Functional reprogramming of regulatory T cells in the absence of Foxp3.

Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.

The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods.

ChEMBL (https://www.ebi.ac.uk/chembl/) is a manually curated, high-quality, large-scale, open, FAIR and Global Core Biodata Resource of bioactive molecules with drug-like properties, previously described in the 2012, 2014, 2017 and 2019 Nucleic Acids Research Database Issues. Since its introduction in 2009, ChEMBL's content has changed dramatically in size and diversity of data types. Through incorporation of multiple new datasets from depositors since the 2019 update, ChEMBL now contains slightly more bioactivity data from deposited data vs data extracted from literature. In collaboration with the EUbOPEN consortium, chemical probe data is now regularly deposited into ChEMBL. Release 27 made curated data available for compounds screened for potential anti-SARS-CoV-2 activity from several large-scale drug repurposing screens. In addition, new patent bioactivity data have been added to the latest ChEMBL releases, and various new features have been incorporated, including a Natural Product likeness score, updated flags for Natural Products, a new flag for Chemical Probes, and the initial annotation of the action type for ∼270 000 bioactivity measurements.

ASK1/ p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer.

BACKGROUND AND AIMS: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. APPROACH AND RESULTS: Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. CONCLUSIONS: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

Whole-genome sequencing and comparative genomics reveal candidate genes associated with quality traits in Dioscorea alata.

BACKGROUND: Quality traits are essential determinants of consumer preferences. Dioscorea alata (Greater Yam), is a starchy tuber crop in tropical regions. However, a comprehensive understanding of the genetic basis underlying yam tuber quality remains elusive. To address this knowledge gap, we employed population genomics and candidate gene association approaches to unravel the genetic factors influencing the quality attributes of boiled yam. METHODS AND RESULTS: Comparative genomics analysis of 45 plant species revealed numerous novel genes absent in the existing D. alata gene annotation. This approach, adding 48% more genes, significantly enhanced the functional annotation of three crucial metabolic pathways associated with boiled yam quality traits: pentose and glucuronate interconversions, starch and sucrose metabolism, and flavonoid biosynthesis. In addition, the whole-genome sequencing of 127 genotypes identified 27 genes under selection and 22 genes linked to texture, starch content, and color through a candidate gene association analysis. Notably, five genes involved in starch content and cell wall composition, including 1,3-beta Glucan synthase, ß-amylase, and Pectin methyl esterase, were common to both approaches and their expression levels were assessed by transcriptomic data. CONCLUSIONS: The analysis of the whole-genome of 127 genotypes of D. alata and the study of three specific pathways allowed the identification of important genes for tuber quality. Our findings provide insights into the genetic basis of yam quality traits and will help the enhancement of yam tuber quality through breeding programs.

Effects of treatment methods on cutaneous melanoma related mortality and all-cause mortality in Texas: TCR-Medicare 2007-2017 database.

PURPOSE: The incidence of cutaneous melanoma is rising, and Melanoma related deaths are highest among people aged 65-74. Herein, we aim to understand the impact of novel and established melanoma treatment methods on CM related mortality and all-cause mortality. We further compared these effects among Hispanic and non-Hispanic Whites (NHW). METHODS: The data was extracted from the Texas Cancer Registry from 2007 to 2017. A Cox Proportional Hazard regression analysis was performed to assess treatment effect on melanoma mortality and all-cause mortality, with race-ethnicity as an effect modifier. RESULTS: A higher percentage of Hispanic patients presented with CM-related mortality (22.11%) compared to NHW patients (14.39%). In both the Hispanic and NHW, post-diagnosis radiation (HR = 1.610, 95% CI 0.984-2.634, HR = 2.348, 95% CI 2.082-2.648, respectively), post-diagnosis chemotherapy (HR = 1.899, 95% CI 1.085-3.322, HR = 2.035, 95% CI 1.664-2.489, respectively), and post-diagnosis immunotherapy (HR = 2.100, 95% CI 1.338-3.296, HR = 2.402, 95% CI 2.100-2.748) are each associated with an increased risk in CM-related mortality. Similar results were seen with post-diagnosis radiation (Hispanic HR = 1.640, 95% CI 1.121-2.400, NHW HR = 1.800, 95% CI 1.644-1.971), post-diagnostic chemotherapy (Hispanic HR = 1.457, 95% CI 0.898-2.364, NHW HR = 1.592, 95% CI 1.356-1.869), and post-diagnosis immunotherapy (Hispanic HR = 2.140, 95% CI 1.494-3.065, NHW HR = 2.190, 95% CI 1.969-2.435) with respect to all-cause mortality. Post-diagnosis surgery (HR = 0.581, 95% CI 0.395-0.856, HR = 0.622, 95% CI 0.571-0.678) had the opposite effect in CM-related mortality for Hispanics and NHWs respectively. CONCLUSION: Our results propose differences in all-cause and CM-only related mortality with separate treatment modalities, particularly with chemotherapy, radiation therapy and immunotherapy. In addition, this retrospective cohort study showed that health disparities exist in the Hispanic Medicare population of Texas with CM.

Carbohydrate antigen 125 on epicardial fat and its association with local inflammation and fibrosis-related markers.

BACKGROUND: Carbohydrate antigen 125 (CA125) is a proteolytic fragment of MUC-16 that is increased in heart failure (HF) and associated with inflammation, fluid overload, and worse adverse events. Our main objective was to study the expression of CA125 on epicardium and its association with inflammation, adipogenesis, and fibrosis. METHODS: Epicardial fat biopsies and blood were obtained from 151 non-selected patients undergoing open heart surgery. Immunohistochemistry, ELISA, or real-time PCR were used for analyzing protein or mRNA expression levels of CA125 and markers of inflammatory cells, fibroblasts, and adipocytes. Epithelial or stromal cells from epicardium were isolated and cultured to identify CA125 and its association with the adipogenesis and fibrosis pathways, respectively. RESULTS: The median age was 71 (63-74) years, 106 patients (70%) were male, and 62 (41%) had an established diagnosis of HF before surgery. The slice of epicardial fat biopsy determined a positive and colorimetric staining on the epithelial layer after incubating with the CA125 M11 antibody, providing the first description of CA125 expression in the human epicardium. Epicardial CA125 showed a strong and positive correlation with markers of inflammation and fibrosis in the epicardial fat tissue while exhibiting a negative correlation with markers of the adipogenesis pathway. This relationship remained significant after adjusting for potential confounders such as a prior HF diagnosis and plasma CA125 levels. CONCLUSION: Epicardial cells express CA125, which is positively associated with inflammatory and fibroblast markers in epicardial adipose tissue. These results suggest that CA125 may be biologically involved in HF progression (transition from adipogenesis to fibrosis).

Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.

BACKGROUND AND AIMS: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). APPROACH AND RESULTS: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis. CONCLUSIONS: Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies.

Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network.

BACKGROUND: Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients suffers cardiovascular disease (CVD). The network among glucose, immune system, endothelium and epicardial fat has an important role on pro-inflammatory and thrombotic mechanisms of atherogenesis. Since semaglutide, long-acting glucagon like peptide 1- receptor agonist (GLP-1-RA), a glucose-lowering drug, reduces body weight, we aimed to study its effects on human epicardial fat (EAT), aortic endothelial cells and neutrophils as atherogenesis involved-cardiovascular cells. METHODS: EAT and subcutaneous fat (SAT) were collected from patients undergoing cardiac surgery. Differential glucose consumption and protein cargo of fat-released exosomes, after semaglutide or/and insulin treatment were analyzed by enzymatic and TripleTOF, respectively. Human neutrophils phenotype and their adhesion to aortic endothelial cells (HAEC) or angiogenesis were analyzed by flow cytometry and functional fluorescence analysis. Immune cells and plasma protein markers were determined by flow cytometry and Luminex-multiplex on patients before and after 6 months treatment with semaglutide. RESULTS: GLP-1 receptor was expressed on fat and neutrophils. Differential exosomes-protein cargo was identified on EAT explants after semaglutide treatment. This drug increased secretion of gelsolin, antithrombotic protein, by EAT, modulated CD11b on neutrophils, its migration and endothelial adhesion, induced by adiposity protein, FABP4, or a chemoattractant. Monocytes and neutrophils phenotype and plasma adiposity, stretch, mesothelial, fibrotic, and inflammatory markers on patients underwent semaglutide treatment for 6 months showed a 20% reduction with statistical significance on FABP4 levels and an 80% increase of neutrophils-CD88. CONCLUSION: Semaglutide increases endocrine activity of epicardial fat with antithrombotic properties. Moreover, this drug modulates the pro-inflammatory and atherogenic profile induced by the adiposity marker, FABP4, which is also reduced in patients after semaglutide treatment.

Estimating the likelihood of epilepsy from clinically noncontributory electroencephalograms using computational analysis: A retrospective, multisite case-control study.

OBJECTIVE: This study was undertaken to validate a set of candidate biomarkers of seizure susceptibility in a retrospective, multisite case-control study, and to determine the robustness of these biomarkers derived from routinely collected electroencephalography (EEG) within a large cohort (both epilepsy and common alternative conditions such as nonepileptic attack disorder). METHODS: The database consisted of 814 EEG recordings from 648 subjects, collected from eight National Health Service sites across the UK. Clinically noncontributory EEG recordings were identified by an experienced clinical scientist (N = 281; 152 alternative conditions, 129 epilepsy). Eight computational markers (spectral [n = 2], network-based [n = 4], and model-based [n = 2]) were calculated within each recording. Ensemble-based classifiers were developed using a two-tier cross-validation approach. We used standard regression methods to assess whether potential confounding variables (e.g., age, gender, treatment status, comorbidity) impacted model performance. RESULTS: We found levels of balanced accuracy of 68% across the cohort with clinically noncontributory normal EEGs (sensitivity =61%, specificity =75%, positive predictive value =55%, negative predictive value =79%, diagnostic odds ratio =4.64, area under receiver operated characteristics curve =.72). Group level analysis found no evidence suggesting any of the potential confounding variables significantly impacted the overall performance. SIGNIFICANCE: These results provide evidence that the set of biomarkers could provide additional value to clinical decision-making, providing the foundation for a decision support tool that could reduce diagnostic delay and misdiagnosis rates. Future work should therefore assess the change in diagnostic yield and time to diagnosis when utilizing these biomarkers in carefully designed prospective studies.

Testing the Effectiveness of a Motivational Interviewing Intervention to Reduce HIV Risk and Drug Use in Young Sexual Minority Men in a Community-Based Organization Setting.

Younger sexual minority men (YSMM) remain at high risk for HIV infection and substance use increases this risk. This study evaluated the effectiveness of a (4-session) motivational interviewing (MI) intervention to reduce substance use and sexual risk taking when delivered at two community-based organizations (CBOs) in the New York City metropolitan area. Participants included 86 YSMM aged 15-29 who reported recent sexual HIV transmission risk and substance use. Overall, 86% of the sample identified as a racial or ethnic minority. Within each CBO, participants were randomized to receive either the MI intervention or enhanced treatment as usual (an HIV testing session plus PrEP information and referrals to CBO services). Contrary to hypotheses, results provided no indication that the MI intervention was associated with reductions in substance use (alcohol, cannabis, or other illicit drug use) or sexual risk taking or current PrEP use. Results are discussed in terms of challenges in real world intervention implementation, study enrollment, and the COVID-19 pandemic.

Differential association between dairy intake patterns and incident prostate cancer: a potential dairy matrix effect.

OBJECTIVE: To evaluate the association between dairy intake patterns and the risk of prostate cancer (PC), and its histological differentiation, among men from Mexico City. METHODS: We analyzed the information from 394 incident PC cases paired by age (± 5 years) with 794 population controls. According to the Gleason score at diagnosis, cases were classified as well- (≤ 6), moderately- (= 7), and poorly differentiated PC (≥ 8). Based on a semiquantitative-food frequency questionnaire and using energy-density approach, we estimated the energy-adjusted daily intake of whole milk, cheese (fresh, Oaxaca, and Manchego), cream, and yogurt. Through a principal component analysis, we identified three dairy intake patterns: whole milk, cheese, and yogurt. The association between each dairy intake pattern and PC was evaluated from independent nonconditional logistic regression models. We also evaluated the mediator role of calcium and saturated fat intake. RESULTS: After adjustment, a high intake of whole milk pattern was associated with a 63% increased risk of PC (ORhigh vs low: 1.63; 95% CI 1.17-2.25, p trend = 0.002); at expenses of moderately (ORhigh vs low: 1.77; 95% CI 1.09-2.85, p trend = 0.015) and poorly differentiated PC (ORhigh vs low: 1.75; 95% CI 1.05- 2.92, p trend = 0.031). The association was mainly mediated by calcium intake (proportion mediated = 1.17; p < 0.01). No associations were found between cream and yogurt intake patterns with risk of PC, and its histological grade. CONCLUSIONS: A differential association of dairy intake patterns with risk of PC, and the poorly differentiated PC, was identified. This association seems to be determined by different dairy matrices and it is mediated by calcium content. Longitudinal studies are needed to confirm these findings and be able to identify other potential mediators in the etiology of PC.

Clinical characteristics, bacterial coinfections and outcomes in COVID-19-associated pulmonary aspergillosis in a third-level Mexican hospital during the COVID-19 pre-vaccination era.

BACKGROUND: Damage due to respiratory viruses increases the risk of bacterial and fungal coinfections and superinfections. High rates of invasive aspergillosis are seen in severe influenza and COVID-19. This report describes CAPA cases diagnosed during the first wave in the biggest reference centre for severe COVID-19 in Mexico. OBJECTIVES: To describe the clinical, microbiological and radiological characteristics of patients with invasive pulmonary aspergillosis associated with critical COVID-19, as well as to describe the variables associated with mortality. METHODS: This retrospective study identified CAPA cases among individuals with COVID-19 and ARDS, hospitalised from 1 March 2020 to 31 March 2021. CAPA was defined according to ECMM/ISHAM consensus criteria. Prevalence was estimated. Clinical and microbiological characteristics including bacterial superinfections, antifungal susceptibility testing and outcomes were documented. RESULTS: Possible CAPA was diagnosed in 86 patients among 2080 individuals with severe COVID-19, representing 4.13% prevalence. All CAPA cases had a positive respiratory culture for Aspergillus species. Aspergillus fumigatus was the most frequent isolate (64%, n = 55/86). Seven isolates (9%, n = 7/80) were resistant to amphotericin B (A. fumigatus n = 5/55, 9%; A. niger, n = 2/7, 28%), two A. fumigatus isolates were resistant to itraconazole (3.6%, n = 2/55). Tracheal galactomannan values ranged between 1.2 and 4.05, while serum galactomannan was positive only in 11% (n = 3/26). Bacterial coinfection were documented in 46% (n = 40/86). Gram negatives were the most frequent cause (77%, n = 31/40 isolates), from which 13% (n = 4/31) were reported as multidrug-resistant bacteria. Mortality rate was 60% and worse prognosis was seen in older persons, high tracheal galactomannan index and high HbA1c level. CONCLUSIONS: One in 10 individuals with CAPA carry a resistant Aspergillus isolate and/or will be affected by a MDR bacteria. High mortality rates are seen in this population.

Sex differences in autism-like behavior and dopaminergic neurons in substantia nigra of juvenile mice prenatally exposed to valproate.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication and repetitive and restricted behaviors. Sex dimorphism in the brain, including midbrain dopaminergic circuits, can explain differences in social behavior impairment and stereotypic behaviors between male and female individuals with ASD. These abnormal patterns may be due to alterations in dopamine synthesis in the ventral tegmental area (VTA) and substantia nigra (SN). We used an autism-like mouse model by prenatal valproic acid (VPA) exposure. CD1 pregnant female mice were injected with 500 mg/kg VPA or 0.9% NaCl as a vehicle on gestational day 12.5. In the offspring, on postnatal day 31, we examined the social and repetitive behaviors and the number of tyrosine hydroxylase (TH)-positive cells in VTA and SN by sex. Male VPA mice showed impaired social behavior and increased repetitive behaviors when compared to male vehicles. In females, we did not find statistically significant differences in social or repetitive behaviors between the groups. Male VPA mice had fewer TH+ cells in the SN than control-vehicle mice. Interestingly, no cellular changes were observed between females. This study supports the notion that sex dimorphism of certain brain regions is involved in the etiopathogenesis and clinical presentation of ASD.

Practical RGB-to-XYZ Color Transformation Matrix Estimation under Different Lighting Conditions for Graffiti Documentation.

Color data are often required for cultural heritage documentation. These data are typically acquired via standard digital cameras since they facilitate a quick and cost-effective way to extract RGB values from photos. However, cameras' absolute sensor responses are device-dependent and thus not colorimetric. One way to still achieve relatively accurate color data is via camera characterization, a procedure which computes a bespoke RGB-to-XYZ matrix to transform camera-dependent RGB values into the device-independent CIE XYZ color space. This article applies and assesses camera characterization techniques in heritage documentation, particularly graffiti photographed in the academic project INDIGO. To this end, this paper presents COOLPI (COlor Operations Library for Processing Images), a novel Python-based toolbox for colorimetric and spectral work, including white-point-preserving camera characterization from photos captured under diverse, real-world lighting conditions. The results highlight the colorimetric accuracy achievable through COOLPI's color-processing pipelines, affirming their suitability for heritage documentation.

Ex-vivo evaluation of a percutaneous looped thread desmotomy of the accessory ligament of the deep digital flexor tendon in horses.

OBJECTIVE: To determine the ability to completely transect the equine accessory ligament of the deep digital flexor tendon (AL-DDFT) via an ultrasonographically-guided, percutaneous looped thread desmotomy using FiberWire suture as a cutting device. STUDY DESIGN: Ex-vivo study. SAMPLE POPULATION: A total of 24 normal equine distal forelimb specimens. METHODS: Under ultrasonographic guidance, a Jamshidi needle was placed between the suspensory ligament and the AL-DDFT, and between the AL-DDFT and the deep digital flexor tendon, through two stab incisions. FiberWire suture was fed through the needle and looped around the AL-DDFT. Using a sawing motion, the ligament was transected, and the suture exited through the lateral incision. Surgical sites were dissected and assessed for completeness of transection, iatrogenic injuries, and suture remnants. Descriptive statistics were reported. RESULTS: The procedure met the successful criteria in 18/24 (75%) of the limbs. The median surgical time was 11 min (range 7-25). No suture failure or suture remnants were noted in any of the specimens. Complications included iatrogenic injury to the medial and lateral neurovascular bundles in 4/24 and 1/24 specimens, respectively. CONCLUSION: Complete transection of the AL-DDFT was achieved in 22/24 (92%) of the specimens; however, the neurovascular bundles were injured in 5/24 (21%) of the specimens. CLINICAL SIGNIFICANCE: A percutaneous looped thread desmotomy of the AL-DDFT can be studied as an alternative technique for use in equine models prior to its clinical use in patients. Additional studies are required to evaluate efficacy and safety in anesthetized or standing horses.

Prognostic value of neutrophil-to-lymphocyte ratio at diagnosis in colorectal cancer: propensity score analysis.

INTRODUCTION: Baseline neutrophil-to-lymphocyte ratio (NLR) at the time of colorectal cancer (CRC) diagnosis has been proposed as a predictor of long-term survival. The aim of the study was to analyse its usefulness in a homogeneous population with control of the main confounding factors. METHODOLOGY: Observational study of 836 patients operated on for CRC who were divided into two groups: NLR ≤ 3.3 vs NLR > 3.3. To control for confounders, they were matched one-to-one by propensity analysis. A final sample of 526 patients remained for study. RESULTS: The two groups were mismatched in terms of age, comorbidity, tumour stage, rectal location, and neoadjuvant therapy. Once matching was performed, baseline NLR was statistically significantly associated with long-term survival (p < 0.001) and behaved as an independent prognostic factor for survival (p = 0.001; HR: 1,996; 95% CI: 1.32-3.00) when adjusted in a Cox regression model using age (p < 0,001; HR: 1,04; IC95%: 1,02-1,06) and the Charlson Comorbidity Index (p < 0,001; HR: 1,40; IC95%: 1,27-1,55). Neoadjuvant therapy lost its statistical significance (p = 0,137; HR: 1,59; IC95%: 0,86-2,93). CONCLUSIONS: A high baseline NLR (> 3.3) in patients with colorectal cancer at diagnosis represents a poor prognostic factor in terms of survival. Its use in routine practice could intensify therapeutic strategies and follow-up in these patients.

Late puberty onset and lack of acne during adolescence reduce high-grade prostate cancer at adulthood.

BACKGROUND: The interplay between pubertal events patterns (PEP) and prostate cancer (PCa) remains poorly understood. Therefore, we investigated the association of PEP with the odds of PCa, and PCa histological differentiation in men residents of Mexico city. METHODS: In this case-control study, we analyzed the information of 371 incident prostate cancer cases and 775 controls matched on age (±5 years). High-grade prostate cancer was classified with Gleason score at diagnosis as ≥8. With information related to beard growth, age at maximum height attainment, and acne severity, the k-medoids algorithm was used to identify three mutually exclusive PEP (early, intermediate, and late). This association was evaluated using multivariable nonconditional logistic regression models. RESULTS: Men with late PEP, characterized by age at maximum height attainment at around 23 years and no history of acne, was inversely associated with incident (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.15-0.48, p trend <0.01) and high-grade prostate cancer (OR: 0.24; 95% CI: 0.09-0.59, p trend <0.01). Similar associations were observed even after adjusting by IGF-1 (OR: 0.19; 95% CI: 0.06-0.58) and androgens excretion (OR: 0.21; 95% CI: 0.06-0.66). Only the association between the absence of acne and prostate cancer remained significant after adjustment by these biomarkers. CONCLUSIONS: This study suggests that pubertal characteristics might be helpful in identifying risk groups, among which, secondary prevention strategies could be applied. Also, the results agree with previous work suggesting other potential biological mechanisms involved in the etiology of prostate cancer such as the infectious and inflammatory pathways.

Changes in the heartbeat-evoked potential are associated with functional seizures.

BACKGROUND: Patients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation reflects disembodiment, which may be related to changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalogram (EEG) marker of interoceptive processing. AIM: To assess whether alterations in interoceptive processing indexed by HEP occur prior to FS and compare this with epileptic seizures (ES). METHODS: HEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and were compared between interictal and preictal states. HEP amplitude difference was calculated as preictal HEP amplitude minus interictal HEP amplitude. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of HEP amplitude difference in discriminating FS from ES. RESULTS: The FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, false discovery rate (FDR)-corrected q=0.030) and C4 (rB=0.600, FDR-corrected q=0.035). No differences in HEP amplitude were found between states in the ES group. Between diagnostic groups, HEP amplitude difference differed between the FS and ES groups at F8 (rB=0.423, FDR-corrected q=0.085) and C4 (rB=0.457, FDR-corrected q=0.085). Using HEP amplitude difference at frontal and central electrodes plus sex, we found that the ROC curve demonstrated an area under the curve of 0.893, with sensitivity=0.840 and specificity=0.842. CONCLUSION: Our data support the notion that aberrant interoception occurs prior to FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS and may have diagnostic utility in differentiating FS and ES.

The Relationship Between Molecular Symmetry and Physicochemical Properties Involving Boiling and Melting of Organic Compounds.

OBJECTIVE AND METHODS: The reliable estimation of phase transition physicochemical properties such as boiling and melting points can be valuable when designing compounds with desired physicochemical properties. This study explores the role of external rotational symmetry in determining boiling and melting points of select organic compounds. Using experimental data from the literature, the entropies of boiling and fusion were obtained for 541 compounds. The statistical significance of external rotational symmetry number on entropies of phase change was determined by using multiple linear regression. In addition, a series of aliphatic hydrocarbons, polysubstituted benzenes, and di-substituted napthalenes are used as examples to demonstrate the role of external symmetry on transition temperature. RESULTS: The results reveal that symmetry is not well correlated with boiling point but is statistically significant in melting point. CONCLUSION: The lack of correlation between the boiling point and the symmetry number reflects the fact that molecules have a high degree of rotational freedom in both the liquid and the vapor. On the other hand, the strong relationship between symmetry and melting point reflects the fact that molecules are rotationally restricted in the crystal but not in the liquid. Since the symmetry number is equal to the number of ways that the molecule can be properly oriented for incorporation into the crystal lattice, it is a significant determinant of the melting point.

Epidemiology and clinical domains of Behçet's disease in the Cantabria region, Northern Spain.

OBJECTIVES: The prevalence of Behçet's disease (BD) has a considerable geographical and temporal variability. Data regarding epidemiology in Spain are limited. Our study aimed to assess the epidemiology and clinical domains of BD in a population-based cohort from Northern Spain and to compare the results with other geographical areas of other countries. METHODS: We conducted a cross-sectional study of a well-defined population in Northern Spain. Cases of suspected BD between January 1980 and December 2018 were identified. The diagnosis of BD was established according to the International Study Group (ISG) for Behçet's Disease. The incidence of BD between 1999 and 2018 was estimated by sex, age, and year of diagnosis. RESULTS: Of 120 patients with probable BD, 59 patients met ISG criteria and were finally included in the study, with a male/female ratio of 0.97; mean age 49.7±14.7 years. Incidence during the period of study was 0.492 per 100,000 people, observing an increase from January 1999 to December 2018. Prevalence was 10.14 per 100,000 inhabitants in 2018. Clinical manifestations were relapsing aphthous stomatitis (100%), genital ulcers (78%), skin involvement (84.7%), joint involvement (64.4%), uveitis (55.9%), central nervous system (16.9%), vascular (10.2%), and gastrointestinal manifestations (6.8%). CONCLUSIONS: The prevalence of BD in Cantabria is higher than in other Southern European countries. This difference may reflect a combination of geographic, genetic, or methodological variations, as well as the free accessibility to the Spanish Public Health System for the entire population. Clinical phenotypes observed are similar to those described in other world regions.