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Effective community engagement in T3–T4 research is widespread, however, similar stakeholder involvement is missing in T1–T2 research. As part of an effort to embed community stakeholders in T1–T2 research, an academic community partnered team conducted discussion groups with researchers to assess perspectives on (1) barriers/challenges to including community stakeholders in basic science, (2) skills/training required for stakeholders and researchers, and (3) potential benefits of these activities. Engaging community in basic science research was perceived as challenging but with exciting potential to incorporate “real-life” community health priorities into basic research, resulting in a new full-spectrum translational research model.
Clay mineral ‘Crystallinity Index Standards’ (CIS) composed of Palaeozoic mudrocks from southwest England were investigated systematically in five sub-fractions per sample for the first time. X-ray diffraction was used to determine mineral assemblages, calibrated 001 illite full-width-at-half-maximum (FWHM) values and illite polytype compositions, in addition to K–Ar isotopic analyses of all fine fractions. The FWHM results of the <2 µm fraction are consistent with previous studies and reflect the range of diagenetic to epizonal grades covered by the sample set SW1 to SW7 (~0.61–0.26°2θ). Diagenetic and lower anchizone samples also show significant broadening of 001 illite reflections in the finer fractions and contain mixtures of authigenic 1M + 1Md illite and detrital 2M1 white mica polytypes suitable for illite age analysis. The estimated end-member ages of the Bude (SW1-1992) and younger Crackington (SW3-2000) mudstones yield detrital ages of Late Cambrian to Middle Ordovician (493–457 Ma) and a broad range of 1M + 1Md illite ages between Middle Permian and Early Jurassic (271–190 Ma). The detrital age of the stratigraphically older Crackington Formation mudrock (SW2-1992) is Late Devonian (384–364 Ma) with 1M + 1Md illite ages between Late Triassic and Early Jurassic (219–176 Ma). The origin of Mesozoic 1M + 1Md illite ages may represent neocrystallized illite associated with Mesozoic hydrothermal events or similar events that thermally reset older authigenic illite with partial loss of radiogenic argon and no renewed crystal growth. In contrast, upper anchizonal and epizonal Devonian slates (SW3-2012, SW4-1992, SW6-1992 and SW7-2012) contain only the 2M1 polytype, with K–Ar ages younger than the stratigraphic age. The three finest fractions of SW4-1992 yield consistent Late Carboniferous ages (331–304 ± 7 Ma) that are considered to date the neocrystallized 2M1 mica. Most fractions of epizonal slate (SW6-1992, SW7-2012) yield Early Permian ages (293.6–273 Ma) corresponding to published cooling ages of the Tintagel High-Strain Zone and the intrusion of the Bodmin granite (291.4 ± 0.8 Ma). These first K–Ar age constraints for the fine fractions of the CIS should provide useful reference values for testing analytical procedures of illite age analysis.
Objectives: Bipolar disorder (BD) is associated with impairments in facial emotion and emotional prosody perception during both mood episodes and periods of remission. To expand on previous research, the current study investigated cross-modal emotion perception, that is, matching of facial emotion and emotional prosody in remitted BD patients. Methods: Fifty-nine outpatients with BD and 45 healthy volunteers were included into a cross-sectional study. Cross-modal emotion perception was investigated by using two subtests out of the Comprehensive Affective Testing System (CATS). Results: Compared to control subjects patients were impaired in matching sad (p < .001) and angry emotional prosody (p = .034) to one of five emotional faces exhibiting the corresponding emotion and significantly more frequently matched sad emotional prosody to happy faces (p < .001) and angry emotional prosody to neutral faces (p = .017). In addition, patients were impaired in matching neutral emotional faces to the emotional prosody of one of three sentences (p = .006) and significantly more often matched neutral faces to sad emotional prosody (p = .014). Conclusions: These findings demonstrate that, even during periods of symptomatic remission, patients suffering from BD are impaired in matching facial emotion and emotional prosody. As this type of emotion processing is relevant in everyday life, our results point to the necessity to provide specific training programs to improve psychosocial outcomes. (JINS, 2019, 25, 336–342)
BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.
Traditionally, personalised nutrition was delivered at an individual level. However, the concept of delivering tailored dietary advice at a group level through the identification of metabotypes or groups of metabolically similar individuals has emerged. Although this approach to personalised nutrition looks promising, further work is needed to examine this concept across a wider population group. Therefore, the objectives of this study are to: (1) identify metabotypes in a European population and (2) develop targeted dietary advice solutions for these metabotypes. Using data from the Food4Me study (n 1607), k-means cluster analysis revealed the presence of three metabolically distinct clusters based on twenty-seven metabolic markers including cholesterol, individual fatty acids and carotenoids. Cluster 2 was identified as a metabolically healthy metabotype as these individuals had the highest Omega-3 Index (6·56 (sd 1·29) %), carotenoids (2·15 (sd 0·71) µm) and lowest total saturated fat levels. On the basis of its fatty acid profile, cluster 1 was characterised as a metabolically unhealthy cluster. Targeted dietary advice solutions were developed per cluster using a decision tree approach. Testing of the approach was performed by comparison with the personalised dietary advice, delivered by nutritionists to Food4Me study participants (n 180). Excellent agreement was observed between the targeted and individualised approaches with an average match of 82 % at the level of delivery of the same dietary message. Future work should ascertain whether this proposed method could be utilised in a healthcare setting, for the rapid and efficient delivery of tailored dietary advice solutions.
OBJECTIVES/SPECIFIC AIMS: In this pilot case-control study, the metabolome was quantified in subjects with previously measured serum and clinical biomarkers. The serum metabolome was then integrated with existing serum and clinical biomarkers of WTC-exposed firefighters to identify pathways significant to loss of lung function following acute PM-exposure. This robust subset of metabolite and serum biomarkers may be clinically relevant to predicting progression to lung disease in a larger cohort. METHODS/STUDY POPULATION: Serum drawn within 6 months of 9/11 was analyzed in this pilot. Clinical measures were obtained from electronic medical records. Never-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated based on FEV1 percent predicted (FEV1 %Pred) at symptomatic presentation. Cases of WTC-LI (FEV1 %Pred <LLN, n=15) and controls (n=15) were identified from previous cohorts. Ultrahigh performance liquid chromatography tandem mass spectroscopy quantified the metabolomic fingerprints of a group with previously assessed (by multiplex panels; ELISA and Luminex) serum chemokines and cytokines. High-dimensional data analysis and dimension reduction techniques integrated metabolites, cytokines, chemokines, and clinical data to identify pathways of WTC-LI on curated data. Random Forest (RF) out-of-bag estimated success rates were used to measure classification utility of the refined biomarker profile. Principal components analysis (PCA) was used to visualize class separation produced by the refined profile. RESULTS/ANTICIPATED RESULTS: Of the 765 metabolites detected, 580 metabolites were quantified in more than 80% of subjects/group with relative standard deviation ≥15%. Relevant chemokines, cytokines, and clinical biomarkers were included based on previously established clinical importance. Initial PCA explained 34.7% of the variance in the first 3 components. RF was used to identify the top 5% of biomarkers important to class separation. RF of the refined biomarker profile correctly classified cases and controls with a 96.7% estimated success rate. A PCA of the refined metabolic profile now explained 46.2% of the variance in components 1–3, demonstrating improved class separation. Differentiators between cases of WTC-LI and controls included elevated sphingolipids in cases of WTC-LI. The metabolic-inflammatory serum biomarkers MDC, Apo AI, GM-CSF, and heart rate play an important role in class separation. Phospholipids and lysolipids also appeared to differentiate cases of WTC-LI from controls. Specifically, several glycero-phosphatidylcholines (GPC) were elevated in cases of WTC-LI. DISCUSSION/SIGNIFICANCE OF IMPACT: High-dimensional data analysis on the metabolic fingerprints, serum, and clinical biomarker data of a subset of WTC-exposed 9/11 rescue workers has identified pathways associated with the loss of lung function. Sphingolipids, known to function as inflammatory signaling mediators, are thought to play important roles in lung function under both physiological and pathological conditions. Changes in sphingolipid metabolism have been linked to several pulmonary disorders, including asthma, COPD, and acute lung injury. Interestingly, a relation between sphingolipid metabolism and the metabolic-inflammatory pathway is suggested by similarities observed in PCA. Findings of elevated GPCs are similar to COPD literature. Higher levels of GPCs could correspond to elevated levels of lysophosphatidic acid (LPA), a ligand of RAGE. RAGE is a known proinflammatory mediator; LPA species have well-described roles as lipid signaling molecules, function as synthetic intermediates in other metabolic pathways, and were found to be predictive of WTC-LI. Since metabolites are more proximal markers of disease processes, metabolites could capture the complexity of past exposures and, therefore, may better inform treatment. These pathways warrant further investigation into their mechanisms and therapeutic importance.
OBJECTIVES/SPECIFIC AIMS: Obstructive lung disease following particulate matter (PM) exposure is a major health concern. Coexisting metabolic syndrome (MetSyn) often occurs. Receptor for advanced glycation end products (RAGE) is highly expressed in the lung, is a strong predictor of FEV1, and is a key mediator of MetSyn. To determine if the loss of RAGE protects from the persistence of effects of particulate associated lung injury in a murine model. METHODS/STUDY POPULATION: Wild type (WT) and RAGE knockout (RKO) mice were exposed to 100 μg of PM (WTC-Aggregate, PM53) or PBS control by oropharyngeal aspiration. Lung function, methacholine challenge, and bronchoalveolar lavage (BAL) were quantified 28 days after PM exposure using flexiVent (Scireq Montreal, QC). BAL was obtained and cell differentials, cytokines and transcription factors were assayed. Bio-volume to airspace ratio and mean chord length were measured (Image J and Adobe Photoshop). RESULTS/ANTICIPATED RESULTS: WT mice were hyper-reactive to methacholine compared with their PBS controls 28 days after a single exposure to PM. They recovered from increased neutrophilia, loss of FEV, decreased compliance, and increased resistance, which were previously observed 24-hours after exposure. RKO were not hyper-reactive when compared with their own PBS controls. Lung histology shows persistence of loss of alveolar space in WT mice exposed to PM after 28 days. Area fraction was significantly higher in PM exposed WT mice after 28 days which was not significant after 24 hours. Mean chord length was significantly shorter for PM exposed at both time points for WT mice. The relative expression of phosphorylated to total CREB and ERK1/2 proteins was lower in RKO PM exposed mice compared with WT PM while STAT3 expression was lower in WT PM compared with WT PBS. PM induced a lower fold change of total proteins from the PBS controls in RKO for CREB, p38, ERK1/2, STAT3, and STAT5. JNK and p70S6k total proteins expressed a decreased fold change in WT PM exposed mice compared with WT PBS controls. DISCUSSION/SIGNIFICANCE OF IMPACT: A single dose of PM can produce persistent airway hyper-reactivity after 28 days of exposure. This PM induced injury is alleviated in the absence of RAGE, similar to what was seen at 24 hours. Inhibiting RAGE may be key to limiting the persistent inflammatory effects of high intensity PM exposure.
Objectives: Social cognitive deficits have been discussed to be endophenotypes for schizophrenia and other serious mental illnesses. The current study aimed to assess emotional intelligence (EI) in unaffected siblings of schizophrenia patients to investigate its potential role as endophenotype for schizophrenia. Methods: EI was measured in 56 schizophrenia patients, 57 unaffected siblings, and 127 healthy control subjects by using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). In addition, non-social cognition was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Linear mixed models with compound symmetric correlation structure were used for of the three groups with respect to EI and non-social cognition. Results: Schizophrenia patients showed significantly lower overall EI and performed significantly worse in three out of four MSCEIT branches compared to unaffected siblings and control subjects, whereas the two latter groups had comparable EI levels. Similar performance patterns (patients<unaffected siblings=control subjects) were found with respect to non-social cognition. Solely in the “Tower of London” test, siblings achieved significantly lower task scores compared to control subjects. Conclusions: Based on our results, EI as measured with the MSCEIT does not seem to represent a marker of risk for schizophrenia. Further investigations should concentrate on other EI measures to reassess this finding. (JINS, 2017, 23, 577–583)
Background: Ross syndrome is diagnosed by the presence of segmental anhidrosis, areflexia, and tonic pupils. Fewer than 60 cases have been described in literature so far. There have been reports of presence of antibodies in such patients, suggesting an autoimmune pathogenesis. Methods: We describe the clinical profile in this case series of 11 patients with Ross syndrome and discuss the current status of autoimmunity in its pathogenesis and the management. Results: Of the 11 patients with Ross syndrome there was an almost equal sex distribution (male:female ratio was 1.17:1) and the mean age of onset of symptoms was 26 years. Patients took an average of 6 years to present to a tertiary center. Sixty-three percent of the patients presented with complaints of excessive sweating, whereas only 27% had complaints of decreased sweating over a particular area of the body. Only 45% of the patients had the complete triad of Ross syndrome, which included segmental anhidrosis, tonic pupil, and absent reflexes. Eighty-nine percent of the patients had documented absent sympathetic skin response on electromyography. The various markers of autoimmunity were negative in all patients who were investigated for the same in this series. Ninety percent of the patients were managed conservatively. Conclusions: These findings suggest that, in Ross syndrome, generalized injury to ganglion cells or their projections are not purely autoimmune-mediated.
DNA methylation is an epigenetic marker that has been shown to vary significantly across different tissues. Taking advantage of the methylation differences between placenta-derived cell-free DNA and maternal blood, several groups employed different approaches for the discovery of fetal-specific biomarkers. The aim of this study was to analyse whole-genome fetal and maternal methylomes in order to identify and confirm the presence of differentially methylated regions (DMRs). We have initially utilized methylated DNA immunoprecipitation (MeDIP) and next-generation sequencing (NGS) to identify genome-wide DMRs between chorionic villus sampling (CVS) and female non-pregnant plasma (PL) and peripheral blood (WBF) samples. Next, using specific criteria, 331 fetal-specific DMRs were selected and confirmed in eight CVS, eight WBF and eight PL samples by combining MeDIP and in-solution targeted enrichment followed by NGS. Results showed higher enrichment in CVS samples as compared to both WBF and PL samples, confirming the distinct methylation levels between fetal and maternal DNA for the selected DMRs. We have successfully implemented a novel approach for the discovery and confirmation of a significant number of fetal-specific DMRs by combining for the first time MeDIP and in-solution targeted enrichment followed by NGS. The implementation of this double-enrichment approach is highly efficient and enables the detailed analysis of multiple DMRs by targeted NGS. Also, this is, to our knowledge, the first reported application of MeDIP on plasma samples, which leverages the implementation of our enrichment methodology in the detection of fetal abnormalities in maternal plasma.
To characterise clusters of individuals based on adherence to dietary recommendations and to determine whether changes in Healthy Eating Index (HEI) scores in response to a personalised nutrition (PN) intervention varied between clusters.
Food4Me study participants were clustered according to whether their baseline dietary intakes met European dietary recommendations. Changes in HEI scores between baseline and month 6 were compared between clusters and stratified by whether individuals received generalised or PN advice.
Individuals in cluster 1 (C1) met all recommended intakes except for red meat, those in cluster 2 (C2) met two recommendations, and those in cluster 3 (C3) and cluster 4 (C4) met one recommendation each. C1 had higher intakes of white fish, beans and lentils and low-fat dairy products and lower percentage energy intake from SFA (P<0·05). C2 consumed less chips and pizza and fried foods than C3 and C4 (P<0·05). C1 were lighter, had lower BMI and waist circumference than C3 and were more physically active than C4 (P<0·05). More individuals in C4 were smokers and wanted to lose weight than in C1 (P<0·05). Individuals who received PN advice in C4 reported greater improvements in HEI compared with C3 and C1 (P<0·05).
The cluster where the fewest recommendations were met (C4) reported greater improvements in HEI following a 6-month trial of PN whereas there was no difference between clusters for those randomised to the Control, non-personalised dietary intervention.
To characterise participants who dropped out of the Food4Me Proof-of-Principle study.
The Food4Me study was an Internet-based, 6-month, four-arm, randomised controlled trial. The control group received generalised dietary and lifestyle recommendations, whereas participants randomised to three different levels of personalised nutrition (PN) received advice based on dietary, phenotypic and/or genotypic data, respectively (with either more or less frequent feedback).
Seven recruitment sites: UK, Ireland, The Netherlands, Germany, Spain, Poland and Greece.
Adults aged 18–79 years (n 1607).
A total of 337 (21 %) participants dropped out during the intervention. At baseline, dropouts had higher BMI (0·5 kg/m2; P<0·001). Attrition did not differ significantly between individuals receiving generalised dietary guidelines (Control) and those randomised to PN. Participants were more likely to drop out (OR; 95 % CI) if they received more frequent feedback (1·81; 1·36, 2·41; P<0·001), were female (1·38; 1·06, 1·78; P=0·015), less than 45 years old (2·57; 1·95, 3·39; P<0·001) and obese (2·25; 1·47, 3·43; P<0·001). Attrition was more likely in participants who reported an interest in losing weight (1·53; 1·19, 1·97; P<0·001) or skipping meals (1·75; 1·16, 2·65; P=0·008), and less likely if participants claimed to eat healthily frequently (0·62; 0·45, 0·86; P=0·003).
Attrition did not differ between participants receiving generalised or PN advice but more frequent feedback was related to attrition for those randomised to PN interventions. Better strategies are required to minimise dropouts among younger and obese individuals participating in PN interventions and more frequent feedback may be an unnecessary burden.
The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AAv. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.