The relation between musical ability and sentence-level intonation perception:A meta-analysis comparing L1 and non-native listening

Studies investigating the relationship between musical abilities and speech prosody report that musicians show an altered—often enhanced—perception of prosody, or report positive correlations between music perception and prosody perception. However, some studies on L1 perception find no such benefits, but show good prosody perception across listeners. In contrast, even advanced L2 users may show difficulties in processing sentence intonation. We hypothesised that musicality might especially be beneficial in challenging circumstances of non-native intonation perception. To test this, we conducted a meta-analysis of previous research investigating the effect of musical abilities on the perception of sentence-level intonation in L1, L2, and unfamiliar languages. Studies were systematically collected, and included various measures of musicality and intonation perception. The meta-analysis combining these outcomes showed a robust positive correlation between musical ability and intonation perception. This effect did not differ between studies on L1 and unfamiliar languages. We suggest intonation perception in unfamiliar languages might be relatively easy due to the absence of semantic interference. Data on L2 users was lacking. Because semantic processing plays a role in L2 perception, we suggest further research is needed to investigate the influence of musical ability on intonation perception in L2 listening

HbA1c in Nondiabetic Dutch Infants Aged 8–12 Months: The GECKO-Drenthe birth cohort study

OBJECTIVE-An international committee of experts recommended using HbA(1c) for diagnostic testing for diabetes. Little is known about normal values of HbA(1c) in infants. The aim of this study is to describe the distribution of HbA(1c) in 8- to 12-month-old nondiabetic infants. RESEARCH DESIGN AND METHODS-HbA(1c) was measured in 86 infants participating in the Groningen Expert Center for Kids with Obesity (GECKO)-Drenthe birth cohort study. Anthropometric measurements were performed at Well Baby Clinics. Data on parents and children were collected prospectively using questionnaires. RESULTS-HbA(1c) was normally distributed with a mean (SD) HbA(1c) level of 5.38% (0.24), range 4.8-6.0% or 35.29 mmol/mol (2.65), range 29.1-42.1 mmol/mol. Age, sex, birth weight, duration of breastfeeding, anthropometric measurements, and maternal BMI were not associated with HbA(1c). CONCLUSIONS-We found a normal distribution of HbA(1c) with a relatively high mean HbA(1c) of 5.38%. No significant association between risk factors for type 2 diabetes and HbA(1c) levels was found

Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma

Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1–8) and 6 (range 0–8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34–56%) and 49% (95%CI 38–60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging

Внебрачный секс и его психопрофилактика

Описана предложенная автором поэтапная система психопрофилактики супружеской дезадаптации, ведущей к внебрачному сексу.The original staged system of psychoprevention of spouse deadaptation causing extramarital sex is described

Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals

Anemia is a major and currently poorly understood clinical manifestation of hematopoietic aging. Upon aging, hematopoietic clones harboring acquired leukemia-associated mutations expand and become detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly, we explored the landscape and dynamics of CH in older individuals with anemia. From the prospective, population-based Lifelines cohort (n = 167 729), we selected all individuals at least 60 years old who have anemia according to World Health Organization criteria (n = 676) and 1:1 matched control participants. Peripheral blood of 1298 individuals was analyzed for acquired mutations at a variant allele frequency (VAF) of 1% or higher in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n = 943). CH was more frequently detected in individuals with anemia (46.6%) compared with control individuals (39.1%; P = .007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in individuals with anemia compared with control individuals, other mutations were enriched in the anemia cohort, including TP53 and SF3B1. Unlike individuals with nutrient deficiency (P = .84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P = .035 and P = .017, respectively) compared with their matched control individuals. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF (mean, 0.56%) over the course of 44 months, irrespective of the presence of anemia. Specific mutations were associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (<5% VAF), which did not affect overall survival, larger clones were associated with increased risk for death

Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands

Background: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. Methods: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). Results: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8–2.3) and 5.4 months (95% CI, 4.0–6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0–1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. Conclusions: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. Funding: Johannes J.M. Kwakman received an unrestricted research grant from Servier

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice

<p>Abstract</p> <p>Background</p> <p>Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice.</p> <p>Methods</p> <p>Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays.</p> <p>Results</p> <p>The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance.</p> <p>Conclusion</p> <p>During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.</p