LPS vs. Poly I:C Model: Comparison of Long-Term Effects of Bacterial and Viral Maternal Immune Activation (MIA) on the Offspring

Am J Physiol Regul Integr Comp Physiol. 2021 Dec 7. doi: 10.1152/ajpregu.00087.2021. Online ahead of print.

ABSTRACT

A prominent health issue nowadays is the COVID-19 pandemic, which poses acute risks to human health. However, the long-term health consequences are largely unknown and cannot be neglected. An especially vulnerable period for infection is pregnancy, when infections could have long-term health effect on the child. Evidence suggests that maternal immune activation (MIA) induced by either bacteria or viruses presents various effects on the offspring, leading to adverse phenotypes in many organ systems. This review compares the mechanisms of bacterial and viral MIA and the possible long-term outcomes for the offspring by summarizing the outcome in animal LPS and Poly I:C models. Both models are activated immune responses mediated by Toll-like receptors. The outcomes for MIA offspring include neurodevelopment, immune response, circulation, metabolism and reproduction. Some of these changes keep existing until later life. Besides different doses and batches of LPS and Poly I:C, the injection day, administration route and also different animal species influence the outcomes. Here, we specifically aim to support colleagues when choosing their animal models for future studies.

PMID:34874190 | DOI:10.1152/ajpregu.00087.2021

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Nat Genet. 2021 Dec;53(12):1636-1648. doi: 10.1038/s41588-021-00973-1. Epub 2021 Dec 6.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

PMID:34873335 | DOI:10.1038/s41588-021-00973-1

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The value of anticancer drugs – a regulatory view

Nat Rev Clin Oncol. 2021 Dec 6. doi: 10.1038/s41571-021-00584-z. Online ahead of print.

ABSTRACT

The high prices of new anticancer drugs and the marginal added benefit perceived by some stakeholders have fuelled a debate on the value of anticancer drugs in the European Union, even though an agreed definition of what constitutes a drug’s value does not exist. In this Perspective, we discuss the value of drugs from different viewpoints and objectives of decision makers: for regulators, assessment of the benefit-risk balance of a drug is a cornerstone for approval; payers rely on cost-effectiveness analyses carried out by health technology assessment agencies for reimbursement decisions; for patients, treatment choices are based on personal preferences and attitudes to risk; and clinicians can use several scales (such as the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)) that have been developed as an attempt to measure value objectively. Although a unique definition that fully captures the concept of value is unlikely to emerge, herein we discuss the importance of understanding different perspectives, and how regulators can help to inform different decision makers.

PMID:34873312 | DOI:10.1038/s41571-021-00584-z

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miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia

Leukemia. 2021 Dec 6. doi: 10.1038/s41375-021-01480-2. Online ahead of print.

ABSTRACT

T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.

PMID:34873301 | DOI:10.1038/s41375-021-01480-2

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Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

Nat Med. 2021 Dec 6. doi: 10.1038/s41591-021-01539-8. Online ahead of print.

ABSTRACT

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10-9), with an ORR of 75% (95% confidence interval 57-89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

PMID:34873345 | DOI:10.1038/s41591-021-01539-8

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Overall Survival Prognostic Modelling of Non-small Cell Lung Cancer Patients Using Positron Emission Tomography/Computed Tomography Harmonised Radiomics Features: The Quest for the Optimal Machine Learning Algorithm

Clin Oncol (R Coll Radiol). 2021 Dec 3:S0936-6555(21)00433-7. doi: 10.1016/j.clon.2021.11.014. Online ahead of print.

ABSTRACT

AIMS: Despite the promising results achieved by radiomics prognostic models for various clinical applications, multiple challenges still need to be addressed. The two main limitations of radiomics prognostic models include information limitation owing to single imaging modalities and the selection of optimum machine learning and feature selection methods for the considered modality and clinical outcome. In this work, we applied several feature selection and machine learning methods to single-modality positron emission tomography (PET) and computed tomography (CT) and multimodality PET/CT fusion to identify the best combinations for different radiomics modalities towards overall survival prediction in non-small cell lung cancer patients.

MATERIALS AND METHODS: A PET/CT dataset from The Cancer Imaging Archive, including subjects from two independent institutions (87 and 95 patients), was used in this study. Each cohort was used once as training and once as a test, followed by averaging of the results. ComBat harmonisation was used to address the centre effect. In our proposed radiomics framework, apart from single-modality PET and CT models, multimodality radiomics models were developed using multilevel (feature and image levels) fusion. Two different methods were considered for the feature-level strategy, including concatenating PET and CT features into a single feature set and alternatively averaging them. For image-level fusion, we used three different fusion methods, namely wavelet fusion, guided filtering-based fusion and latent low-rank representation fusion. In the proposed prognostic modelling framework, combinations of four feature selection and seven machine learning methods were applied to all radiomics modalities (two single and five multimodalities), machine learning hyper-parameters were optimised and finally the models were evaluated in the test cohort with 1000 repetitions via bootstrapping. Feature selection and machine learning methods were selected as popular techniques in the literature, supported by open source software in the public domain and their ability to cope with continuous time-to-event survival data. Multifactor ANOVA was used to carry out variability analysis and the proportion of total variance explained by radiomics modality, feature selection and machine learning methods was calculated by a bias-corrected effect size estimate known as ω2.

RESULTS: Optimum feature selection and machine learning methods differed owing to the applied radiomics modality. However, minimum depth (MD) as feature selection and Lasso and Elastic-Net regularized generalized linear model (glmnet) as machine learning method had the highest average results. Results from the ANOVA test indicated that the variability that each factor (radiomics modality, feature selection and machine learning methods) introduces to the performance of models is case specific, i.e. variances differ regarding different radiomics modalities and fusion strategies. Overall, the greatest proportion of variance was explained by machine learning, except for models in feature-level fusion strategy.

CONCLUSION: The identification of optimal feature selection and machine learning methods is a crucial step in developing sound and accurate radiomics risk models. Furthermore, optimum methods are case specific, differing due to the radiomics modality and fusion strategy used.

PMID:34872823 | DOI:10.1016/j.clon.2021.11.014

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Determinants of safe sexual behavior of female sex workers in Tehran: the woman, her network, and the sexual partner

BMC Public Health. 2021 Dec 6;21(1):2219. doi: 10.1186/s12889-021-12266-7.

ABSTRACT

BACKGROUND: Despite the steady growth of sexual transmission of HIV, there is little evidence about safe sexual behavior of FSWs, and social network effects on this behavior, in Iran. Our aim in this study was to determine the effect of social network characteristics on condom use among FSWs, considering individual characteristics of the FSWs and of their sexual partners, characteristics of their relationship, and the FSW’s personal network.

METHODS: A cross-sectional ego-centric network survey of 170 FSWs was carried out in Tehran between January and June 2017. A multilevel ordered logistic regression analysis was conducted to examine the effects of individual and relational characteristics simultaneously.

RESULTS: Condom use in sexual relationships of the FSWs on average was rather low. Important determinants of safe sexual behavior were found both at the level of the individual FSW and at the level of the sexual partner. The main determinants at the level of the individual FSW were FSWs’ age and HIV knowledge. At the level of the sexual partner, age and education of sexual partners, as well as intimacy, duration of tie, frequency of contacts with a given partner, frequency of contact, perceived social support, and perceived safe sex norms were significantly associated with condom use.

CONCLUSIONS: The findings highlighted that considering only the individual characteristics of female sex workers is not sufficient for effectively promoting condom use. Factors at the network and dyadic level should also be considered, especially the role of sexual partners. Network-based interventions may be useful which modify social relationships to create a social environment that can facilitate changes in sexual behavior.

PMID:34872543 | DOI:10.1186/s12889-021-12266-7

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DNA methylation in childhood dental caries and hypomineralization

J Dent. 2021 Dec 4:103913. doi: 10.1016/j.jdent.2021.103913. Online ahead of print.

ABSTRACT

OBJECTIVES: Epigenetic modulation of gene expression may be important in dental conditions, including dental caries and enamel hypomineralisation. The aims of this study were to assess associations between DNA methylation in cord blood leucocytes at birth, and caries experience and enamel hypomineralisation at six years of age.

METHOD: The study sample was from a birth cohort study of twins. Dental examinations at six years identified the presence/absence of (i) ‘any caries’ (untreated and treated caries), (ii) ‘advanced caries’ (untreated, advanced caries and/or past treatment) and (iii) hypomineralised second primary molars (HSPM). Genome-wide analysis of DNA methylation was performed on cord blood of 27 twin pairs (14 dizygotic and 13 monozygotic) using the Illumina Infinium MethylationEPIC BeadChip array. Differentially methylated CpGs (DMCpGs) and regions (DMRs) associated with each dental outcome were investigated, while accounting for the relatedness of twins. Results with a false discovery rate <0.05 were treated as statistically significant.

RESULTS: 19 children had ‘any caries’, 15 had ‘advanced’ caries, and 18 had HSPM. No DMCpGs were associated with ‘any caries’, 16 and 19 DMCpGs were associated with ‘advanced caries’ and HSPM, respectively. DMRs were identified in association with all three outcomes. Genes implicated by these analyses included PBX1, ACAT2, LTBP3 and DDR1 which have been linked with dental tissue development in genetic studies.

CONCLUSION: This exploratory study identified differential methylation in several genes at birth associated with dental caries and HSPM at six years. Further research may provide valuable insights into aetiology of dental disease and/or reveal novel molecular-based approaches for early risk stratification.

CLINICAL SIGNIFICANCE: Epigenetic differences at birth are likely to be associated with dental health at six years and may be valuable biomarkers of early influences on dental health.

PMID:34875274 | DOI:10.1016/j.jdent.2021.103913

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Lessons learned: A critical reflection on child- and contextual variables related to the development of children with a significant cognitive and motor developmental delay

Res Dev Disabil. 2021 Dec 4;120:104142. doi: 10.1016/j.ridd.2021.104142. Online ahead of print.

ABSTRACT

BACKGROUND: The scientific study of young children with a significant cognitive and motor developmental delay is challenging due to the children’s complex disabilities and high demands on family life and professional support. We aim to critically reflect on the measurement and analysis of child- and contextual variables within an ongoing research project on these children’s developmental trajectories.

METHOD: The OJKO-project tracked the development of a sample of children (n = 45) between the age of 6 months and 4 years with a significant cognitive and motor developmental delay, in Belgium and the Netherlands.

RESULTS: The complexity of the children’s disabilities and daily life context, and subsequent challenges in measurement and analysis of variables, were confirmed and reflected upon.

CONCLUSIONS: Due to the uniqueness and complexity of this target group, research should be characterized by creativity, perseverance and substantial modesty in the immediate generalization of results.

PMID:34875547 | DOI:10.1016/j.ridd.2021.104142

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Pharmacological treatment for psychotic depression

Cochrane Database Syst Rev. 2021 Dec 7;12:CD004044. doi: 10.1002/14651858.CD004044.pub5.

ABSTRACT

BACKGROUND: Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: monotherapy with an antidepressant, monotherapy with an antipsychotic, another treatment (e.g. mifepristone), or combination of an antidepressant plus an antipsychotic. This is an update of a review first published in 2005 and last updated in 2015.

OBJECTIVES: 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy, mifepristone monotherapy, and the combination of an antidepressant plus an antipsychotic versus placebo and/or each other. 2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment.

SEARCH METHODS: A search of the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR); Ovid MEDLINE (1950-); Embase (1974-); and PsycINFO (1960-) was conducted on 21 February 2020. Reference lists of all included studies and related reviews were screened and key study authors contacted.

SELECTION CRITERIA: All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies, according to criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. Primary outcomes were clinical response for efficacy and overall dropout rate for harm/tolerance. Secondary outcome were remission of depression, change from baseline severity score, quality of life, and dropout rate due to adverse effects. For dichotomous efficacy outcomes (i.e. response and overall dropout), risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Regarding the primary outcome of harm, only overall dropout rates were available for all studies. If the study did not report any of the response criteria as defined above, remission as defined here could be used as an alternative. For continuously distributed outcomes, it was not possible to extract data from the RCTs. MAIN RESULTS: The search identified 3947 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction in severity (response) of depression, not of psychosis. For depression response, we found no evidence of a difference between antidepressant and placebo (RR 8.40, 95% CI 0.50 to 142.27; participants = 27, studies = 1; very low-certainty evidence) or between antipsychotic and placebo (RR 1.13, 95% CI 0.74 to 1.73; participants = 201, studies = 2; very low-certainty evidence). Furthermore, we found no evidence of a difference in overall dropouts with antidepressant (RR 1.24, 95% CI 0.34 to 4.51; participants = 27, studies = 1; very low-certainty evidence) or antipsychotic monotherapy (RR 0.79, 95% CI 0.57 to 1.08; participants = 201, studies = 2; very low-certainty evidence). No evidence suggests a difference in depression response (RR 2.09, 95% CI 0.64 to 6.82; participants = 36, studies = 1; very low-certainty evidence) or overall dropouts (RR 1.79, 95% CI 0.18 to 18.02; participants = 36, studies = 1; very low-certainty evidence) between antidepressant and antipsychotic. For depression response, low- to very low-certainty evidence suggests that the combination of an antidepressant plus an antipsychotic may be more effective than antipsychotic monotherapy (RR 1.83, 95% CI 1.40 to 2.38; participants = 447, studies = 4), more effective than antidepressant monotherapy (RR 1.42, 95% CI 1.11 to 1.80; participants = 245, studies = 5), and more effective than placebo (RR 1.86, 95% CI 1.23 to 2.82; participants = 148, studies = 2). Very low-certainty evidence suggests no difference in overall dropouts between the combination of an antidepressant plus an antipsychotic versus antipsychotic monotherapy (RR 0.79, 95% CI 0.63 to 1.01; participants = 447, studies = 4), antidepressant monotherapy (RR 0.91, 95% CI 0.55 to 1.50; participants = 245, studies = 5), or placebo alone (RR 0.75, 95% CI 0.48 to 1.18; participants = 148, studies = 2). No study measured change in depression severity from baseline, quality of life, or dropouts due to adverse events. We found no RCTs with mifepristone that fulfilled our inclusion criteria. Risk of bias is considerable: we noted differences between studies with regards to diagnosis, uncertainties around randomisation and allocation concealment, treatment interventions (pharmacological differences between various antidepressants and antipsychotics), and outcome criteria.

AUTHORS’ CONCLUSIONS: Psychotic depression is heavily under-studied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. Evidence for efficacy of mifepristone is lacking.

PMID:34875106 | DOI:10.1002/14651858.CD004044.pub5

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Atrial disease and heart failure: the common soil hypothesis proposed by the Heart Failure Association of the European Society of Cardiology

Eur Heart J. 2021 Dec 7:ehab834. doi: 10.1093/eurheartj/ehab834. Online ahead of print.

NO ABSTRACT

PMID:34875053 | DOI:10.1093/eurheartj/ehab834

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Fat metabolism is associated with telomere length in six population-based studies

Hum Mol Genet. 2021 Dec 7:ddab281. doi: 10.1093/hmg/ddab281. Online ahead of print.

ABSTRACT

Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer, and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold pmeta = 6.5×10-4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-ce %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-ce) became significantly associated with LTL (p = 3.6×10-4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (p = 1.9×10-4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.

PMID:34875050 | DOI:10.1093/hmg/ddab281

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Practical guidelines for the early diagnosis of Sjögren’s syndrome in primary healthcare

Clin Exp Rheumatol. 2021 Nov 29. Online ahead of print.

ABSTRACT

Primary care physicians can play a crucial role by recognising Sjögren’s syndrome (SS) in the early stages identifying those patients with the greatest probability of being diagnosed with SS. SS has a very specific epidemiological profile at presentation (female aged 30-50 years), which may aid an early diagnosis. Although the disease may be expressed in many guises, there are three predominant clinical presentations that should be considered as key clues to increased clinical suspicion (multiple symptoms of dryness, asthenia-polyalgia syndrome and systemic organ-specific manifestations). The physical examination may provide important clues to systemic involvement (parotid gland enlargement, skin lesions suggestive of purpura or annular erythema, respiratory crackles, arthritis, neurological sensory or motor deficits). Simple laboratory studies may be very useful in reinforcing the clinical suspicion of SS, and the triad of cytopenia, raised erythrocyte sedimentation rate and high serum gamma globulin levels is a very specific “biological” pattern suggesting SS. A solid clinical suspicion of SS requires both the patient reporting sicca symptoms and objective evidence that these symptoms are associated with dysfunction of the lachrymal and salivary glands. Ultrasonography of the parotid glands, a non-invasive method, may be a major advance in the diagnostic approach to SS in primary care. Primary care physicians must be considered essential members of the multidisciplinary team in charge of the follow-up of SS patients, due to their key role in the continuum of patient care and their cross-sectional knowledge of common diseases that frequently coexist in patients with SS.

PMID:34874832

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An International Multi-Center Cohort Study on β-blockers for the Treatment of Symptomatic Children with Catecholaminergic Polymorphic Ventricular Tachycardia

Circulation. 2021 Dec 7. doi: 10.1161/CIRCULATIONAHA.121.056018. Online ahead of print.

ABSTRACT

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. Beta-blockers (BBs) decrease this risk, but studies comparing individual BBs in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of BB in a large cohort of symptomatic children with CPVT. Methods: From two international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest prior to BB initiation and age at start of BB therapy <18 years), treated with a BB were included. Cox-regression analyses with time-dependent covariates for BB and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 [interquartile range, 2.8-12.5] years. Two-hundred sixteen patients (66.0%) used a non-selective BB (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective BB (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial BB. Baseline characteristics did not differ. The HR for both the primary and secondary outcomes were higher for β1-selective compared with non-selective BBs (HR, 2.04 95% CI, 1.31-3.17; and HR, 1.99; 95% CI, 1.20-3.30, respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68; 95% CI, 1.44-4.99), bisoprolol (HR, 3.24; 95% CI, 1.47-7.18), and metoprolol (HR, 2.18; 95% CI, 1.08-4.40) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68; 95% CI, 1.30-5.55). Conclusions: B1-selective BBs were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with non-selective BBs, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred BB for treating symptomatic children with CPVT.

PMID:34874747 | DOI:10.1161/CIRCULATIONAHA.121.056018

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Negative valence of hallucinatory voices as predictor of cortical glutamatergic metabolite levels in schizophrenia patients

Brain Behav. 2021 Dec 7:e32446. doi: 10.1002/brb3.2446. Online ahead of print.

ABSTRACT

OBJECTIVES: Negative emotional valence of auditory verbal hallucinations (AVHs) in schizophrenia can be a source of distress and is considered a strong predictor of illness severity. Previous studies have found glutamate to mediate AVH severity in frontal and temporal brain regions, however, they do not specifically address emotional valence of AVH. The role of glutamate for the experience of negative- versus positive emotional valence of AVH is therefore unknown and was investigated in the current study.

METHODS: Using magnetic resonance spectroscopy (MRS), 37 schizophrenia patients had Glx (glutamate+glutamine) measured in the left superior temporal gyrus (STG), and additionally in the anterior cingulate cortex (ACC) and the right STG, or in the left inferior frontal gyrus (IFG). Self-reported emotional valence in AVH was measured with the Beliefs About Voices Questionnaire (BAVQ-R).

RESULTS: Results from linear mixed models showed that negative emotional valence was associated with reduced Glx levels across all four measured brain regions in the frontal and temporal lobe. More specifically, voices that were experienced to be omnipotent (p = 0.04) and that the patients attempted to resist (p = 0.04) were related to lower Glx levels. Follow-up analysis of the latter showed that voices that evoked emotional resistance (i.e., fear, sadness, anger), rather than behavioral resistance, was a significant predictor of reduced glutamate (p = 0.02).

CONCLUSION: The findings could indicate aberrant glutamatergic signaling, or increased NMDA-receptor hypoactivity in patients who experience their voices to be more emotionally negative. Overall, the study provides support for the glutamate hypothesis of schizophrenia.

PMID:34874613 | DOI:10.1002/brb3.2446

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The Hippo signaling pathway effector YAP promotes salivary gland regeneration after injury

Sci Signal. 2021 Dec 7;14(712):eabk0599. doi: 10.1126/scisignal.abk0599. Epub 2021 Dec 7.

ABSTRACT

[Figure: see text].

PMID:34874744 | DOI:10.1126/scisignal.abk0599

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Hepatitis C virus in hemophilia: Health-related quality of life after successful treatment in the sixth Hemophilia in the Netherlands study

Res Pract Thromb Haemost. 2021 Nov 17;5(8):e12616. doi: 10.1002/rth2.12616. eCollection 2021 Dec.

ABSTRACT

INTRODUCTION: Persons with hemophilia and hepatitis C virus (HCV) infection have a lower health-related quality of life (HRQoL) than those never HCV infected. However, it is unknown whether HRQoL after HCV eradication is comparable to individuals never HCV infected. We aimed to compare HRQoL between HCV-cured and never chronically HCV-infected persons with hemophilia.

METHODS: All persons with hemophilia in the Netherlands were invited for a nationwide study conducted in 2018-2019. For the current analysis, participants born before 1992 with data on HRQoL and HCV status were included. HCV status was collected from medical records. HRQoL was measured by RAND-36 questionnaire, with a minimally important difference set at 4.0 points. Multivariable linear regression was used to adjust for age, hemophilia severity, HIV status, and self-reported joint impairment.

RESULTS: In total, 486 persons were eligible; 180 were HCV cured and 306 never chronically HCV infected. Compared with those never HCV infected, HCV-cured individuals were older (57 vs. 53 years), more often had severe hemophilia (67% vs. 21%), and reported more impaired joints (median 3 vs. 0). Compared with those never HCV infected, adjusted RAND-36 domain scores of HCV-cured individuals cured were lower on all RAND-36 domains except Pain, ranging from a difference of 4.5 (95% CI, -8.8 to -0.3) for Physical functioning to 11.3 (95% CI, -19.4 to -3.1) for Role limitations due to physical problems.

CONCLUSION: Despite effective HCV treatment, HRQoL of HCV-cured persons with hemophilia is still lower than HRQoL of those never chronically HCV-infected on all RAND-36 domains. This implies that careful psychosocial follow-up and support are indicated.

PMID:34870068 | PMC:PMC8599142 | DOI:10.1002/rth2.12616

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Polyphenols and Novel Insights Into Post-kidney Transplant Complications and Cardiovascular Disease: A Narrative Review

Front Cardiovasc Med. 2021 Nov 16;8:751036. doi: 10.3389/fcvm.2021.751036. eCollection 2021.

ABSTRACT

Kidney transplantation is the preferred treatment for end-stage kidney disease. It is, however, not devoid of complications. Delayed graft function related to ischemia-reperfusion injury (IRI), calcineurin inhibitor (CNI) nephrotoxicity, diabetes, and a particularly high-rate cardiovascular disease (CVD) risk, represent important complications following kidney transplantation. Oxidative stress and chronic low-grade inflammation are mechanisms of disease incompletely abrogated in stable kidney transplant recipient (KTR), contributing to the occurrence of these complications. Polyphenols, bioactive compounds with recognized antioxidant and anti-inflammatory properties have been strongly associated with prevention of CVD in the general population and have been shown to decrease IRI and antagonize CNI nephrotoxicity in animal experimental models, therefore they may have a role in prevention of complications in KTR. This narrative review aims to summarize and discuss current evidence on different polyphenols for prevention of complications, particularly prevention of CVD in KTR, pointing toward the need of further studies with potential clinical impact.

PMID:34869655 | PMC:PMC8635050 | DOI:10.3389/fcvm.2021.751036

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Higher Animal Protein Intake During the Second Trimester of Pregnancy Is Associated With Risk of GDM

Front Nutr. 2021 Nov 15;8:718792. doi: 10.3389/fnut.2021.718792. eCollection 2021.

ABSTRACT

Background and Aims: This study aimed to examine the associations between the total protein intake as well as types and sources of proteins with the gestational diabetes mellitus (GDM) risk. Method and Results: This was a prospective cohort study of the pregnant women in Malaysia. In this study, the total, animal, and plant protein intakes were assessed using a semi-quantitative food frequency questionnaire. Of the 452 women, 48 (10.62%) were diagnosed with GDM. From pre-pregnancy to second trimester, most of the women had 10-20% of energy intake from protein (88.9-90.3%) and ≥75% of recommended protein intake (74.6-86.5%). The women in the highest tertile (T3) of total animal protein intake [adjusted odds ratio (AOR) = 2.76, 95% CI = 1.27-6.04] and red meat protein (AOR = 2.69, 95% CI = 1.27-5.70), specifically in the second trimester, had significantly higher GDM risk compared with the women in the middle tertile of intake (T2). Interestingly, the women in the T3 of egg protein in the second trimester were significantly at lower GDM risk (AOR = 0.43, 95% CI = 0.18-0.91) compared with those in T2. Conclusion: The highest tertile of animal protein (≥42.15 g/day) intake, particularly red meat protein in the second trimester was positively associated with the GDM risk, whereas the highest tertile of egg protein was inversely associated with the GDM risk. Protein intake before or during early pregnancy was not associated with the GDM risk. These findings underscore the importance of sources and types of protein intake, particularly after the first trimester of pregnancy, in relation to GDM risk.

PMID:34869515 | PMC:PMC8634888 | DOI:10.3389/fnut.2021.718792

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Process Evaluation of Internet-Based Cognitive Behavioral Therapy Intervention for Informal Caregivers

Front Med (Lausanne). 2021 Nov 12;8:725510. doi: 10.3389/fmed.2021.725510. eCollection 2021.

ABSTRACT

Background: Informal caregivers are individuals who provide care for ill, frail, or otherwise dependent family members, siblings, or friends. Due to the caregiving demands, informal caregivers are known to experience negative mental health symptoms, such as stress or anxiety. Interventions based on Internet-based Cognitive Behavioral Therapy (ICBT) principles have been previously found to be effective for different populations and could also be considered as a plausible support option for informal caregivers. However, findings regarding effectiveness alone might not be sufficient for informing about the overall feasibility of the intervention. Objective: The aim of this process evaluation study was to evaluate the feasibility of a previously developed ICBT intervention for informal caregivers in Lithuania. More specifically, we evaluated the suitability of the intervention in relation to its content and delivery mode. Methods: Two studies were conducted. Study 1 consisted of participant evaluations of an 8-week, 8-module long therapist supported ICBT intervention. Evaluations for the Study 1 were retrieved from previously unused data, obtained from pilot testing of the intervention in which 63 informal caregivers took part. The evaluations contained of qualitative data (participant comments), as well as quantitative data (evaluations of each of the sessions). The Study 2 was an online stakeholder focus-group discussion conducted via Zoom. Eight stakeholders took part in the discussion, among whom there were social workers, medical professionals as well as individuals with caregiving experience themselves. Data were analyzed using descriptive statistics, thematic analysis, and data coding. Results: Results of the Study 1 showed that most of the pilot randomized controlled trial participants evaluated content and format of the intervention positively. These results were complemented by the findings in the Study 2, in which stakeholders evaluated the intervention as suitable and promising. In addition, stakeholders made certain suggestions for improving the intervention’s usability for the informal caregivers. This included improving the instructions, providing with more guidance, and considering personalization options. Conclusion: The process evaluation helped to evaluate the feasibility of the ICBT intervention for informal caregivers in Lithuania from the two perspectives: users and stakeholders. Our findings suggest that the intervention is suitable for the target population.

PMID:34869422 | PMC:PMC8632733 | DOI:10.3389/fmed.2021.725510

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