Chronic disease incidence explained by stepwise models and co-occurrence among them.

Multimorbidity (MM) is the co-occurrence of two or more chronic diseases. We provided a dynamic approach revealing the MM complexity constructing a multistep incidence-age model for all patients with MM between 2014 and 2021 in the Basque Health System, Spain. The multistep model, with eight steps for males and nine for females, is a very well-fitting representation of MM. To gain insight into the MM components, we modeled the 19 diseases used to calculate the Charlson Comorbidity Index (CCI). We observed that the CCI diseases formed a complex interaction network. Hierarchical clustering of the incidence-age profiles clustered the CCI diseases into low- and high-risk of dying pathologies. Diseases with a higher number of steps are better represented by a multistep model. Anatomically, diseases associated with the central nervous system have the highest number of steps, followed by those associated with the kidney, heart, peripheral vasulature, pancreas, joints, cerebral vasculature, lung, stomach, and liver.

Spencermartinsiella nicolii sp. nov., a potential opportunistic pathogenic yeast species isolated from rotting wood in Brazil.

Nineteen isolates representing a candidate for a novel yeast species belonging to the genus Spencermartinsiella were recovered from rotting wood samples collected at different sites in Atlantic Rainforest and Amazonian Forest ecosystems in Brazil. Similarity search of the nucleotide sequence of the intergenic spacer (ITS)-5.8S and large subunit D1/D2 regions of the ribosomal gene cluster showed that this novel yeast is closely related to Spencermartinsiella cellulosicola. The isolates differ by four nucleotide substitutions in the D1/D2 domain and six substitutions and 31 indels in the ITS region from the holotype of S. cellulosicola. Phylogenomic analysis based on 1474 single-copy orthologues for a set of Spencermartinsiella species whose whole genome sequences are available confirmed that the novel species is phylogenetically close to S. cellulosicola. The low average nucleotide identity value of 83% observed between S. cellulosicola and the candidate species confirms that they are distinct. The novel species produced asci with hemispherical ascospores. The name Spencermartinsiella nicolii sp. nov. is proposed. The holotype is CBS 14238T. The MycoBank number is MB855027. Interestingly, the D1/D2 sequence of the S. nicolii was identical to that of an uncultured strain of Spencermartinsiella causing systemic infection in a male adult crocodile (Crocodylus niloticus). The characterization of some virulence factors and antifungal susceptibility of S. nicolii isolates suggest that this yeast may be an opportunistic pathogen for animals, including humans; the isolates grow at 37 °C.

HL-60 cells as a valuable model to study LPS-induced neutrophil extracellular traps release.

Neutrophil Extracellular Traps (NETs) present a paradoxical role in infectious diseases, contributing to both immunity and pathogenesis. The complex nature of this process necessitates further characterization to elucidate its clinical implications. However, studying NETs faces challenges with primary neutrophils due to their heterogeneity, short lifespan, and lack of adequate cryopreservation. Researchers often turn to alternative models, such as differentiated HL-60 cells (dHL-60). This study explored LPS-induced NETs formation in dHL-60 cells, revealing significant responses to LPS from Pseudomonas aeruginosa, although significantly lower than primary neutrophils. Moreover, Spleen Tyrosine Kinase (SYK) inhibition with R406, the active metabolite of the drug Fostamatinib, previously demonstrated to suppress NETs in primary neutrophils, effectively reduced NETs release in dHL-60 cells. dHL-60 cells, offering easier manipulation, consistent availability, and no donor variability in functional responses, possess characteristics suitable for high-throughput studies evaluating NETosis. Overall, dHL-60 cells may be a valuable in vitro model for deciphering the molecular mechanisms of NETosis in response to LPS, contributing to our available tools for understanding this complex immune process.

External validation of the natriuretic response prediction equation to discriminate diuretic response in heart failure.

AIMS: Incomplete decongestion due to lack of titration of diuretics to effective doses is a common reason for readmission in patients with acute decompensated heart failure (ADHF). The natriuretic response prediction equation (NRPE) is a novel tool that proved to be rapid and accurate to predict natriuretic response and does not need urine collection. However, the NRPE has not been externally validated. The goal of this study was to externally validate the discrimination capacity of the NRPE in patients with ADHF and fluid overload. METHODS AND RESULTS: Patients admitted with ADHF who required intravenous loop diuretics were included. A spot urine sample was obtained ~2 h following diuretic administration, and a timed 6-h urine collection by study staff was carried out. Urine sodium and urine creatinine from the spot urine sample were used to predict the 6-h natriuretic response using the NRPE. The primary goal was to validate the NRPE to discriminate poor loop diuretic natriuretic response (sodium output <50 mmol in the 6 h following diuretic administration). The NRPE was compared with urine sodium and measured urine output which are the methods currently recommended by international guidelines to assess diuretic response. Eighty-seven diuretic administrations from 49 patients were analysed. Mean age of patients was 57 ± 17 years and 67% were male. Mean estimated glomerular filtration rate was 65 ± 28 mL/min/1.73 m2, and ejection fraction was 35 ± 15%. Median dose of intravenous furosemide equivalents administered the day of the study was 80 mg (IQR 40 - 160). Poor natriuretic response occurred in 39% of the visits. The AUC of the NRPE to predict poor natriuretic response during the 6-h urine collection was 0.91 (95% CI 0.85-0.98). Compared with the NRPE, spot urine sodium concentration (AUC 0.75) and urine output during the corresponding nursing shift (AUC 0.74) showed lower discrimination capacity. CONCLUSIONS: In this cohort of patients with ADHF, the NRPE outperformed spot urine sodium concentration and all other metrics related to diuretic response to predict poor natriuretic response. Our findings support the use of this equation at other settings to allow rapid and accurate prediction of natriuretic response.

Evaluation of Open-Source Ciliary Analysis Software in Primary Ciliary Dyskinesia: A Comparative Assessment.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD.

Single-cell transcriptomic analysis to identify endomembrane regulation of metalloproteins and motor proteins in autoimmunity.

TMEM230 promotes antigen processing, trafficking, and presentation by regulating the endomembrane system of membrane bound organelles (lysosomes, proteosomes and mitochondria) and phagosomes. Activation of the immune system requires trafficking of various cargos between the endomembrane system and cell plasma membrane. The Golgi apparatus is the hub of the endomembrane system and essential for the generation, maintenance, recycling, and trafficking of the components of the endomembrane system itself and immune system. Intracellular trafficking and secretion of immune system components depend on mitochondrial metalloproteins for ATP synthesis that powers motor protein transport of endomembrane cargo. Glycan modifying enzyme genes and motor proteins are essential for the activation of the immune system and trafficking of antigens between the endomembrane system and the plasma membrane. Recently, TMEM230 was identified as co-regulated with RNASET2 in lysosomes and with metalloproteins in various cell types and organelles, including mitochondria in autoimmune diseases. Aberrant metalloproteinase secretion by motor proteins is a major contributor to tissue remodeling of synovial membrane and joint tissue destruction in rheumatoid arthritis (RA) by promoting infiltration of blood vessels, bone erosion, and loss of cartilage by phagocytes. In this study, we identified that specific glycan processing enzymes are upregulated in certain cell types (fibroblast or endothelial cells) that function in destructive tissue remodeling in rheumatoid arthritis compared to osteoarthritis (OA). TMEM230 was identified as a regulator in the secretion of metaloproteinases and heparanase necessary tissue remodeling in OA and RA. In dendritic (DC), natural killer and T cells, TMEM230 was expressed at low or no levels in RA compared to OA. TMEM230 expression in DC likely is necessary for regulatory or helper T cells to maintain tolerance to self-antigens and prevent susceptibility to autoimmune disease. To identify how TMEM230 and the endomembrane system contribute to autoimmunity we investigated, glycan modifying enzymes, metalloproteinases and motor protein genes co-regulated with or regulated by TMEM230 in synovial tissue by analyzing published single cell transcriptomic datasets from RA patient derived synovial tissue.

May Measurement Month 2021: an analysis of blood pressure screening results from Argentina.

Hypertension continues to be the leading cause of death and disability in the industrialized world, with a high level of unawareness and unacceptably poor control rates. Therefore, the Argentinian Society of Hypertension, in association with the May Measurement Month (MMM) charity, implemented an awareness campaign during May 2021. A voluntary cross-sectional survey was carried out during the month of May 2021 in public spaces and health centres across 29 cities in Argentina. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg based on the mean of the second and third of three BP measurements or in those volunteers on treatment for high BP. Statistical analysis including multiple imputation followed the MMM protocol. A total of 26 070 individuals (average age 53.4 years, 14 816 women and 11 254 men) were evaluated. The age- and sex-standardized mean BP was 125.1/77.6 mmHg. Of all participants, 54.4% had hypertension. Although 79.8% of the hypertensive participants were aware of their condition and 76.9% were on antihypertensive treatment, only 42.5% of all individuals with hypertension had their BP controlled (<140/90 mmHg). Of those on antihypertensive medication, 55.3% were controlled. The low level of hypertension control highlights the critical need for community-based prevention strategies to increase the awareness and control of hypertension, thereby reducing the enormous health burden attributed to this condition.

hTERT Epigenetics Provides New Perspectives for Diagnosis and Evidence-Based Guidance of Chemotherapy in Cancer.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

R406 reduces lipopolysaccharide-induced neutrophil activation.

Modulating SYK has been demonstrated to have impacts on pathogenic neutrophil responses in COVID-19. During sepsis, neutrophils are vital in early bacterial clearance but also contribute to the dysregulated immune response and organ injury when hyperactivated. Here, we evaluated the impact of R406, the active metabolite of fostamatinib, on neutrophils stimulated by LPS. We demonstrate that R406 was able to effectively inhibit NETosis, degranulation, ROS generation, neutrophil adhesion, and the formation of CD16low neutrophils that have been linked to detrimental outcomes in severe sepsis. Further, the neutrophils remain metabolically active, capable of releasing cytokines, perform phagocytosis, and migrate in response to IL-8. Taken together, this data provides evidence of the potential efficacy of utilizing fostamatinib in bacterial sepsis.

Incidence and Risk Factors for Retinal Detachment Following Pediatric Cataract Surgery.

Background: Retinal detachment is a major postsurgical threat in pediatric cataract surgery; however, the effect of axial length remains unclear. This study aimed to assess the relationship between axial length and detachment risk in vulnerable patients. Methods: This retrospective cohort study analyzed 132 eyes of 84 pediatric cataract surgery patients aged <20 years old. Axial length was measured preoperatively, and the incidence of retinal detachment was recorded over a median follow-up of 4 years. Logistic regression analysis was used to examine the axial length-detachment relationship. Results: Twenty eyes had postoperative retinal detachments. The median axial length was longer in the detachment group (23.6 mm) than in the non-detachment group (21.6 mm). Eyes with axial length ≤23.4 mm had 0.55-fold decreased odds of detachment compared to longer eyes. Preexisting myopia and glaucoma confer heightened risk. Approximately half of the patients retained some detachment risk eight years postoperatively. Conclusion: Shorter eyes (axial length ≤23.4 mm) appear to be protected against pediatric retinal detachment after cataract surgery, whereas myopia, glaucoma, and axial elongation > 23.4 mm elevate the postoperative risk. Understanding these anatomical risk profiles requires surgical planning and follow-up care of children undergoing lensectomy.

This study investigated the protective role of a shorter axial length in preventing retinal detachment after pediatric cataract surgery. This highlights the correlation between smaller eye sizes and reduced detachment risk, emphasizing the need for careful consideration of anatomical factors in surgical planning and patient monitoring, particularly for patients with preexisting myopia or postoperative glaucoma.

Tag SNP selection for prediction of adaptation traits in Braford and Hereford cattle using Bayesian methods.

This study utilized Bayesian inference in a genome-wide association study (GWAS) to identify genetic markers associated with traits relevant to the adaptation of Hereford and Braford cattle breeds. We focused on eye pigmentation (EP), weaning hair coat (WHC), yearling hair coat (YHC), and breeding standard (BS). Our dataset comprised 126,290 animals in the pedigree. Out of these, 233 sires were genotyped using high-density (HD) chips, and 3750 animals with medium-density (50 K) single-nucleotide polymorphism (SNP) chips. Employing the Bayes B method with a prior probability of π = 0.99, we identified and tagged single nucleotide polymorphisms (Tag SNPs), ranging from 18 to 117 SNPs depending on the trait. These Tag SNPs facilitated the construction of reduced SNP panels. We then evaluated the predictive accuracy of these panels in comparison to traditional medium-density SNP chips. The accuracy of genomic predictions using these reduced panels varied significantly depending on the clustering method, ranging from 0.13 to 0.65. Additionally, we conducted functional enrichment analysis that found genes associated with the most informative SNP markers in the current study, thereby providing biological insights into the genomic basis of these traits.

HIV latency-reversing activity of latex from Euphorbia umbellata (Pax) Bruyns and three diterpenes isolated from this species.

Two unusual phorbol esters, namely 20-deoxyphorbol-3,4,12-triacetate-13-phenylacetate (1) and phorbol-3,4,12,13-tetraacetate-20-phenylacetate (2) plus ingol-3,8,12-triacetate-7-phenylacetate (3) were isolated from the latex of Euphorbia umbellata and identified by HRESIMS and 2D NMR. Compound 1 is herein described for the first time. Assignment of the phenylacetyl group at C-7 in compound 3 was suggested by the HMBC and NOESY spectra obtained in pyridine-d5. In addition to the latex and its distinct terpenoid fractions, the isolated compounds were tested as latent reversal agents against HIV-1-infected J-Lat cells, with reference to phorbol-12-myristate-13-acetate and ingenol-B. Compound 2 reverted 75-80% the viral latency on the GFP-positive cells, resulting EC50 3.70 µg/mL (SI 6.7), while 1 induced 34-40% reactivation at the same concentration range (4-20 µg/mL). The ingol derivative 3 was ineffective. Phorbol esters were confirmed as effective constituents in the latex since the fraction containing them was 2.4-fold more active than the lyophilised latex at the lowest concentration assayed.

Correction: Medeiros-Ventura et al. The Impact of Phytase and Different Levels of Supplemental Amino Acid Complexed Minerals in Diets of Older Laying Hens. Animals 2023, 13, 3709.

To allow the original publication to be better understood [...].

Measurable Residual FLT3 Internal Tandem Duplication Before Allogeneic Transplant for Acute Myeloid Leukemia.

Importance: Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown. Objective: To examine the association between pre-allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR. Design, Setting, and Participants: In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023. Exposure: Centralized DNA sequencing for FLT3-ITD in pre-allogeneic HCT first CR blood using a commercially available kit. Main Outcomes and Measures: The primary outcomes were overall survival and cumulative incidence of relapse, with non-relapse-associated mortality as a competing risk post-allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points. Results: Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning. Conclusions and Relevance: This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.

Neutrophil-to-Lymphocyte Ratio Dynamics From Pre-diagnosis to End-Stage Amyotrophic Lateral Sclerosis (ALS): A Case Study on Association With Progression and Clinical Events.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, resulting in muscle weakness and paralysis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential marker for monitoring disease severity and progression in ALS, yet longitudinal analyses of NLR are limited. Our study conducts an in-depth examination of NLR dynamics from before diagnosis through the disease's progression to its end stage. We analyze the case of a 56-year-old Puerto Rican male with ALS, tracking his NLR over 13 years - six years before and seven years after his diagnosis - alongside assessments of clinical symptoms and lung function. Our findings indicate that NLR values were initially normal but significantly increased with the onset of symptoms. NLR remained elevated above the normal range, with a notable exception during a period of edaravone therapy when levels normalized. The study demonstrates a clear elevation in NLR associated with ALS progression and critical clinical events, such as symptom onset, diagnosis, and the initiation of respiratory support. This research is, to our knowledge, the first to provide a detailed characterization of NLR changes from the pre-diagnostic phase to end-stage ALS, showing its correlation with clinical deterioration, decreased pulmonary function, and key clinical events. Our results contribute to the body of evidence on NLR's role in ALS while enhancing our understanding of ALS's natural progression.

Epigenetics Meets CAR-T-Cell Therapy to Fight Cancer.

Based on the impressive success of Car-T-cell therapy in the treatment of hematological malignancies, a broad application for solid tumors also appears promising. However, some important hurdles need to be overcome. One of these is certainly the identification of specific target antigens on cancer cells. Hypomethylation is a characteristic epigenetic aberration in many tumor entities. Genome-wide screenings for consistent DNA hypomethylations in tumors enable the identification of aberrantly upregulated transcripts, which might result in cell surface proteins. Thus, this approach provides a new perspective for the discovery of potential new Car-T-cell target antigens for almost every tumor entity. First, we focus on this approach as a possible treatment for prostate cancer.

Acetylated galactopyranosyl N-heterocyclic monocarbene complexes of Silver(I) as novel anti-proliferative agents in a rhabdomyosarcoma cell line.

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric ß-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy.

+Ciencia: a training program to increase evidence-based science communication and literacy for Hispanic high school and undergraduate students.

Science misinformation represents a significant challenge for the scientific community. Hispanic communities are particularly vulnerable due to language barriers and the lack of accessible information in Spanish. We identified that a key step toward enhancing the accessibility of information for non-native English-speaking communities involves imparting science communication education and training to Hispanic youth. Our goal was to provide them with the skills to become science ambassadors who can effectively engage with their communities and bridge communication gaps. To address this, we developed the first science communication training program in Spanish for Hispanic high school and undergraduate students in Puerto Rico. The program called +Ciencia aims to provide training and education on science communication for Hispanic minorities through experiential and collaborative learning. In the short term, our multifaceted approach works to counter misinformation and promote science literacy within the broader community. Over the long term, our grassroots efforts with students will evolve into a generation of professionals equipped with strong engagement skills and comprehensive training in science communication with a specific focus on Hispanic audiences. Herein, we describe the components of this educational program and provide open access to educational materials and articles developed by three cohorts.