Search

Abstract Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos (‘microPhos’), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in 90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.

Abstract Prognostic factors for overall survival (OS), percutaneous endoscopic gastrostomy (PEG) dependency, and long-term speech rehabilitation via voice prosthesis (VP) after laryngectomy for laryngeal or hypopharyngeal cancer were investigated in a retrospective population-based study in Thuringia, Germany. A total of 617 patients (68.7% larynx; hypopharynx; 31.3%; 93.7% men; median age 62 years; 66.0% stage IV) from 2001 to 2020 were included. Kaplan–Meier and Cox multivariable regression analyses were performed. 23.7% of patients received a PEG. 74.7% received a VP. Median OS was 131 months. Independent factors for lower OS were stage IV (compared to stage II; hazard ratio [HR] = 3.455; confidence interval [CI] 1.395–8.556) and laryngectomy for a recurrent disease (HR = 1.550; CI 1.078–2.228). Median time to PEG removal was 7 months. Prior partial surgery before laryngectomy showed a tendency for independent association for later PEG removal (HR = 1.959; CI 0.921–4.167). Postoperative aspiration needing treatment was an independent risk factor (HR = 2.679; CI 1.001–7.167) for later definitive VP removal. Laryngectomy continuously plays an important role in a curative daily routine treatment setting of advanced laryngeal or hypopharyngeal cancer in Germany. Long-term dependency on nutrition via PEG is an important issue, whereas use of VP is a stable long-term measure for voice rehabilitation.

Resource efficient processing of polymers is of paramount importance to minimize energy consumption, processing time, and material losses in the polymer industry. This study is concerned with polymer processing in planetary roller extruders. A three-dimensional numerical flow simulation was tailored to understand the polymer flow through the extruder in detail. Using the simulation software ANSYS Polyflow, we quantified both directly measurable process parameters, such as pressure build-up, and more intangible parameters, such as material shear. By varying operational and material parameters in a sensitivity analysis, we showed that the dynamics, material stress and pressure build-up are controlled primarily by the number of spindles and their rotational speed. Notably, this work provides the first successful validation of a 3D simulation of a polymer flow in a planetary roller extruder against actual experimental data. The simulation showed robust agreement between the simulated and experimental values, provided that a critical backpressure length is reached. This computational approach minimizes labor-intensive experimental testing in polymer processing.

Abstract Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.

Abstract Background There are established links between the accumulation of body fat as visceral adipose tissue (VAT) and the risk of developing obesity‐associated metabolic disease. Previous studies have suggested that levels of intake of specific foods and nutrients are associated with VAT accumulation after accounting for total energy intake. Objective This study assessed associations between a priori selected dietary factors on VAT quantified using abdominal magnetic resonance imaging. Methods The cross‐sectional Multiethnic Cohort Adiposity Phenotype Study included n = 395 White, n = 274 Black, n = 269 Native Hawaiian, n = 425 Japanese American and n = 358 Latino participants (mean age = 69 years ± 3 SD). Participants were enrolled stratified on sex, race, ethnicity and body mass index. General linear models were used to estimate the mean VAT area (cm2) for participants categorized into quartiles based on their dietary intake of selected foods/nutrients adjusting for age, sex, racial and ethnic groups, the total percentage fat from whole‐body dual energy X‐ray absorptiometry and total energy. Results There were significant inverse associations with VAT for dietary intake of total vegetables, total fruits (including juice), cereals, whole grains, calcium, copper and dietary fiber (p‐trend ≤0.04). Positive trends were observed for VAT for participants who reported higher intake of potatoes, total fat and saturated fatty acids (SFA) (p‐trend ≤0.02). Foods/nutrients that met the multiple testing significance threshold were total fruits, whole grains, copper, dietary fiber and SFA intake. Conclusions These results highlight foods and nutrients including SFA, total fruit, whole grains, fiber and copper as potential candidates for future research to inform dietary guidelines for the prevention of chronic disease among older adults.

BackgroundWe previously developed a prediction score for MRI-quantified abdominal visceral adipose tissue (VAT) based on concurrent measurements of height, body mass index (BMI), and nine blood biomarkers, for optimal performance in five racial/ethnic groups. Here we evaluated the VAT score for prediction of future VAT and examined if enhancement with additional biomarkers, lifestyle behavior information, and medical history improves the prediction.MethodsWe examined 500 participants from the Multiethnic Cohort (MEC) with detailed data (age 50-66) collected 10 years prior to their MRI assessment of VAT. We generated three forecasted VAT prediction models: first by applying the original VAT equation to the past data on the predictors ("original"), second by refitting the past data on anthropometry and biomarkers ("refit"), and third by building a new prediction model based on the past data enhanced with lifestyle and medical history ("enhanced"). We compared the forecasted prediction scores to future VAT using the coefficient of determination (R2). In independent nested case-control data in MEC, we applied the concurrent and forecasted VAT models to assess association of the scores with subsequent incident breast cancer (950 pairs) and colorectal cancer (831 pairs).ResultsCompared to the VAT prediction by the concurrent VAT score (R2 = 0.70 in men, 0.68 in women), the forecasted original VAT score (R2 = 0.54, 0.48) performed better than past anthropometry alone (R2 = 0.47, 0.40) or two published scores (VAI, METS-VF). The forecasted refit (R2 = 0.61, 0.51) and enhanced (R2 = 0.62, 0.55) VAT scores each showed slight improvements. Similar to the concurrent VAT score, the forecasted VAT scores were associated with breast cancer, but not colorectal cancer. Both the refit score (adjusted OR for tertile 3 vs. 1 = 1.27; 95% CI: 1.00-1.62) and enhanced score (1.27; 0.99-1.62) were associated with breast cancer independently of BMI.ConclusionsPredicted VAT from midlife data can be used as a surrogate to assess the effect of VAT on incident diseases associated with obesity, as illustrated for postmenopausal breast cancer.

Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy–TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II–III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m2/d)/oxaliplatin (50 mg/m2), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Purpose: Motion-induced magnetic resonance imaging (MRI) artifacts can deteriorate image quality and reduce diagnostic accuracy, but motion by human subjects is inevitable and can even be caused by involuntary physiological movements. Deep-learning-based motion correction methods might provide a solution. However, most studies have been based on directly applying existing models, and the trained models are rarely accessible. Therefore, we aim to develop and evaluate a deep-learning-based method (Motion Correction-Net, or MC-Net) for suppressing motion artifacts in brain MRI scans. Methods: A total of 57 subjects, providing 20,889 slices in four datasets, were used. Furthermore, 3T 3D sagittal magnetization-prepared rapid gradient-echo (MP-RAGE) and 2D axial fluid-attenuated inversion-recovery (FLAIR) sequences were acquired. The MC-Net was derived from a UNet combined with a two-stage multi-loss function. T1-weighted axial brain images contaminated with synthetic motions were used to train the network to remove motion artifacts. Evaluation used simulated T1- and T2-weighted axial, coronal, and sagittal images unseen during training, as well as T1-weighted images with motion artifacts from real scans. The performance indices included the peak-signal-to-noise ratio (PSNR), the structural similarity index measure (SSIM), and visual reading scores from three blinded clinical readers. A one-sided Wilcoxon signed-rank test was used to compare reader scores, with p < 0.05 considered significant. Intraclass correlation coefficients (ICCs) were calculated for inter-rater evaluations. Results: The MC-Net outperformed other methods in terms of PSNR and SSIM for the T1 axial test set. The MC-Net significantly improved the quality of all T1-weighted images for all directions (i.e., the mean SSIM of axial, sagittal, and coronal slices improved from 0.77, 0.64, and 0.71 to 0.92, 0.75, and 0.84; the mean PSNR improved from 26.35, 24.03, and 24.55 to 29.72, 24.40, and 25.37, respectively) and for simulated as well as real motion artifacts, both using quantitative measures and visual scores. However, MC-Net performed poorly for images with untrained T2-weighted contrast because the T2 contrast was unseen during training and is different from T1 contrast. Conclusion: The proposed two-stage multi-loss MC-Net can effectively suppress motion artifacts in brain MRI without compromising image quality. Given the efficiency of MC-Net (with a single-image processing time of ~40 ms), it can potentially be used in clinical settings.

Abstract Aims Clonal haematopoiesis of indeterminate potential (CHIP)‐associated mutation is a risk factor for the development of ischaemic cardiomyopathy (ICM), but its association with non‐ischaemic dilated cardiomyopathy (DCM) remains unclear. We aimed to determine the prevalence of CHIP in patients with DCM and define its risk for disease progression. Methods and results Next‐generation sequencing targeting 54 common CHIP‐associated genes was performed in 48 ICM and 52 DCM patients. The patients were monitored for a median of 3.1 years, and a COX proportional hazards model was used to examine the association between CHIP and adverse clinical outcome with regard to all‐cause death or all‐cause hospitalization. Overall, the prevalence of CHIP mutations was 19% and 13% in DCM and ICM, respectively. Seventeen per cent of ICM patients over 75 years were CHIP carriers. In DCM cohort, mutation event had already been observed in the patients who were under the age of 45 (13%). Among 54 genes analysed, DNMT3A had the highest mutation frequency, followed by TET2 and CUX1. Kaplan–Meier curve over a median of 3.1 year tracking period showed a trend towards poor clinical outcome in the DCM patients who carried DNMT3A or TET2 mutation; however, such association was not statistically significant. Conclusions The prevalence of CHIP is detected at a young age in DCM, and accumulation of mutational frequency in DCM patients is independent of age. However, a larger patient cohort is required to validate the association between CHIP and clinical progression in the DCM patients.

Bullying victimization is associated with a doubled risk of attempting suicide in adulthood. Two longitudinal brain morphometry studies identified the fusiform gyrus and putamen as vulnerable to bullying. No study identified how neural alterations may mediate the effect of bullying on cognition. We assessed participants with caregiver-reported bullying (N = 323) and matched non-bullied controls (N = 322) from the Adolescent Brain Cognitive Development Study dataset to identify changes in brain morphometry associated with ongoing bullying victimization over two years and determine whether such alterations mediated the effect of bullying on cognition.Bullied children (38.7% girls, 47.7% racial minorities, 9.88 ± 0.62 years at baseline) had poorer cognitive performance (P

In this paper, we propose a novel approach to utilize silicon nanowires as high-sensitivity pH sensors. Our approach works based on fixing the current bias of silicon nanowires Ion Sensitive Field Effect Transistors (ISFETs) and monitor the resulting drain voltage as the sensing signal. By fine tuning the injected current levels, we can optimize the sensing conditions according to different sensor requirements. This method proves to be highly suitable for real-time and continuous measurements of biomarkers in human biofluids. To validate our approach, we conducted experiments, with real human sera samples to simulate the composition of human interstitial fluid (ISF), using both the conventional top-gate approach and the optimized constant current method. We successfully demonstrated pH sensing within the physiopathological range of 6.5 to 8, achieving an exceptional level of accuracy in this complex matrix. Specifically, we obtained a maximum error as low as 0.92% (equivalent to 0.07 pH unit) using the constant-current method at the optimal current levels (1.71% for top-gate). Moreover, by utilizing different pools of human sera with varying total protein content, we demonstrated that the protein content among patients does not impact the sensors’ performance in pH sensing. Furthermore, we tested real-human ISF samples collected from volunteers. The obtained accuracy in this scenario was also outstanding, with an error as low as 0.015 pH unit using the constant-current method and 0.178 pH unit in traditional top-gate configuration.

Background Inflammatory skin reactions and skin alterations are still a potential side effect in radiation therapy (RT), which also need attention for patients’ health care. Method In a pre-clinical study we consider alterations in irradiated in-vitro skin models of epidermal and dermal layers. Typical dose regimes in radiation therapy are applied for irradiation. For non-invasive imaging and characterization optical coherence tomography (OCT) is used. Histological staining method is additionally applied for comparison and discussion. Results Structural features, such as keratinization, modifications in epidermal cell layer thickness and disorder in the layering—as indications for reactions to ionizing radiation and aging—could be observed by means of OCT and confirmed by histology. We were able to recognize known RT induced changes such as hyper-keratosis, acantholysis, and epidermal hyperplasia as well as disruption and/or demarcation of the dermo-epidermal junction. Conclusion The results may pave the way for OCT to be considered as a possible adjunctive tool to detect and monitor early skin inflammation and side effects of radiotherapy, thus supporting patient healthcare in the future.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Holmium-166 microspheres are used for the transarterial radioembolization (TARE) treatment of primary and secondary liver cancers. In this study, its efficacy regarding local tumor control and integration into the oncological treatment sequence of the first 20 patients treated in our institution were examined. A total of twenty-nine 166Ho-TARE procedures were performed to treat hepatocellular carcinoma (HCC, fourteen patients), metastatic colorectal cancer (mCRC, four patients), intrahepatic cholangiocarcinoma (ICC, one patient), and hemangioendothelioma of the liver (HE, one patient). In eight patients, 166Ho-TARE was the initial oncologic treatment. In patients with HCC, the median treated-liver progression-free survival (PFS), overall PFS, and overall survival after 166Ho-TARE were 10.3, 7.3, and 22.1 months; in patients with mCRC, these were 2.6, 2.9, and 20.6 months, respectively. Survival after 166Ho-TARE in the patients with ICC and HE were 5.2 and 0.8 months, respectively. Two patients with HCC were bridged to liver transplantation, and one patient with mCRC was downstaged to curative surgery. In patients with HCC, a median treatment-free interval of 7.3 months was achieved. In line with previous publications, 166Ho-TARE was a feasible treatment option in patients with liver tumors, with favorable clinical outcomes in the majority of cases. It was able to achieve treatment-free intervals, served as bridging-to-transplant, and did not prevent subsequent therapies.

Parents often report behavioral problems in children with symptoms of sleep disordered breathing (oSDB), such as snoring. Here, the authors show that lower brain volumes within the frontal lobe are associated with parent-reported problem behaviors in children with parent-reported symptoms of oSDB.

Abstract Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]101-b-[n-(butyl methacrylate)124-co-(lipoic acid methacrylate)22]} (P(DMAEMA101-b-[nBMA124-co-LAMA22])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.

The purpose of this article is to study how q-real numbers can be used for computations of convergence regions, q-integral representations of certain multiple triple q-Lauricella functions. The corresponding q-difference equations are also given without proof. In the process, we slightly improve Exton’s original formulas. We also survey the current attempts to generalize the above functions to triple and quadruple hypergeometric functions. Finally, we compute some q-analogues of transformation formulas for Horn functions.

BackgroundAdaptive computerized working memory (WM) training has shown favorable effects on cerebral cortical thickness as compared to non-adaptive training in healthy individuals. However, knowledge of WM training-related morphological changes in mild cognitive impairment (MCI) is limited.ObjectiveThe primary objective of this double-blind randomized study was to investigate differences in longitudinal cortical thickness trajectories after adaptive and non-adaptive WM training in patients with MCI. We also investigated the genotype effects on cortical thickness trajectories after WM training combining these two training groups using longitudinal structural magnetic resonance imaging (MRI) analysis in Freesurfer.MethodMagnetic resonance imaging acquisition at 1.5 T were performed at baseline, and after four- and 16-weeks post training. A total of 81 individuals with MCI accepted invitations to undergo 25 training sessions over 5 weeks. Longitudinal Linear Mixed effect models investigated the effect of adaptive vs. non-adaptive WM training. The LME model was fitted for each location (vertex). On all statistical analyzes, a threshold was applied to yield an expected false discovery rate (FDR) of 5%. A secondary LME model investigated the effects of LMX1A and APOE-ε4 on cortical thickness trajectories after WM training.ResultsA total of 62 participants/patients completed the 25 training sessions. Structural MRI showed no group difference between the two training regimes in our MCI patients, contrary to previous reports in cognitively healthy adults. No significant structural cortical changes were found after training, regardless of training type, across all participants. However, LMX1A-AA carriers displayed increased cortical thickness trajectories or lack of decrease in two regions post-training compared to those with LMX1A-GG/GA. No training or training type effects were found in relation to the APOE-ε4 gene variants.ConclusionThe MCI patients in our study, did not have improved cortical thickness after WM training with either adaptive or non-adaptive training. These results were derived from a heterogeneous population of MCI participants. The lack of changes in the cortical thickness trajectory after WM training may also suggest the lack of atrophy during this follow-up period. Our promising results of increased cortical thickness trajectory, suggesting greater neuroplasticity, in those with LMX1A-AA genotype need to be validated in future trials.

In chronic myelogenous leukemia (CML), treatment with tyrosine kinase inhibitors (TKI) is unable to eradicate leukemic stem cells (LSC). Polymethine dye-functionalized nanoparticles can be internalized by specific cell types using transmembrane carrier proteins. In this study we investigated the uptake behavior of various polymethine dyes on leukemia cell lines and searched for carrier proteins that guide dye transport using RNA interference. The results show that the uptake of DY-635 is dependent on organic anion transport protein 1B3 (OATP1B3) in CML cells and immature myeloid precursor cells of CML patients. In contrast to nonspecific poly(lactide-co-glycolic acid) (PLGA) nanoparticle constructs, DY-635-functionalization of nanoparticles led to an uptake in CML cells. Investigation of these nanoparticles on bone marrow of CML patients showed a preferred uptake in LSC. The transcription of OATP1B3 is known to be induced under hypoxic conditions via the hypoxia-inducing factor 1 alpha (HIF1α), thus also in the stem cells niche. Since these cells have the potential to repopulate the bone marrow after CML treatment discontinuation, eliminating them by means of drug-loaded DY-635-functionalized PLGA nanoparticles deployed as a selective delivery system to LSC is highly relevant to the ongoing search for curative treatment options for CML patients.

The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population‐specific genetic variants associated with liver fat. We conducted a genome‐wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population‐based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin‐like phospholipase domain containing 3 (PNPLA3) at 22q13 was confirmed to be associated with percent liver fat (P = 3.52 × 10−15) but more strongly in women than men (P heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA‐IR) (beta = 0.028; P = 0.009) and circulating levels of insulin (beta = 0.022; P = 0.020) and alanine aminotransferase (beta = 0.016; P = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [LMBRD1] and collagen type XIX alpha 1 chain [COL19A1] (P = 1.42 × 10−8) was also observed. Rs7724941 was associated with HOMA‐IR (beta = 0.12; P = 0.0005), insulin (beta = 0.11; P = 0.0003), triglycerides (beta = 0.059; P = 0.01), high‐density lipoprotein (beta = −0.046; P = 0.04), and sex hormone binding globulin (beta = −0.084; P = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). Conclusion: We replicated the PNPLA3 rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.

Abstract Background Individualization and patient-specific optimization of treatment is a major goal of modern health care. One way to achieve this goal is the application of high-resolution diagnostics together with the application of targeted therapies. However, the rising number of different treatment modalities also induces new challenges: Whereas randomized clinical trials focus on proving average treatment effects in specific groups of patients, direct conclusions at the individual patient level are problematic. Thus, the identification of the best patient-specific treatment options remains an open question. Systems medicine, specifically mechanistic mathematical models, can substantially support individual treatment optimization. In addition to providing a better general understanding of disease mechanisms and treatment effects, these models allow for an identification of patient-specific parameterizations and, therefore, provide individualized predictions for the effect of different treatment modalities. Results In the following we describe a software framework that facilitates the integration of mathematical models and computer simulations into routine clinical processes to support decision-making. This is achieved by combining standard data management and data exploration tools, with the generation and visualization of mathematical model predictions for treatment options at an individual patient level. Conclusions By integrating model results in an audit trail compatible manner into established clinical workflows, our framework has the potential to foster the use of systems-medical approaches in clinical practice. We illustrate the framework application by two use cases from the field of haematological oncology.

Light detection and ranging technology allows for the creation of detailed 3D point clouds of physical objects and environments. Therefore, it has the potential to provide valuable information for the operation of various kinds of cyber-physical systems that need to be aware of, and interact with, their surroundings, such as autonomous vehicles and robots. Point clouds can also become the basis for the creation of digital representations of different assets and a system’s operational environment. This article outlines a system architecture that integrates the geo-spatial context information provided by LiDAR scans with behavioral models of the components of a cyber-physical system to create a digital twin. The clear distinction between behavior and data sets the proposed digital twin architecture apart from existing approaches (that primarily focus on the data aspect), and promotes contextual digital twin generation through executable process models. A vaccine logistics automation use case is detailed to illustrate how information regarding the environment can be used for the operation of an autonomous robot carrying out transport preparation tasks. Besides supporting operation, we propose to combine context data retrieved from the system at different points in the logistics process with information regarding instances of executable behavior models as part of the digital twin architecture. The twin can subsequently be used to facilitate system and process monitoring through relevant stakeholders and structure context data in a user-centric fashion.

Objectives The aim of the study is to compare how member states of the European Union (EU) develop their national physical activity (PA) recommendations and to provide an overview of the methodologies they apply in doing so. Information was collected directly from the physical activity focal points of EU member states in 2018. Five countries were chosen for detailed case study analysis of development processes.Design Cross-sectional survey.Participants The representatives of the 28 EU member state governments to the EU physical activity Focal Point Network.Outcome measures From national documents we extracted data on (1) the participants of the development process, (2) the different methods used during development, and (3) on which sources national PA recommendations were based. An additional survey for case study countries provided details on (1) anonymised information on the participants of development process, (2) methods employed and rationale for choosing them, (3) development process and timeline, and (4) main source documents used for recommendation development.Results Eighteen national documents on PA recommendations contained information about development process. The results showed that countries used different approaches to develop national recommendations. The main strategies were (1) adoption of WHO 2010 recommendations or (2) a combination of analysis and adoption of other national and international recommendations and literature review. All of the five case study countries relied on review processes rather than directly adopting WHO recommendations.Conclusions While there are arguments for the use of particular strategies for PA recommendation development, there is currently no evidence for the general superiority of a specific approach. Instead, our findings highlight the broad spectrum of potential development methods, resources utilisation and final recommendations design currently available to national governments. These results may be a source of inspiration for other countries currently planning the development or update of national PA recommendations.

Digital publishing in the humanities has become an established and widely used component of scholarly communication. A digital publishing culture has become an integral part of scientific work. However, not all questions about digital publishing have been answered and many experimental approaches still exist. This working paper by the Digital Publishing Working Group of the Digital Humanities Association in the German-speaking countries (DHd) aims to re-examine digital publishing and look at current developments, discourses and best practice examples.

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9–10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study—a multi-site sample of 9–10 year-olds (n = 11,875)—and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child’s weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9–10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Precise quantification of molecular targets in a biological sample across a wide dynamic range is a key requirement in many diagnostic procedures, such as monitoring response to therapy or detection of measurable residual disease. State of the art digital PCR assays provide for a dynamic range of four orders of magnitude. However digital assays are complex and require sophisticated microfluidic tools. Here we present an assay format that enables ultra-precise quantification of RNA targets in a single measurement across a dynamic range of more than six orders of magnitude. The approach is based on hydrogel beads that provide for microfluidic free compartmentalization of the sample as they are used as nanoreactors for reverse transcription, PCR amplification and combined real time and digital detection of gene transcripts. We have applied these nanoreactor beads for establishing an assay for the detection and quantification of BCR-ABL1 fusion transcripts. The assay has been characterized for its precision and linear dynamic range. A comparison of the new method against conventional real time RT-PCR analysis (reference method) with clinical samples from patients with chronic myeloid leukemia (CML) revealed excellent concordance with Pearsons correlation coefficient of 0.983 and slope of 1.08.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

The quality of functional MRI (fMRI) data is affected by head motion. It has been shown that fMRI data quality can be improved by prospectively updating the gradients and radio-frequency pulses in response to head motion during image acquisition by using an MR-compatible optical tracking system (prospective motion correction, or PMC). Recent studies showed that PMC improves the temporal Signal to Noise Ratio (tSNR) of resting state fMRI data (rs-fMRI) acquired from subjects not moving intentionally. Besides that, the time courses of Independent Components (ICs), resulting from Independent Component Analysis (ICA), were found to present significant temporal correlation with the motion parameters recorded by the camera. However, the benefits of applying PMC for improving the quality of rs-fMRI acquired under large head movements and its effects on resting state networks (RSN) and connectivity matrices are still unknown. In this study, subjects were instructed to cross their legs at will while rs-fMRI data with and without PMC were acquired, which generated head motion velocities ranging from 4 to 30 ​mm/s. We also acquired fMRI data without intentional motion. Independent component analysis of rs-fMRI was performed to evaluate IC maps and time courses of RSNs. We also calculated the temporal correlation among different brain regions and generated connectivity matrices for the different motion and PMC conditions.In our results we verified that the crossing leg movements reduced the tSNR of sessions without and with PMC by 45 and 20%, respectively, when compared to sessions without intentional movements. We have verified an interaction between head motion speed and PMC status, showing stronger attenuation of tSNR for acquisitions without PMC than for those with PMC. Additionally, the spatial definition of major RSNs, such as default mode, visual, left and right central executive networks, was improved when PMC was enabled. Furthermore, motion altered IC-time courses by decreasing power at low frequencies and increasing power at higher frequencies (typically associated with artefacts). PMC partially reversed these alterations of the power spectra. Finally, we showed that PMC provides temporal correlation matrices for data acquired under motion conditions more comparable to those obtained by fMRI sessions where subjects were instructed not to move.

The purpose of this article is to introduce a new complete multiple q-hypergeometric symbolic calculus, which leads to q-Euler integrals and a very similar canonical system of q-difference equations for multiple q-hypergeometric functions. q-analogues of recurrence formulas in Horns paper and Borngässers thesis lead to a more exact way to find these Frobenius solutions. To find the right formulas, the parameters in q-shifted factorials can be changed to negative integers, which give no extra q-factors. In proving these q-formulas, in the limit q→1 we obtain versions of the paper by Debiard and Gaveau for the solution of differential or q-difference equations. The paper is also a correction of some of the statements in the paper by Debiard and Gaveau, e.g., the Euler integrals and other solutions to differential equations for Appell functions, also without references to page numbers in the standard work of Appell and Kampé de Fériet. Sometimes the q-binomial theorem is used to simplify q-integral formulas. By the Horn method, we find another solution to the Appell Φ1 function partial differential equation, which was not mentioned in the thesis by Le Vavasseur 1893.

Hydroxy-terminated polyoxymethylene-co-polyoxyalkylene multi-block telechels were obtained by a new methodology that allows for the formal substituting of ether units in polyether polyols with oxymethylene moieties. An interesting feature is that, unlike carbonate groups in polycarbonate and polyethercarbonate polyols, homopolymer blocks of polyoxymethylene moieties can be formed. The regular nature of polyoxymethylene blocks imparts a certain crystallinity to the polymer that can give rise to new properties of polyurethanes derived from such telechels. The synthesis, reaction sequence and kinetics of the formation of oligomeric hydroxy-terminated multi-block telechel polyoxymethylene moieties are discussed in this paper and the preparation of a polyurethane material is demonstrated.

Excess body fat, especially intra-abdominal fat, is a leading risk factor for metabolic diseases. Differentially methylated regions (DMRs) of two imprinted genes, insulin-like growth factor 2 (IGF2) and H19, have been associated with obesity due to their important roles in regulating body composition, but have not been examined in relation to intra-abdominal fat depots. Total body fat from whole-body dual energy X-ray absorptiometry and visceral and liver fat contents from abdominal magnetic resonance imaging in 48 healthy women aged 60–65 years (of White or Japanese ancestry) were each regressed on circulating leukocyte DNA methylation levels of IGF2 (at DMR0, DMR2a, and DMR2b) and H19 (at CTCF3) as assessed by pyrosequencing, while adjusting for age and race/ethnicity. Total fat mass was inversely associated with methylation levels of IGF2 DMR2b (P = 0.016). Total fat-adjusted visceral fat area (P = 0.062) and percent visceral fat measured at L4-L5 (P = 0.045) were associated with higher methylation levels of IGF2 DMR2b. Both total fat-adjusted percent liver fat (P = 0.039) and the presence of fatty liver (P = 0.015) were positively associated with IGF2 DMR2a methylation. Methylation levels of H19 CTCF3 were not associated with overall or intra/abdominal adiposity. The findings indicate that methylation levels of IGF2 DMR regions in leukocytes are associated with total body fat and with fat distribution in the viscera and liver independently of total adiposity.

This paper reports a novel miniaturized pseudo reference electrode (RE) design for biasing Ion Sensitive Field Effect Transistors (ISFETs). It eliminates the need for post-CMOS processing and can scale up in numbers with the CMOS scaling. The presented design employs silane-mediated transfer of patterned gold electrode lines onto PDMS microfluidics such that the gold conformally coats the inside of microfluidic channel. Access to this electrode network is made possible by using “through-PDMS-vias” (TPV), which consist of high metal-coated SU-8 pillars manufactured by a novel process that employs a patterned positive resist layer as SU-8 adhesion depressor. When integrated with pneumatic valves, TPV and pseudo-RE network were able to bias 1.5 nanoliters (nL) of isolated electrolyte volumes. We present a detailed characterization of our pseudo-RE design demonstrating ISFET operation and its DC characterization. The stability of pseudo-RE is investigated by measuring open circuit potential (OCP) against a commercial Ag/AgCl reference electrode.

The data presented in this article are related to the research article entitled “Mapping the Critical Gestational Age at Birth that Alters Brain Development in Preterm-born Infants using Multi-Modal MRI” (Wu et al., 2017) [1]. Brain immaturity at birth poses critical neurological risks in the preterm-born infants. We used a novel change-point model to analyze the critical gestational age at birth (GAB) that could affect postnatal development, based on diffusion tensor MRI (DTI) acquired from 43 preterm and 43 term-born infants in 126 brain regions. In the corresponding research article, we presented change-point analysis of fractional anisotropy (FA) and mean diffusivities (MD) measurements in these infants. In this article, we offered the relative changes of axonal and radial diffusivities (AD and RD) in relation to the change of FA and FA-based change-points, and we also provided the AD- and RD-based change-point results.

The low-power sensing platform proposed by the Convergence project is foreseen as a wireless, low-power and multifunctional wearable system empowered by energy-efficient technologies. This will allow meeting the strict demands of life-style and healthcare applications in terms of autonomy for quasi-continuous collection of data for early-detection strategies. The system is compatible with different kinds of sensors, able to monitor not only health indicators of individual person (physical activity, core body temperature and biomarkers) but also the environment with chemical composition of the ambient air (NOx, COx, NHx particles) returning meaningful information on his/her exposure to dangerous (safety) or pollutant agents. In this article, we introduce the specifications and the design of the low-power sensing platform and the different sensors developed in the project, with a particular focus on pollutant sensing capabilities and specifically on NO2 sensor based on graphene and CO sensor based on polyaniline ink.

Probabilistic maps of white matter pathways related to motor, somatosensory, auditory, visual, and limbic functions, and major white matter tracts (the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle) were applied to evaluate the developmental trajectories of these tracts, using longitudinal diffusion tensor imaging (DTI) obtained in term-born and preterm-born healthy infants. Nineteen term-born and 30 preterm-born infants completed MR scans at three time points: Time-point 1, 41.6±2.7 postmenstrual weeks; Time-point 2, 46.0±2.9 postmenstrual weeks; and Time-point 3, 50.8±3.7 postmenstrual weeks. The DTI-derived scalar values (fractional anisotropy, eigenvalues, and radial diffusivity) of the three time points are available in this Data article. Keywords: Term, Preterm, Infant, Diffusion tensor imaging, Atlas

Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.

The Horn–Karlsson approach to find convergence regions is applied to find convergence regions for triple q-hypergeometric functions. It turns out that the convergence regions are significantly increased in the q-case; just as for q-Appell and q-Lauricella functions, additions are replaced by Ward q-additions. Mostly referring to Krishna Srivastava 1956, we give q-integral representations for these functions.

The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.

In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, “GAI,” from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA—long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI.

Objective. The aim of the present study was to assess the association between muscle strength, lower extremity function, employment status, and work ability in RA patients. Methods. One hundred seropositive RA outpatients of working age were included in this cross-sectional study. Employment status was assessed by interview and work ability by the Work Ability Index-Single Item Scale (WAS). Muscle strength was determined using dynamometer measurement of isometric hand grip and knee extensor strength. Lower extremity function was measured using the short physical performance battery (SPPB). Regression models estimate the association between unemployment, work ability and muscle strength, and lower extremity function, controlling for sociodemographic and disease-related factors. Results. Forty-one percent of the RA patients were not gainfully employed, and their median work ability had a good WAS value (7.00 [4.00-7.00]). Patients with better knee extensor strength (OR=1.07, 95% CI [1.02-1.12) and better physical performance (OR=1.71, 95% CI [1.18-2.49]) had a significantly better chance of gainful employment. The odds for hand grip strength remained significant when adjusted for sociodemographic (OR=1.5, 95% CI [1.00-1.09]), but not for disease-specific variables. Better hand grip strength (β=0.25, p=0.039) and better knee extensor strength (β=0.45, p=0.001) as well as better lower extremity function (SPPB) (β=0.51, p

In this article, we move back almost 200 years to Christoph Gudermann, the great expert on elliptic functions, who successfully put the twelve Jacobi functions in a didactic setting. We prove the second hyperbolic series expansions for elliptic functions again, and express generalizations of many of Gudermann’s formulas in Carlson’s modern notation. The transformations between squares of elliptic functions can be expressed as general Möbius transformations, and a conjecture of twelve formulas, extending a Gudermannian formula, is presented. In the second part of the paper, we consider the corresponding formulas for hyperbolic modular functions, and show that these Möbius transformations can be used to prove integral formulas for the inverses of hyperbolic modular functions, which are in fact Schwarz-Christoffel transformations. Finally, we present the simplest formulas for the Gudermann Peeta functions, variations of the Jacobi theta functions. 2010 Mathematics Subject Classification: Primary 33E05; Secondary 33D15.

In an earlier paper, we found transformation and summation formulas for 43 q-hypergeometric functions of 2n variables. The aim of the present article is to find convergence regions and a few conjectures of convergence regions for these functions based on a vector version of the Nova q-addition. These convergence regions are given in a purely formal way, extending the results of Karlsson (1976). The Γq-function and the q-binomial coefficients, which are used in the proofs, are adjusted accordingly. Furthermore, limits and special cases for the new functions, e.g., q-Lauricella functions and q-Horn functions, are pointed out.

The aim of the study was to compare the effects of home visits with physical training and nutritional support on inflammatory parameters to home visits with social support alone within a randomized controlled trial. Prefrail and frail persons received home visits from lay volunteers twice a week for 12 weeks. Participants in the physical training and nutritional intervention group (PTN, n = 35) conducted two sets of six strength exercises and received nutritional support. The social support group (SoSu, n = 23) received visits only. TNF-α, IL-6, CRP, and total leukocyte count were assessed at baseline and after 12 weeks. Changes over time within groups were analyzed with paired t-tests; differences between groups were analyzed with ANCOVA for repeated measurements. In the PTN group, IL-6 and CRP remained stable, whereas in the SoSu group, IL-6 increased significantly from a median value of 2.6 pg/l (min-max = 2.0-10.2) to 3.0 pg/l (min-max = 2.0-20.8), and CRP rose from 0.2 mg/dl (min-max = 0.1-0.9) to 0.3 mg/dl (min-max = 0.1-3.0) after 12 weeks. In CRP, a significant difference between groups was found. TNF-α and total leukocyte count did not change in either the PTN group or the SoSu group. Persons showing an increase in physical performance (OR 4.54; 95% CI = 1.33-15.45) were more likely to have constant or decreased IL-6 values than persons who showed no improvement. In conclusion, in non-robust older adults, a physical training and nutritional support program provided by lay volunteers can delay a further increase in some inflammatory parameters.