Effects of mindfulness-based stress reduction on psychological distress in health workers: A three-arm parallel randomized controlled trial.

Mindfulness-based Stress Reduction (MBSR) has shown good efficacy for improving wellbeing in employees experiencing occupational stress. However, comparisons with other interventions, longer-term follow-up, and data from varying sociocultural contexts are lacking. This three-arm, parallel randomised controlled trial (RCT) examined the effects of MBSR on psychological distress in non-physician health workers in direct contact with patients. 105 participants were randomly allocated to either: (1) MBSR (N = 35), (2) Stress Management Course (SMC; N = 34) or (3) wait-list (N = 36). Participants and those assessing outcomes were blinded to group assignment. Participants completed questionnaires pre- and post-intervention and four months after the intervention. Psychological distress was measured using the General Health Questionnaire (GHQ-12) and Outcome Questionnaire (OQ-45). Secondary outcomes included perceived stress, job satisfaction, mindfulness skills and changes in salivary cortisol. 77 participants completed measures post-intervention and 52 at 4-month follow-up. MBSR showed a post-intervention effect in reducing GHQ-12 (ß = -0.80 [SE = 1.58] p < 0.01) and OQ-45 (ß = -0.72, [SE = 5.87] p < 0.05) psychological distress, compared to SMC and in reducing GHQ-12 (ß = -1.30 [SE = 1.38] p < 0.001) and OQ-45 (ß = -0.71, [SE = 5.58] p < 0.01) psychological distress compared to wait-list condition. In our secondary outcome, only MBSR was associated with a decrease in the cortisol awaking response by 23% (p < 0.05). At follow-up, only effects of MBSR on the psychological distress 'social role' subscale (ß = -0.76 [SE = 1.31] p < 0.05) remained significant, compared to SMC. In conclusion, MBSR appears useful in reducing short-term psychological distress in healthcare workers, but these effects were not maintained at follow-up. Trial registration: ISRCTN12039804.

Association between serum sphingolipids and eudaimonic well-being in white U.S. adults.

Emerging research has linked psychological well-being with many physiological markers as well as morbidity and mortality. In this analysis, the relationship between components of eudaimonic well-being and serum sphingolipids levels was investigated using data from a large national survey of middle-aged American adults (Midlife in the United States). Health behaviors (i.e., diet, exercise, and sleep) were also examined as potential mediators of these relationships. Serum levels of total ceramides-the main molecular class of sphingolipids previously associated with several disease conditions-were inversely linked with environmental mastery. In addition, significant correlations were found between specific ceramide, dihydroceramide, and hexosylceramides species with environmental mastery, purpose in life, and self-acceptance. Using hierarchical regression and mediation analyses, health behaviors appeared to mediate these associations. However, the link between ceramides and environmental mastery was partially independent of health behaviors, suggesting the role of additional mediating factors. These findings point to sphingolipid metabolism as a novel pathway of health benefits associated with psychological well-being. In particular, having a sense of environmental mastery may promote restorative behaviors and benefit health via improved blood sphingolipid profiles.

Analytical and Clinical Validation for RT-qPCR Detection of SARS-CoV-2 Without RNA Extraction.

Background: The recent COVID-19 pandemic has posed an unprecedented challenge to laboratory diagnosis, based on the amplification of SARS-CoV-2 RNA. With global contagion figures exceeding 4 million persons, the shortage of reagents for RNA extraction represents a bottleneck for testing globally. We present the validation results for an RT-qPCR protocol without prior RNA extraction. Due to its simplicity, this protocol is suitable for widespread application in resource-limited settings. Methods: Optimal direct protocol was selected by comparing RT-qPCR performance under a set of thermal (65, 70, and 95° for 5, 10, and 30 min) and amplification conditions (3 or 3.5 uL loading volume; 2 commercial RT-qPCR kits with a limit of detection below 10 copies/reaction) in nasopharyngeal swabs stored at 4°C in sterile Weise's buffer pH 7.2. The selected protocol was evaluated for classification concordance with a standard protocol (automated RNA extraction) in 130 routine samples and 50 historical samples with Cq values near to the clinical decision limit. Results: Optimal selected conditions for direct protocol were: thermal shock at 70°C for 10 min, loading 3.5 ul in the RT-qPCR. Prospective evaluation in 130 routine samples showed a 100% classification concordance with the standard protocol. The evaluation in historical samples, selected because their Cqs were at the clinical decision limit, showed 94% concordance with our confirmatory standard, which includes manual RNA extraction. Conclusions : Our results validate the use of this direct RT-qPCR protocol as a safe alternative for SARS-CoV-2 diagnosis in the case of a shortage of reagents for RNA extraction, with minimal clinical impact.

Mutations in sphingolipid metabolism genes are associated with ADHD.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75-80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.

A Thyroid Genetic Classifier Correctly Predicts Benign Nodules with Indeterminate Cytology: Two Independent, Multicenter, Prospective Validation Trials.

Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77-97] and 91% [95% CI 79-98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82-94] and 87% [95% CI 77-94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

Genetic testing for indeterminate thyroid cytology: review and meta-analysis.

Thyroid cancer is the most frequent endocrine malignancy, and its incidence is increasing. A current limitation of cytological evaluation of thyroid nodules is that 20-25% are reported as indeterminate. Therefore, an important challenge for clinicians is to determine whether an indeterminate nodule is malignant, and should undergo surgery, or benign, and should be recommended to follow-up. The emergence of precision medicine has offered a valuable solution for this problem, with four tests currently available for the molecular diagnosis of indeterminate cytologies. However, efforts to critically analyze the quality of the accumulated evidence are scarce. This systematic review and meta-analysis is aimed to contribute to a better knowledge about the four available molecular tests, their technical characteristics, clinical performance, and ultimately to help clinicians to make better decisions to provide the best care options possible. For this purpose, we address three critical topics: (i) the proper theoretical accuracy, considering the intended clinical use of the test (rule-in vs rule-out) and the impact on clinical decisions; (ii) the quality of the evidence reported for each test (iii) and how accurate and effective have the tests proved to be after their clinical use. Together with the upcoming evidence, this work provides significant and useful information for healthcare system decision-makers to consider the use of molecular testing as a public health need, avoiding unnecessary surgical risks and costs.

From Molecules to the Clinic: Linking Schizophrenia and Metabolic Syndrome through Sphingolipids Metabolism.

Metabolic syndrome (MS) is a prevalent and severe comorbidity observed in schizophrenia (SZ). The exact nature of this association is controversial and very often accredited to the effects of psychotropic medications and disease-induced life-style modifications, such as inactive lifestyle, poor dietary choices, and smoking. However, drug therapy and disease-induced lifestyle factors are likely not the only factors contributing to the observed converging nature of these conditions, since an increased prevalence of MS is also observed in first episode and drug-naïve psychosis populations. MS and SZ share common intrinsic susceptibility factors and etiopathogenic mechanisms, which may change the way we approach clinical management of SZ patients. Among the most relevant common pathogenic pathways of SZ and MS are alterations in the sphingolipids (SLs) metabolism and SLs homeostasis. SLs have important structural functions as they participate in the formation of membrane "lipid rafts." SLs also play physiological roles in cell differentiation, proliferation, and inflammatory processes, which might be part of MS/SZ common pathophysiological processes. In this article we review a plausible mechanism to explain the link between MS and SZ through a disruption in SL homeostasis. Additionally, we provide insights on how this hypothesis can lead to the developing of new diagnostic/therapeutic technologies for SZ patients.

Low serum sphingolipids in children with attention deficit-hyperactivity disorder.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric condition in childhood. ADHD is a multifactorial trait with a strong genetic component. One neurodevelopmental hypothesis is that ADHD is associated with a lag in brain maturation. Sphingolipids are essential for brain development and neuronal functioning, but their role in ADHD pathogenesis is unexplored. We hypothesized that serum sphingolipid levels distinguish ADHD patients from unaffected subjects. METHODS: We characterized serum sphingolipid profiles of ADHD patients and two control groups: non-affected relatives and non-affected subjects without a family history of ADHD. Sphingolipids were measured by LC-MS/MS in 77 participants (28 ADHD patients, 28 related controls, and 21 unrelated controls). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). Diagnostic criteria were assessed by two independent observers. Groups were compared by parametrical statistics. RESULTS: Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20-30% relative reductions. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity and 78% specificity. CONCLUSIONS: Our results showed lower levels of all major serum sphingomyelins in ADHD. These findings may reflect brain maturation and affect neuro-functional pathways characteristic for ADHD.

Intratask Variability As a Correlate for DRD4 and SLC6A3 Variants: A Pilot Study in ADHD.

UNLABELLED: Behavioral variability may be an ADHD key feature. Currently used ex-Gaussian/Fast Fourier Transform analyses characterize general distribution and oscillatory/rhythmic components of performance but are unable to demonstrate slow cumulative changes over entire tasks. OBJECTIVE: To explore how performance of ADHD children and unaffected sibs gradually evolves in relation to genetic variants linked to ADHD. METHOD: A total of 40 kids (20 ADHD-discordant sib pairs) between 8 and 13 years resolved a visual Go/NoGo with 10% NoGo probability. Variable number tandem repeats (VNTRs) at DRD4 and SLC6A3 were identified following standard protocols. Performance changes were assessed by linear/logistic mixed-effect models. RESULTS: Models exploring SLC6A3 effects demonstrated less accentuated increments of response time (RT) (p = .046) and cumulative increments in the correct responses to "NoGo" (p = .00027) in 10R/10R participants. Models for DRD4 showed faster decline of correct responses to "Go" (p = .0078) in 2R/7R carriers. CONCLUSION: Dynamical analysis of attention/inhibition measures may unravel new correlates to DRD4 and SLC6A3 variants.

ω-3 Long-Chain Polyunsaturated Fatty Acids and Fatty Acid Desaturase Activity Ratios as Eventual Endophenotypes for ADHD.

OBJECTIVE: Epidemiological studies suggest that long-chain polyunsaturated fatty acids (LC-PUFAs) may be suitable as endophenotypes for ADHD. To be appropriated vulnerability traits, endophenotypes should be altered in unaffected relatives of index cases. Serum profiles of LC-PUFAs in unaffected relatives of ADHD patients remain understudied. The main objective of this study was to compare serum LC-PUFAs in ADHD patients, unaffected relatives of index cases, and general-population unaffected participants. METHOD: LC-PUFA profiles of 72 participants (27 ADHD patients, 27 unaffected relatives, and 18 general-population participants) were obtained by gas chromatography-mass spectrometry (GC-MS). Groups were compared by parametrical statistics. RESULTS: Unaffected females from the general population presented lower Docosapentaenoic acid (DPA; p = .0012) and a-linolenic acid (ALA; p = .0091) levels compared with ADHD females and unaffected relatives. In addition, docosahexaenoic acid (DHA)/ALA and DHA/DPA ratios, addressing desaturase activity, were significantly lower in ADHD patients and unaffected relatives of ADHD patients in the female-subgroup (p = .022 and .04, respectively). CONCLUSION: DHA/ALA, DHA/DPA, serum DPA, and serum ALA may be suitable as endophenotypes for ADHD women.

Blood component usage during extracorporeal membrane oxygenation: experience in 98 patients at a Latin-American tertiary hospital.

BACKGROUND/AIMS: Hemorrhagic complications during ECMO may affect a large proportion of the patients depending on the clinical setting. To guarantee optimal delivery of blood products to these patients, blood banks require updated information on the transfusion requirements. Few studies to date provide this information. This work assesses transfusion requirements in neonates and children during ECMO during the past 9 years. METHODS: We reviewed blood bank and hospital records of patients who underwent ECMO at our institution between May 2003 and May 2012. Data obtained included age, weight, diagnosis, type, length of ECMO, and daily transfusion requirements during ECMO. Descriptive and non-parametric inferential statistic analyses were performed. Our series included 98 patients. RESULTS: Mean time of patients on ECMO was 9.2 days, with the longest treatment spanning 22 days. Mean daily transfusion requirements were 39.5 ml/kg of RBC, 12.9 ml/kg of plasma, 34.3 ml/kg of platelets and 1.4 ml/kg of cryoprecipitate. Patients who underwent ECMO due to cardiac disease or congenital diaphragmatic hernia (CDH) required significantly higher transfusion volumes of plasma (p<0.05), platelets (p< 0.05) and cryoprecipitate (p<0.05) when compared to patients underwent ECMO due to respiratory disease. Concomitant with the aging of ECMO circuits, patients showed increased requirements of RBC, plasma, and CRYO around the seventh day of the ECMO run. This effect was not observed for platelets, which remained nearly consistent around 2.2 transfusions/day. CONCLUSIONS: ECMO patients required significant transfusion support, which was particularly higher among patients who underwent ECMO due to cardiac disease or congenital diaphragmatic hernia.

Intra-Individual Response Variability Assessed by Ex-Gaussian Analysis may be a New Endophenotype for Attention-Deficit/Hyperactivity Disorder.

Intra-individual variability of response times (RTisv) is considered as potential endophenotype for attentional deficit/hyperactivity disorder (ADHD). Traditional methods for estimating RTisv lose information regarding response times (RTs) distribution along the task, with eventual effects on statistical power. Ex-Gaussian analysis captures the dynamic nature of RTisv, estimating normal and exponential components for RT distribution, with specific phenomenological correlates. Here, we applied ex-Gaussian analysis to explore whether intra-individual variability of RTs agrees with criteria proposed by Gottesman and Gould for endophenotypes. Specifically, we evaluated if normal and/or exponential components of RTs may (a) present the stair-like distribution expected for endophenotypes (ADHD > siblings > typically developing children (TD) without familiar history of ADHD) and (b) represent a phenotypic correlate for previously described genetic risk variants. This is a pilot study including 55 subjects (20 ADHD-discordant sibling-pairs and 15 TD children), all aged between 8 and 13 years. Participants resolved a visual Go/Nogo with 10% Nogo probability. Ex-Gaussian distributions were fitted to individual RT data and compared among the three samples. In order to test whether intra-individual variability may represent a correlate for previously described genetic risk variants, VNTRs at DRD4 and SLC6A3 were identified in all sibling-pairs following standard protocols. Groups were compared adjusting independent general linear models for the exponential and normal components from the ex-Gaussian analysis. Identified trends were confirmed by the non-parametric Jonckheere-Terpstra test. Stair-like distributions were observed for µ (p = 0.036) and σ (p = 0.009). An additional "DRD4-genotype" × "clinical status" interaction was present for τ (p = 0.014) reflecting a possible severity factor. Thus, normal and exponential RTisv components are suitable as ADHD endophenotypes.

[Neurocognitive models for attention deficit hyperactivity disorder and their consequences on the searching of endophenotypes]. / Modelos neurocognitivos para el trastorno por deficit de atencion/hiperactividad y sus implicaciones en el reconocimiento de endofenotipos.

INTRODUCTION: The influence of genetics in attention deficit hyperactivity disorder (ADHD) is well confirmed. However, identification of the specific genes involved in the pathogenesis of the disorder has proved to be difficult. Some authors suggest that the statistical power of molecular genetic studies could improve by replacing the diagnosis of the disease on the basis of clinical phenotype by quantitative risk markers closer to underlying genetic pathophysiology and gene action. Such markers, generically called 'endophenotypes', have attracted considerable scientific interest. When searching for new endophenotypes, priority must be given to markers that are based or anchored in the actual neuro-cognitive etiological models for ADHD. AIM: To describe the principal concepts involved in current models of ADHD and to briefly discuss their implication for identification of endophenotypes in ADHD. DEVELOPMENT: Herein we discuss the evolution of causal models for ADHD, from simple core deficit models to complex multiple-pathways models. Additionally, we describe the thalamo-cortico-striatal circuits, which is the common anatomic substrate for all causal models for ADHD. CONCLUSION: Thalamo-cortico-striatal circuits are recognized as the anatomic and functional substrate for all causal neuro-cognitive models for ADHD. In this context, any electrophysiological, behavioral, neuro-humoral or anatomic marker related with functions commanded by such system (mainly executive functions and reward functions) could be a promising endophenotype for ADHD. Special interest must be taken in markers that potentially allow us to 'dissect' parallels etiological pathways, like electrophysiological parameters or functional neuroimages. Finally, the psychometric properties of potential endophenotypes must be adequate for a reliable, sensitive and specific quantification.

Loss of heterozygosity on chromosome arms 3p and 6q in microdissected adenocarcinomas of the uterine cervix and adenocarcinoma in situ.

BACKGROUND: Despite the increasing frequency of adenocarcinomas of the uterine cervix, little is known regarding inactivation of tumor suppressor genes (TSGs) in this tumor type. The authors analyzed loss of heterozygosity (LOH) in 36 carcinomas of the cervix with glandular differentiation, and 5 adenocarcinoma in situ in 40 patients. METHODS: The authors analyzed samples using laser capture microdissection from archival material and DNA amplified with microsatellite markers on the following loci: 3p14.2 (D3S1234, D3S1300), 3p21.3 (D3S1029, D3S1447), 3p22-24 (D3S1537, D3S1351), 6q21-23.3 (D6S250), 6q25.1 (ESR), 6q25.2 (D6S255), 8p21 (D8S136, D8S1820), 13q12.3 (D13S220, D13S267), 17q21 (D17S579, D17S855). Eight additional markers spanning the short arm of chromosome 3 (3p12-p25) and six spanning the long arm of chromosome 6 (6q11-q27) were studied in the cases showing LOH to further define the deletion intervals. RESULTS: The frequency of allelic loss in cancers was chromosome 3p: 49% (p14.2: 35%, p21.3: 23%, p22-24: 41%), 6q: 48% (q21-23.1: 39%, q25.1: 45%, q25.2: 7%), 13q: 22%, 17q: 6%, and 8p: 18%. On chromosome arm 3p, the authors' data suggest at least two discrete areas of deletion: a proximal area between markers D3S1234 (p12) and D3S1766 (p14.2-14.3), and a second distal interval, telomeric from marker D3S4623 (p21.3). On chromosome 6q, the deletion area is between marker D6S300 (q22) and D6S255 (q25.2). Two of five preneoplastic lesions showed LOH on chromosome arm 3p, and two five showed allelic loss on chromosome arm on 6q, suggesting the genes might be inactivated early in cervical tumorigenesis. CONCLUSIONS: The authors have identified three chromosomal regions that may harbor TSGs involved in the development/progression of adenocarcinomas of the uterine cervix, 3p12-14.2, 3p21.3-pter, and 6q22-25.2. Deletions also were detected in adenocarcinoma in situ, suggesting the genes may be inactivated early in cervical tumorigenesis.