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OBJECTIVE: Proliferative verrucous leukoplakia (PVL) is considered a clinically distinct entity from other oral leucoplakias (OLs) due to its clinical presentation and evolution. However, molecular differences between them remain unclear. We aimed to determine whether there are methylation differences between PVL and other forms of OLs. MATERIALS AND METHODS: Oral biopsies from 12 patients with PVL, eight patients with homogeneous leucoplakia (HL), and 10 healthy individuals were obtained for a genome-wide DNA methylation analysis via the Infinium EPIC Platform. RESULTS: A total of 1815 differentially methylated CpGs were found between PVL and HL, with a prominent state of hypermethylation in HL patients. CpGs covered 813 genes with distinct roles, including cell adhesion, extracellular matrix organization, and cell and synaptic signaling. 43% of these genes had been previously described in cancer and associated with prognosis. We developed a multinomial logistic regression model able to differentiate HL, PVL, and control samples. The model had a cross-validated estimate of 73% and included differentially methylated cancer-related genes between the pathological conditions and the healthy donors, including ADNP, BRCA2, CDK13, GNB1, NIN, NUMB, PIK3C2B, PTK2, SHISA4, THSD7B, WWP1, and ZNF292. It also included CpGs covering differentially methylated genes in HL (MEN1 and TNRC6B) and PVL (ACOXL, ADH1B, CAMTA1, CBFA2T3, CPXM2, LRFN2, SORCS2, and SPN). CONCLUSIONS: PVL and HL present differential methylation patterns that could be linked to their differential clinical behavior. Our findings show the potential of methylation markers and suggest novel diagnostic biomarkers.
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Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.
Subject(s)
Alzheimer Disease , DNA Methylation , Epigenesis, Genetic , Humans , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Female , Male , Middle Aged , Brain/metabolism , Brain/pathology , Genome-Wide Association Study , Aged , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Frontotemporal Dementia/metabolism , CpG Islands/genetics , Cell Line , Lymphocytes/metabolismABSTRACT
BACKGROUND: Fat malabsorption in children with cystic fibrosis (CF) leads to poor nutritional status and altered colonic microbiota. This study aimed at establishing the faecal lipid profile in children with CF, and exploring associations between the faecal lipidome and microbiota. METHODS: Cross-sectional observational study with children with CF and an age-matched control group. Faecal lipidome was analysed by UHLC-HRMS and microbiota profiling by 16S rRNA amplicon sequencing. RESULTS: Among 234 identified lipid species, five lipidome clusters (LC) were obtained with significant differences in triacylglycerols (TG), diacylglycerols (DG), monoacylglycerols (MG) and fatty-acids (FA): LC1 subjects with good digestion and absorption: low TG and low MG and FA; LC2 good digestion and poor absorption: low TG and high MG and FA; LC3 Mild digestion and poor absorption: intermediate TG and high MG and FA; LC4 poor digestion and absorption: high TG and high MG and FA; LC5 outliers. Bacteroidota and Verrucomicrobiota decreased over LC1-LC4, while Proteobacteria increased. Nutritional status indicators were significantly higher in LC1 and decreased over LC2-LC4. CONCLUSION: Assessing faecal lipidome may be relevant to determine how dietary lipids are digested and absorbed. This new evidence might be a method to support targeted nutritional interventions towards reverting fat maldigestion or malabsorption. IMPACT: Lipidomic analysis enabled the identification of the lipid species related to maldigestion (triglycerides) or malabsorption (monoglycerides and fatty acids). Children with cystic fibrosis can be grouped depending on the faecal lipidome profile related to dietary fat maldigestion or malabsorption. The lipidome profile in faeces is related to the composition of microbiota and nutritional status indicators.
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BACKGROUND: Recent research suggests that children born after suspected preterm labor may observe a potential cluster with different attention deficit hyperactivity disorder features, depending on the time of birth. However, the evolution of symptoms and their predictors remain unknown in this population. OBJECTIVE: This study aimed to examine the trajectories of attention deficit hyperactivity disorder symptoms of children born after suspected preterm labor, between ages 2 and 6 years, considering prematurity condition and comparing with controls. In addition, this study aimed to find potential modifiable predictors of evolution to enhance prognosis. STUDY DESIGN: In this prospective cohort study, 119 mother-child pairs who experienced suspected preterm labor and 60 controls were included. Patients were divided according to prematurity condition in full term (n=27), late preterm (n=55), and very preterm (n=37). Attention deficit hyperactivity disorder symptoms were assessed at ages 2 and 6 years. The association between potential modifying factors (group, time of assessment, sex, birthweight percentile, maternal history of trauma, maternal anxiety at diagnosis, and maternal anxiety during the children's assessments) and disorder trajectories was assessed by adjusting the Bayesian mixed linear models. All analyses were performed in R (version 4.3.0; R Foundation for Statistical Computing, Vienna, Austria). RESULTS: An interaction emerged between time and group, with late-preterm neonates born after suspected preterm labor being the only group to improve from ages 2 to 6 years (-2.26 points in Conners scale per percentile decrease and 0.98 probability of effect). Another interaction between time and maternal anxiety at postnatal time assessments intensified over time (0.07 and 0.84). Predictors of symptom severity included lower weight percentile at birth (-0.2 and 0.96), male sex (-2.99 and <0.99), higher maternal anxiety at diagnosis (+0.08 and 0.99), and maternal history of trauma (+0.23 and 0.98). CONCLUSION: Unlike very-preterm and full-term children, those born late preterm showed an improvement over time, probably because late-preterm children do not carry the sequelae derived from severe prematurity but benefit from close monitoring. As maternal psychopathology emerged as a determinant modifier of course and severity, it is crucial to develop targeted psychological interventions for pregnant individuals and reevaluate monitoring programs for their offspring, regardless of prematurity.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Infant, Newborn, Diseases , Obstetric Labor, Premature , Infant, Newborn , Pregnancy , Female , Humans , Male , Cohort Studies , Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/etiology , Prospective Studies , Bayes Theorem , Obstetric Labor, Premature/diagnosis , Obstetric Labor, Premature/epidemiology , Obstetric Labor, Premature/etiologyABSTRACT
Spinal muscular atrophy (SMA) is a devastating genetic neurodegenerative disease caused by the insufficient production of Survival Motor Neuron (SMN) protein. It presents different phenotypes with frequent contractures and dislocations, scoliosis, and pain. This study aims to report the prevalence and description of pain and how it affects daily life by analyzing a new ad hoc questionnaire. An observational study of patients under 18 years of age with SMA was conducted at two referral centers in Spain. Data were analyzed using a descriptive analysis and a Bayesian ordinal regression model to assess the association with clinical and demographic variables. Fifty-one individuals were included in this study, 27% of whom reported pain with a median duration of 5.2 years and a mean Visual Analogic Scale (VAS) score of 5. Notably, 77% were receiving disease-modifying treatment, with more than 50% receiving analgesic treatment. The Bayesian model showed that functional status, lower limb contractures, and number of visits have a high probability (>90%) of influencing pain. Thus, the prevalence of pain in the SMA population under 18 years is substantial, and its presence could be associated with lower limb contractures, better functional status, and higher RULM (Revised Upper Limb Module) scores.
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Introduction: There are no data on the association of type of pneumonia and long-term mortality by the type of pneumonia (COVID-19 or community-acquired pneumonia [CAP]) on long-term mortality after an adjustment for potential confounding variables. We aimed to assess the type of pneumonia and risk factors for long-term mortality in patients who were hospitalized in conventional ward and later discharged. Methods: Retrospective analysis of two prospective and multicentre cohorts of hospitalized patients with COVID-19 and CAP. The main outcome under study was 1-year mortality in hospitalized patients in conventional ward and later discharged. We adjusted a Bayesian logistic regression model to assess associations between the type of pneumonia and 1-year mortality controlling for confounders. Results: The study included a total of 1,693 and 2,374 discharged patients in the COVID-19 and CAP cohorts, respectively. Of these, 1,525 (90.1%) and 2,249 (95%) patients underwent analysis. Until 1-year follow-up, 69 (4.5%) and 148 (6.6%) patients from the COVID-19 and CAP cohorts, respectively, died (p = 0.008). However, the Bayesian model showed a low probability of effect (PE) of finding relevant differences in long-term mortality between CAP and COVID-19 (odds ratio 1.127, 95% credibility interval 0.862-1.591; PE = 0.774). Conclusion: COVID-19 and CAP have similar long-term mortality after adjusting for potential confounders.
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Resveratrol (RSV) holds promise as cerebroprotective treatment in cerebral ischemia. This systematic review aims to assess the effects and mechanisms of RSV in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 75 and 57 eligible rodent studies for qualitative and quantitative syntheses, respectively. Range of evidence met 10 of 13 STAIR criteria. Median (Q1, Q3) quality score was 7 (5, 8) on the CAMARADES 15-item checklist. Bayesian meta-analysis showed SMD estimates (95% CI) favoring RSV: infarct size (-1.72 [-2.03; -1.41]), edema size (-1.61 [-2.24; -0.98]), BBB impairment (-1.85 [-2.54; -1.19]), neurofunctional impairment (-1.60 [-1.92; -1.29]), and motor performance (1.39 [0.64; 2.08]); and less probably neuronal survival (0.63 [-1.40; 2.48]) and apoptosis (-0.96 [-2.87; 1.02]). Species (rat vs mouse) was associated to a larger benefit. Sensitivity analyses confirmed robustness of the estimates. Reduction of oxidative stress, inflammation, and apoptosis underlie these effects. Our results quantitatively state the beneficial effects of RSV on structural and functional outcomes in rodent stroke models, update the evidence on the mechanisms of action, and provide an exhaustive list of targeted signaling pathways. Current evidence highlights the need for conducting further high-quality preclinical research to better inform clinical research.
Subject(s)
Ischemic Stroke , Stroke , Animals , Rats , Mice , Resveratrol/pharmacology , Resveratrol/therapeutic use , Bayes Theorem , Stroke/drug therapy , Ischemic Stroke/drug therapy , Disease Models, AnimalABSTRACT
Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.
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The role of NETs and platelet activation in COVID-19 is scarcely known. We aimed to evaluate the role of NETs (citrullinated histone H3 [CitH3], cell-free DNA [cfDNA]) and platelet activation markers (soluble CD40 ligand [CD40L] and P-selectin) in estimating the hazard of different clinical trajectories in patients with COVID-19. We performed a prospective study of 204 patients, categorized as outpatient, hospitalized and ICU-admitted. A multistate model was designed to estimate probabilities of clinical transitions across varying states, such as emergency department (ED) visit, discharge (outpatient), ward admission, ICU admission and death. Levels of cfDNA, CitH3 and P-selectin were associated with the severity of presentation and analytical parameters. The model showed an increased risk of higher levels of CitH3 and P-selectin for ED-to-ICU transitions (Hazard Ratio [HR]: 1.35 and 1.31, respectively), as well as an elevated risk of higher levels of P-selectin for ward-to-death transitions (HR: 1.09). Elevated levels of CitH3 (HR: 0.90), cfDNA (HR: 0.84) and P-selectin (HR: 0.91) decreased the probability of ward-to-discharge transitions. A similar trend existed for elevated levels of P-selectin and ICU-to-ward transitions (HR 0.40); In conclusion, increased NET and P-selectin levels are associated with more severe episodes and can prove useful in estimating different clinical trajectories.
Subject(s)
COVID-19 , Cell-Free Nucleic Acids , Extracellular Traps , Humans , P-Selectin , Prospective Studies , Histones , Platelet ActivationABSTRACT
BACKGROUND: Pharmacogenetics is a personalized medicine tool that aims to optimize treatments by adapting them to each individual's genetics, maximizing their efficacy while minimizing their toxicity. Infants with cancer are especially vulnerable, and their co-morbidities have vital repercussions. The study of their pharmacogenetics is new in this clinical field. METHODS: A unicentric, ambispective study of a cohort of infants receiving chemotherapy (from January 2007 to August 2019). The genotypes of 64 patients under 18 months of age were correlated with severe drug toxicities and survival. A pharmacogenetics panel was configured based on PharmGKB, drug labels, and international experts' consortiums. RESULTS: Associations between SNPs and hematological toxicity were found. Most meaningful were: MTHFR rs1801131 GT increasing the anemia risk (OR 1.73); rs1517114 GC, XPC rs2228001 GT, increasing neutropenia risk (OR 1.50 and 4.63); ABCB1 rs1045642 AG, TNFRSF11B rs2073618 GG, CYP2B6 rs4802101 TC and SOD2 rs4880 GG increasing thrombocytopenia risk (OR 1.70, 1.77, 1.70, 1.73, respectively). Regarding survival, MTHFR rs1801133 GG, TNFRSF11B rs2073618 GG, XPC rs2228001 GT, CYP3A4 rs2740574 CT, CDA rs3215400 del.del, and SLC01B1 rs4149015 GA were associated with lower overall survival probabilities (HR 3.12, 1.84, 1.68, 2.92, 1.90, and 3.96, respectively). Lastly, for event-free survival, SLC19A1 rs1051266 TT and CDA rs3215400 del.del increased the relapse probability (HR 1.61 and 2.19, respectively). CONCLUSIONS: This pharmacogenetic study is a pioneer in dealing with infants under 18 months of age. Further studies are needed to confirm the utility of the findings in this work to be used as predictive genetic biomarkers of toxicity and therapeutic efficacy in the infant population. If confirmed, their use in therapeutic decisions could improve the quality of life and prognosis of these patients.
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OBJECTIVE: Proliferative verrucous leukoplakia (PVL) has high rates of malignant transformation into oral squamous cell carcinoma (OSCC), but the clinical and evolutionary pattern of OSCC from PVL (PVL-OSCC) is more favorable than that of OSCC not preceded by PVL (OSCC). Here, we aimed to explore the pathophysiologic differences between PVL-OSCC and OSCC through transcriptomic and DNA methylation analyses. MATERIALS AND METHODS: In this case-control study, oral biopsies from 8 PVL-OSCC and 10 OSCC patients were obtained for global sequencing using RNAseq and a genome-wide DNA methylation analysis via the Infinium EPIC Platform (graphical abstract). RESULTS: One hundred and thirty-three differentially expressed genes (DEGs) were detected, 94 of them upregulated in OSCC. Most of these genes were previously described in cancer and associated with prognosis. The integrative analysis revealed 26 DEGs, corresponding to 37 CpGs, whose promoters were regulated by DNA methylation. Twenty-nine of the CpGs were found as hypermethylated in PVL-OSCC. Only 5 of the genes that were aberrantly methylated and differentially expressed were upregulated in PVL-OSCC patients, whereas 21 were underexpressed. CONCLUSIONS: PVL-OSCC patients presented lower expression of cancer-related genes. Hypermethylation of the promoter region of many genes was also noticed, indicating that DNA methylation could be a regulatory mechanism.
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The role of dysbiosis in the development and progression of oral potentially malignant disorders (OPMDs) remains largely unknown. Here, we aim to characterize and compare the oral microbiome of homogeneous leucoplakia (HL), proliferative verrucous leukoplakia (PVL), oral squamous cell carcinoma (OSCC), and OSCC preceded by PVL (PVL-OSCC). Fifty oral biopsies from HL (n = 9), PVL (n = 12), OSCC (n = 10), PVL-OSCC (n = 8), and healthy (n = 11) donors were obtained. The sequence of the V3-V4 region of the 16S rRNA gene was used to analyze the composition and diversity of bacterial populations. In the cancer patients, the number of observed amplicon sequence variants (ASVs) was lower and Fusobacteriota constituted more than 30% of the microbiome. PVL and PVL-OSCC patients had a higher abundance of Campilobacterota and lower Proteobacteria than any other group analyzed. A penalized regression was performed to determine which species were able to distinguish groups. HL is enriched in Streptococcus parasanguinis, Streptococcus salivarius, Fusobacterium periodonticum, Prevotella histicola, Porphyromonas pasteri, and Megasphaera micronuciformis; PVL is enriched in Prevotella salivae, Campylobacter concisus, Dialister pneumosintes, and Schaalia odontolytica; OSCC is enriched in Capnocytophaga leadbetteri, Capnocytophaga sputigena, Capnocytophaga gingivalis, Campylobacter showae, Metamycoplasma salivarium, and Prevotella nanceiensis; and PVL-OSCC is enriched in Lachnospiraceae bacterium, Selenomonas sputigena, and Prevotella shahii. There is differential dysbiosis in patients suffering from OPMDs and cancer. To the best of our knowledge, this is the first study comparing the oral microbiome alterations in these groups; thus, additional studies are needed.
Subject(s)
Carcinoma, Squamous Cell , Microbiota , Mouth Neoplasms , Humans , Mouth Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Dysbiosis , RNA, Ribosomal, 16S/genetics , Leukoplakia, OralABSTRACT
BACKGROUND: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. RESULTS: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. CONCLUSIONS: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.
Subject(s)
Neoplastic Cells, Circulating , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Biomarkers, Tumor/genetics , Neoplastic Cells, Circulating/pathology , Nitriles/therapeutic use , Prognosis , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Androgen/geneticsABSTRACT
Introduction: The COVID-19 pandemic has led to unprecedented social and mobility restrictions on a global scale. Since its start in the spring of 2020, numerous scientific papers have been published on the characteristics of the virus, and the healthcare, economic and social consequences of the pandemic. However, in-depth analyses of the evolution of single coronavirus outbreaks have been rarely reported. Methods: In this paper, we analyze the main properties of all the tracked COVID-19 outbreaks in the Valencian Region between September and December of 2020. Our analysis includes the evaluation of the origin, dynamic evolution, duration, and spatial distribution of the outbreaks. Results: We find that the duration of the outbreaks follows a power-law distribution: most outbreaks are controlled within 2 weeks of their onset, and only a few last more than 2 months. We do not identify any significant differences in the outbreak properties with respect to the geographical location across the entire region. Finally, we also determine the cluster size distribution of each infection origin through a Bayesian statistical model. Discussion: We hope that our work will assist in optimizing and planning the resource assignment for future pandemic tracking efforts.
Subject(s)
COVID-19 , Humans , Spain/epidemiology , COVID-19/epidemiology , Pandemics , Bayes Theorem , Disease OutbreaksABSTRACT
Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We assessed clinical data from patients with breast cancer receiving anthracyclines and searched for discriminating microRNAs between patients that developed cardiotoxicity (cases) and those that did not (controls), using RNA sequencing and regression analysis. Serum levels of 25 microRNAs were differentially expressed in cases versus controls within the first year after anthracycline treatment, as assessed by three different regression models (elastic net, Robinson and Smyth exact negative binomial test and random forest). MiR-4732-3p was the only microRNA identified in all regression models and was downregulated in patients that experienced cardiotoxicity. MiR-4732-3p was also present in neonatal rat cardiomyocytes and cardiac fibroblasts and was modulated by anthracycline treatment. A miR-4732-3p mimic was cardioprotective in cardiac and fibroblast cultures, following doxorubicin challenge, in terms of cell viability and ROS levels. Notably, administration of the miR-4732-3p mimic in doxorubicin-treated rats preserved cardiac function, normalized weight loss, induced angiogenesis, and decreased apoptosis, interstitial fibrosis and cardiac myofibroblasts. At the molecular level, miR-4732-3p regulated genes of TGFß and Hippo signaling pathways. Overall, the results indicate that miR-4732-3p is a novel biomarker of cardiotoxicity that has therapeutic potential against anthracycline-induced heart damage.
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OBJECTIVE: The objective of the present study was to define and validate an anastomotic leak prognostic score based on previously described and reported anastomotic leak risk factors (OVA-LEAK: https://n9.cl/ova-leakscore) and to establish if the use of OVA-LEAK score is better than clinical criteria (surgeon's choice) selecting anastomosis to be protected with a diverting ileostomy. MATERIAL & METHODS: This is a retrospective, multicentre cohort study that included patients who underwent cytoreductive surgery for primary advanced or relapsed ovarian cancer with colorectal resection and anastomosis between January 2011 and June 2021. Data from patients already included in the previous predictive model were not considered in the present analysis. To validate the performance of our logistic regression model, we used the OVA-LEAK formula (Annex I: https://n9.cl/ova-leakscore) for estimating leakage probabilities in a new independent cohort. Then, receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was used to measure the performance of the model. Additionally, the Brier score was also estimated. 95% confidence intervals (CI) for each of the estimated performance measures were also calculated. RESULTS: 848 out of 1159 recruited patients were finally included in the multivariable logistic regression model validation. The AUC of the new cohort was 0.63 for predicting anastomotic leak. Considering a cut-off point of 22.1% to be 'positive' (to get a leak) this would provide a sensitivity of 0.45, specificity of 0.80, positive predictive value of 0.09 and negative predictive value of 0.97 for anastomotic leak. If we consider this cut-off point to select patients at risk of leak for bowel diversion, up to 22.5% of the sampled patients would undergo a diverting ileostomy and 47% (18/40) of the anastomotic leaks would be 'protected' with the stoma. Nevertheless, if we consider only the 'clinical criteria' for performing or not a diverting ileostomy, only 12.5% (5/40) of the leaks would be 'protected' with a stoma, with a rate of diverting ileostomy of up to 24.3%. CONCLUSIONS: Compared with subjective clinical criteria, the use of a predictive model for anastomotic leak improves the selection of patients who would benefit from a diverting ileostomy without increasing the rate of stoma use.
Subject(s)
Anastomotic Leak , Ovarian Neoplasms , Anastomosis, Surgical/adverse effects , Anastomotic Leak/diagnosis , Anastomotic Leak/etiology , Cohort Studies , Female , Humans , Ileostomy/adverse effects , Neoplasm Recurrence, Local/etiology , Ovarian Neoplasms/complications , Prognosis , Retrospective StudiesABSTRACT
Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible; thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients. We demonstrated that BCAT1 is the candidate that achieves high diagnostic efficacy in circulating DNA derived from plasma (area under the curve: 0.85). Impact of potentially confounding variables was also explored.
Subject(s)
Cell-Free Nucleic Acids , Lung Neoplasms , Biomarkers, Tumor/genetics , Cell-Free Nucleic Acids/genetics , DNA , DNA Methylation , Epigenesis, Genetic , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Transaminases/geneticsABSTRACT
BACKGROUND AND PURPOSE: Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients. METHODS: Patients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales. RESULTS: The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs > 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE < 5 and RULM < 10), and a ceiling effect was found in stronger patients (HFMSE > 60 and RULM > 35). The ALSFRS-R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non-sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS-R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non-sitters (0.60). CONCLUSIONS: This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.
Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Child , Adult , Humans , Outcome Assessment, Health Care , Upper ExtremityABSTRACT
Objectives: The fatty acid (FA) composition of breast milk is a relevant aspect related to the development of the lactating infant. The present study aimed at exploring correlations between dietary intake of macro- and micronutrients with the FA profile in breast milk, and the possible implication for infants' growth. Study Design: Breast milk samples from a cohort of lactating women were collected 7-15 days postpartum. The FA profiles in triacylglycerol (TAG) and phospholipid (PL)-rich fractions were analyzed by gas chromatography. Diet was registered during the third trimester of pregnancy by means of a food frequency questionnaire (FFQ). In addition, anthropometric measurements of infants were collected from gestation and up to 12 months postpartum. Results: The FA profile in breast milk was characterized by a median of 37.4, 41.3 and 16.8% of saturated, monounsaturated, and polyunsaturated FAs, respectively. From the dietary components, zinc, iron, and B group vitamins were correlated positively with the proportion of total n-3 FAs in TAG and C20:5 n-3 in PL. Lycopene, vitamin E, zinc, and vitamin B2 showed a similar correlation with total polyunsaturated fatty acid (PUFA), total n-6 FAs, C20:4 n-6, and C18:2 n-6 in TAG. Regarding food groups, nuts showed the strongest association with several PUFA both in TAG and PL, while the vegetable group was also positively associated with C18:3 n-3. Furthermore, the concentration of linolenic acid (C18:3 n-3) and palmitic acid (C16:0) were positively associated with increased length for age (LFA) and weight for age (WFA) at 12 months compared with birth [ΔLFA -0.16 (-0.85, 0.37); ΔWFA -0.26 (-0.77, 0.21)]. Conclusions: Mothers' intake of nuts, dietary sources of zinc, iron, and B group vitamins were identified as potential predictors of a high-unsaturated FA profile in breast milk. In addition, linolenic and palmitic acids in breast milk were positively associated with infants' growth in the first year of life.
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OBJECTIVE: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. METHODS: This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. RESULTS: The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. INTERPRETATION: We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806.