Gene variants for the WNT pathway are associated with severity in periodontal disease.

OBJECTIVE: Studies of Wnt variants-related to bone resorption in periodontitis are limited. The aim of this study was to establish the genotype and allele frequency of gene variants associated with the Wnt pathway in systemically healthy individuals with and without periodontitis (PD). MATERIALS AND METHODS: One hundred fifty-seven systemically healthy individuals were evaluated, 90 with PD and 67 without PD. Periodontal clinical indexes, serological and clinical indices of inflammation, and the following variants associated with the Wnt pathway: DKK, SOST, LRP5, and KREMEN were analyzed by high resolution melting and confirmed by Sanger sequencing. RESULTS: In the PD-free group, 67.2% of the individuals presented the variant for DKKrs1896367 (p = 0.008) and 82.6% had the variant for KREMEN rs132274 (p = 0.016). The heterozygous variant for the DKK rs1896367 polymorphism was associated with the absence of PD and lower severity OR: 0.33 (CI95% 0.15-0.70) and OR: 0.24 (CI95% 0.11-0.53), respectively. Similarly, KREMEN rs132274 was the homozygous variant associated with the absence of PD (OR: 0.33 (CI95% 0.13-0.88)). On the contrary, 85.6% of individuals with PD presented a variant for DKK rs1896368 (p = 0.042), all suffering severe forms of periodontitis. CONCLUSION: The presence of DKKrs1896367 and KREMENrs132274 variants in individuals without PD suggests that these single nucleotide polymorphisms could be protective factors for bone loss in PD. A very interesting finding is that the DKKrs1896368 variant was found in a high percentage of severe cases, suggesting that the presence of this variant may be related to the severe bone loss observed in PD.

The Linguistic-Cognitive Profile in an Adult Population with Parkinson's Disease and Deep Brain Stimulation: A Comparative Study.

Introduction. Individuals with Parkinson's disease (PD) exhibit general impairments, particularly non-motor symptoms that are related to language, communication, and cognition processes. People with this disease may undergo a surgical intervention for the placement of a deep brain stimulation device, which improves their motor symptoms. However, this type of intervention leads to a decline in their linguistic and cognitive abilities that becomes increasingly noticeable as the disease progresses. Objective. The objective of this research was to compare the performance and linguistic-cognitive profile of individuals with Parkinson's disease who underwent deep brain stimulation treatment based on the stage of the disease. Method. A total of 60 participants who were diagnosed with PD by their reference hospital were selected. These participants were divided into three groups based on the stage of the disease that they were in, forming three groups: a Stage I group (n = 20), a Stage II group (n = 20), and a Stage III group (n = 20). The linguistic-cognitive profile was assessed using the MoCA, ACE-III, and MetAphas tests. The design of this study was established as a quasi-experimental, cross-sectional investigation, and statistical analysis was performed using MANOVA to compare the scores between the study groups. Results. The results indicate that individuals in Stage I exhibit better linguistic and cognitive performance compared to the other groups of participants in Stage II and Stage III, with statistically significant differences (p < 0.05). Conclusion. In conclusion, the progression of PD leads to significant linguistic and cognitive decline in individuals with this disease who have a deep brain stimulation device, greatly limiting the autonomy and quality of life for people with PD.

Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.

Pitch as a Recipient, Channel, and Context Factor Affecting Thought Reliance and Persuasion.

Three experiments tested how low versus high pitch generated from sources beyond a message communicator can affect reliance on thoughts and influence recipients' attitudes. First, participants wrote positive or negative thoughts about an exam proposal (Experiments 1, 2) or their academic abilities (Experiment 3). Then, pitch from the message recipient (Experiment 1), channel (Experiment 2), or context (Experiment 3) was manipulated to be high or low. Experiment 1 showed that when participants vocally expressed their thoughts using low (vs. high) pitch, thoughts had a greater effect on attitudes toward exams. Experiment 2 revealed low (vs. high) pitch sounds from the keyboard participants used to write their thoughts produced the same effect on thought usage. Experiment 3 demonstrated that thoughts influenced attitudes more when listed while background music was low (vs. high) Pitch can influence attitudes through a meta-cognitive thought reliance process whether emerging from the recipient, channel, or context.

New Pieces for an Old Puzzle: Approaching Parkinson's Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.

Porphyromonas gulae and PPAD antibodies are not related to citrullination in rheumatoid arthritis.

INTRODUCTION: Porphyromonas gulae have the enzyme PPAD, as P. gingivalis, which is responsible for citrullination related to the pathophysiology of rheumatoid arthritis and periodontitis; this implies the presence of two species of PPAD-producing bacteria in the mouth as well as the presence of citrullinated proteins. There are no previous reports or studies investigating an association between P. gulae PPAD in rheumatoid arthritis (RA). OBJECTIVE: To assess the presence of P. gulae and anti-citrullinated peptide antibodies of P. gulae PAD in patients with RA and their possible relationship with clinical activity markers. SUBJECTS AND METHODS: A total of 95 patients with RA and 95 controls were included. Erythrocyte sedimentation rate (ESR), C-reactive protein, anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) were measured. Activity index-28 (DAS28) and SCDAI. The periodontal diagnosis was established. Presence of P. gulae and P. gingivalis. An ELISA was used to determine antibodies against citrullinated peptides of P. gulae PAD. RESULTS: A P. gulae frequency of 15.8% was observed in the RA group and 9.5% in the control group. Higher levels of ACPA were found in the P. gulae-positive patients of the RA group, finding no significant difference, but if in patients positive for P. gingivalis with statistical significance (p = 0.0001). The frequency of anti-VDK-cit and anti-LPQ-cit9 antibodies to PPAD of P. gulae was higher in the RA group than in the control group without significant difference. No relationship was found with the clinical variables despite the presence of P. gulae and anti-citrullinated peptide antibodies of P. gulae PPAD in patients with RA CONCLUSIONS: It was not possible to establish a connection with clinical variables in RA and P. gulae; as a result, the presence of P. gingivalis continues to contribute significantly to the increase in antibodies against citrullinated proteins/peptides from exogenous sources of citrullination in RA and periodontitis.

Self-Validation Theory: Confidence can Increase but also Decrease Performance in Applied Settings.

This article presents self-validation theory (SVT) as a framework predicting when mental contents guide performance. First, we illustrate how confidence can validate people's thoughts (goals, beliefs, identity) increasing and decreasing performance, depending on what thoughts are validated. This first section reviews examples of validation processes in guiding intellectual performance in academic settings, sport performance in athletes, as well as performance on diverse social tasks. SVT specifies moderating conditions for validation processes to operate. Therefore, in the second section of this review, we identify unique and testable moderators for metacognitive processes demonstrating when and for whom validation processes are more likely to occur. A third section calls for future research identifying new validating variables (e.g., preparation, courage) capable of increasing usage of unexplored thoughts relevant to performance (e.g., expectations). This final section examines new domains for validation (e.g., group performance, cheating in performance), discusses to what extent people can use self-validation strategies deliberatively to improve their performance and addresses when performance can be impaired by invalidation (e.g., due to identity threat).

Self-Validation Theory: Confidence can Increase but also Decrease Performance in Applied Settings

This article presents self-validation theory (SVT) as a framework predicting when mental contents guide performance. First, we illustrate how confidence can validate people’s thoughts (goals, beliefs, identity) increasing and decreasing performance, depending on what thoughts are validated. This first section reviews examples of validation processes in guiding intellectual performance in academic settings, sport performance in athletes, as well as performance on diverse social tasks. SVT specifies moderating conditions for validation processes to operate. Therefore, in the second section of this review, we identify unique and testable moderators for metacognitive processes demonstrating when and for whom validation processes are more likely to occur. A third section calls for future research identifying new validating variables (e.g., preparation, courage) capable of increasing usage of unexplored thoughts relevant to performance (e.g., expectations). This final section examines new domains for validation (e.g., group performance, cheating in performance), discusses to what extent people can use self-validation strategies deliberatively to improve their performance and addresses when performance can be impaired by invalidation (e.g., due to identity threat). (AU)

High Levels of Leptin and Adipsin Are Associated with Clinical Activity in Early Rheumatoid Arthritis Patients with Overweight and Periodontal Infection.

Adipokines are associated with the pathogenesis of rheumatoid arthritis (RA) and are potential biomarkers of disease activity, periodontitis, and obesity. The aim of this was to establish the association between adipokine profile, RA disease activity, body mass index, and periodontal infection. This study evaluated 51 patients with early-RA and 51 controls including serum rheumatological markers, adipokine levels, detection of Porphyromonas gingivalis and serum anti-Porphyromonas gingivalis antibodies, clinical and periodontal measurements. Statistical analyses were run with SPSS® V26, with a logistic regression model to confirm associations. The results show high levels of leptin were more frequent in patients (p = 0.001) who simultaneously showed a higher frequency of Porphyromonas gingivalis (p = 0.004). Patients with concomitant presence of Porphyromonas gingivalis, high clinical activity score, and overweight were correlated with high levels of leptin (OR, 7.20; 95% CI, 2.68-19.33; p = 0.0001) and adipsin (OR, 2.69; 95% CI, 1.00-7.28; p = 0.005). The conclusion is that high levels of leptin and adipsin are associated with greater clinical activity in early-RA patients with overweight and periodontal infection, whereby overweight and Porphyromonas gingivalis may enhance RA activity. This may represent a pathological mechanism between these conditions, where adipokines seem to have a key role.

Adipokine Profile on Joint and Periodontal Conditions in First-degree Relatives of Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation and destruction. OBJECTIVE: Establish the association between Porphyromonas gingivalis (P. gingivalis) infection, body mass index (BMI), joint involvement, and serum adipokines in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA). METHODS: The cross-sectional study evaluated 124 FDR and 124 healthy controls (HC). The clinical examination included joint and radiographic evaluation and calculation of BMI. Serum adipokine levels were measured (leptin, vaspin, adiponectin, resistin, and adipsin), as were the erythrocyte sedimentation rate, C-reactive protein, and anti-citrullinated protein antibodies. Investigations were performed to detect P. gingivalis, and anti-P. gingivalis antibodies. Statistical analyses were performed to confirm associations. RESULTS: Leptin levels in FDR were associated with BMI >25 (OR, 2.64; 95%CI, 1.17-5.97; P=0.019), radiographic damage (Simple Erosion Narrowing Score [SENS])/hands, total SENS, and joint space narrowing in feet (P=0.037, 0.026, 0.020, respectively). FDR had more tender joints (P=0.018); this finding was associated with high levels of leptin and resistin and low levels of adipsin (P=0.040, 0.040, and 0.019, respectively). The presence of P. gingivalis was related to FDR, low levels of adipsin, resistin, adiponectin, and a trend toward higher levels of leptin (P=0.002, 0.001, 0.003, and 0.060, respectively), whereas anti-P. gingivalis antibodies were related to low levels of adipsin (P=0.001). CONCLUSION: In FDR, serum adipokine levels were associated with overweight and the presence of P. gingivalis. Adipokine levels were also associated with joint involvement. Hence, adipokines may be involved in the pathogenesis of RA in FDR and warrant further investigation.

Maximal Sensitivity to Child Maltreatment at the Ages of 6 and 11 Years is Associated with the Risk of Bipolar Disorder.

Adverse childhood experiences, including child maltreatment (CM), are relevant environmental risk factors for bipolar disorder (BD). However, little is known about the interaction of the type, duration and frequency of abuse with the timing of abuse in BD. The aim of this study was to investigate the different patterns of childhood trauma (frequency, type and chronology) between BD patients and healthy controls (HCs) and to identify BD-sensitive periods of exposure to CM that could influence functioning outcomes. The Maltreatment and Abuse Chronology Exposure (MACE) scale was used to evaluate the importance of the type and timing of maltreatment in a sample of 60 patients diagnosed with euthymic BD. Additionally, 76 HCs were recruited for comparison. All participants were of European-Caucasian origin and were assessed in the 2016-2019 period. To identify the variables that maximally differentiated the type and timing of exposure to CM between the BD and HC groups, a linear mixed effects model and random forest (RF) analyses were applied. We showed that multiplicity and severity, nonverbal emotional abuse, witnessing interparental violence and emotional neglect were the main factors associated with BD. In addition, regarding the occurrence of maltreatment in BD patients, we identified two sensitive periods with a principal peak at the age of 6 and a secondary peak at the age of 11. Functionality at the assessment time was associated with CM in adolescence for both HC and BD participants. Although the sample size and retrospective nature of the MACE instrument were the main limitations of our study, we were unable to explore the role of variables such as sex or socioeconomic status. We concluded that the multiplicity and sensitivity of CM exposure, mainly of the emotional type, during middle childhood are important risk factors for BD, at least in the European-Caucasian cultural setting.

Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

Implementation of screening criteria for inflammatory bowel disease in patients with spondyloarthritis and its association with disease and endoscopic activity.

There is little literature on the implementation of screening criteria for inflammatory bowel disease (IBD) in patients with spondyloarthritis (SpA). This study aimed to apply IBD screening criteria in a group of patients with SpA without IBD diagnosis and correlate them to endoscopic findings and disease activity. A total of 82 patients with SpA were included. The IBD screening test and ileocolonoscopy with digital chromoendoscopy with magnification and histological analysis were performed. The data were analysed with Chi-square test/Fisher's exact test and multiple correspondence analysis. The major screening criteria found in 48.7% of the patients were associated with a history of infection (p = 0.037). Rectal bleeding was associated with the diagnosis of ankylosing spondylitis, acute inflammation, enthesitis and tissue architecture alteration in the ileum (p < 0.050). Diarrhoea was associated with a higher disease activity score (p = 0.02). Minor screening criteria were associated with painful inflammatory joint (p = 0.05), high disease activity score (p = 0.001) and high calprotectin levels (p = 0.050). Abdominal pain (36.9%) was associated with axial/peripheral compromise (p = 0.017), inflammatory back pain (p = 0.01), enthesitis (p = 0.021), higher disease activity score (p = 0.023) and acute ileum inflammation (p = 0.046). Diarrhoea of 4 weeks and abdominal pain were the most prevalent major and minor screening criteria, respectively, being related to early manifestations of inflammatory bowel compromise and higher disease activity score. This screening test grants a chance of opportune referral of SpA patients from rheumatology to gastroenterology.

Oral manifestations associated with inflammatory bowel disease and early endoscopic findings in patients with spondyloarthritis.

BACKGROUND AND AIMS: Spondyloarthritis (SpA) is a group of autoinflammatory disorders, of which the primary extra-articular manifestation is inflammatory bowel disease (IBD). The oral cavity being a part of gastrointestinal tract, is significantly compromised in IBD, and in many cases, it is the first site of clinical manifestations of IBD. This study aimed to identify changes in the oral mucosa associated with the onset of IBD and their association with endoscopic/histological findings. MATERIALS AND METHODS: The study assessed 80 patients with SpA and 52 healthy controls. Oral, rheumatological, and gastroenterological assessments were performed. The ileocolonoscopy was performed via digital magnification chromoendoscopy. The statistical analysis consisted of Chi-square, Fisher's exact, and multiple correspondence discriminant analysis tests. RESULTS: From the disease cohort, 63.0% patients showed oral lesions (p = 0.050). These manifestations ranged from gingivitis (55.0%, p = 0.001), aphthous stomatitis (3.8%, p = 0.091), angular cheilitis (2.6%, p = 0.200), and perioral erythema with scaling (1.3%, p = 0.300). All patients who presented with alterations in colonic mucosa also had oral lesions associated with IBD (p = 0.039), specifically gingivitis/aphthous stomatitis (p = 0.029). CONCLUSION: The patients with SpA without IBD present significant oral signs and symptoms. Gingivitis seems to be the most relevant because of its associations with early endoscopic and histological findings. CLINICAL RELEVANCE: An integral approach to the diagnostic tests that includes evaluations of oral, rheumatological and gastroenterological tissues may favor timely attention and improve patients' quality of life.

Strengthening the Link between Vaccine Predispositions and Vaccine Advocacy through Certainty.

BACKGROUND: Instruments designed to assess individual differences in predispositions towards vaccination are useful in predicting vaccination-related outcomes. Despite their importance, there is relatively little evidence regarding the conditions under which these instruments are more predictive. The current research was designed to improve the ability of these kinds of instruments to predict vaccination advocacy by considering the certainty associated with the responses to vaccination scales. METHOD: Across two studies, participants completed the Beliefs about Medicines Questionnaire BMQ scale (Study 1) or the Vaccination Attitudes Examination (VAX) scale (Study 2). The certainty participants had in their responses to each scale was either measured (Study 1) or manipulated (Study 2). Intentions to advocate in favor of vaccination served as the criterion measure in both studies. RESULTS: As expected, the scales significantly predicted vaccination advocacy, contributing to enhancing the predictive validity of the instruments used in the studies. Most relevant, certainty moderated the extent to which these scales predicted vaccination advocacy, with greater consistency between the initial scores and the subsequent advocacy willingness obtained for those with higher certainty. CONCLUSIONS: Certainty can be useful to predict when the relationship between vaccination-related cognitions (i.e., beliefs or attitudes) and advocacy willingness is likely to be stronger.

Familial component of early-onset colorectal cancer: opportunity for prevention.

BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Serum Orotidine: A Novel Biomarker of Increased CVD Risk in Type 2 Diabetes Discovered Through Metabolomics Studies.

OBJECTIVE: To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked in previous metabolomics studies of CVD. RESEARCH DESIGN AND METHODS: We conducted a global serum metabolomics analysis using the Metabolon platform in a discovery set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed up with absolute quantification assays in a validation set from the Joslin Heart Study including 599 individuals with T2D with and without clinical evidence of significant coronary heart disease (CHD). RESULTS: In the discovery set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39-2.72], P = 0.0001, and 1.62 [1.26-2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [1.11-1.75]), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (P < 0.05) C statistics and discrimination indices for CVD risk (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with the clinical predictors alone. CONCLUSIONS: Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.

Epigenome-Wide DNA Methylation Profiling of Normal Mucosa Reveals HLA-F Hypermethylation as a Biomarker Candidate for Serrated Polyposis Syndrome.

Serrated polyposis syndrome (SPS) is associated with a high risk for colorectal cancer. Intense promoter hypermethylation is a frequent molecular finding in the serrated pathway and may be present in normal mucosa, predisposing to the formation of serrated lesions. To identify novel biomarkers for SPS, fresh-frozen samples of normal mucosa from 50 patients with SPS and 19 healthy individuals were analyzed by using the 850K BeadChip Technology (Infinium). Aberrant methylation levels were correlated with gene expression using a next-generation transcriptome profiling tool. Two validation steps were performed on independent cohorts: first, on formalin-fixed, paraffin-embedded tissue of the normal mucosa; and second, on 24 serrated lesions. The most frequently hypermethylated genes were HLA-F, SLFN12, HLA-DMA, and RARRES3; and the most frequently hypomethylated genes were PIWIL1 and ANK3 (Δß = 10%; P < 0.05). Expression levels of HLA-F, SLFN12, and HLA-DMA were significantly different between SPS patients and healthy individuals and correlated well with the methylation status of the corresponding differentially methylated region (fold change, >20%; r > 0.55; P < 0.001). Significant hypermethylation of CpGs in the gene body of HLA-F was also found in serrated lesions (Δß = 23%; false discovery rate = 0.01). Epigenome-wide methylation profiling has revealed numerous differentially methylated CpGs in normal mucosa from SPS patients. Significant hypermethylation of HLA-F is a novel biomarker candidate for SPS.

Metabolomics study of COVID-19 patients in four different clinical stages.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the coronavirus strain causing the respiratory pandemic COVID-19 (coronavirus disease 2019). To understand the pathobiology of SARS-CoV-2 in humans it is necessary to unravel the metabolic changes that are produced in the individuals once the infection has taken place. The goal of this work is to provide new information about the altered biomolecule profile and with that the altered biological pathways of patients in different clinical situations due to SARS-CoV-2 infection. This is done via metabolomics using HPLC-QTOF-MS analysis of plasma samples at COVID-diagnose from a total of 145 adult patients, divided into different clinical stages based on their subsequent clinical outcome (25 negative controls (non-COVID); 28 positive patients with asymptomatic disease not requiring hospitalization; 27 positive patients with mild disease defined by a total time in hospital lower than 10 days; 36 positive patients with severe disease defined by a total time in hospital over 20 days and/or admission at the ICU; and 29 positive patients with fatal outcome or deceased). Moreover, follow up samples between 2 and 3 months after hospital discharge were also obtained from the hospitalized patients with mild prognosis. The final goal of this work is to provide biomarkers that can help to better understand how the COVID-19 illness evolves and to predict how a patient could progress based on the metabolites profile of plasma obtained at an early stage of the infection. In the present work, several metabolites were found as potential biomarkers to distinguish between the end-stage and the early-stage (or non-COVID) disease groups. These metabolites are mainly involved in the metabolism of carnitines, ketone bodies, fatty acids, lysophosphatidylcholines/phosphatidylcholines, tryptophan, bile acids and purines, but also omeprazole. In addition, the levels of several of these metabolites decreased to "normal" values at hospital discharge, suggesting some of them as early prognosis biomarkers in COVID-19 at diagnose.

Association of Serum and Crevicular Fluid Dickkopf-1 Levels with Disease Activity and Periodontitis in Patients with Early Rheumatoid Arthritis.

BACKGROUND: The aim of this study was to assess DKK-1 levels, in Gingival Crevicular Fluid (GCF) and serum, as a biomarker for bone loss and disease activity in periodontitis and early RA (eRA). METHODS: In this cross-sectional study, we obtained serum and GCF from 10 interproximal sites (Distal Buccal I/S, Mesio Buccal I/S, Distal Palatal/Lingual, Mesio Palatal/Lingual) according to the highest degree of inflammation by a patient for 240 sites from eRA patients. Patients received a periodontal assessment, a radiographic evaluation, tomography of interproximal sites, and DKK1 levels were determined by ELISA. Comparisons were performed by the Mann-Whitney U test and analysis by Chi2 test, and a logistic regression model was applied. RESULTS: The mean age was 46.33 ± 12.0 years, the Disease Activity Score (DAS-28-ESR) was 4.08 ± 1.4. Periodontitis was present in 65.2% of the patients, and 59.6% of these patients had bone loss in interproximal sites. DISCUSSION: Higher GCF-DKK1 levels were associated with serum-DKK1 (OR:2.41 IC95% 1.14-5.09, p=0.021) and were related with DAS28-ESR (p=0.001), Routine Assessment of Patient Index Data 3 (RAPID 3) (p=0.001), and tender joints (p=0.040). Foot bone erosion and juxta-articular osteopenia were associated with high levels of serum-DKK1 (p=0.009 and 0.001, respectively). Serum-DKK1 were associated with SDAI (OR: 2.38 IC95% 1.03-5.52, p=0.043), RAPID 3 (p=0.001), and rheumatoid factor (p=0.018). The GCF-DKK1 levels were associated with periodontal bone loss (p=0.011), periodontitis (p=0.070) and its severity (OR: 2.58 IC95% 2.28-7.28, p=0.001). Bone loss was more frequent in buccal sites (73.5%) and was associated with increased levels of DKK1 (p=0.033). CONCLUSION: In the early stages of the eRA disease, serum and GCF-DKK1 could be a biomarker for clinical disease activity and periodontal and articular bone erosion.