Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications.

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

The research landscape concerning environmental factors in neurodevelopmental disorders: Endocrine disrupters and pesticides-A review.

In recent years, environmental epidemiology and toxicology have seen a growing interest in the environmental factors that contribute to the increased prevalence of neurodevelopmental disorders, with the purpose of establishing appropriate prevention strategies. A literature review was performed, and 192 articles covering the topic of endocrine disruptors and neurodevelopmental disorders were found, focusing on polychlorinated biphenyls, polybrominated diphenyl ethers, bisphenol A, and pesticides. This study contributes to analyzing their effect on the molecular mechanism in maternal and infant thyroid function, essential for infant neurodevelopment, and whose alteration has been associated with various neurodevelopmental disorders. The results provide scientific evidence of the association that exists between the environmental neurotoxins and various neurodevelopmental disorders. In addition, other possible molecular mechanisms by which pesticides and endocrine disruptors may be associated with neurodevelopmental disorders are being discussed.

BRCA2 promotes DNA-RNA hybrid resolution by DDX5 helicase at DNA breaks to facilitate their repair‡.

The BRCA2 tumor suppressor is a DNA double-strand break (DSB) repair factor essential for maintaining genome integrity. BRCA2-deficient cells spontaneously accumulate DNA-RNA hybrids, a known source of genome instability. However, the specific role of BRCA2 on these structures remains poorly understood. Here we identified the DEAD-box RNA helicase DDX5 as a BRCA2-interacting protein. DDX5 associates with DNA-RNA hybrids that form in the vicinity of DSBs, and this association is enhanced by BRCA2. Notably, BRCA2 stimulates the DNA-RNA hybrid-unwinding activity of DDX5 helicase. An impaired BRCA2-DDX5 interaction, as observed in cells expressing the breast cancer variant BRCA2-T207A, reduces the association of DDX5 with DNA-RNA hybrids, decreases the number of RPA foci, and alters the kinetics of appearance of RAD51 foci upon irradiation. Our findings are consistent with DNA-RNA hybrids constituting an impediment for the repair of DSBs by homologous recombination and reveal BRCA2 and DDX5 as active players in their removal.

Femtosecond Core-Level Spectroscopy Reveals Involvement of Triplet States in the Gas-Phase Photodissociation of Fe(CO)5.

Excitation of iron pentacarbonyl [Fe(CO)5], a prototypical photocatalyst, at 266 nm causes the sequential loss of two CO ligands in the gas phase, creating catalytically active, unsaturated iron carbonyls. Despite numerous studies, major aspects of its ultrafast photochemistry remain unresolved because the early excited-state dynamics have so far eluded spectroscopic observation. This has led to the long-held assumption that ultrafast dissociation of gas-phase Fe(CO)5 proceeds exclusively on the singlet manifold. Herein, we present a combined experimental-theoretical study employing ultrafast extreme ultraviolet transient absorption spectroscopy near the Fe M2,3-edge, which features spectral evolution on 100 fs and 3 ps time scales, alongside high-level electronic structure theory, which enables characterization of the molecular geometries and electronic states involved in the ultrafast photodissociation of Fe(CO)5. We assign the 100 fs evolution to spectroscopic signatures associated with intertwined structural and electronic dynamics on the singlet metal-centered states during the first CO loss and the 3 ps evolution to the competing dissociation of Fe(CO)4 along the lowest singlet and triplet surfaces to form Fe(CO)3. Calculations of transient spectra in both singlet and triplet states as well as spin-orbit coupling constants along key structural pathways provide evidence for intersystem crossing to the triplet ground state of Fe(CO)4. Thus, our work presents the first spectroscopic detection of transient excited states during ultrafast photodissociation of gas-phase Fe(CO)5 and challenges the long-standing assumption that triplet states do not play a role in the ultrafast dynamics.

Whole-Genome Sequencing Analysis of Male Breast Cancer Unveils Novel Structural Events and Potential Therapeutic Targets.

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of 10 MaBC cases (n = 10) were delineated and correlated with clinical and histopathologic characteristics. Using fluorescence in situ hybridization, an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes, such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants that impact cancer-associated genes, such as ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in 2 cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least 1 potential therapeutic target in 8 of the 10 cases, including high tumor mutational burden, FGFR1 amplification, and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants, including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this understudied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.

Natural proliferative phase frozen embryo transfer-a new approach which may facilitate scheduling without hindering pregnancy outcomes.

STUDY QUESTION: How does a natural proliferative phase (NPP) strategy for frozen embryo transfer (FET) compare with the conventional artificial (AC) and natural (NC) endometrial preparation protocols in terms of live birth rates (LBR)? SUMMARY ANSWER: This study supports the hypothesis that, just as for NC, NPP-FET may be a superior alternative to AC in terms of LBR. WHAT IS KNOWN ALREADY: Although FETs are increasing worldwide, the optimal FET protocol is still largely controversial. Despite recent evidence supporting a possibly higher efficacy and safety of NC FETs, their widespread use is limited by the difficulties encountered during cycle monitoring and scheduling. STUDY DESIGN, SIZE, DURATION: In this single center retrospective cohort study, we describe the NPP-FET protocol, in which vaginal progesterone is initiated during the proliferative phase as soon as an endometrium with a thickness of at least 7 mm is identified and ovulation is ruled out, regardless of mean diameter of the dominant follicle. PARTICIPANTS/MATERIALS, SETTING, METHODS: For comparison, we considered all blastocyst stage FET cycles preformed at a private infertility center between January 2010 and June 2022, subdivided according to the following subgroups of endometrial preparation: AC, NPP, and NC. We performed multivariable generalized estimating equations regression analysis to account for the following potential confounding variables: oocyte age at retrieval, oocyte source (autologous without preimplantation genetic testing for aneuploidies (PGT-A) versus autologous with PGT-A versus donated), number of oocytes retrieved/donated, embryo developmental stage (Day 5 versus Day 6), number of embryos transferred, quality of the best embryo transferred, and year of treatment. The main outcome measure was LBR. The secondary outcomes included hCG positive, clinical pregnancy and miscarriage rates, and the following perinatal outcomes: first trimester bleeding, second/third trimester bleeding, preterm rupture of membranes, gestational diabetes, gestational hypertensive disorders (GHD), and gestational age at delivery. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5791 FET cycles were included in this analysis (2226 AC, 349 NPP, and 3216 NC). The LBR for FET was lower in the AC subgroup when compared to the NPP and NC (38.4%, 49.1%, and 45.2%, respectively; P < 0.01 AC versus NPP and AC versus NC). The rates of miscarriage were also lower in the NPP and NC subgroups when compared to AC (19.7%, 25.0%, and 34.9%, respectively; P < 0.01 NPP versus AC and NC versus AC). Considering perinatal outcomes, NPP-FET and NC were associated with a significantly lower first trimester bleeding compared to AC (17.3%, 14.7%, and 37.6%, respectively; P < 0.01 NPP versus AC and NC versus AC). Additionally, NC was associated with a lower rate of GHD when compared with AC (8.6% versus 14.5%, P < 0.01), while the rate following NPP-FET was 9.4%. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Moreover, there was also a low number of patients in the NPP subgroup, which may have led the study to be underpowered to detect clinically relevant differences between the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Our study posits that the NPP-FET protocol may be an effective and safe alternative to both NC and AC, while still allowing for enhanced practicality in patient follow-up and FET scheduling. Further investigation on NPP-FET is warranted, with prospective studies including a larger and more homogeneous subsets of patients. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the IVI-RMA-Lisbon (2008-LIS-053-CG). The authors did not receive any funding for this study. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

US businesses engaged in direct-to-consumer marketing of perinatal stem cell interventions following the Food and Drug Administration's enforcement discretion era.

BACKGROUND AIMS: The goal of this study was to analyze online marketing representations made by 300 US businesses selling allogeneic perinatal stem cell products. The study was conducted after a period of enforcement discretion by the US Food and Drug Administration (FDA). METHODS: Data mining and content analysis were used to identify, analyze and categorize marketing claims made on the websites of 300 businesses selling perinatal stem cell interventions. RESULTS: The study identified types of perinatal interventions companies advertised, geographic locations of clinics selling such products, types of companies operating in this space, diseases and injuries such businesses claim to treat, prices companies charge for such interventions, brand names of advertised perinatal cell products and identities of suppliers. CONCLUSIONS: A substantial number of US businesses market unapproved perinatal stem cell products for various indications. This widespread commercial activity occurred following the conclusion of a period of enforcement discretion by the FDA and suggests the need for more robust and comprehensive regulatory responses to businesses selling unapproved perinatal stem cell products.

Different Reaction Modes Operating in ansa-Half-Sandwich Magnesium Catalysts.

Magnesium-based catalysts are becoming popular for hydroelementation reactions specially using p-block reagents. Based on the seminal report from Schäfer's group (ChemCatChem 2022, 14, e202201007), our study demonstrates that the reaction mechanisms exhibit a far greater degree of complexity than originally presumed. Magnesium has a variety of coordination modes (and access to different hybridizations) which allows this electron-deficient centre to modulate its catalytic power depending on the σ-donor properties of the reagent. DFT calculations demonstrate several reaction channels closely operating in these versatile catalysts. In addition, variations in limiting energy barriers resulting from catalyst modifications were examined as a function of the Hammett constant, thereby predicting enhanced efficiency in reaction conversions.

Anthraquinone-Modified Silica Nanoparticles as Heterogeneous Photocatalyst for the Oxidative Hydroxylation of Arylboronic Acids.

In this work, the synthesis and characterization of a heterogeneous photocatalyst based on spherical silica nanoparticles superficially modified with anthraquinone 2-carboxylic acid (AQ-COOH) are presented. The nanomaterial was characterized by TEM, SEM, FT-IR, diffuse reflectance, fluorescence, NMR, DLS, XRD and XPS. These analyses confirm the covalent linking of AQ-COOH with the NH2 functionality in the nanomaterial and, more importantly, the photocatalyst retains its photophysical properties once bound. The heterogeneous photocatalyst was successfully employed in the aerobic hydroxylation of arylboronic acids to phenols under sustainable reaction conditions. Phenols were obtained in high yields (up to 100 %) with low catalyst loading (3.5 mol %), reaching TOF values of 3.7 h-1 . Using 2-propanol as solvent at room temperature, the visible light photocatalysis produced H2 O2 as a key intermediate to promote the aerobic hydroxylation of arylboronic acids. The heterogeneous photocatalyst was reused at least 5 times, without modification of the nanomaterial structure and morphology. This simple heterogeneous system showed great catalytic activity under sustainable reaction conditions.

Correlation of EUS-guided portal pressure gradient measurements with hepatic venous pressure gradient: a prospective study.

BACKGROUND AND AIMS: Hepatic Venous Portal Gradient (HVPG) measurement remains the gold standard for estimating portal pressure gradient (PPG). AIM: To evaluate the correlation between EUS-guided portal pressure gradient (EUS-PPG) and HVPG in patients with chronic portal hypertension. PATIENTS AND METHODS: Patients with chronic portal hypertension in whom HVPG assessment was clinically indicated were invited to undergo transjugular HVPG and EUS-PPG with a 22G needle in separate sessions for comparison. Intra-class correlation coefficient (ICC), and Bland-Altman method were used to evaluate the agreement between techniques. RESULTS: 33 patients were included. No significant differences in technical success were observed: EUS-PPG (31/33, 93.9%) vs. HVPG (31/33, 93.9%). Thirty patients who underwent successful EUS-PPG and HVPG were analysed. Correlation between the two techniques showed an ICC: 0.82(0.65-0.91). Four patients had major discrepancies (≥ 5 mmHg) between HVPG and EUS-PPG. No significant differences in adverse events were observed. CONCLUSIONS: The correlation between EUS-PPG and HVPG was almost perfect. EUS-PPG could be a safe and reliable method for direct PPG measurement in cirrhotic patients and a valid alternative to HVPG. NCT05689268.

Polymyxin B-Enriched Exogenous Lung Surfactant: Thermodynamics and Structure.

The use of an exogenous pulmonary surfactant (EPS) to deliver other relevant drugs to the lungs is a promising strategy for combined therapy. We evaluated the interaction of polymyxin B (PxB) with a clinically used EPS, the poractant alfa Curosurf (PSUR). The effect of PxB on the protein-free model system (MS) composed of four phospholipids (diC16:0PC/16:0-18:1PC/16:0-18:2PC/16:0-18:1PG) was examined in parallel to distinguish the specificity of the composition of PSUR. We used several experimental techniques (differential scanning calorimetry, small- and wide-angle X-ray scattering, small-angle neutron scattering, fluorescence spectroscopy, and electrophoretic light scattering) to characterize the binding of PxB to both EPS. Electrostatic interactions PxB-EPS are dominant. The results obtained support the concept of cationic PxB molecules lying on the surface of the PSUR bilayer, strengthening the multilamellar structure of PSUR as derived from SAXS and SANS. A protein-free MS mimics a natural EPS well but was found to be less resistant to penetration of PxB into the lipid bilayer. PxB does not affect the gel-to-fluid phase transition temperature, Tm, of PSUR, while Tm increased by ∼+ 2 °C in MS. The decrease of the thickness of the lipid bilayer (dL) of PSUR upon PxB binding is negligible. The hydrophobic tail of the PxB molecule does not penetrate the bilayer as derived from SANS data analysis and changes in lateral pressure monitored by excimer fluorescence at two depths of the hydrophobic region of the bilayer. Changes in dL of protein-free MS show a biphasic dependence on the adsorbed amount of PxB with a minimum close to the point of electroneutrality of the mixture. Our results do not discourage the concept of a combined treatment with PxB-enriched Curosurf. However, the amount of PxB must be carefully assessed (less than 5 wt % relative to the mass of the surfactant) to avoid inversion of the surface charge of the membrane.

A randomised trial of short- vs long-term androgen deprivation with salvage radiotherapy for biochemical failure following radical prostatectomy: URONCOR 06-24.

BACKGROUND: Salvage radiotherapy (SRT) and androgen-deprivation therapy (ADT) are widely used in routine clinical practice to treat patients with prostate cancer who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, there is no standard-of-care consensus on optimal duration ADT. Investigators propose three distinct risk groups in patients with prostate cancer treated with SRT in order to better define the indications and duration of ADT combined with SRT. STUDY DESIGN: The URONCOR 06-24 trial (ClinicalTrials.gov identifier NCT05781217) is a prospective, multicentre, randomised, open-label, phase III, clinical trial. The aim of the trial is to determine the impact of short-term (6 months) vs long-term (24 months) ADT in combination with SRT on distant metastasis-free survival (MFS) in patients with prostate cancer with BCR after RP (intermediate and high risk). ENDPOINTS: The primary endpoint is 5-year MFS rates in patients with prostate cancer treated with long- vs short-term ADT in combination with SRT. Secondary objectives are biochemical-relapse free interval, pelvic progression-free survival, time to start of systemic treatment, time to castration resistance, cancer-specific survival, overall survival, acute and late toxicity, and quality of life. METHODS AND ANALYSIS: Total of 534 patients will be randomised 1:1 to ADT 6 months or ADT 24 months with a luteinizing hormone-releasing hormone analogue in combination with SRT, stratified by risk group and pathological lymph node status. ETHICS AND DISSEMINATION: The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT number 2021-006975-41.

Water Sorption and Structural Properties of Human Airway Mucus in Health and Muco-Obstructive Diseases.

Muco-obstructive diseases change airway mucus properties, impairing mucociliary transport and increasing the likelihood of infections. To investigate the sorption properties and nanostructures of mucus in health and disease, we investigated mucus samples from patients and cell cultures (cc) from healthy, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) airways. Atomic force microscopy (AFM) revealed mucin monomers with typical barbell structures, where the globule to spacer volume ratio was the highest for CF mucin. Accordingly, synchrotron small-angle X-ray scattering (SAXS) revealed more pronounced scattering from CF mucin globules and suggested shorter carbohydrate side chains in CF mucin and longer side chains in COPD mucin. Quartz crystal microbalance with dissipation (QCM-D) analysis presented water sorption isotherms of the three types of human airway mucus, where, at high relative humidity, COPD mucus had the highest water content compared to cc-CF and healthy airway mucus (HAM). The higher hydration of the COPD mucus is consistent with the observation of longer side chains of the COPD mucins. At low humidity, no dehydration-induced glass transition was observed in healthy and diseased mucus, suggesting mucus remained in a rubbery state. However, in dialyzed cc-HAM, a sorption-desorption hysteresis (typically observed in the glassy state) appeared, suggesting that small molecules present in mucus suppress the glass transition.

Development of QSARs for cysteine-containing di- and tripeptides with antioxidant activity:influence of the cysteine position.

Antioxidants agents play an essential role in the food industry for improving the oxidative stability of food products. In the last years, the search for new natural antioxidants has increased due to the potential high toxicity of chemical additives. Therefore, the synthesis and evaluation of the antioxidant activity in peptides is a field of current research. In this study, we performed a Quantitative Structure Activity Relationship analysis (QSAR) of cysteine-containing 19 dipeptides and 19 tripeptides. The main objective is to bring information on the relationship between the structure of peptides and their antioxidant activity. For this purpose, 1D and 2D molecular descriptors were calculated using the PaDEL software, which provides information about the structure, shape, size, charge, polarity, solubility and other aspects of the compounds. Different QSAR model for di- and tripeptides were developed. The statistic parameters for di-peptides model (R2train = 0.947 and R2test = 0.804) and for tripeptide models (R2train = 0.923 and R2test = 0.847) indicate that the generated models have high predictive capacity. Then, the influence of the cysteine position was analyzed predicting the antioxidant activity for new di- and tripeptides, and comparing them with glutathione. In dipeptides, excepting SC, TC and VC, the activity increases when cysteine is at the N-terminal position. For tripeptides, we observed a notable increase in activity when cysteine is placed in the N-terminal position.

Argentophilic Interactions, Flexibility, and Dynamics of Pyrrole Cages Encapsulating Silver(I) Clusters.

Recently, pyrrole cages have been synthesized that encapsulate ion pairs and silver(I) clusters to form intricate supramolecular capsules. We report here a computational analysis of these structures using density functional theory combined with a semiempirical tight-binding approach. We find that for neutral pyrrole cages, the Gibbs free energies of formation provide reliable predictions for the ratio of bound ions. For charged pyrrole cages, we find strong argentophilic interactions between Ag ions on the basis of the calculated bond indices and molecular orbitals. For the cage with the Ag4 cluster, we find two minimum-geometry conformations that differ by only 6.5 kcal/mol, with an energy barrier <1 kcal/mol, suggesting a very flexible structure as indicated by molecular dynamics. The predicted energies of formation of [Agn⊂1]n-3+ (n = 1-5) cryptands provide low energy barriers of formation of 5-20 kcal/mol for all cases, which is consistent with the experimental data. Furthermore, we also examined the structural variability of mixed-valence silver clusters to test whether additional geometrical conformations inside the organic cage are thermodynamically accessible. In this context, we show that the time-dependent density functional theory UV-vis spectra may potentially serve as a diagnostic probe to characterize mixed-valence and geometrical configurations of silver clusters encapsulated into cryptands.

Predictive risk model of recurrence of acute diverticulitis after the first episode.

INTRODUCTION: The recurrence of acute diverticulitis (AD) of the colon is frequent and leads to hospital readmissions and the need for elective surgery in selected cases. It is important to individualize risk factors and develop predictive tools for their identification. MATERIALS AND METHODS: This prospective observational study included 368 patients who were diagnosed with AD between 2016 and 2021 in a tertiary general university hospital during their first episode and who had a good response to antibiotic, percutaneous, or peritoneal lavage treatment. Univariate and multivariate Cox regression analyses of the variables associated with recurrence were performed. Subsequently, a predictive risk score was developed and validated through survival studies. RESULTS: After a median follow-up of 50 months, there were 71 (19.3%) cases of recurrence out of a total of 368 patients. The mean time of recurrence was 15 months, and 73.3% of cases of recurrence occurred before 2 years of follow-up. Recurrence was independently associated with presentation with colonic perforation in the antimesenteric location (HR 3.67 95% CI [1.59-8.4]) and a CRP level greater than 100 mg/dl (HR 1.69 95% CI [1.04-2.77). A score with 5 variables was created that differentiated two risk groups: intermediate risk (0-3 points), with 19% recurrence and high risk (more than 3 points), with 42% recurrence. CONCLUSIONS: The risk of recurrence after the first episode of diverticulitis can be estimated using predictive scores. The detection of high-risk patients facilitates the individualization of follow-up and treatment.

Evaluation of the presence of gingivitis as confounding factor in assessing inflammatory status in serum and saliva of dogs with diabetes mellitus.

The aim of this study was to evaluate the changes in the serum and salivary inflammatory markers induced by Diabetes mellitus (DM) in dogs and to assess the possible confounding effect of gingivitis. A panel of 13 cytokines was measured in the serum and saliva of dogs diagnosed with DM and compared with healthy dogs without gingivitis (control group 1; CG1) and dogs with gingivitis but otherwise healthy (control group 2; CG2). The results of the present study showed statistically significantly higher levels of IL-8, KC-like and MCP1 in the serum of dogs with DM compared to CG1 dogs. In the case of saliva, the DM group presented statistically higher GM-CSF, IL6, IL15, and MCP1 levels compared to CG1, and lower KC-like chemokine compared to CG2. Finally, gingivitis produced changes in saliva, with salivary levels of GM-CSF, IL-6, IL-7, IL-15, IP-10, KC-like, IL-10, IL-18, MCP1, TNFα being statistically significantly higher in the saliva of CG2 dogs compared to CG1. The results of the present study indicate that dogs with DM have altered cytokine levels in serum and saliva compared to healthy dogs. In addition, this study highlights the importance of taking oral health into account when determining cytokines in dogs, as gingivitis can significantly alter their concentrations. .

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

BACKGROUND/AIMS: Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. METHODS: An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. RESULTS: A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. CONCLUSION: The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Prediction of Deleterious Single Amino Acid Polymorphisms with a Consensus Holdout Sampler.

Background: Single Amino Acid Polymorphisms (SAPs) or nonsynonymous Single Nucleotide Variants (nsSNVs) are the most common genetic variations. They result from missense mutations where a single base pair substitution changes the genetic code in such a way that the triplet of bases (codon) at a given position is coding a different amino acid. Since genetic mutations sometimes cause genetic diseases, it is important to comprehend and foresee which variations are harmful and which ones are neutral (not causing changes in the phenotype). This can be posed as a classification problem. Methods: Computational methods using machine intelligence are gradually replacing repetitive and exceedingly overpriced mutagenic tests. By and large, uneven quality, deficiencies, and irregularities of nsSNVs datasets debase the convenience of artificial intelligence-based methods. Subsequently, strong and more exact approaches are needed to address these problems. In the present work paper, we show a consensus classifier built on the holdout sampler, which appears strong and precise and outflanks all other popular methods. Results: We produced 100 holdouts to test the structures and diverse classification variables of diverse classifiers during the training phase. The finest performing holdouts were chosen to develop a consensus classifier and tested using a k-fold (1 ≤ k ≤5) cross-validation method. We also examined which protein properties have the biggest impact on the precise prediction of the effects of nsSNVs. Conclusion: Our Consensus Holdout Sampler outflanks other popular algorithms, and gives excellent results, highly accurate with low standard deviation. The advantage of our method emerges from using a tree of holdouts, where diverse LM/AI-based programs are sampled in diverse ways.

Photobiomodulation increases brain metabolic activity through a combination of 810 and 660 wavelengths: a comparative study in male and female rats.

Photobiomodulation (PBM), an emerging and non-invasive intervention, has been shown to benefit the nervous system by modifying the mitochondrial cytochrome c-oxidase (CCO) enzyme, which has red (620-680 nm) or infrared (760-825 nm) spectral absorption peaks. The effect of a single 810-nm wavelength with a combination of 810 nm and 660 nm lights in the brain metabolic activity of male and female rats was compared. PBM, with a wavelength of 810 nm and a combination of 810 nm and 660 nm, was applied for 5 days on the prefrontal cortex. Then, brain metabolic activity in the prefrontal area, hippocampus, retrosplenial, and parietal cortex was explored. Sex differences were found in cortical and subcortical regions, indicating higher male brain oxidative metabolism, regardless of treatment. CCO activity in the cingulate and prelimbic area, dentate gyrus, retrosplenial and parietal cortex was enhanced in both treatments (810 + 660 nm and 810 nm). Moreover, using the combination of waves, CCO increased in the infralimbic area, and in CA1 and CA3 of the hippocampus. Thus, employment of a single NIR treatment or a combination of red to NIR treatment led to slight differences in CCO activity across the limbic system, suggesting that a combination of lights of the spectrum may be relevant.