Unveiling the solution structure of a DNA duplex with continuous silver-modified Watson-Crick base pairs.

The challenge of transforming organized DNA structures into their metallized counterparts persists in the scientific field. In this context, utilizing DNA molecules modified with 7-deazapurine, provides a transformative solution. In this study, we present the solution structure of a DNA duplex that can be transformed into its metallized equivalent while retaining the natural base pairing arrangement through the creation of silver-modified Watson-Crick base pairs. Unlike previously documented X-ray structures, our research demonstrates the feasibility of preserving the intrinsic DNA self-assembly while incorporating AgI into the double helix, illustrating that the binding of silver does not disrupt the canonical base-pairing organization. Moreover, in our case, the uninterrupted AgI chain deviates from forming conventional straight linear chains; instead, it adheres to a helical arrangement dictated by the underlying DNA structure. This research challenges conventional assumptions and opens the door to precisely design structures based on the organization of highly stable Ag-DNA assemblies.

A new type of Class C ß-lactamases defined by PIB-1. A metal-dependent carbapenem-hydrolyzing ß-lactamase, from Pseudomonas aeruginosa: Structural and functional analysis.

Antibiotic resistance is one of most important health concerns nowadays, and ß-lactamases are the most important resistance determinants. These enzymes, based on their structural and functional characteristics, are grouped in four categories (A, B, C and D). We have solved the structure of PIB-1, a Pseudomonas aeruginosa chromosomally-encoded ß-lactamase, in its apo form and in complex with meropenem and zinc. These crystal structures show that it belongs to the Class C ß-lactamase group, although it shows notable differences, especially in the Ω- and P2-loops, which are important for the enzymatic activity. Functional analysis showed that PIB-1 is able to degrade carbapenems but not cephalosporins, the typical substrate of Class C ß-lactamases, and that its catalytic activity increases in the presence of metal ions, especially zinc. They do not bind to the active-site but they induce the formation of trimers that show an increased capacity for the degradation of the antibiotics, suggesting that this oligomer is more active than the other oligomeric species. While PIB-1 is structurally a Class C ß-lactamase, the low sequence conservation, substrate profile and its metal-dependence, prompts us to position this enzyme as the founder of a new group inside the Class C ß-lactamases. Consequently, its diversity might be wider than expected.

Results of Adjustable Trans-Obturator Male System for Stress Urinary Incontinence after Transurethral Resection or Holmium Laser Enucleation of the Prostate: International Multicenter Study.

Background: Male stress urinary incontinence (SUI) after surgical treatment of benign prostatic enlargement (BPE) is an infrequent but dreadful complication and constitutes a therapeutic challenge. The efficacy and safety of the adjustable trans-obturator male system (ATOMS®) in these patients is rather unknown, mainly due to the rarity of this condition. We aimed to assess the results of ATOMS to treat SUI after transurethral resection (TURP) or holmium laser enucleation (HoLEP) of the prostate. Methods: Retrospective multicenter study evaluating patients with SUI after TURP or HoLEP for BPE primarily treated with silicone-covered scrotal port (SSP) ATOMS implants in ten different institutions in Europe and Canada between 2018 and 2022. Inclusion criteria were pure SUI for >1 year after endoscopic treatment for BPE and informed consent to receive an ATOMS. The primary endpoint of the study was a dry rate (pad test ≤ 20 mL/day after adjustment). The secondary endpoints were: the total continence rate (no pads and no leakage), complication rate (Clavien-Dindo classification) and self-perceived satisfaction (Patient Global Impression of Improvement (PGI-I) scale 1 to 3). Descriptive analytics, Wilcoxon's rank sum test and Fisher's exact test were performed. Results: A total of 40 consecutive patients fulfilled the inclusion criteria, 23 following TURP and 17 HoLEP. After ATOMS adjustment, 32 (80%) patients were dry (78.3% TURP and 82.4% HoLEP; p = 1) and total continence was achieved in 18 (45%) patients (43.5% TURP and 47% HoLEP; p = 0.82). The median pad test was at a 500 (IQR 300) mL baseline (648 (IQR 650) TURP and 500 (IQR 340) HoLEP; p = 0.62) and 20 (IQR 89) mL (40 (IQR 90) RTUP and 10 (IQR 89) HoLEP; p = 0.56) after adjustment. Satisfaction (PGI-I ≤ 3) was reported in 37 (92.5%) patients (95.6% TURP and 88.2% HoLEP; p = 0.5). There were no significant differences between patients treated with TURP or HoLEP regarding the patient age, radiotherapy and number of adjustments needed. After 32.5 (IQR 30.5) months, median follow-up postoperative complications occurred in seven (17.5%) cases (two grade I and five grade II; three after TURP and four HoLEP) and two devices were removed (5%, both HoLEP). Conclusions: ATOMS is an efficacious and safe alternative to treat SUI due to sphincteric damage produced by endoscopic surgery for BPE, both TURP and HoLEP. Future studies with a larger number of patients may identify predictive factors that would allow better patient selection for ATOMS in this scenario.

A novel approach to forecast surgery durations using machine learning techniques.

This study presents a methodology for predicting the duration of surgical procedures using Machine Learning (ML). The methodology incorporates a new set of predictors emphasizing the significance of surgical team dynamics and composition, including experience, familiarity, social behavior, and gender diversity. By applying ML techniques to a comprehensive dataset of over 77,000 surgeries, we achieved a 24% improvement in the mean absolute error (MAE) over a model that mimics the current approach of the decision maker. Our results also underscore the critical role of surgeon experience and team composition dynamics in enhancing prediction accuracy. These advancements can lead to more efficient operational planning and resource allocation in hospitals, potentially reducing downtime in operating rooms and improving healthcare delivery.

Total Gestational Weight Gain Is Explained by Leptin and Body Fat, Regardless of Pre-Pregnancy Body Mass Index and Other Adipokines, in Mexican Adolescents.

Pre-pregnancy body mass index (pBMI) is a predictor of gestational weight gain (GWG). However, other factors, such as adipokines and inflammation markers, may also be associated with GWG. The aim of the study was to determine the association of leptin, adiponectin, irisin, and C-reactive protein, with GWG in adolescents. A longitudinal study was conducted from 2018 to 2023 in adolescents with a clinically healthy pregnancy. The assessments included sociodemographic and clinical data, pBMI, percent of body fat, serum concentrations of leptin, adiponectin, irisin, and high-sensitivity C-reactive protein (hsCRP), and total GWG adequacy. Cox regression models were performed, the outcome variables were inadequate and excessive GWG. In 198 participants, being overweight/obesity was marginally associated with a protective effect against inadequate GWG (HR = 0.44, 95%CI = 0.18-1.06), regardless of maternal characteristics and adipokines. Leptin (HR = 1.014, 95%CI = 1.008-1.021), and body fat percent (HR = 1.11, 95%CI = 1.05-1.17) were associated with a higher risk of excessive GWG, independent of other maternal variables such as pBMI, while adiponectin was associated with a lower risk. These findings suggest that, in Mexican adolescents, adipose tissue and its adipokines during pregnancy may play a more significant role in the final GWG than body weight.

Comparative Bioavailability of a Novel Fixed-dose Combination Etoricoxib and Tramadol.

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed-dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open-label, 3-way, crossover, single-dose, prospective, and longitudinal study with a 14-day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Forty-two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0-t), and (area under the plasma drug concentration-time curve from 0 up to infinity (AUC0-∞) data were within the range of 80%-125%. Non-serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed-dose combination are comparable to those of the reference products.

The systemic cellular immune response against allogeneic mesenchymal stem cells is influenced by inflammation, differentiation and MHC compatibility: in vivo study in the horse.

The effectiveness and safety of allogeneic mesenchymal stem/stromal cells (MSCs) can be affected by patient's immune recognition. Thus, MSC immunogenicity and their immunomodulatory properties are crucial aspects for therapy. Immune responses after allogeneic MSC administration have been reported in different species, including equine. Interactions of allogenic MSCs with the recipient's immune system can be influenced by factors like matching or mismatching for the major histocompatibility complex (MHC) between donor-recipient, and by the levels of MHC expression in MSCs. The latter can vary upon MSC inflammatory exposure or differentiation, such as chondrogenic induction, making both priming and differentiation interesting therapeutic strategies. This study investigated the systemic in vivo immune cellular response against allogeneic equine MSCs in these situations. Either MSCs in basal conditions (MSC-naïve), pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) were repeatedly administered subcutaneously into autologous, MHC-matched or MHC-mismatched allogeneic equine recipients. At different time-points after each administration, lymphocytes were obtained from recipient horses and exposed in vitro to the same type of MSCs to assess the proliferative response of different T cell subsets (cytotoxic, helper, regulatory), B cells, and interferon gamma (IFNγ) secretion. Higher proliferative response of helper and cytotoxic T lymphocytes and IFNγ secretion was observed in response to all types of MHC-mismatched MSCs over MHC-matched ones. MSC-primed produced the highest immune response, followed by MSC-naïve, and MSC-chondro. However, MSC-primed activated Treg and had a mild effect on B cells, and the response after their second administration was similar to the first one. On the other hand, both MSC-chondro and MSC-naïve barely induced Treg response but promoted B lymphocyte activation, and proportionally induced a higher cell response after the second administration. In conclusion, both the type of MSC conditioning and the MHC compatibility influenced systemic immune recognition of equine MSCs after single and repeated administrations, but the response was different. Selecting MHC-matched donors would be particularly recommended for MSC-primed and repeated MSC-naïve administrations. While MHC-mismatching in MSC-chondro would be less critical, B cell response should not be ignored. Comprehensively investigating the in vivo immune response against equine allogeneic MSCs is crucial for advancing veterinary cell therapies.

Pharmacokinetic Profile and Comparative Bioavailability of an Oral Fixed-Dose Combination of Metformin and Acetylsalicylic Acid (Aspirin).

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2 × 2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

A Randomized Control Trial of Dexketoprofen/Vitamin B (Thiamine, Pyridoxine and Cyanocobalamin) Fixed-Dose Combination in Post-Traumatic Grade I-II Cervical Sprains.

BACKGROUND: Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders. OBJECTIVE: The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I-II cervical sprains. METHODS: We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0. RESULTS: A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (- 3.1 ± - 1.5 and - 2.6 ± - 1.1 cm, respectively) measured using the VAS (p = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028). A lower proportion of adverse events was reported when using the FDC. CONCLUSIONS: The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I-II cervical sprains. CLINICAL TRIALS REGISTRATION: NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).

Use of Knotless Barbed Sutures in Laparoscopic Inguinal Hernioplasty in Horses: 40 Cases.

Inguinal hernias (IHs) and ruptures are a relatively common condition in horses, occurring in foals (congenital) and adult (acquired) animals. A retrospective observational analysis was conducted on 40 cases that underwent laparoscopic surgery to close the VRs using barbed sutures alone or combined with other techniques. Signalment, clinical presentation, surgery, and follow-up data were obtained. In total, fifty-nine VRs were closed using barbed sutures (alone or in combination with other methods), with six cases performed prophylactically and forty-four due to acquired IH. Of the forty-four cases with IH, four were non-strangulated hernias, while thirty presented with strangulated small intestines (twenty-eight acquired and two congenital). The results obtained in this study suggest that laparoscopic hernioplasty with barbed sutures is an effective and safe surgical procedure that could be recommended as a standard practice for managing inguinal hernias in horses, particularly when sparing testicles or preserving reproductive capabilities is a priority.

Structure-function characterization of two enzymes from novel subfamilies of manganese peroxidases secreted by the lignocellulose-degrading Agaricales fungi Agrocybe pediades and Cyathus striatus.

BACKGROUND: Manganese peroxidases (MnPs) are, together with lignin peroxidases and versatile peroxidases, key elements of the enzymatic machineries secreted by white-rot fungi to degrade lignin, thus providing access to cellulose and hemicellulose in plant cell walls. A recent genomic analysis of 52 Agaricomycetes species revealed the existence of novel MnP subfamilies differing in the amino-acid residues that constitute the manganese oxidation site. Following this in silico analysis, a comprehensive structure-function study is needed to understand how these enzymes work and contribute to transform the lignin macromolecule. RESULTS: Two MnPs belonging to the subfamilies recently classified as MnP-DGD and MnP-ESD-referred to as Ape-MnP1 and Cst-MnP1, respectively-were identified as the primary peroxidases secreted by the Agaricales species Agrocybe pediades and Cyathus striatus when growing on lignocellulosic substrates. Following heterologous expression and in vitro activation, their biochemical characterization confirmed that these enzymes are active MnPs. However, crystal structure and mutagenesis studies revealed manganese coordination spheres different from those expected after their initial classification. Specifically, a glutamine residue (Gln333) in the C-terminal tail of Ape-MnP1 was found to be involved in manganese binding, along with Asp35 and Asp177, while Cst-MnP1 counts only two amino acids (Glu36 and Asp176), instead of three, to function as a MnP. These findings led to the renaming of these subfamilies as MnP-DDQ and MnP-ED and to re-evaluate their evolutionary origin. Both enzymes were also able to directly oxidize lignin-derived phenolic compounds, as seen for other short MnPs. Importantly, size-exclusion chromatography analyses showed that both enzymes cause changes in polymeric lignin in the presence of manganese, suggesting their relevance in lignocellulose transformation. CONCLUSIONS: Understanding the mechanisms used by basidiomycetes to degrade lignin is of particular relevance to comprehend carbon cycle in nature and to design biotechnological tools for the industrial use of plant biomass. Here, we provide the first structure-function characterization of two novel MnP subfamilies present in Agaricales mushrooms, elucidating the main residues involved in catalysis and demonstrating their ability to modify the lignin macromolecule.

[Study of the metabolic syndrome severity index as a predictive factor of a major cardiovascular event in premenopausal women with systemic lupus erythematosus]. / Estudio del índice de gravedad del síndrome metabólico como factor predictivo de un episodio cardiovascular mayor en mujeres premenopáusicas con lupus eritematoso sistémico.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have an increased risk of metabolic syndrome (MS) and cardiovascular (CV) disease. MS is evaluated binary, limiting the understanding of each component's severity individually. Therefore, severity scores for MS that evaluate them separately have been developed. This study aims to determine the prognosis between MS severity and the occurrence of major adverse cardiovascular events (MACE) in SLE patients. METHODS: Ten-year follow-up cohort study. Premenopausal>18-year-old women with a previous diagnosis of SLE were included. Patients with recent CV events, pregnancy, thyroid disease, and liposuction were excluded. The variables of interest were CV events; the confounding variables, and the MS severity indexes were examined. Hazard ratios and Kaplan-Meier survival curves were estimated through Cox regression. RESULTS: A total of 238 women were analyzed: 22 presented MACE, and 216 did not. MS prevalence, measured according to consensus and ATP-III criteria, was higher in MACE patients (50 and 40,95%, respectively). The MetSx-IMC severity index was higher within the MACE group. Cox analysis showed an increase in the MetSx-IMC associated with the risk of suffering MACE in a 1.107 ratio. CONCLUSIONS: The MetSx-IMC severity index, contrary to the binary approaches, is recommended to evaluate MS as a predictor of MACE in SLE patients. Offering improved and more accurate prognosis in patients at risk of developing MCE.

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Risk factors associated with COVID-19 mortality in Mexico.

BACKGROUND: On December 31, 2019, one of the most serious pandemics in recent times made its appearance. Certain health conditions, such as obesity and diabetes mellitus, have been described to be related to COVID-19 unfavorable outcomes. OBJECTIVE: To identify factors associated with mortality in patients with COVID-19. MATERIAL AND METHODS: Retrospective cohort of 998,639 patients. Patient sociodemographic and clinical characteristics were analyzed, with survivors being compared with the deceased individuals. Cox proportional hazards model was used to identify variables predictive of COVID-19-associated mortality. RESULTS: Among the deceased patients, men accounted for 64.3%, and women, for 35.7%, with the difference being statistically significant. Subjects older than 80 years had a 13-fold higher risk of dying from COVID-19 (95% CI = 12,469, 13,586), while chronic kidney disease entailed a risk 1.5 times higher (95% CI = 1,341, 1,798), and diabetes mellitus involved a risk 1.25 times higher (95% CI = 1.238,1.276). CONCLUSIONS: Age, sex, diabetes mellitus and obesity were found to be predictors of COVID-19 mortality. Further research related to chronic obstructive pulmonary disease, cardiovascular diseases, smoking and pregnancy is suggested.

ANTECEDENTES: El 31 de diciembre de 2019, se inició una de las pandemias más graves de los últimos tiempos. Se ha descrito que ciertas condiciones de salud, como la obesidad y la diabetes mellitus, están relacionadas con desenlaces desfavorables por COVID-19. OBJETIVO: Identificar factores asociados a mortalidad en pacientes con COVID-19. MATERIAL Y MÉTODOS: Cohorte retrospectiva de 998 639 pacientes. Se analizaron las características sociodemográficas y clínicas de los pacientes, y se compararon supervivientes con fallecidos. Se utilizó el modelo de riesgos proporcionales de Cox para la identificación de variables predictivas de defunción por COVID-19. RESULTADOS: Entre los fallecidos, los hombres representaron 64.3 % y las mujeres 35.7 %, diferencia que resultó estadísticamente significativa. Las personas con más de 80 años presentaron un riesgo 13 veces mayor de morir por COVID-19 (IC 95 % = 12.469,13.586) y la enfermedad renal crónica, un riesgo de 1.5 (IC 95 % = 1.341, 1.798); la diabetes mellitus tuvo un riesgo de 1.25 (IC 95 % = 1.238,1.276). CONCLUSIONES: La edad, el sexo, la diabetes mellitus y la obesidad resultaron ser entidades predictivas de muerte por COVID-19. Se sugiere más investigación relacionada con enfermedad pulmonar obstructiva crónica, enfermedades cardiovasculares, tabaquismo y embarazo.

The effectiveness of adjustable trans-obturator male system (ATOMS) in radiated patients is reduced: A propensity score-matched analysis.

Objectives: This study aimed to compare the effectiveness and safety of the adjustable trans-obturator male system (ATOMS®) to treat post-prostatectomy incontinence (PPI) in radiated patients compared with non-radiated patients, using propensity score-matching analysis to enhance the validity of the comparison. Patients and methods: Consecutive men with PPI treated with silicone-covered scrotal port ATOMS (A.M.I., Feldkirch, Austria) in nine different institutions between 2016 and 2022 were included. Preoperative assessment evaluated 24-h pad usage, urethroscopy and urodynamics, if indicated. Propensity score-matching analysis was based on age, length of follow-up, previous PPI treatment, previous bladder neck stricture, androgen deprivation and pad usage. The primary endpoint was dry rate, defined as no pads post-operatively with a security pad allowed. The secondary endpoints were complications, device removal and self-perceived satisfaction with the Patient Global Impression of Improvement (PGI-I) scale. Results: Of the 710 included patients, 342 were matched, and the study groups were balanced for the baseline matched variables. The mean baseline 24-h pad was 4.8 in both groups (p = 0.48). The mean follow-up was 27.5 ± 18.6 months, which was also equivalent between groups (p = 0.36). The primary outcome was achieved in 73 (42.7%) radiated patients and in 115 (67.3%) non-radiated patients (p < 0.0001). The mean pad count at the last follow-up was 1.5 and 0.8, respectively (p < 0.0001). There was no significant difference in complications (p = 0.94), but surgical revision and device explant rates were higher (p = 0.03 and p = 0.01, respectively), and the proportion of patients highly satisfied (PGI-I = 1) was lower in the radiated group (p = 0.01). At sensitivity analysis, the study was found to be reasonably robust to hidden bias. Conclusion: ATOMS implantation significantly outperformed in patients without adjuvant radiation over radiated patients.

Cardiac Troponin Activator CK-963 Increases Cardiac Contractility in Rats.

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit 2 increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of 1 and 2 was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of CK-963 and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition. Rat echocardiography studies using CK-963 demonstrated concentration-dependent increases in cardiac fractional shortening up to 95%. Isothermal calorimetry studies confirmed a direct interaction between CK-963 and a cardiac troponin chimera with a dissociation constant of 11.5 ± 3.2 µM. These results provide evidence that direct activation of cardiac troponin without the confounding effects of PDE-3 inhibition may provide benefit for patients with cardiovascular conditions where contractility is reduced.

Factores de riesgo asociados a mortalidad por COVID-19 en México / Risk factors associated with COVID-19 mortality in Mexico

Resumen Antecedentes: El 31 de diciembre de 2019, se inició una de las pandemias más graves de los últimos tiempos. Se ha descrito que ciertas condiciones de salud, como la obesidad y la diabetes mellitus, están relacionadas con desenlaces desfavorables por COVID-19. Objetivo: Identificar factores asociados a mortalidad en pacientes con COVID-19. Material y métodos: Cohorte retrospectiva de 998 639 pacientes. Se analizaron las características sociodemográficas y clínicas de los pacientes, y se compararon supervivientes con fallecidos. Se utilizó el modelo de riesgos proporcionales de Cox para la identificación de variables predictivas de defunción por COVID-19. Resultados: Entre los fallecidos, los hombres representaron 64.3 % y las mujeres 35.7 %, diferencia que resultó estadísticamente significativa. Las personas con más de 80 años presentaron un riesgo 13 veces mayor de morir por COVID-19 (IC 95 % = 12.469,13.586) y la enfermedad renal crónica, un riesgo de 1.5 (IC 95 % = 1.341, 1.798); la diabetes mellitus tuvo un riesgo de 1.25 (IC 95 % = 1.238,1.276). Conclusiones: La edad, el sexo, la diabetes mellitus y la obesidad resultaron ser entidades predictivas de muerte por COVID-19. Se sugiere más investigación relacionada con enfermedad pulmonar obstructiva crónica, enfermedades cardiovasculares, tabaquismo y embarazo.

Abstract Background: On December 31, 2019, one of the most serious pandemics in recent times made its appearance. Certain health conditions, such as obesity and diabetes mellitus, have been described to be related to COVID-19 unfavorable outcomes. Objective: To identify factors associated with mortality in patients with COVID-19. Material and methods: Retrospective cohort of 998,639 patients. Patient sociodemographic and clinical characteristics were analyzed, with survivors being compared with the deceased individuals. Cox proportional hazards model was used to identify variables predictive of COVID-19-associated mortality. Results: Among the deceased patients, men accounted for 64.3%, and women, for 35.7%, with the difference being statistically significant. Subjects older than 80 years had a 13-fold higher risk of dying from COVID-19 (95% CI = 12,469, 13,586), while chronic kidney disease entailed a risk 1.5 times higher (95% CI = 1,341, 1,798), and diabetes mellitus involved a risk 1.25 times higher (95% CI = 1.238,1.276). Conclusions: Age, sex, diabetes mellitus and obesity were found to be predictors of COVID-19 mortality. Further research related to chronic obstructive pulmonary disease, cardiovascular diseases, smoking and pregnancy is suggested.

Selective Formation of Pd-DNA Hybrids Using Tailored Palladium-Mediated Base Pairs: Towards Heteroleptic Pd-DNA Systems.

The formation of highly organized metal-DNA structures has significant implications in bioinorganic chemistry, molecular biology and material science due to their unique properties and potential applications. In this study, we report on the conversion of single-stranded polydeoxycytidine (dC15 ) into a Pd-DNA supramolecular structure using the [Pd(Aqa)] complex (Aqa=8-amino-4-hydroxyquinoline-2-carboxylic acid) through a self-assembly process. The resulting Pd-DNA assembly closely resembles a natural double helix, with continuous [Pd(Aqa)(C)] (C=cytosine) units serving as palladium-mediated base pairs, forming interbase hydrogen bonds and intrastrand stacking interactions. Notably, the design of the [Pd(Aqa)] complex favours the interaction with cytosine, distinguishing it from our previously reported [Pd(Cheld)] complex (Cheld=chelidamic acid). This finding opens possibilities for creating heteroleptic Pd-DNA hybrids where different complexes specifically bind to nucleobases. We confirmed the Pd-DNA supramolecular structural assembly and selective binding of the complexes using NMR spectroscopy, circular dichroism, mass spectrometry, isothermal titration calorimetry, and DFT calculations.