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Inertial measurement units (IMUs) enable easy to operate and low-cost data recording for gait analysis. When combined with treadmill walking, a large number of steps can be collected in a controlled environment without the need of a dedicated gait analysis laboratory. In order to evaluate existing and novel IMU-based gait analysis algorithms for treadmill walking, a reference dataset that includes IMU data as well as reliable ground truth measurements for multiple participants and walking speeds is needed. This article provides a reference dataset consisting of 15 healthy young adults who walked on a treadmill at three different speeds. Data were acquired using seven IMUs placed on the lower body, two different reference systems (Zebris FDMT-HQ and OptoGait), and two RGB cameras. Additionally, in order to validate an existing IMU-based gait analysis algorithm using the dataset, an adaptable modular data analysis pipeline was built. Our results show agreement between the pressure-sensitive Zebris and the photoelectric OptoGait system (r = 0.99), demonstrating the quality of our reference data. As a use case, the performance of an algorithm originally designed for overground walking was tested on treadmill data using the data pipeline. The accuracy of stride length and stride time estimations was comparable to that reported in other studies with overground data, indicating that the algorithm is equally applicable to treadmill data. The Python source code of the data pipeline is publicly available, and the dataset will be provided by the authors upon request, enabling future evaluations of IMU gait analysis algorithms without the need of recording new data.

Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A 1c (HbA 1c) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets. In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range 4·0–5·5 mmol/L) to their blood-glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA 1c from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00641056. 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA 1c were available were included in the primary efficacy analysis. Change in HbA 1c at 26 weeks was greater in patients taking exenatide (n=228; −1·5%, SE 0·05) than in those taking insulin glargine (n=220; −1·3%, 0·06; treatment difference −0·16%, 0·07, 95% CI −0·29 to −0·03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0·012). A planned extension period (up to 2·5 years' duration) is in progress. Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. Amylin Pharmaceuticals; Eli Lilly and Company.

OBJECTIVE: To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: Obese subjects (n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m², IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks. RESULTS: Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide - placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was -3.3 ± 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, -449 cal; placebo, -387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS: Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective at limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term Ab development after ART. We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC) activity in the later stages of AHI and that Ab development continues in the absence of detectable viremia during the first year of suppressive ART. The development of therapeutic interventions that can enhance earlier development of GCs in AHI and Abs after ART initiation could provide important protection against the viral reservoir that is seeded in individuals treated early in the disease.

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphKl), thereby enabling inside-out signaling of sphingosine-l-phosphate. We have shown before that [G.sub.q]-coupled receptors and constitutively active [G[alpha].sub.q/11] specifically induced a rapid and long-lasting SphKl translocation, independently of canonical [G.sub.q]/phospholipase C (PLC) signaling. Here, we further characterized [G.sub.q/11] regulation of SphKl. SphKl translocation by the [M.sub.3] receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLC[[beta].sub.3], but accelerated by wild-type PLC[[beta].sub.3] and the PLC[delta] PH domain. Both wild-type SphKl and catalytically inactive SphKl-G82D reduced [M.sub.3] receptor-stimulated inositol phosphate production, suggesting competition at [G[alpha].sub.q]. Embryonic fibroblasts from [G[alpha].sub.q/11] double-deficient mice were used to show that amino acids W263 and T257 of [G[alpha].sub.q], which interact directly with PLC[[beta].sub.3] and p63RhoGEF, were important for bradykinin [B.sub.2] receptor-induced SphKl translocation. Finally, an AIXXPL motif was identified in vertebrate SphKl (positions 100-105 in human SphKla), which resembles the [G[alpha].sub.q] binding motif, ALXXPI, in PLC[beta] and p63RhoGEF. After [M.sub.3] receptor stimulation, SphKl-AlOOE-IlOlE and SphKl-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLC[beta]/PLC[delta](PH) expression are important for regulation of SphKl by [G.sub.q/11].

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that G -coupled receptors and constitutively active Gα specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical G /phospholipase C (PLC) signaling. Here, we further characterized G regulation of SphK1. SphK1 translocation by the M receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ , but accelerated by wild-type PLCβ and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M receptor-stimulated inositol phosphate production, suggesting competition at Gα . Embryonic fibroblasts from Gα double-deficient mice were used to show that amino acids W263 and T257 of Gα , which interact directly with PLCβ and p63RhoGEF, were important for bradykinin B receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100-105 in human SphK1a), which resembles the Gα binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by G .