for persons with tetraplegia. This has implications for acute clinical trials and for prognostication early after SCI.

An association between age-related hearing loss (ARHL) and Alzheimer's Disease (AD) has been widely reported. However, the nature of this relationship remains poorly understood. Quantification of hearing loss as it relates to AD is imperative for the creation of reliable, hearing-related biomarkers for earlier diagnosis and development of ARHL treatments that may slow the progression of AD. Previous studies that have measured the association between peripheral hearing function and AD have yielded mixed results. Most of these studies have been small and underpowered to reveal an association. Therefore, in the current report, we sought to estimate the degree to which AD patients have impaired hearing by performing a meta-analysis to increase statistical power. We reviewed 248 published studies that quantified peripheral hearing function using pure-tone audiometry for subjects with AD. Six studies, with a combined total of 171 subjects with AD compared to 222 age-matched controls, met inclusion criteria. We found a statistically significant increase in hearing threshold as measured by pure tone audiometry for subjects with AD compared to controls. For a three-frequency pure tone average calculated for air conduction thresholds at 500–1,000–2,000 Hz (0.5–2 kHz PTA), an increase of 2.3 decibel hearing level (dB HL) was found in subjects with AD compared to controls (p = 0.001). Likewise, for a four-frequency pure tone average calculated at 500–1,000–2,000–4,000 (0.5–4 kHz PTA), an increase of 4.5 dB HL was measured (p = 0.002), and this increase was significantly greater than that seen for 0.5–2 kHz PTA. There was no difference in the average age of the control and AD subjects. These data confirm the presence of poorer hearing ability in AD subjects, provided a quantitative estimate of the magnitude of hearing loss, and suggest that the magnitude of the effect is greater at higher sound frequencies.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier: CRD42021288280.

Dear Colleagues! We are glad to present the 9th Edition (revised) of Standards of Diabetes Care. These evidence-based guidelines were designed to standardize and facilitate diabetes care in all regions of the Russian Federation. The Standards are updated on the regular basis to incorporate new data and relevant recommendations from national and international clinical societies, including World Health Organization Guidelines (WHO, 2011, 2013), International Diabetes Federation (IDF, 2011, 2012, 2013), American Diabetes Association (ADA, 2018, 2019), American Association of Clinical Endocrinologists (AACE, 2019), International Society for Pediatric and Adolescent Diabetes (ISPAD, 2014, 2018) and Russian Association of Endocrinologists (RAE, 2011, 2012, 2015). Current edition of the “Standards” also integrates results of completed randomized clinical trials (ADVANCE, ACCORD, VADT, UKPDS, SAVOR, TECOS, LEADER, EXAMINE, ELIXA, SUSTAIN, DEVOTE, EMPA-REG OUTCOME, CANVAS, DECLARE, CARMELINA, REWIND, etc.), as well as findings from the national studies of diabetes mellitus (DM), conducted in close partnership with a number of Russian hospitals. Latest data indicates that prevalence of DM in the world increased during the last decade more than two-fold, reaching some 463 million patients by the end of 2019. According to the current estimation by the International Diabetes Federation, 578 million patients will be suffering from diabetes mellitus by by 2030 and 700 million by 2045. Like many other countries, Russian Federation experiences a sharp rise in the prevalence of DM. According to Russian Federal Diabetes Register, there are at least 4 584 575 patients with DM in this country by the end of 2018 (3,1% of population) with 92% (4 238 503) – Type 2 DM, 6% (256 202) – Type 1 DM and 2% (89 870) – other types of DM, including 8 006 women with gestational DM. However, these results underestimates real quantity of patients, because they consider only registered cases. Results of Russian epidemiological study (NATION) con- firmed that only 54% of Type 2 DM are diagnosed. So real number of patients with DM in Russia is 9 million patients (about 6% of population). This is a great long-term problem, because a lot of patients are not diagnosed, so they don’t receive any treatment ant have high risk of vascular complications. Severe consequences of the global pandemics of DM include its vascular complications: nephropathy, retinopathy, coronary, cerebral, coronary and peripheral vascular disease. These conditions are responsible for the majority of cases of diabetes-related disability and death. In сurrent edition of the “Standards”: New goals of glycemic control for the elderly, based on the presence of functional dependence, as well as for pregnant women, children and adolescents, are given. Added a snippet that describes the continuous glucose monitoring. Only low-density lipoprotein cholesterol level is used as a target for lipid metabolism. Proposes more stringent target levels of blood pressure. It also features updated guidelines on stratification of treatment in newly diagnosed Type 2 diabetes: the excess of the initial level of HbA1c over the target level was used as a criterion. In the recommendations for the personalization of the choice of antidiabetic agents, it is taken into account that in certain clinical situations (the presence of atherosclerotic cardiovascular diseases and their risk factors, chronic heart failure, chronic kidney disease, obesity, the risk of hypoglycemia) certain classes of hypoglycemic agents (or individual drugs) have proven advantages. Recommendations for psychosocial support are added. The position of metabolic surgery as a method of treatment of DM with morbid obesity is updated. Recommendations for diagnostic and treatment of hypogonadism syndrome in men with DM are added. For the first time, evidence levels of confidence and credibility levels of recommendations for diagnostic, therapeutic, rehabilitative and preventive interventions based on a systematic review of the literature are given in accordance with the recommendations of the Center for Healthcare Quality Assessment and Control of the Ministry of Health of the Russian Federation. This text represents a consensus by the absolute majority of national experts, achieved through a number of fruitful discus- sions held at national meetings and forums. These guidelines are intended for endocrinologists, primary care physicians and other medical professionals involved in the treatment of DM. On behalf of the Working Group

Recent work has suggested that lift and drag may be employed differently in slow, flapping flight compared to classic flight aerodynamics. Here the authors develop a method to measure vertical and horizontal aerodynamic forces simultaneously and use it to quantify lift and drag during slow flight.

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Various studies have suggested that the immune response plays a key role in this pathology. While a predominantly pro-inflammatory peripheral immune response has been reported in treated and untreated PD patients, the study of the role of the regulatory immune response has been restricted to regulatory T cells. Other immune suppressive populations have been described recently, but their role in PD is still unknown. This study was designed to analyze the pro and anti-inflammatory immune response in untreated PD patients, with emphasis on the regulatory response. Methods Thirty-two PD untreated patients and 20 healthy individuals were included in this study. Peripheral regulatory cells (CD4+Tregs, Bregs, CD8+Tregs, and tolerogenic dendritic cells), pro-inflammatory cells (Th1, Th2, and Th17 cells; active dendritic cells), and classical, intermediate, and non-classical monocytes were characterized by flow cytometry. Plasmatic levels of TNF-α, IFN-γ, IL-6, GM-CSF, IL-12p70, IL-4, IL-13, IL-17α, IL-1β, IL-10, TGF-β, and IL-35 were determined by ELISA. Results Decreased levels of suppressor Tregs, active Tregs, Tr1 cells, IL-10-producer CD8regs, and tolerogenic PD-L1+ dendritic cells were observed. With respect to the pro-inflammatory response, a decrease in IL-17-α and an increase in IL-13 levels were observed. Conclusion A decrease in the levels of regulatory cell subpopulations in untreated PD patients is reported for the first time in this work. These results suggest that PD patients may exhibit a deficient suppression of the pro-inflammatory response, which could contribute to the pathophysiology of the disease.

New organic ligands 3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides (L) have been synthesized by a two or three step reaction sequence starting from substituted benzaldehydes and 2-acetyl pyridine. Copper(II) complexes with LCuCl2 composition were obtained by the reactions of these ligands with CuCl2·2H2O. The crystal structure of two synthesized complexes has been determined by X-ray analysis. Copper atoms located in a strongly distorted square piramidal environment and coordinated by pyrazoline and pyridine nitrogen atoms, thiocarbamoyl sulfur atom and two chloride-anions. All complexes undergo reversible or quasi-reversible electrochemical reduction at 0.45–0.28 V with the formation of Cu(I) containing intermediates. The cytotoxicity of copper containing complexes, comparable to cisplatin and doxorubicin, was demonstrated using cancer cell lines MCF-7, A549 and HEK293. Keywords: Copper(II) complexes, 4,5-Dihydro-1H-pyrazole-1-thiocarboxamides, X-ray analysis, Voltammetry

In the title polymeric complex, {[Fe(CN)2(C10H8N2)2(H2O)2][Au(CN)2]}n, the FeII ion, which is located on a twofold rotation axis, has a slightly distorted FeN4O2 octahedral geometry. It is coordinated by two phenylpyrazine molecules, two water molecules and two dicyanoaurate anions, the Au atom also being located on a second twofold rotation axis. In the crystal, the coordinated dicyanoaurate anions bridge the FeII ions to form polymeric chains propagating along the b-axis direction. In the crystal, the chains are linked by Owater—H...Ndicyanoaurate anions hydrogen bonds and aurophillic interactions [Au...Au = 3.5661 (3) Å], forming layers parallel to the bc plane. The layers are linked by offset π–π stacking interactions [intercentroid distance = 3.643 (3) Å], forming a supramolecular metal–organic framework.

Bat genomes are characterized by a diverse transposable element (TE) repertoire. In particular, the genomes of members of the family Vespertilionidae contain both active retrotransposons and active DNA transposons. Each TE type is characterized by a distinct pattern of accumulation over the past ~40 million years. Each also exhibits its own target site preferences (sometimes shared with other TEs) that impact where they are likely to insert when mobilizing. Therefore, bats provide a great resource for understanding the diversity of TE insertion patterns. To gain insight into how these diverse TEs impact genome structure, we performed comparative spatial analyses between different TE classes and genomic features, including genic regions and CpG islands. Our results showed a depletion of all TEs in the coding sequence and revealed patterns of species- and element-specific attraction in the transcript. Trends of attraction in the distance tests also suggested significant TE activity in regions adjacent to genes. In particular, the enrichment of small, non-autonomous TE insertions in introns and near coding regions supports the hypothesis that the genomic distribution of TEs is the product of a balance of the TE insertion preference in open chromatin regions and the purifying selection against TEs within genes.

Objectives: To evaluate the occurrence of drug-related problems (DRP) associates to the use of oral drugs in hospitalized pediatric patients. Method: A cross-sectional study, with data collection performed on the prescriptions of patients using oral medications admitted to the pediatric ward at a reference institute in maternal and child care in Rio de Janeiro. Data collection was carried out from September/2020 to November/2020. Convenience sample was used. Patients aged 0 to 18 years, with oral medications prescribed during the hospitalization period and with a hospital stay of more than 48 hours, were included. DRP were collected and classified based on the pharmacotherapy clinical review guide. Data related to drug interactions were collected in order to identify a possible association with the occurrence of DRP. Pharmaceutical interventions were performed when necessary. Results: Thirty-eight patients were evaluated in this study, most of them male (57.9%) and aged between 0 and 4 years (65.8%). Sixteen patients (42.1%) had at least one DRP. We found 50 DRP, representing a rate of 131.6 DRP per 100 patients. Among the oral medications used, 42.4% were related to DRP. Drugs with action on the nervous system were related to most DRP (37%), with emphasis on the class of antiepileptics. Conclusion: The number of medications used during hospitalization and the number of drug interactions showed statistically significant diferences in patients who had DRP. The review of oral pharmacotherapy identified drug classes and profiles of patients with greater susceptibility to the occurrence of DRP and demonstrated its importance in promoting safety in the use of drugs in the pediatric population.

Regulated in Development and DNA Damage Response 1 (REDD1)/DNA Damage-Induced Transcript 4 (DDIT4) is an immediate early response gene activated by different stress conditions, including growth factor depletion, hypoxia, DNA damage, and stress hormones, i.e., glucocorticoids. The most known functions of REDD1 are the inhibition of proliferative signaling and the regulation of metabolism via the repression of the central regulator of these processes, the mammalian target of rapamycin (mTOR). The involvement of REDD1 in cell growth, apoptosis, metabolism, and oxidative stress implies its role in various pathological conditions, including cancer and inflammatory diseases. Recently, REDD1 was identified as one of the central genes mechanistically involved in undesirable atrophic effects induced by chronic topical and systemic glucocorticoids widely used for the treatment of blood cancer and inflammatory diseases. In this review, we discuss the role of REDD1 in the regulation of cell signaling and processes in normal and cancer cells, its involvement in the pathogenesis of different diseases, and the approach to safer glucocorticoid receptor (GR)-targeted therapies via a combination of glucocorticoids and REDD1 inhibitors to decrease the adverse atrophogenic effects of these steroids.

A transparent Yb:YMgB5O10 single crystal with dimensions up to 25 × 23 × 25 mm and weight 10.337 g was grown using a high-temperature solution growth on dipped seeds technique with a K2Mo3O10 solvent. The Yb3+ concentration was calculated to be 4.7 at.% (NYb = 3.71 × 1020 atoms/cm3) with a distribution coefficient Kd of 0.59. The grown crystal was characterized by means of PXRD, TGA-DSC and ATR-FTIR techniques. The spectroscopic characteristics of the Yb:YMgB5O10 crystal were demonstrated. Absorption cross-section spectra were produced. The luminescence spectra of the Yb:YMgB5O10 crystal were measured in the spectral range of 950–1100 nm. The luminescence kinetics of the 2F5/2 energy level were investigated and the lifetime was determined.

Purpose: Although local control is an important issue for longer-term survivors of spinal metastases treated with conventional external beam radiation therapy (EBRT), the literature on radiographic local failure (LF) in these patients is sparse. To inform clinical decision-making, we evaluated rates, consequences, and predictors of radiographic LF in patients with spinal metastases managed with palliative conventional EBRT alone. Methods and Materials: We retrospectively reviewed 296 patients with spinal metastases who received palliative EBRT at a single institution (2006-2013). Radiographic LF was defined as radiologic progression within the treatment field, with death considered a competing risk. Kaplan-Meier, cumulative incidence, and Cox regression analyses determined overall survival estimates, LF rates, and predictors of LF, respectively. Results: There were 182 patients with follow-up computed tomography or magnetic resonance imaging; median overall survival for these patients was 7.7 months. Patients received a median of 30 Gy in 10 fractions to a median of 4 vertebral bodies. Overall, 74 of 182 patients (40.7%) experienced LF. The 6-, 12-, and 18-month LF rates were 26.5%, 33.1%, and 36.5%, respectively, while corresponding rates of death were 24.3%, 38.1%, and 45.9%. Median time to LF was 3.8 months. Of those with LF, 51.4% had new compression fractures, 39.2% were admitted for pain control, and 35.1% received reirradiation; median time from radiation therapy (RT) to each of these events was 3.0, 5.7, and 9.2 months, respectively. Independent predictors of LF included single-fraction RT (8 Gy) (hazard ratio [HR], 2.592; 95% confidence interval [CI], 1.437-4.675; P = .002), lung histology (HR, 3.568; 95% CI, 1.532-8.309; P = .003), and kidney histology (HR, 4.937; 95% CI, 1.529-15.935; P = .008). Conclusions: Patients experienced a >30% rate of radiographic LF by 1 year after EBRT. Single-fraction RT and lung or kidney histology predicted LF. Given the high rates of LF for patients with favorable prognosis, assessing the risk of death versus LF is important for clinical decision-making.

Background: Several studies have found that women who are overweight or obese have an increased risk of miscarriage. There is also some evidence of associations of other aspects of cardiometabolic health, including blood pressure and lipids, with miscarriage risk, although these have not been examined to the same extent as body-mass index (BMI). Methods: Our objective was to investigate the risk of miscarriage according to pre-pregnancy cardiometabolic health. We examined pre-pregnancy levels of BMI, blood pressure, fasting insulin and metabolites profile at age 18 and risk of miscarriage by age 24. The study included adult female offspring in the Avon Longitudinal Study of Parents and Children with a pregnancy between 18 and 24 years of age (n=434 for BMI and blood pressure; n=265 for metabolites). We used log-binomial regression to calculate adjusted associations between cardiometabolic health measures and miscarriage. Results: The overall risk of miscarriage was 22%. The adjusted relative risks for miscarriage were 0.96 (95% CI: 0.92-1.00) for BMI (per unit increase), 0.98 (0.96-1.00) for systolic blood pressure, and 1.00 (0.97-1.04) for diastolic blood pressure (per 1 mmHg increase). Total cholesterol, total lipids and phospholipids in HDL-cholesterol were associated with increased likelihood of miscarriage, but none of the p-values for the metabolites were below the corrected threshold for multiple testing (p-value ≤0.003). Conclusions: Our findings indicate no strong evidence to support a relationship between pre-pregnancy cardiometabolic health and risk of miscarriage in young, healthy women who became pregnant before age 24. Future studies are necessary that are able to evaluate this question in samples with a wider age range.

Background: Allergic diseases are under-investigated and overlooked health conditions in developing countries. We measured the prevalence of food allergy (FA), airborne allergic disease, and allergic sensitisation among adolescents living in 2 socio-demographically disparate regions in Ecuador. We investigated which risk factors are associated with these conditions. Methods: A cross-sectional study involved 1338 students (mean age: 13 ± 0.9 years old) living in Cuenca (n = 876) and Santa Isabel (n = 462). History of allergic symptoms (noted by parents or doctor) to food, house dust mites (HDM), pollen, and pets were recorded. Sociodemographic characteristics, environmental exposures, and parental history of allergic disorders data were collected. Sensitisation to 19 food and 20 aeroallergens was measured by skin-prick testing (SPT). FA and airborne allergic diseases (to HDM, pollen, cat, or dog) were defined as a report of allergic symptoms noted by doctor, together with a positive SPT (wheal size ≥3 mm). Logistic regression models were used to identify environmental and parental factors associated with allergic conditions. Results: FA was prevalent among 0.4% (95% CI 0.2%–0.9%), and food sensitisation among 19.1% of the adolescents. Shrimp was the most frequent food linked with FA and food sensitisation. Risk factors associated with FA could not be evaluated due to the low prevalence. Food sensitisation was higher among adolescents exposed to family smoking (OR 1.63, 95% CI 1.14–2.34, p = 0.008) and those with parental history of allergic disorders (OR 1.68, 95% CI 1.13–2.49, p = 0.01), but less common among adolescents owning dogs (OR 0.59, 95% CI 0.41–0.84, p = 0.003).Airborne allergic diseases were prevalent amongst 12.0% of the adolescents (95% CI: 10.4–13.9, n = 1321), with HDM as the primary allergen (11.2%). Airborne allergic diseases were less common among adolescents with more siblings (OR 0.79, 95% CI 0.65–0.96, p = 0.02) and those who lived with farm animals in the first year of life (OR 0.47, 95% CI 0.23–0.95, p = 0.04), but, most common among adolescents with a smoking family (OR 1.67, 95% CI 1.04–2.70, p = 0.03) and with a parental history of allergic disorders (OR self-perceived: 2.62, 95% CI 1.46–4.71, p = 0.001; OR diagnosed by a doctor: 4.07, 95% CI 2.44–6.80, p

Background: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes. Methods: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. Findings: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. Interpretation: Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new ‘precision medicine’ for carriers of these inactive ALDH2.

BackgroundSome evidence support the notion that microglia activation in acute state of schizophrenia might contribute to damage of oligodendrocytes and myelinated fibers. Previously we found dystrophic changes of oligodendrocytes in prefrontal white matter in schizophrenia subjects displaying predominantly positive symptoms as compared to controls. The aim of the study was to verify whether microglial activation might contribute to dystrophic changes of oligodendrocytes in prefrontal gray matter in this clinical subgroup.MethodsTransmission electron microscopy and morphometry of microglia and adjacent oligodendrocytes were performed in layer 5 of the prefrontal cortex (BA10) in the schizophrenia subjects displaying predominantly positive symptoms (SPPS, n = 12), predominantly negative symptoms (SPNS, n = 9) and healthy controls (n = 20).ResultsQualitative study showed microglial activation and dystrophic alterations of microglia and oligodendrocytes adjacent to each other in both subgroups as compared to controls. A significant reduction in volume density (Vv) and the number (N) of mitochondria and an increase in N of lipofuscin granules were found in oligodendrocytes and adjacent microglia in both subgroups. Vv of lipofuscin granules, Vv and N of vacuoles of endoplasmic reticulum in microglia were increased significantly in the SPPS subgroup as compared to controls. In the SPPS subgroup Vv and N of mitochondria in microglia were correlated with N of vacuoles in microglia (r = -0.61, p < 0.05) and with Vv (r = 0.79, p < 0.01) and N (r = 0.59, p < 0.05) of mitochondria in oligodendrocytes. Vv of mitochondria in microglia was also correlated with Vv and N of vacuoles in oligodendrocytes in the SPPS subgroup (r = 0.76, p < 0.01). Area of nucleus of microglial cells was correlated negatively with age (r = -0.76, p < 0.01) and age at illness onset (r = -0.65, p < 0.05) in the SPPS subgroup. In the SPNS subgroup N of mitochondria in microglia was correlated with Vv of lipofuscin granules in oligodendrocytes (r = -0.9, p < 0.01). There were no significant correlations between these parameters in the control group.DiscussionMicroglial dystrophy might contribute to oligodendrocyte dystrophy in the schizophrenia subjects with predominantly positive symptoms during relapse. Mitochondria in microglia and oligodendrocytes may be a target for treatment strategy of schizophrenia.

The purpose of this study was to develop a sequential process of personalized valproic acid (VPA) prescription in patients with epilepsy. Materials and Methods: We randomly selected 167 patients with epilepsy receiving VPA, based on carriage of CYP2C9*2 and/or CYP2C9*3 and therapeutic drug monitoring. The patients’ CYP2C9 status was determined by CYP2C9 genotyping before the beginning of anticonvulsant therapy. Results: The sequence of personalized valproic acid prescription has been developed. Conclusion: Using the sequential process of personalized VPA prescription will allow neurologists, psychiatrists and general practitioners to select starting and maintenance dosages of VPA with respect to the individual patient’s pharmacogenetic profile and thereby, significantly improve the safety of pharmacotherapy in epilepsy patients.

Abstract Background WHO data shows that female immigrants in Europe attempt suicide at higher rates than ‘native’ women and ‘native’ and immigrant men. Empirical studies addressing attempted suicide of female immigrants of Caribbean (Antillean-Dutch and Creole-Surinamese-Dutch) as well as Cape Verdean descent in Europe are however scarce. We aim to increase knowledge about rates and risk factors of girls of Caribbean and Cape Verdean descent living in the Netherlands. Methods We conducted logistic regression on a dataset that consisted of self-reported health and well-being surveys filled out by 5611 female students, age 14–16, in Rotterdam, the Netherlands (Antillean Dutch N = 357, Creole-Surinamese-Dutch N = 130, and Cape Verdean-Dutch N = 402, and Dutch ‘natives’ N = 4691). We studied if girls of these minority groups had elevated risk for attempted suicide. Risk indicators that were suspected to play a role were investigated i.e. household composition, socio-economic class, externalizing problems, emotional problems and sexual abuse. Results We found that rates of attempted suicide among Antillean (14%), Creole-Surinamese young women (15.4%) were higher than of ‘native’ Dutch girls (9.1%), while rates of Cape-Verdean girls (8.3%) were rather similar to those of ‘native’ girls. Not living with two biological parents was a risk factor for ‘native’ girls, but not for girls of Caribbean and Cape Verdean descent. Emotional problems and sexual abuse seems to be a risk indicator for suicidality across all ethnicities. Aggressive behaviour was a risk factor for Antillean Dutch and ‘native’ girls. Conclusions Our findings underscore the need for developing suicide prevention programs for minority girls in multicultural cities in western Europe, in particular those of Caribbean descent. Results suggest the importance of addressing socio-economic class and educational background for suicide prevention, which bear particular relevance for Caribbean populations. Referral in the case of sexual trauma and low psychological wellbeing seems critical for reducing suicidal behaviour in girls, regardless of ethnicity.