Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In multiple myeloma (MM), measurable residual disease (MRD) is assessed in bone marrow (BM). However, less invasive evaluation of peripheral residual disease (PRD) in blood could be advantageous and less cumbersome. We investigated the prognostic value of PRD monitoring after 24 cycles of maintenance in 138 transplant-eligible patients with MM enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials. PRD was assessed using next-generation flow (NGF) and mass spectrometry (MS). Positive PRD by NGF in 16/138 (11.5%) patients was associated with a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and overall survival (OS) were 2.5 and 47 months, respectively. Considering patients' MRD status in BM as the reference, PRD detection using NGF showed positive and negative predictive values of 100% and 73%, respectively. Presence of PRD helped identifying patients at risk of imminent progression among those with positive MRD in BM. Patients with undetectable PRD according to both NGF and MS showed 2-year PFS and OS rates of 97% and 100%, respectively. In multivariate analyses including the Revised International Staging System and the complete remission status, only MRD in BM and PRD by NGF showed independent prognostic value for PFS. This study supports the use of less invasive PRD monitoring during maintenance or observation in transplant-eligible patients with MM.

Symptoms of attention deficit hyperactivity disorder and oral health problems among children in Spain.

INTRODUCTION: The aim of this study was to explore the association between symptoms of attention deficit hyperactivity disorder (ADHD) and oral health in a representative sample of the Spanish population aged 6 to 14 years, we examined the contribution of several sociodemographic and behavioral determinants of children/adolescents and their family environment. METHODS: A cross-sectional study involving 3,402 subjects aged between 6 and 14 years from the Spanish National Health Survey. The presence of ADHD symptoms was determined using the self-reported hyperactivity/inattention subscale of the Strength and Difficulties Questionnaire. Oral health was assessed using five indicators: caries, extraction, restorations, gingival bleeding, and presence of teeth in poor condition (e.g. broken or misaligned). Logistic regressions were used to examine the association between the presence of ADHD symptoms and oral health indicators. These models were adjusted for sociodemographic factors, lifestyle variables, and oral hygiene behaviors relating to both the children and their parents. RESULTS: Compared to children without ADHD symptoms, children with ADHD symptoms had a higher risk of caries (fully adjusted odds ratio: 2.16; 95% confidence interval: 1.66-2.82), extraction (1.42; 1.09-1.85), restoration (1.47; 1.19-1.82) and gingival bleeding (1.64; 1.11-2.41). The increased risk of caries was maintained when the analyses were restricted to middle/high social class families and to children with low sugar intake, good oral hygiene behaviors and regular dental visits. CONCLUSIONS: Children with ADHD symptoms in Spain had worse oral health indicators than those without ADHD symptoms. Our results suggest that the association of ADHD symptoms with caries was independent of socioeconomic level, cariogenic diet, frequency of toothbrushing and dental visits.

Assessment of care provision integration in a community-based mental health system: balanced care model implementation in Andalusia (Spain).

BACKGROUND: Andalusia is the second largest region in Spain, and it has developed a comprehensive mental health (MH) plan that encourages the consolidation of the balanced care model. However, its geographical and socioeconomic disparity is a great challenge for a community-based MH system. Both the assessment of the implementation of the MH plan and the development of new tools to support decision-making can be considered critical. OBJECTIVES: The present study aims (i) to assess how the integration of different types of MH care may influence system performance and (ii) to check the performance evolution of the integration process geographically regarding the small MH areas of Andalusia. METHODS: The performance of the Andalusian MH system was assessed by combining Monte Carlo simulation, fuzzy inference and data envelopment analysis. The relative technical efficiency was the main performance indicator. RESULTS: A correct integration of appropriate types of MH care, according to population needs, increases the performance of the Andalusian MH system both from global and regional perspectives. The spatial representation (based on small MH areas) of the results highlights how the performance depends on specific geographical characteristics. By analyzing the identified spatial clusters, defined by different management patterns depending on user and socioeconomic characteristics, benchmark areas and areas for improvement can be studied to design evidence-informed policies and interventions. CONCLUSIONS: A global analysis of MH system performance was carried out, including both the successive integration of different types of care and its spatial evolution. Although an appropriate integration of different types of MH care has a positive effect on the Andalusian MH system, this process has different profiles depending on specific geographically based user and socioeconomic characteristics. The balanced care model can be considered the paradigm for assessing the performance of a large and populated territory such as Andalusia, which has a community-based MH system. This methodological approach (performance assessment and spatial analysis) may be used as a guide for developing future evidence-informed policies and managerial interventions.

Connecting high-resolution 3D chromatin maps with cell division and cell differentiation at the root apical meristem.

KEY MESSAGE: We used marker-free technologies to study chromatin at cellular resolution. Our results show asymmetric chromatin distribution, explore chromatin dynamics during mitosis, and reveal structural differences between trichoblast and atrichoblast cell. The shapes, sizes, and structural organizations of plant nuclei vary considerably among cell types, tissues, and species. This diversity is dependent on various factors, including cellular function, developmental stage, and environmental or physiological conditions. The differences in nuclear structure reflect the state of chromatin, which, in turn, controls gene expression and regulates cell fate. To examine the interrelationship between nuclear structure, cell morphology, and tissue-specific cell proliferation and differentiation processes, we conducted multiple visualizations of H3K4me1, H3K9me2, 4',6-diamidino-2-phenylindole, 5-ethynyl 2'-deoxyuridine, and SCRI Renaissance 2200, followed by subsequent quantitative analysis of individual cells and nuclei. By assigning cylindrical coordinates to the nuclei in the iRoCS toolbox, we were able to construct in situ digital three-dimensional chromatin maps for all the tissue layers of individual roots. A detailed analysis of the nuclei features of H3K4me1 and H3K9me2 in the mitotic and the elongation zones in trichoblast and atrichoblast cells at the root apical meristem revealed cell type-specific chromatin dynamics with asymmetric distribution of euchromatin and heterochromatin marks that may be associated with cell cycle and cell differentiation characteristics of specific cells. Furthermore, the spatial distribution of nuclei stained with 5-ethynyl 2'-deoxyuridine in the epidermis and cortex tissues suggests short-range coordination of cell division and nuclear migration in a linear sequence through an unknown regulatory mechanism.

Entomo-virological surveillance of Flavivirus in mosquitoes in Yucatan State, Mexico.

The genus Flavivirus (Family: Flaviviridae) comprises arboviruses with the capacity to infect humans and animals. It also integrates insect-specific viruses. This study aimed to identify Flavivirus in mosquitoes captured in 17 municipalities in Yucatan State, Mexico. The mosquitoes were caught in households from November 2021 to May 2022. A total of 4,321 adult mosquitoes from five species were caught. The most abundant were Culex quinquefasciatus (n = 3,563) and Aedes aegypti (n = 734). For molecular investigations, 600 female mosquitoes were split into groups of 10, mostly for species and site location. Reverse transcriptase polymerase chain reaction (RT-PCR) amplified a region of the NS5 gene to find the Flavivirus ribonucleic acids (RNA). A total of 24 pools that were positive for Flavivirus were detected in Ae. aegypti specimens and subsequently subjected to sequencing using the Sanger method. A total of 12 sequences matched the established quality criteria and were subsequently employed for sequence homology analysis. We found that one sequence corresponded to the Zika virus (ZIKV), and 11 sequences had sequence similarity with Phlebotomus-associated flavivirus (PAFV), an insect-specific virus (ISF). In conclusion, we found ZIKV in the Merida municipality, Yucatan State, which suggests that the virus is silently circulating. Phlebotomus-associated flavivirus is distributed in five municipalities in Yucatan State, Mexico. Future studies could focus on isolating this virus and studying its biological role within Ae. aegypti.

The Relationship between Laissez-Faire Leadership and Cyberbullying at Work: The Role of Interpersonal Conflicts.

A person can experience cyberbullying at work when exposed to repetitive and intrusive negative acts facilitated by new information and communication technologies (ICTs). The incidence of workplace cyberbullying has rapidly increased following the COVID-19 pandemic. This issue does not arise in isolation; leadership plays a critical role. Leaders who fail to set clear rules and provide minimal supervision may exacerbate interpersonal conflicts among subordinates. This study explores the role of laissez-faire leadership and interpersonal conflicts on workplace cyberbullying from a gender perspective. A two-wave panel study was conducted (N = 1995; 53.6% women; M age = 42.02 years old; SD = 9.23; age range: 18-74 years old). Our findings indicate no direct relationship between laissez-faire leadership and workplace cyberbullying; however, there is a significant indirect relationship. Laissez-faire leadership is associated with a higher frequency of interpersonal conflicts, which in turn are related to cyberbullying, making interpersonal conflicts a mediator. Additionally, gender moderates the relationship between interpersonal conflicts and workplace cyberbullying. Our results suggest that interpersonal conflicts may increase exposure to cyberbullying, particularly for men under laissez-faire leadership. These findings have managerial implications for introducing tailored interventions to prevent workplace cyberbullying.

Lactate/Pyruvate Ratio as an Early Predictor of Mortality in Patients with Sepsis: A Cohort Study.

Background: The lactate/pyruvate (LP) ratio has been studied as an alternative to serum lactate to determine clinical prognosis. Despite its clinical utility, there is a paucity of evidence evaluating the role of the L/P ratio in patients with sepsis. Methods: We assessed the clinical utility of the L/P ratio in patients with sepsis. The L/P ratio was measured at baseline, 4 and 8 h after admission. Our primary outcome was to determine the prognostic utility of the L/P ratio on the 15-day mortality risk. Our secondary outcomes were to compare the L/P ratio across time and its prognostic utility against standard risk calculators such as APACHE-II and SOFA scores. Results: We had a total of 80 patients, with 18 (22.5%) survivors and 62 (77.5%) non-survivors. While we found that patients having higher L/P ratios at 8 h had an increased 30-mortality risk (OR 1.08, 95% CI 1.02-1.18), the model's performance showed no difference when compared to other measurements of the L/P ratio that showed no association with mortality (p-value: 0.45). For our secondary outcome, we found that the APACHE-II and SOFA scores have better performance and predictability than the L/P ratio (AUC 0.83 and AUC 0.80, respectively), but showed no association with mortality (OR 1.07, 95% CI 1.01-1.17 and OR 1.08, 95% CI 1.02-1.18). Conclusions: Based on our findings, the L/P ratio appears to function more effectively as an early predictor of mortality when used as an adjuvant biomarker with other clinical parameters.

Chemoinformatic Characterization of NAPROC-13: A Database for Natural Product 13C NMR Dereplication.

Natural products (NPs) are secondary metabolites of natural origin with broad applications across various human activities, particularly the discovery of bioactive compounds. Structural elucidation of new NPs entails significant cost and effort. On the other hand, the dereplication of known compounds is crucial for the early exclusion of irrelevant compounds in contemporary pharmaceutical research. NAPROC-13 stands out as a publicly accessible database, providing structural and 13C NMR spectroscopic information for over 25 000 compounds, rendering it a pivotal resource in natural product (NP) research, favoring open science. This study seeks to quantitatively analyze the chemical content, structural diversity, and chemical space coverage of NPs within NAPROC-13, compared to FDA-approved drugs and a very diverse subset of NPs, UNPD-A. Findings indicated that NPs in NAPROC-13 exhibit properties comparable to those in UNPD-A, albeit showcasing a notably diverse array of structural content, scaffolds, ring systems of pharmaceutical interest, and molecular fragments. NAPROC-13 covers a specific region of the chemical multiverse (a generalization of the chemical space from different chemical representations) regarding physicochemical properties and a region as broad as UNPD-A in terms of the structural features represented by fingerprints.

Haplotype-Aware Detection of SERPINA1 Variants by Nanopore Sequencing.

α-1 Antitrypsin (AAT) is an acute-phase reactant with immunomodulatory properties that mainly inhibits neutrophil elastase. Low serum levels cause AAT deficiency (AATD), an underdiagnosed condition that predisposes to pulmonary and hepatic diseases. The SERPINA1 gene, which encodes AAT, contains >500 variants. PI∗Z and PI∗S alleles are the most diagnosed causes of AATD, but the role of the SERPINA1 haplotypes in AAT function remains unknown. SERPINA1 gene was PCR amplified from 94 patients with asthma, using primers with tails for indexing. Sequencing libraries were loaded into a MinION-Mk1C, and MinKNOW was used for basecalling and demultiplexing. Nanofilt and Minimap2 were used for filtering and mapping/alignment. Variant calling/phasing were performed with PEPPER-Margin-DeepVariant. SERPINA1 gene was 100% covered for all samples, with a minimum sequencing depth of 500×. A total of 75 single-nucleotide variants (SNVs) and 4 insertions/deletions were detected, with 45 and 2 of them highly polymorphic (minor allele frequency >0.1), respectively. Nine of the SNVs showed differences in allele frequencies when compared with the overall Spanish population. More than 90% of heterozygous SNVs were phased, yielding 91 and 58 different haplotypes for each SERPINA1 amplified region. Haplotype-based linkage disequilibrium analysis suggests that a recombination hotspot could generate variation in the SERPINA1 gene. The proposed workflow enables haplotype-aware genotyping of the SERPINA1 gene by nanopore sequencing, which will allow the development of novel AATD diagnostic strategies.

Neural Basis of Number Sense in Larval Zebrafish.

Number sense, the ability to discriminate the quantity of objects, is crucial for survival. To understand how neurons work together and develop to mediate number sense, we used two-photon fluorescence light sheet microscopy to capture the activity of individual neurons throughout the brain of larval Danio rerio, while displaying a visual number stimulus to the animal. We identified number-selective neurons as early as 3 days post-fertilization and found a proportional increase of neurons tuned to larger quantities after 3 days. We used machine learning to predict the stimulus from the neuronal activity and observed that the prediction accuracy improves with age. We further tested ethanol's effect on number sense and found a decrease in number-selective neurons in the forebrain, suggesting cognitive impairment. These findings are a significant step towards understanding neural circuits devoted to discrete magnitudes and our methodology to track single-neuron activity across the whole brain is broadly applicable to other fields in neuroscience.

Botulinum Toxin Type A (BoNT-A) Use for Post-Stroke Spasticity: A Multicenter Study Using Natural Language Processing and Machine Learning.

We conducted a multicenter and retrospective study to describe the use of botulinum toxin type A (BoNT-A) to treat post-stroke spasticity (PSS). Data were extracted from free-text in electronic health records (EHRs) in five Spanish hospitals. We included adults diagnosed with PSS between January 2015 and December 2019, stratified into BoNT-A-treated and untreated groups. We used EHRead® technology, which incorporates natural language processing and machine learning, as well as SNOMED CT terminology. We analyzed demographic data, stroke characteristics, BoNT-A use patterns, and other treatments. We reviewed the EHRs of 1,233,929 patients and identified 2190 people with PSS with a median age of 69 years; in total, 52.1% were men, 70.7% had cardiovascular risk factors, and 63.2% had suffered an ischemic stroke. Among the PSS patients, 25.5% received BoNT-A at least once. The median time from stroke to spasticity onset was 205 days, and the time from stroke to the first BoNT-A injection was 364 days. The primary goal of BoNT-A treatment was pain control. Among the study cohort, rehabilitation was the most common non-pharmacological treatment (95.5%). Only 3.3% had recorded monitoring scales. In conclusion, a quarter of patients with PSS received BoNT-A mainly for pain relief, typically one year after the stroke. Early treatment, disease monitoring, and better data documentation in EHRs are crucial to improve PSS patients' care.

Drought risk in Moldova under global warming and possible crop adaptation strategies.

This study analyzes the relationship between drought processes and crop yields in Moldova, together with the effects of possible future climate change on crops. The severity of drought is analyzed over time in Moldova using the Standard Precipitation Index, the Standardized Precipitation Evapotranspiration Index, and their relationship with crop yields. In addition, rainfall variability and its relationship with crop yields are examined using spectral analysis and squared wavelet coherence. Observed station data (1950-2020 and 1850-2020), ERA5 reanalysis data (1950-2020), and climate model simulations (period 1970-2100) are used. Crop yield data (maize, sunflower, grape), data from experimental plots (wheat), and the Enhanced Vegetation Index from Moderate Resolution Imaging Spectroradiometer satellites were also used. Results show that although the severity of meteorological droughts has decreased in the last 170 years, the impact of precipitation deficits on different crop yields has increased, concurrent with a sharp increase in temperature, which negatively affected crop yields. Annual crops are now more vulnerable to natural rainfall variability and, in years characterized by rainfall deficits, the possibility of reductions in crop yield increases due to sharp increases in temperature. Projections reveal a pessimistic outlook in the absence of adaptation, highlighting the urgency of developing new agricultural management strategies.

[Detection of people at risk of having diabetes in the community pharmacy with the Findrisc test 2014-2021]. / Detección de personas en riesgo de padecer diabetes en la farmacia comunitaria con el test de Findrisc en los años 2014-2021.

Aim: To analyze diabetes risk screening using the Findrisc questionnaire, performed in Spanish community pharmacies (CP) since 2014. Methods: Descriptive cumulative study of the results of campaigns from Global Diabetes Day, in 2014, 2016-2018, 2020 and 2021. Subjects: Users ≥18 years not diagnosed with diabetes with signed consent. Variables: Findrisc test score, mean (m) and standard deviation (SD) and subjects at risk intervals, n (%). Demographic (sex, age) and anthropometric variables, body mass index (BMI) (kg/m2), waist circumference (cm), capillary glycaemia (SD) (mg/dL). Results: A total of 1146 pharmacists took part; 12,402 users. A total of 8799 (70.9%) had BMI ≥25 kg/m2; 7366 (59.4%) were taking anti-hypertensives, 6047 (48.8%) with excessive abdominal circumference. In total, 5962 (48.0%) had a family history of diabetes.Average risk (Findrisc score) was 11.3 (4.6), without any sex differences (P>0.05). The number of subjects with high/very high risk (F≥15) was 3107 (25.0%) without any sex differences (P>0.05). The high/very high risk increased with age, from 282 (15.1%) people aged 45 to 54 up to 1695 (40.1%) people aged >64. A total of 1762 (14.2%) were referred to the doctor. There are no data on the result.Average interview time: 10.3 (5.3) minutes, no differences between sexes (P>0.05). Conclusions: One quarter of those surveyed had a high/very high risk and one in seven were referred to the doctor.The most prevalent risk factors were BMI, hypertension, abdominal circumference and family history of diabetes.Interprofessional communication should be improved as no result was obtained from referrals to the doctor.

Performance Enhancement of Biopolyester Blends by Reactive Compatibilization with Maleic Anhydride-Grafted Poly(butylene succinate-co-adipate).

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is a very promising biodegradable copolyester of high interest in food packaging. Its inherent brittleness and narrow processing window make it necessary to blend it with flexible biopolyesters, such as poly(butylene succinate-co-adipate) (PBSA). However, the resultant biopolyester blends are thermodynamically immiscible, which impairs their performance and limits their applications. This study is the first to explore the use of poly(butylene succinate-co-adipate) grafted with maleic anhydride (PBS-g-MAH) as a novel reactive additive to compatibilize PHBV/PBSA blends. The compatibilizer was prepared by a reactive melt-mixing process of PBSA and maleic anhydride (MAH) using dicumyl peroxide (DCP) as an organic radical initiator, achieving a grafting degree (Gd) of 5.4%. Biopolyester blend films were thereafter prepared via cast extrusion and their morphological, thermal, mechanical, and barrier properties were characterized. Compatibilization by PBSA-g-MAH was confirmed by observing an improved phase interaction and lower dispersed domain sizes in the blends with 15 wt% PBSA. These compatibilized PHBV/PBSA blends were thermally stable up to 285 °C, showed enhanced ductility and toughness, as well as providing an improved barrier against water and limonene vapors and oxygen. These findings suggest that the use of MAH-grafted biopolyesters can represent an effective strategy to improve the properties of biopolyester blends and open up new opportunities for the application of PHBV-based formulations for food packaging.

[Continuous glucose monitoring devices in people over 65 years: literature review]. / Dispositivos de monitorización continua de glucosa en mayores de 65 años: revisión bibliográfica.

Background: The use of continuous glucose monitoring (CGM) in elderly patients with diabetes is not well documented. The present study search to know the current status of use of CGM devices in patients with diabetes over 65 years of age. Methods: A systematic literature search was performed in PubMed and Scopus databases in November 2023. The following descriptors were used, linked using the Boolean operators AND and OR: Diabetes, Continuous glucose monitoring, Flash glucose monitoring, Glycemia, Glycemic control, Controlled diabetes, Diabetes care, Metrics, Older and Elder. The CASPe critical reading system and the PRISMA methodology were applied to document the review. Results: Fourteen selected studies published between 2019 and 2023 were reviewed. Publications from European countries used small sample sizes and were intervention studies. The duration of the interventions was generally short: 7 were ≤14 days in duration and only 3 were 6-12 months in duration. Overall, the selected articles found that CGM improved glycemic outcomes due to a decrease in glycosylated hemoglobin value and an improvement in CGM metrics, and diabetes-associated complications in elderly patients with diabetes. Conclusion: CGM seems to be a useful and effective tool to improving glycemic outcomes of people with diabetes over age 65. Further studies under real-world conditions and of longer duration are needed to expand and improve the evidence.

Outpatient ATG-free hematopoietic transplantation for aplastic anemia in limited-resource environments offers excellent results: Data from a single LATAM center.

OBJECTIVE: To document the results of outpatient hematopoietic stem cell transplantation (HSCT) from the peripheral blood (PB) of sibling donors without anti-thymocyte globulin (ATG) in the conditioning regimen. MATERIAL AND METHODS: Patients from a low-income population with severe AA who received a PB, unmanipulated sibling HLA-identical HSCT between 2000 and 2020 at a single institution were studied. Survival was the primary outcome. RESULTS: Forty-one transplants were performed. Time between diagnosis and transplant was five months (1-104). Median age was 37 (range, 4-61) years; 25 (61 %) recipients were males and 32 (78 %) had treatment failure, 9 (22 %) have not received treatment. ATG was administered in 5 (12.2 %) cases; the graft source was PB in 38 (92.7 %) transplants. Twenty-six (63.4 %) transplants were carried out in the outpatient setting. Infections developed in 14 (34.1 %) patients. Primary graft failure (GF) occurred in 3 (7.3 %) patients. The 15-year OS was 81 %, EFS was 77.4 %. Patients with high pre-HSCT transfusion burden had lower OS (p = 0.035) and EFS (p = 0.026). Previous treatment failure and age were not associated with lower OS (p = 0.115, p = 0.069) or EFS (p = 0.088, p = 0.5, respectively). CONCLUSIONS: HLA-identical T-cell replete outpatient HSCT from the PB of sibling donors for AA patients using ATG-free conditioning offers excellent long-term survival.