Trichophycins B–F, Chlorovinylidene-Containing Polyketides Isolated from a Cyanobacterial Bloom

NMR-guided isolation (based on 1D 1H and 13C NMR resonances consistent with a chlorovinylidene moiety) resulted in the characterization of five new highly functionalized polyketides, trichophycins B-F (1-5) and one non-chlorinated metabolite tricholactone (6) from a collection of Trichodesmium bloom material from the Gulf of Mexico. The planar structures of 1-6 were determined using 1D and 2D NMR spectroscopy, mass spectrometry and complementary spectroscopic procedures. Absolute configuration analysis of 1 and 2 were carried out by 1H NMR analysis of diastereomeric Mosher esters in addition to ECD spectroscopy, J-based configuration analysis and DFT calculations. The absolute configurations of 3-6 were proposed based on comparative analysis of 13C NMR chemical shifts, relative configurations, and optical rotation values to compounds 1 and 2. Compounds 1-5 represent new additions to the trichophycin family and are hallmarked by a chlorovinylidene moiety. These new trichophycins and tricholactone (1-6) feature intriguing variations with respect to putative biosynthetic starting units, halogenation, and terminations and trichophycin E (4) features a rare alkynyl bromide functionality. The phenyl-containing trichophycins showed low cytotoxicity to neuro-2A cells, while the alkyne-containing trichophycins showed no toxicity

Fourier analysis of collagen bundle orientation in myocardial infarction scars

[EN] Collagen bundle orientation (CBO) in myocardial infarct scars plays a major role in scar mechanics and complications after infarction. We aim to compare four histopathological methods for CBO measurement in myocardial scarring. Myocardial infarction was induced in 21 pigs by balloon coronary occlusion. Scar samples were obtained at 4 weeks, stained with Masson's trichrome, Picrosirius red, and Hematoxylin-Eosin (H&E), and photographed using light, polarized light microscopy, and confocal microscopy, respectively. Masson's trichrome images were also optimized to remove non-collagenous structures. Two observers measured CBO by means of a semi-automated, Fourier analysis protocol. Interrater reliability and comparability between techniques were studied by the intraclass correlation coefficient (ICC) and Bland-Altman (B&A) plots and limits of agreement. Fourier analysis showed an almost perfect interrater reliability for each technique (ICC >= 0.95, p < 0.001 in all cases). CBO showed more randomly oriented values in Masson's trichrome and worse comparability with other techniques (ICC vs. Picrosirius red: 0.79 [0.47-0.91], p = 0.001; vs. H&E-confocal: 0.70 [0.26-0.88], p = 0.005). However, optimized Masson's trichrome showed almost perfect agreement with Picrosirius red (ICC 0.84 [0.6-0.94], p < 0.001) and H&E-confocal (ICC 0.81 [0.54-0.92], p < 0.001), as well as these latter techniques between each other (ICC 0.84 [0.60-0.93], p < 0.001). In summary, a semi-automated, Fourier-based method can provide highly reproducible CBO measurements in four different histopathological techniques. Masson's trichrome tends to provide more randomly oriented CBO index values, probably due to non-specific visualization of non-collagenous structures. However, optimization of Masson's trichrome microphotographs to remove non-collagenous components provides an almost perfect comparability between this technique, Picrosirius red and H&E-confocal.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from "Instituto de Salud Carlos III" and "Fondos Europeos de Desarrollo Regional FEDER" [Grant numbers PI20/00637, and CIBERCV16/11/00486, a postgraduate contract FI18/00320 to C.R.-N. and CM21/00175 to V. M.-G.], by Conselleria de Educacion-Generalitat Valenciana (PROMETEO/2021/008). J. G. acknowledges financial support from the "Agencia Estatal de Investigacion" (Grant FJC2020-043981-I/AEI/1013039/501100011033).Marcos-Garcés, V.; Rios-Navarro, C.; Gómez-Torres, F.; Gavara-Doñate, J.; De Dios, E.; Diaz, A.; Miñana, G.... (2022). Fourier analysis of collagen bundle orientation in myocardial infarction scars. 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Supervised Analysis for Phenotype Identification: The Case of Heart Failure Ejection Fraction Class

Artificial Intelligence is creating a paradigm shift in health care, with phenotyping patients through clustering techniques being one of the areas of interest. Objective: To develop a predictive model to classify heart failure (HF) patients according to their left ventricular ejection fraction (LVEF), by using available data from Electronic Health Records (EHR). Subjects and methods: 2854 subjects over 25 years old with a diagnosis of HF and LVEF, measured by echocardiography, were selected to develop an algorithm to predict patients with reduced EF using supervised analysis. The performance of the developed algorithm was tested in heart failure patients from Primary Care. To select the most influentual variables, the LASSO algorithm setting was used, and to tackle the issue of one class exceeding the other one by a large amount, we used the Synthetic Minority Oversampling Technique (SMOTE). Finally, Random Forest (RF) and XGBoost models were constructed. Results: The full XGBoost model obtained the maximum accuracy, a high negative predictive value, and the highest positive predictive value. Gender, age, unstable angina, atrial fibrillation and acute myocardial infarct are the variables that most influence EF value. Applied in the EHR dataset, with a total of 25,594 patients with an ICD-code of HF and no regular follow-up in cardiology clinics, 6170 (21.1%) were identified as pertaining to the reduced EF group. Conclusion: The obtained algorithm was able to identify a number of HF patients with reduced ejection fraction, who could benefit from a protocol with a strong possibility of success. Furthermore, the methodology can be used for studies using data extracted from the Electronic Health Records

Miniaturization of Popular Reactions from the Medicinal Chemists’ Toolbox for Ultrahigh-Throughput Experimentation

Miniaturization is a tactic employed in many technologies to accelerate discovery and enable new applications such as systems-level evaluation. The miniaturization of chemical synthesis to the limits of chemoanalytical and bioanalytical limits of detection could accelerate drug discovery by increasing the amount of experimental data collected per milligram of material consumed. Here we demonstrate the miniaturization of popular reactions used in drug discovery such as reductive amination, N-alkylation, N-Boc deprotection and Suzuki coupling for utilization in 1.2 μL reaction droplets. Reaction methods were evolved to perform in high boiling solvents at room temperature, enabling the diversification of precious starting materials, such as the complex natural product staurosporine

Comparison of GLP-1 receptor agonists and other Glucose-Lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and Obesity: A Spanish Real-World Population-Based study

[EN] Aims: Assess the impact of glucagon-like peptide receptor agonists (GLP-1RA) compared to other glucose-lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and obesity in a Spanish metropolitan area. Methods: A retrospective population-based type 2 diabetes cohort was identified from the Valencia Clinic-Malvarrosa Department electronic databases (2014-2019). Study groups included GLP-1RA, sodium-glucose co-transporter-2 inhibitors (SGLT2i), Insulin, and Miscellany (other glucose-lowering agents). 1:1:1:1 propensity score matching was conducted. The primary outcome was a composite of major adverse cardiovascular events (4-point MACE) comprising myocardial infarction, stroke, all-cause mortality, and heart failure. Secondary outcomes included individual 4-point MACE components. Hazard ratios were estimated using Cox regression analyses against the Miscellany group. Results: From 26,944 subjects, 1,848 adults were selected per group. GLP-1RA did not show a significant reduction in 4-point MACE risk (HR 1.05 [95%CI 0.82-1.34]). SGLT2i significantly reduced the risk of heart failure (HR 0.16 [95%CI 0.05-0.54]) and atrial fibrillation (HR 0.58, [95%CI 0.35-0.95]). The Insulin group exhibited a higher risk for 4-point MACE and most individual outcomes compared to GLP-1RA and SGLT2i. Conclusions: Our findings do not provide evidence of a reduced cardiovascular risk, as assessed by 4-point MACE, with GLP-1RA. In contrast, SGLT2i demonstrated protective effects against heart failure and atrial fibrillation.Funding We would like to acknowledge the financial support provided by Novo Nordisk for this study. AP's research is supported by a Sara Borrell post-doctoral grant from the Instituto de Salud Carlos III (CD22/00012) .Palanca, A.; Ampudia-Blasco, FJ.; Calderon, JM.; Sauri, I.; Martínez-Hervás, S.; Trillo, JL.; Redón, J.... (2024). Comparison of GLP-1 receptor agonists and other Glucose-Lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and Obesity: A Spanish Real-World Population-Based study. Diabetes Research and Clinical Practice. 207. https://doi.org/10.1016/j.diabres.2023.11107120

Acute kidney injury in heart failure: a population study

Abstract Aims The objective of the present study is to assess the prognostic value of acute kidney injury (AKI) in the evolution of patients with heart failure (HF) using real‐world data. Methods and results Patients with a diagnosis of HF and with serial measurements of renal function collected throughout the study period were included. Estimated glomerular filtration rate (GFR) was calculated with the CKD‐EPI (Chronic Kidney Disease Epidemiology Collaboration). AKI was defined when a sudden drop in creatinine with posterior recovery was recorded. According to the Risk, Injury, Failure, Loss, and End‐Stage Renal Disease (RIFLE) scale, AKI severity was graded in three categories: risk [1.5‐fold increase in serum creatinine (sCr)], injury (2.0‐fold increase in sCr), and failure (3.0‐fold increase in sCr or sCr > 4.0 mg/dL). AKI incidence and risk of hospitalization and mortality after the first episode were calculated by adjusting for potential confounders. A total of 30 529 patients with HF were included. During an average follow‐up of 3.2 years, 5294 AKI episodes in 3970 patients (13.0%) and incidence of 3.3/100 HF patients/year were recorded. One episode was observed in 3161 (10.4%), two in 537 (1.8%), and three or more in 272 (0.9%). They were more frequent in women with diabetes and hypertension. The incidence increases across the GFR levels (Stages 1 to 4: risk 7.6%, 6.8%, 11.3%, and 12.5%; injury 2.1%, 2.0%, 3.3%, and 5.5%; and failure 0.9%, 0.6%. 1.4%, and 8.0%). A total of 3817 patients with acute HF admission were recorded during the follow‐up, with incidence of 38.4/100 HF patients/year, 3101 (81.2%) patients without AKI, 545 (14.3%) patients with one episode, and 171 (4.5%) patients with two or more. The number of AKI episodes [one hazard ratio (HR) 1.05 (0.98–1.13); two or more HR 2.01 (1.79–2.25)] and severity [risk HR 1.05 (0.97–1.04); injury HR 1.41 (1.24–1.60); and failure HR 1.90 (1.64–2.20)] increases the risk of hospitalization. A total of 10 560 deaths were recorded, with incidence of 9.3/100 HF patients/year, 8951 (33.7%) of subjects without AKI episodes, 1180 (11.17%) of subjects with one episode, and 429 (4.06%) with two or more episodes. The number of episodes [one HR 1.05 (0.98–1.13); two or more HR 2.01 (1.79–2.25)] and severity [risk 1.05 confidence interval (CI) (0.97–1.14), injury 1.41 (CI 1.24–1.60), and failure 1.90 (CI 1.64–2.20)] increases mortality risk. Conclusions The study demonstrated the worse prognostic value of sudden renal function decline in HF patients and pointed to those with more future risk who require review of treatment and closer follow‐up

Data: Improving the Performance of J-modulated ADEQUATE Experiments Through Homonuclear Decoupling and Non-Uniform Sampling

<p>Homonuclear ¹³C-¹³C couplings at natural abundance can be measured using the <em>J</em>-modulated ADEQUATE experiment. To somewhat ameliorate F1 digitization requirements, a scaling factor was incorporated into the original pulse sequence. Non-Uniform Sampling (NUS) provides an obvious avenue to further facilitate the acquisition of ¹<em>J</em>_CC and ⁿ<em>J</em>_CC homonuclear coupling constant data. We introduce homonuclear decoupling (HD) analogous to that described for the 1,1- and 1,n-HD-ADEQUATE experiments and evaluate the combination of NUS and homonuclear decoupling on the acquisition of both ¹<em>J</em>_CC and ⁿ<em>J</em>_CC homonuclear ¹³C-¹³C coupling constants using ibuprofen as a model compound.</p

Impact of Long-COVID on Health Care Burden: A Case Control Study

The objective was to identify the chronic impact of SARS-CoV-2 virus infection in new diagnostics, pharmacological prescriptions, and use of healthcare resources in patients after acute infection in a case-control study. Methods: Case-control study with observation of new diagnostics codified in the Electronic Health Recordings, with a total population of 604,000 subjects. Cases included patients diagnosed with acute infection. Matched controls in the absence of infection using a Propensity Score were also included. Observational period was 6 months. New diagnostic (CIE10), prescriptions and visits to Health Care Resources were identified. Results: 38,167 patients with a previous COVID infection and the same number of controls were analyzed. Population included < 18 years old, 7586 (mean age 10.2 years, girls 49%), and 30,581 adults (mean age 46.6 years, females 53%). In adults, 25% presented new diagnoses, while the prevalence was 16% in youth. A total of 40 new diagnostics were identified. The most frequent were diagnostics in the neuropsychiatric sphere, with older age, female, and previous admission in the Critical Care Unit being the factors related in adults, while in youth higher age was also a factor. Prescription of psychoanaleptic, psycholeptic and muscle relaxants had increased. An increment of around 20% in visits to Primary Care Physicians, Specialists and Emergency Departments was registered. Conclusion: Compared with a control group, an increment in the number of new diagnostics, new prescriptions and higher use of Health Care resources were observed. Many of the new diagnoses also occur in non-infected subjects, supporting the complex origin of so-called Long-COVID