Search

Background and Aims: The aging process is often accompanied by high risk of malnutrition and elevated levels of growth differentiation factor 15 (GDF15). GDF15 is an increasingly recognized biomarker for regulation of metabolism, but few studies have investigated the connection between GDF15 and malnutrition in older age and how it relates to other features of aging such as decreased appetite and physical function. Therefore, we investigated the associations between GDF15 levels and nutritional status, appetite, and physical function in acutely admitted older adults., Methods: Plasma GDF15 levels were measured using immunoassays in 302 older adults (≥65 years) admitted to the emergency department (ED). Nutritional status was evaluated with the Mini Nutritional Assessment Short-Form (MNA®-SF), appetite was evaluated with the Simplified Nutritional Appetite Questionnaire (SNAQ), and physical function was evaluated with handgrip strength (HGS), 30-s chair stand test (30s-RSS), and gait speed (GS). Associations between GDF15 and each outcome was determined by logistic regression adjusted for age, sex, and C-reactive protein (CRP)., Results: Each doubling in plasma GDF15 level was associated with an adjusted odds ratio (OR) (95% confidence interval) of 1.59 (1.10-2.29, P = 0.01) for risk of malnutrition compared to normal nutrition and 1.19 (0.85-1.69, P = 0.3)) for malnutrition compared to risk of malnutrition. Each doubling in GDF15 was associated with an adjusted OR of 1.63 (1.21-2.23)) for having poor appetite, 1.46 (1.07-1.99) for having low HGS, 1.74 (1.23-2.51) for having low 30s-RSS, and 1.99 (1.39-2.94) for having low GS., Conclusion: Among older adults admitted to the ED, higher GDF15 levels were significantly associated with malnutrition, poor appetite, and low physical function independent of age, sex, and CRP., Competing Interests: Conflict of interest All authors report no potential conflicts of interest in relation to this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aim: Malnutrition, risk of malnutrition, and risk factors for malnutrition are prevalent among acutely admitted medical patients aged ≥65 years and have significant health-related consequences. Consequently, we aimed to investigate the effectiveness of a multidisciplinary and transitional nutritional intervention on health-related quality of life compared with standard care., Methods: The study was a block randomized, observer-blinded clinical trial with two parallel arms. The Intervention Group was offered a multidisciplinary transitional nutritional intervention consisting of dietary counselling and six sub-interventions targeting individually assessed risk factors for malnutrition, while the Control Group received standard care. The inclusion criteria were a Mini Nutritional Assessment Short-Form score ≤11, age ≥65 years, and an acute admittance to the Emergency Department. Outcomes were assessed on admission and 8 and 16 weeks after hospital discharge. The primary outcome was the difference between groups in change in health-related quality of life (assessed by the EuroQol-5D-5L) from baseline to 16 weeks after discharge. The secondary outcomes were difference in intake of energy and protein, well-being, muscle strength, and body weight at all timepoints., Results: From October 2018 to April 2021, 130 participants were included. Sixteen weeks after discharge, 29% in the Intervention Group and 19% in the Control Group were lost to follow-up. Compliance varied between the sub-interventions targeting nutritional risk factors and was generally low after discharge, ranging from 0 to 61%. No difference was found between groups on change in health-related quality of life or on well-being, muscle strength, and body weight at any timepoint, neither using the intention-to-treat analysis nor the per-protocol analysis. The protein intake was higher in the Intervention Group during hospitalization (1.1 (Standard Deviation (SD) 0.4) vs 0.8 (SD 0.5) g/kg/day, p = 0.0092) and 8 weeks after discharge (1.2 (SD 0.5) vs 0.9 (0.4) g/kg/day, p = 0.0025). The percentual intake of calculated protein requirements (82% (SD 24) vs 61% (SD 32), p = 0.0021), but not of calculated energy requirements (89% (SD 23) vs 80% (SD 37), p = 0.2), was higher in the Intervention Group than in the Control Group during hospitalization. Additionally, the Intervention Group had a significantly higher percentual intake of calculated protein requirements (94% (SD 41) vs 74% (SD 30), p = 0.015) and calculated energy requirements (115% (SD 37) vs 94% (SD 31), p = 0.0070) 8 weeks after discharge. The intake of energy and protein was comparable between the groups 16 weeks after discharge., Conclusion: We found no effect of a multidisciplinary and transitional nutritional intervention for acutely admitted medical patients aged ≥65 years with malnutrition or risk of malnutrition on our primary outcome, health-related quality of life 16 weeks after discharge. Nor did the intervention affect the secondary outcomes, well-being, muscle strength, and body weight from admission to 8 or 16 weeks after discharge. However, the intervention improved energy and protein intake during hospitalization and 8 weeks after discharge. Low compliance with the intervention after discharge may have compromised the effect of the intervention. The study is registered at ClinicalTrials.gov (identifier: NCT03741283)., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To gain insights into the composition and heterogeneity of Earth's interior, the partial pressure of oxygen (oxygen fugacity, or fO 2 ) in igneous rocks is characterized. A surprising observation is that relative to reference buffers, fO 2 s of mantle melts (mid-ocean ridge basalts, or MORBs) and their presumed mantle sources (abyssal peridotites) differ. Globally, MORBs have near-uniform fO 2 s, whereas abyssal peridotites vary by about three orders of magnitude, suggesting these intimately related geologic reservoirs are out of equilibrium. Here, we characterize fO 2 s of mantle melting increments represented by plagioclase-hosted melt inclusions, which were entrapped as basaltic melts migrated from their sources toward the seafloor. At temperatures and fO 2 s constrained by rare earth element distributions, a range of fO 2 s consistent with the abyssal peridotites is recovered. The fO 2 s are correlated with geochemical proxies for mantle melting, suggesting partial melting of Earth's mantle decreases its fO 2 , and that the uniformity of MORB fO 2 s is a consequence of the melting process and plate tectonic cycling., (© 2024. The Author(s).)

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients' lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71-0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis., (© 2024. The Author(s).)

Purpose: In 2019, the Global Leadership Initiative on Malnutrition (GLIM) suggested a 2-step diagnostic format for malnutrition including screening and diagnosis. Prospective validation and feasibility studies, using the complete set of the five GLIM criteria, are needed. The aims of this study were to determine the prevalence of malnutrition, and investigate how the prevalence varied with mode of screening. Furthermore, we assessed the feasibility of GLIM in geriatric patients., Methods: Consecutive patients from two acute geriatric wards were included. For screening risk of malnutrition, the Mini Nutritional Assessment-Short Form (MNA-SF) or Malnutrition Screening Tool (MST) were used. In accordance with GLIM, a combination of phenotypic and etiologic criteria were required for the diagnosis of malnutrition. Feasibility was determined based on % data completeness, and above 80% completeness was considered feasible., Results: One hundred patients (mean age 82 years, 58% women) were included. After screening with MNA-SF malnutrition was confirmed by GLIM in 51%, as compared with 35% after screening with MST (p = 0.039). Corresponding prevalence was 58% with no prior screening. Using hand grip strength as a supportive measure for reduced muscle mass, 69% of the patients were malnourished. Feasibility varied between 70 and 100% for the different GLIM criteria, with calf circumference as a proxy for reduced muscle mass having the lowest feasibility., Conclusion: In acute geriatric patients, the prevalence of malnutrition according to GLIM varied depending on the screening tool used. In this setting, GLIM appears feasible, besides for the criterion of reduced muscle mass., (© 2024. The Author(s).)

The accuracy of multi-frequency (MF) bioelectrical impedance analysis (BIA) to estimate low muscle mass in older hospitalized patients remains unclear. This study aimed to describe the ability of MF-BIA to identify low muscle mass as proposed by The Global Leadership Initiative on Malnutrition (GLIM) and The European Working Group on Sarcopenia in Older People (EWGSOP-2) and examine the association between muscle mass, dehydration, malnutrition, and poor appetite in older hospitalized patients. In this prospective exploratory cohort study, low muscle mass was estimated with MF-BIA against dual-energy X-ray absorptiometry (DXA) in 42 older hospitalized adults (≥65 years). The primary variable for muscle mass was appendicular skeletal muscle mass (ASM), and secondary variables were appendicular skeletal muscle mass index (ASMI) and fat-free mass index (FFMI). Cut-off values for low muscle mass were based on recommendations by GLIM and EWGSOP-2. MF-BIA was evaluated against DXA on the ability to estimate absolute values of muscle mass by mean bias, limits of agreement (LOA), and accuracy (5% and 10% levels). Agreement between MF-BIA and DXA to identify low muscle mass was evaluated with sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). The association between muscle mass, dehydration, malnutrition, and poor appetite was visually examined with boxplots. MF-BIA overestimated absolute values of ASM with a mean bias of 0.63 kg (CI: -0.20:1.46, LOA: -4.61:5.87). Agreement between MF-BIA and DXA measures of ASM showed a sensitivity of 86%, specificity of 94%, PPV of 75% and NPV of 97%. Boxplots indicate that ASM is lower in patients with malnutrition. This was not observed in patients with poor appetite. We observed a tendency toward higher ASM in patients with dehydration. Estimation of absolute ASM values with MF-BIA should be interpreted with caution, but MF-BIA might identify low muscle mass in older hospitalized patients.

Rationale & Objective: Older adults represent nearly half of all hospitalized patients and are vulnerable to inappropriate dosing of medications eliminated through the kidneys. However, few studies in this population have evaluated the performance of equations for estimating the glomerular filtration rate (GFR)-particularly those that incorporate multiple filtration markers., Study Design: Cross-sectional diagnostic test substudy of a randomized clinical trial., Setting & Participants: Adults≥65 years of age presenting to the emergency department of Copenhagen University Hospital Amager and Hvidovre in Hvidovre, Denmark, between October 2018 and April 2021., Tests Compared: Measured GFR (mGFR) determined using 99mTc-DTPA plasma clearance compared with estimated GFR (eGFR) calculated using 6 different equations based on creatinine; 3 based on creatinine and cystatin C combined; and 2 based on panels of markers including creatinine, cystatin C, β-trace protein (BTP) and/or β 2 -microglobulin (B2M)., Outcome: The performance of each eGFR equation compared with mGFR with respect to bias, relative bias, inaccuracy (1-P30), and root mean squared error (RMSE)., Results: We assessed eGFR performance for 106 patients (58% female, median age 78.3 years, median mGFR 62.9mL/min/1.73m 2 ). Among the creatinine-based equations, the 2009 CKD-EPI cr equation yielded the smallest relative bias (+4.2%). Among the creatinine-cystatin C combination equations, the 2021 CKD-EPI comb equation yielded the smallest relative bias (-3.4%), inaccuracy (3.8%), and RMSE (0.139). Compared with the 2021 CKD-EPI comb , the CKD-EPI panel equation yielded a smaller RMSE (0.136) but larger relative bias (-4.0%) and inaccuracy (5.7%)., Limitations: Only White patients were included; only a subset of patients from the original clinical trial underwent GFR measurement; and filtration marker concentration can be affected by subclinical changes in volume status., Conclusions: The 2009 CKD-EPI cr , 2021 CKD-EPI comb , and CKD-EPI panel equations performed best and notably outperformed their respective full-age spectrum equations. The addition of cystatin C to creatinine-based equations improved performance, while the addition of BTP and/or B2M yielded minimal improvement., Funding: Grants from public sector industry (Amgros I/S) and government (Capital Region of Denmark)., Trial Registration: Registered at ClinicalTrials.gov with registration number NCT03741283., Plain-Language Summary: Inaccurate kidney function assessment can lead to medication errors, a common cause of hospitalization and early readmission among older adults. Several novel methods have been developed to estimate kidney function based on a panel of kidney function markers that can be measured from a single blood sample. We evaluated the accuracy of these new methods (relative to a gold standard method) among 106 hospitalized older adults. We found that kidney function estimates combining 2 markers (creatinine and cystatin C) were highly accurate and noticeably more accurate than estimates based on creatinine alone. Estimates incorporating additional markers such as β-trace protein and β 2 -microglobulin did not further improve accuracy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Malnutrition in older patients is linked to poor appetite. Cannabis-based medicine may have orexigenic properties in older patients, but this has to our knowledge never been investigated. In older patients, uncertainty applies to the accuracy of estimated glomerular filtration rate (eGFR) based on creatinine, which is crucial for medication prescribing. In older patients with poor appetite, the study aims (1) to assess the efficacy of Sativex® (8.1-mg delta-9-tetrahydrocannabinol [THC] and 7.5-mg cannabidiol [CBD]) to stimulate appetite and (2) to compare the performance of various GFR-estimates and measured-GFR (mGFR) for determining gentamicin clearance utilizing population pharmacokinetic (popPK) modelling methods., Methods and Objectives: This study is composed of two substudies. Substudy 1 is an investigator-initiated single-center, double-blinded, randomized, placebo-controlled, superiority, cross-over study. Substudy 1 will recruit 17 older patients with poor appetite, who will also be invited to substudy 2. Substudy 2 is a single-dose pharmacokinetics study and will recruit 55 patients. Participants will receive Sativex® and placebo in substudy 1 and gentamicin with simultaneous measurements of GFR in substudy 2. The primary endpoints are as follows: Substudy 1-the difference in energy intake between Sativex® and placebo conditions; substudy 2- the accuracy of different eGFR equations compared to mGFR. The secondary endpoints include safety parameters, changes in the appetite hormones, total ghrelin and GLP-1 and subjective appetite sensations, and the creation of popPK models of THC, CBD, and gentamicin., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Many Aboriginal Australian communities are undergoing language shift from traditional Indigenous languages to contact varieties such as Kriol, an English-lexified Creole. Kriol is reportedly characterised by lexical items with highly variable phonological specifications, and variable implementation of voicing and manner contrasts in obstruents (Sandefur, 1986). A language, such as Kriol, characterised by this unusual degree of variability presents Kriol-acquiring children with a potentially difficult language-learning task, and one which challenges the prevalent theories of acquisition. To examine stop consonant acquisition in this unusual language environment, we present a study of Kriol stop and affricate production, followed by a mispronunciation detection study, with Kriol-speaking children (ages 4-7) from a Northern Territory community where Kriol is the lingua franca . In contrast to previous claims, the results suggest that Kriol-speaking children acquire a stable phonology and lexemes with canonical phonemic specifications, and that English experience would not appear to induce this stability.

The extent to which inflammation impacts food intake remains unclear, serving as a key risk factor for malnutrition as defined by the Global Leadership Initiative on Malnutrition (GLIM). To address this, we analyzed a large, merged dataset of geriatric hospitalized patients across Europe. The study included 1650 consecutive patients aged ≥65 year from Germany, Italy, Finland, Denmark, and Poland. Nutritional intake was assessed using the first item of the Mini Nutritional Assessment Short Form; C-reactive protein (CRP) levels were measured using standard procedures. In total (age 79.6 ± 7.4 year, 1047 females), 23% exhibited moderate to severe inflammation, and 12% showed severe inflammation; 35% showed moderate reductions in food intake, and 28% were considered malnourished. Median CRP levels differed significantly between patients with severe, moderate, and no decrease in food intake. Among patients with a CRP level of 3.0-4.99 mg/dL, 19% experienced a severe decrease in food intake, while 66% experienced moderate to severe decreases. Regression analysis revealed that inflammation was the most prominent risk factor for low food intake and malnutrition, surpassing other factors such as age, gender, infection, and comorbidity. A CRP level of ≥3.0 mg/dL is associated with reduced food intake during last 3 months in two thirds of hospitalized geriatric patients and therefore indicative for a high risk of malnutrition.

Study 1 compared vowels in Child Directed Speech (CDS; child ages 25-46 months) to vowels in Adult Directed Speech (ADS) in natural conversation in the Australian Indigenous language Warlpiri, which has three vowels (/i/, /a/, /u). Study 2 compared the vowels of the child interlocutors from Study 1 to caregiver ADS and CDS. Study 1 indicates that Warlpiri CDS vowels are characterised by fronting, /a/-lowering, f o -raising, and increased duration, but not vowel space expansion. Vowels in CDS nouns, however, show increased between-contrast differentiation and reduced within-contrast variation, similar to what has been reported for other languages. We argue that this two-part CDS modification process serves a dual purpose: Vowel space shifting induces IDS/CDS that sounds more child-like, which may enhance child attention to speech, while increased between-contrast differentiation and reduced within-contrast variation in nouns may serve didactic purposes by providing high-quality information about lexical specifications. Study 2 indicates that Warlpiri CDS vowels are more like child vowels, providing indirect evidence that aspects of CDS may serve non-linguistic purposes simultaneously with other aspects serving linguistic-didactic purposes. The studies have novel implications for the way CDS vowel modifications are considered and highlight the necessity of naturalistic data collection, novel analyses, and typological diversity., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Aims: The study's aim is to compare current and new equations for estimating glomerular filtration rate (GFR) based on creatinine, cystatin C, β-trace protein (BTP) and β2 microglobulin (B2M) among patients undergoing major amputation., Methods: This is a secondary analysis of data from a prospective cohort study investigating patients undergoing nontraumatic lower extremity amputation. Estimated GFR (eGFR) was calculated using equations based on creatinine (eGFRcre[2009] and eGFRcre[2021]), cystatin C (eGFRcys), the combination of creatinine and cystatin C (eGFRcomb[2012] and eGFRcomb[2021]) or a panel of all 4 filtration markers (eGFRpanel). Primary outcome was changed in eGFR across amputation according to each equation. Two case studies of prior amputation with GFR measured by 99mTc-DTPA clearance are described to illustrate the relative accuracies of each eGFR equation., Results: Analysis of the primary outcome included 29 patients (median age 75 years, 31% female). Amputation was associated with a significant decrease in creatinine concentration (-0.09 mg/dL, P = 0.004), corresponding to a significant increase in eGFRcre[2009] (+6.1 mL/min, P = 0.006) and eGFRcre[2021] (+6.3 mL/min, P = 0.006). Change across amputation was not significant for cystatin C, BTP, B2M or equations incorporating these markers (all P > 0.05). In both case studies, eGFRcre[2021] yielded the largest positive bias, eGFRcys yielded the largest negative bias and eGFRcomb[2012] and eGFRcomb[2021] yielded the smallest absolute bias., Conclusion: Creatinine-based estimates were substantially higher than cystatin C-based estimates before amputation and significantly increased across amputation. Estimates combining creatinine and cystatin were stable across amputation, while the addition of BTP and B2M is unlikely to be clinically relevant., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Nonnative or second language (L2) perception of segmental sequences is often characterised by perceptual modification processes, which may "repair" a nonnative sequence that is phonotactically illegal in the listeners' native language (L1) by transforming the sequence into a sequence that is phonotactically legal in the L1. Often repairs involve the insertion of phonetic materials (epenthesis), but we focus, here, on the less-studied phenomenon of perceptual deletion of nonnative phonemes by testing L1 Mandarin listeners' perception of post-vocalic laterals in L2 English using the triangulating methods of a cross-language goodness rating task, an AXB task, and an AX task. The data were analysed in the framework of the Perceptual Assimilation Model (PAM/PAM-L2), and we further investigated the role of L2 vocabulary size on task performance. The experiments indicate that perceptual deletion occurs when the post-vocalic lateral overlaps with the nucleus vowel in terms of tongue backness specification. In addition, Mandarin listeners' discrimination performance in some contexts was significantly correlated with their English vocabulary size, indicating that continuous growth of vocabulary knowledge can drive perceptual learning of novel L2 segmental sequences and phonotactic structures., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries., Objectives: The authors sought to assess protein biomarker signature for CMD., Methods: We quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson's correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts., Results: Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all  P  < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers ( P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM., Conclusions: CMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate., Competing Interests: This study received funding from the Danish Heart Foundation, the Danish Research Council, and the Kaj and Lise Jensen Foundation. Dr Nielsen is a full-time employee at Novo Nordisk Research Centre Oxford, United Kingdom since June 2021. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: A comprehensive characterization of biomarker profile in patients with angina and no obstructive CAD is consistent with inflammation, hypertension, and ventricular remodeling being intrinsically linked to CMD. TRANSLATIONAL OUTLOOK: If validated in other cohorts of patients with microvascular angina, our findings support considering inflammation as a therapeutic target in patients with angina and CMD., (© 2023 The Authors.)

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

In acutely hospitalized older patients (≥65 years), the association between mild cognitive impairment (MCI) and malnutrition is poorly described. We hypothesized that (1) MCI is associated with nutritional status on admission and after discharge; (2) MCI is associated with a change in nutritional status; and (3) a potential association is partly explained by frailty, comorbidity, medication use, and age. We combined data from a randomized controlled trial (control group data) and a prospective cohort study (ClinicalTrials.gov: NCT01964482 and NCT03052192). Nutritional status was assessed on admission and follow-up using the Mini Nutritional Assessment-Short Form. MCI or intact cognition (noMCI) was classified by three cognitive performance tests at follow-up. Data on frailty, comorbidity, medication use, and age were drawn from patient journals. MCI ( n = 42) compared to noMCI ( n = 47) was associated with poorer nutritional status with an average difference of -1.29 points (CI: -2.30; -0.28) on admission and -1.64 points (CI: -2.57; -0.70) at 4-week follow-up. Only age influenced the estimates of -0.85 (CI: -1.86; 0.17) and -1.29 (CI: -2.25; -0.34), respectively. In acutely hospitalized older patients, there is an association between MCI and poorer nutritional status upon admission and four weeks after discharge. The association is partly explained by higher age.

Background: White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood., Methods: We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations., Results: We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρ BCP-ALL  = -.17, ρ T-ALL  = -.19; p < 3 × 10 -4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ = .43, p << 2 × 10 -6 ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation., Conclusion: These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP 1.0 to 17.9 yo) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Internationally, older patients (≥65 years) account for more than 40% of acute admissions. Older patients admitted to the emergency department (ED) are frequently malnourished and exposed to inappropriate medication prescribing, due in part to the inaccuracy of creatinine-based equations for estimated glomerular filtration rate (eGFR). The overall aims of this trial are to investigate: (1) the efficacy of a medication review (MED intervention) independent of nutritional status, (2) the accuracy of eGFR equations based on various biomarkers compared to measured GFR (mGFR) based on 99m Technetium-diethylenetriaminepentaacetic acid plasma clearance, and (3) the efficacy of an individualized multimodal and transitional nutritional intervention (MULTI-NUT-MED intervention) in older patients with or at risk of malnutrition in the ED., Methods: The trial is a single-center block randomized, controlled, observer-blinded, superiority and explorative trial with two parallel groups. The population consists of 200 older patients admitted to the ED: 70 patients without malnutrition or risk of malnutrition and 130 patients with or at risk of malnutrition defined as a Mini Nutritional Assessment-Short Form score ≤11. All patients without the risk of malnutrition receive the MED intervention, which consists of a medication review by a pharmacist and geriatrician in the ED. Patients with or at risk of malnutrition receive the MULTI-NUT-MED intervention, which consists of the MED intervention in addition to, dietary counseling and individualized interventions based on the results of screening tests for dysphagia, problems with activities of daily living, low muscle strength in the lower extremities, depression, and problems with oral health. Baseline data are collected upon study inclusion, and follow-up data are collected at 8 and 16 weeks after discharge. The primary outcomes are (1) change in medication appropriateness index (MAI) score from baseline to 8 weeks after discharge, (2) accuracy of different eGFR equations compared to mGFR, and (3) change in health-related quality of life (measured with EuroQol-5D-5L) from baseline to 16 weeks after discharge., Discussion: The trial will provide new information on strategies to optimize the treatment of malnutrition and inappropriate medication prescribing among older patients admitted to the ED., Trail Registration: ClinicalTrials.gov NTC03741283 . Retrospectively registered on 14 November 2018., (© 2021. The Author(s).)

There is a lack of knowledge about malnutrition and risk of malnutrition upon admission and after discharge in older medical patients. This study aimed to describe prevalence, risk factors, and screening tools for malnutrition in older medical patients. In a prospective observational study, malnutrition was evaluated in 128 older medical patients (≥65 years) using the Nutritional Risk Screening 2002 (NRS-2002), the Mini Nutritional Assessment-Short Form (MNA-SF) and the Eating Validation Scheme (EVS). The European Society of Clinical Nutrition (ESPEN) diagnostic criteria from 2015 were applied for diagnosis. Agreement between the screening tools was evaluated by kappa statistics. Risk factors for malnutrition included polypharmacy, dysphagia, depression, low functional capacity, eating-related problems and lowered cognitive function. Malnutrition or risk of malnutrition were prevalent at baseline (59-98%) and follow-up (30-88%). The baseline, follow-up and transitional agreements ranged from slight to moderate. NRS-2002 and MNA-SF yielded the highest agreement (kappa: 0.31 (95% Confidence Interval (CI) 0.18-0.44) to 0.57 (95%CI 0.42-0.72)). Prevalence of risk factors ranged from 17-68%. Applying ESPEN 2015 diagnostic criteria, 15% had malnutrition at baseline and 13% at follow-up. In conclusion, malnutrition, risk of malnutrition and risk factors hereof are prevalent in older medical patients. MNA-SF and NRS-2002 showed the highest agreement at baseline, follow-up, and transitionally.

There is evolving evidence for an association between dysphagia and sarcopenia in older adults. For optimizing the acute health care initiative across health care settings, this study investigated prevalence and time-course of dysphagia in older patients admitted to an emergency department (ED) as well as its association with parameters for probable sarcopenia, inactivity, malnutrition, disease status, and systemic inflammation. A secondary analysis of data from the FAM-CPH cohort study on acutely admitted older medical patients ( n = 125). Data were collected upon ED admission as well as four and 56 weeks after discharge. Using the Eating Assessment Tool cut-off score ≥ 2, signs of dysphagia were present in 34% of the patients at ED admission and persisted in 25% of the patients 56 weeks after discharge. Signs of dysphagia at 56-week follow-up were significantly ( p < 0.05) associated with probable sarcopenia (low handgrip strength (OR = 3.79), low leg muscle strength (OR = 8.14), and low physical performance (OR = 5.68)) and with baseline swallowing inactivity (OR = 5.61), malnutrition (OR = 4.35), and systemic inflammation (OR = 1.33). Signs of dysphagia in older patients admitted to an ED was prevalent, persisted 56 weeks after discharge, and was associated with probable sarcopenia and related conditions; all modifiable targets for management of dysphagia in older patients.

This paper presents a first detailed analysis of the Voice Onset Time (VOT) and Constriction Duration (CD) of stops /p t ʈ c k/ and flap /ɽ/ in the Indigenous Australian language Warlpiri as spoken in Lajamanu Community, in Australia's Northern Territory. The results show that Warlpiri stops are realised as voiceless, long-lag stops word-initially, as well as word-medially, where /p t k/ are also characterised by CDs in excess of 100 ms. This is similar to what has been reported for Kriol, and for the emerging mixed language Light Warlpiri, also spoken in the community, and by some of the participants. The results indicate that Warlpiri does not obligatorily make a word-medial distinction between stops orthographically represented by 'rt' and 'rd', which have previously been argued to be realised as /ʈ/ and /ɽ/, respectively, at least in some varieties of Warlpiri. Finally, the results also suggest that the realisation of word-initial Warlpiri flap /ɽ/ is highly variable, potentially resulting in a near-merger with /ɻ/., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Thromboembolism (TE) is a common and serious toxicity of acute lymphoblastic leukemia (ALL) treatment, but studies of genetic predisposition have been underpowered with conflicting results. We tested whether TE in ALL and TE in the general adult population have a shared genetic etiology., Materials and Methods: We prospectively registered TE events and collected germline DNA in patients 1.0-45.9 years in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 study (7/2008-7/2016). Based on summary statistics from two large genome-wide association studies (GWAS) on venous TE in adults (the International Network of VENous Thromboembolism Clinical Research Networks (INVENT) consortium and the UK Biobank), we performed polygenic risk score (PRS) analysis on TE development in the NOPHO cohort, progressively expanding the PRS by increasing the p-value threshold of single nucleotide polymorphism (SNP) inclusion., Results and Conclusion: Eighty-nine of 1252 patients with ALL developed TE, 2.5 year cumulative incidence 7.2%. PRS of genome-wide significant SNPs from the INVENT and UK Biobank data were not significantly associated with TE, HR 1.16 (p 0.14) and 1.02 (p 0.86), respectively. Expanding PRS by increasing p-value threshold did not reveal polygenic overlap. However, subgroup analysis of adolescents 10.0-17.9 years (n = 231), revealed significant polygenic overlap with the INVENT GWAS. The best fit PRS, including 16,144 SNPs, was associated with TE with HR 1.76 (95% CI 1.23-2.52, empirical p-value 0.02). Our results support an underlying genetic predisposition for TE in adolescents with ALL and should be explored further in future TE risk prediction models., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diet is an important component in weight management strategies, but heterogeneous responses to the same diet make it difficult to foresee individual weight-loss outcomes. Omics-based technologies now allow for analysis of multiple factors for weight loss prediction at the individual level. Here, we classify weight loss responders (N = 106) and non-responders (N = 97) of overweight non-diabetic middle-aged Danes to two earlier reported dietary trials over 8 weeks. Random forest models integrated gut microbiome, host genetics, urine metabolome, measures of physiology and anthropometrics measured prior to any dietary intervention to identify individual predisposing features of weight loss in combination with diet. The most predictive models for weight loss included features of diet, gut bacterial species and urine metabolites (ROC-AUC: 0.84-0.88) compared to a diet-only model (ROC-AUC: 0.62). A model ensemble integrating multi-omics identified 64% of the non-responders with 80% confidence. Such models will be useful to assist in selecting appropriate weight management strategies, as individual predisposition to diet response varies.

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms., (© 2020 by The American Society of Hematology.)

Words in polysynthetic languages, such as the Australian language Wubuy, can be semantically complex and translate into whole phrases in analytic languages such as English. This raises questions about whether such words are like words in English, or whether they are more like phrases. In the following, we examine Wubuy speakers' knowledge of word-internal morphological complexity in a word-preference task, in which we test the acceptability of complex words into which artificial pauses have been embedded at a range of morphological junctures. The results show that participants prefer unmodified words and words with pauses inserted at semantically transparent morphological junctures over words with pauses at other junctures. There is no preference for unmodified words over words with pauses at transparent junctures. These results suggest that speakers have access to some word-internal morphological information, and that complex words may share characteristics of both words and phrases in, for instance, English., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cisplatin-based chemotherapy may induce nephrotoxicity. This study presents a random forest predictive model that identifies testicular cancer patients at risk of nephrotoxicity before treatment., Methods: Clinical data and DNA from saliva samples were collected for 433 patients. These were genotyped on Illumina HumanOmniExpressExome-8 v1.2 (964 193 markers). Clinical and genomics-based random forest models generated a risk score for each individual to develop nephrotoxicity defined as a 20% drop in isotopic glomerular filtration rate during chemotherapy. The area under the receiver operating characteristic curve was the primary measure to evaluate models. Sensitivity, specificity, and positive and negative predictive values were used to discuss model clinical utility., Results: Of 433 patients assessed in this study, 26.8% developed nephrotoxicity after bleomycin-etoposide-cisplatin treatment. Genomic markers found to be associated with nephrotoxicity were located at NAT1 , NAT2 , and the intergenic region of CNTN6 and CNTN4 . These, in addition to previously associated markers located at ERCC1 , ERCC2 , and SLC22A2 , were found to improve predictions in a clinical feature-trained random forest model. Using only clinical data for training the model, an area under the receiver operating characteristic curve of 0.635 (95% confidence interval [CI] = 0.629 to 0.640) was obtained. Retraining the classifier by adding genomics markers increased performance to 0.731 (95% CI = 0.726 to 0.736) and 0.692 (95% CI = 0.688 to 0.696) on the holdout set., Conclusions: A clinical and genomics-based machine learning algorithm improved the ability to identify patients at risk of nephrotoxicity compared with using clinical variables alone. Novel genetics associations with cisplatin-induced nephrotoxicity were found for NAT1 , NAT2 , CNTN6 , and CNTN4 that require replication in larger studies before application to clinical practice., (© The Author(s) 2020. Published by Oxford University Press.)

Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain., Materials and Methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719., Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64)., Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Worldwide drylands are threatened by changes in resource availability associated with global environmental change. Functional traits may help predict which species will be most responsive to these alterations in nutrient and water availability. Current functional trait work focuses on tissue construction and nutrient concentrations, but plant performance in low resource environments also may be strongly influenced by traits related to nutrient budgets and allocation. Our overall objective was to compare trait responses in a suite of serpentine and nonserpentine congener pairs from the California chaparral, a biodiverse region facing nutrient deposition and future changes in precipitation. In a common garden greenhouse environment, we grew small plants of Arctostaphylos manzanita, A. viscida, Ceanothus cuneatus, C. jepsonii, Quercus berberidifolia, and Q. durata in contrasting soil nutrient and moisture treatments. We measured a suite of traits representing physiological, growth, and mineral nutrient responses to these treatments. Overall, plant growth rate and leaf-level phosphorus use efficiency were greatest in the low water, high nutrient treatment, and lowest in the high water, low nutrient treatment. Variation in growth rate and plasticity among species and treatments was primarily associated with differences in mineral nutrition-based traits as opposed to differences in biomass allocation or specific leaf area. Namely, faster growing species and species with greater plasticity allocated more nitrogen and phosphorous to leaves and demonstrated greater photosynthetic phosphorus use efficiency. Overall, nonserpentine species had greater plasticity and biomass response to resource addition than serpentine species, and congener pairs responded to these resource additions more similarly to each other than species across congener pairs. This study extends our general understanding of how functional traits may influence species responses to environmental change and highlights the need to integrate mineral nutrition-based traits, including allocation of nutrient pools and nutrient use efficiency into this larger trait framework. Ultimately, this insight can help identify, in part, why coexisting species may vary in sensitivity to anthropogenic driven changes in soil resource availability.

Objective: To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality., Design: 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed., Results: 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye., Conclusion: Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation., Trial Registration Number: NCT01731366; Results., Competing Interests: Competing interests: MV Lind was partly supported by an unrestricted grant from Cereal Partners Worldwide, a joint venture between Nestlé SA and General Mills Ltd. There were no conflict of interest to declare for the other authors. Intervention products were sponsored by Kohberg, Lantmännen, AXA, Wasa, Urtekram, Finax and Doves Farm. Sponsors of grants and products played no role in the design, methods, data management and analysis nor in the decision to publish., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Substantial research has established that place of articulation of stop consonants (labial, alveolar, velar) are reliably differentiated using a number of acoustic measures such as closure duration, voice onset time (VOT), and spectral measures such as centre of gravity and the relative energy distribution in the mid-to-high spectral range of the burst. It is unclear, however, whether such measurable acoustic differences are present in multiple place of articulation contrasts among coronal stops. This article presents evidence from the highly endangered indigenous Australian language Wubuy, which maintains a 4-way coronal stop place contrast series in all word positions. The authors examine the temporal and burst characteristics of / t̪ t ʈ/ in three prosodic positions (utterance-initial, word-initial but phrase medial, and word-medial). The results indicate that VOT, closure duration, and the spectral quality of the burst may indeed differentiate multiple coronal place contrasts, in most positions, although measures that distinguish the apical contrast in absolute initial position remain elusive. The authors also examine measures (spectrum kurtosis, spectral tilt) previously used in other studies of multiple coronals in Australian languages. These results suggest that the authors' measures perform at least as well as those previously applied to multiple coronals in other Australian languages.

Background: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines., Results: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing concentrations of docetaxel. Whole exome sequencing performed at five successive stages during this process was used to identify single point mutational events, insertions/deletions and copy number alterations associated with the acquisition of docetaxel resistance. Acquired coding variation undergoing positive selection and harboring characteristics likely to be functional were further prioritized using network-based approaches. A number of genomic changes were found to be undergoing evolutionary selection, some of which were likely to be functional. Of the five stages of progression toward resistance, most resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired several copy number gains on chromosome 7, including ABC transporter genes, including ABCB1 and ABCB4, as well as DMTF1, CLDN12, CROT, and SRI. For MDA-MB-231 numerous copy number losses on chromosome X involving more than 30 genes was observed. Of these genes, CASK, POLA1, PRDX4, MED14 and PIGA were highly prioritized by the applied network-based gene ranking approach. At higher docetaxel concentration MCF-7 subclones exhibited a copy number loss in E2F4, and the gene encoding this important transcription factor was down-regulated in MCF-7 resistant cells., Conclusions: Our study of the evolution of acquired docetaxel resistance identified several genomic changes that might explain development of docetaxel resistance. Interestingly, the most relevant resistance-associated changes appeared to originate midway through the evolution towards fully resistant cell lines. Our data suggest that no single genomic event sufficiently predicts resistance to docetaxel, but require genomic alterations affecting multiple pathways that in concert establish the final resistance stage.

Native speech perception is generally assumed to be highly efficient and accurate. Very little research has, however, directly examined the limitations of native perception, especially for contrasts that are only minimally differentiated acoustically and articulatorily. Here, we demonstrate that native speech perception may indeed be more difficult than is often assumed, where phonemes are highly similar, and we address the nature and extremes of consonant perception. We present two studies of native and non-native (English) perception of the acoustically and articulatorily similar four-way coronal stop contrast /t ʈ [symbol: see text] ȶ/ (apico-alveolar, apico-retroflex, lamino-dental, lamino-alveopalatal) of Wubuy, an indigenous language of Australia. The results show that all listeners find contrasts involving /ȶ/ easy to discriminate, but that, for both groups, contrasts involving /t ʈ [symbol: see text]/ are much harder. Where the two groups differ, the results largely reflect native language (Wubuy vs English) attunement as predicted by the Perceptual Assimilation Model. We also observe striking perceptual asymmetries in the native listeners' perception of contrasts involving the latter three stops, likely due to the differences in input frequency. Such asymmetries have not previously been observed in adults, and we propose a novel Natural Referent Consonant Hypothesis to account for the results.

American mink (Neovison vison) kits are born altricial and fully dependent on maternal care, for which the kits' vocalizations appear essential. We used auditory brainstem responses (ABRs) to determine: (1) hearing sensitivity of adult females from two breeding lines known to differ in maternal behaviour and (2) development of hearing in kits 8-52 days of age. We also studied sound production in 20 kits throughout postnatal days 1 to 44. Adult female mink had a broad hearing range from 1 kHz to above 70 kHz, with peak sensitivity (threshold of 20 dB SPL) at 8-10 kHz, and no difference in sensitivity between the two breeding lines (P>0.22) to explain the difference in maternal care. Mink kits showed no signs of hearing up to postnatal day 24. From day 30, all kits had ABRs indicative of hearing. Hearing sensitivity increased with age, but was still below the adult level at postnatal day 52. When separated from their mothers, kits vocalized loudly. Until the age of 22 days, 90% of all kits vocalized with no significant decline with age (P=0.27). From day 25, concurrent with the start of hearing, the number of vocalizing kits decreased with age (P<0.001), in particular in kits that were re-tested (P=0.004). Large numbers of mink are kept in fur industry farms, and our results are important to the understanding of sound communication, which is part of their natural behaviour. Our results also suggest mink as an interesting model for studying the development of mammalian hearing and its correlation to sound production.

Introduction: The Danish National Board of Health recommends graduated care of type 2 diabetes patients based on risk stratification. This requires a systematic monitoring of indicators for the development of complications., Material and Methods: Retrospective evaluation of type 2 diabetes patients referred from general practice in the 2004-2007 period., Inclusion Criteria: 1) Diabetes duration = two years, 2) Diabetes control exclusively handled in primary care in the previous two years, 3) Referred from general practice to outpatient assessment by the diabetes centre, 4) The physician used a laboratory affiliated to the Aarhus County laboratory database, 5) Written referral could be found. Data was gathered by reviewing records, searching the laboratory database and register of diabetic eye care service., Results: A total of 97 patients were included. By the time at referral (mean): Age 61.5 years, diabetes duration 8.4 years, body mass index 31.7 kg/m2. In the last two years before referral, the following percentage had at least one p-lipid measurement: 85%, eye examination: 61% and measurement of microalbuminuria: 53%. HbA1c at referral was 9.0% (n = 97), 9.1% (n = 93) seven months before and 8.7% (n = 82) 20 months before referral., Conclusion: Glycaemic control was poor 20 months before referral. The prerequisites for the recommendation of The Danish National Board of Health was not present since eye examination was not performed in 39% and assessment of microalbuminuria was not performed in 47% of the patients in the previous two years before referral.

Background: High blood levels of soluble urokinase Plasminogen Activator Receptor (suPAR) are associated with poor outcomes in human immunodeficiency-1 (HIV-1) infected individuals. Research on the clinical value of suPAR in HIV-1 infection led to the development of the suPARnostic(R) assay for commercial use in 2006. The aim of this study was to: 1) Evaluate the prognostic value of the new suPARnostic assay and 2) Determine whether polymorphisms in the active promoter of uPAR influences survival and/or suPAR values in HIV-1 patients who are antiretroviral therapy (ART) naive., Methods: DNA samples were collected retrospectively from 145 Danes infected with HIV-1 with known seroconversion times. In addition, plasma was collected retrospectively from 81 of these participants for use in the suPAR analysis. Survival was analysed using Kaplan Meier analysis., Results: Survival was strongly correlated to suPAR levels (p < 0.001). Levels at or above 6 ng/ml were associated with death in 13 of 27 patients within a two-years period; whereas only one of 54 patients with suPAR levels below 6 ng/ml died during this period. We identified two common uPAR promoter polymorphisms: a G to A transition at -118 and an A to G transition at -465 comparative to the transcription start site. These promoter transitions influenced neither suPAR levels nor patient survival., Conclusion: Plasma suPAR levels, as measured by the suPARnostic(R) assay, were strongly predictive of survival in ART-naïve HIV-1 infected patients. Furthermore, plasma suPAR levels were not influenced by uPAR promoter polymorphisms.

The highly glycosylated protein MUC1 was purified from bovine milk-fat globule membranes by a procedure involving detergent extraction, ion-exchange chromatography and reverse-phase chromatography. The identity of the purified mucin protein was confirmed by N-terminal sequencing and partial amino acid sequences obtained by peptide mapping. The complete amino acid sequence of MUC1 was determined by cloning and sequencing the corresponding bovine mammary gland cDNA, which was shown to encode a protein of 580 amino acid residues comprising a cleavable signal peptide of 22 residues. The deduced amino acid sequence demonstrated structural features characteristic for mucins, including an extracellular tandem repeat region with 11 partially conserved repeats (20 amino acids each), a membrane-proximal SEA module, a transmembrane domain, and a cytoplasmic C-terminal region. Monosaccharide composition determinations suggested significant structural differences between O-linked glycans of MUC1 originating from either bovine or human milk. Interspecies differences of the consensus repeat sequence in MUC1 and the physiological functions are discussed.

The milk fat globule membrane-associated proteins adipophilin (alias adipocyte differentiation-related protein) and butyrophilin were purified from bovine milk by reverse-phase chromatography. The nucleotide sequence of bovine adipophilin was obtained via peptide mapping and sequencing of a mammary gland cDNA clone, which comprises 1841 nucleotides and has an open reading frame of 450 amino acids. By peptide mapping, 19% of the amino acid sequence was confirmed. The obtained amino acid sequence has 87 and 80% identical residues with human and mouse adipophilin, respectively. Alignment with the proteins perilipin and TIP47 revealed two highly conserved segments, which may assemble into amphipathic alpha-helices.

The results of a national segmentation study are reported. The findings extend the empirical work of Finn and Lamb and the benefit-seeking conjectures by Kotler and Clarke that consumers with preferences toward specific hospitals can be segmented into a few distinct groups. The groups described in the findings are identified as the value conscious, the affluents, the old-fashioneds, and the professional want-it-alls. Each segment has a unique demographic profile. The substantial importance of doctors' recommendations in influencing hospital choice is supported for all four consumer segments. Suggestions for additional research and hospital marketing strategies are provided.

Fulminant falciparum malaria with greater than 500,000/mm3 parasites in the peripheral blood portends a poor prognosis. We recently managed a patient who had greater than 1.2 million/mm3 parasitized erythrocytes in her peripheral blood, following initially inadequate antimalarial therapy, with exchange transfusion in addition to conventional chemotherapy. This patient recovered from her disease despite severe cerebral involvement and acute failure. We feel that exchange transfusion was a useful adjunct and should be considered in patients with life threatening falciparum malaria when conventional measures fail to control the disease.

To determine the long-term efficacy of insulin-pump therapy, we analyzed trends in glycosylated hemoglobin concentrations in 127 patients with Type I diabetes using insulin pumps for periods ranging from 13 to 47 months. In the first year of pump therapy the average glycosylated hemoglobin concentration improved in 83 per cent of the patients, as compared with the value before pump therapy. Although only 11 of the 127 subjects had normal glycosylated hemoglobin values before pump therapy, 33 had a normal average value during the first full year of pump use (P = 0.0001). This favorable trend persisted for the three-year duration of the study. Seventeen of the 19 patients who subsequently discontinued insulin-pump therapy had improved glycosylated hemoglobin values during the period of pump use. Eleven of the 19 patients remained available for follow-up study; the glycosylated hemoglobin concentration became worse in 7 when they returned to conventional treatment. We conclude that the improvement in metabolic control repeatedly demonstrated in short-term studies with the insulin pump can be maintained for a period of years.

We determined the frequency of acute complications associated with insulin pump therapy in 161 insulin-dependent patients followed up for a total of 2,978 patient-months. Diabetes control improved substantively with pump therapy, but 42% of the patients experienced one or more acute complications while using insulin pumps. Infected infusion sites, ketoacidosis, and hypoglycemic coma occurred once in every 27, 78, and 175 patient-months, respectively. More patients experienced ketoacidosis after the onset of pump therapy than in an equivalent interval immediately before the onset of pump therapy. Ketoacidosis also occurred in more patients using pump therapy than in a comparison group of 165 patients receiving conventional insulin injections surveyed during an equivalent period. The frequency of hypoglycemic coma was not significantly changed by pump therapy.