7196 research outputs found
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Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium.
No full textAlthough digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates.Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.5 h in the real-world, using a single wearable device worn on the lower back. A reference system combining inertial modules with distance sensors and pressure insoles was used for comparison of DMOs from the single wearable device. We assessed and validated three algorithms for gait sequence detection, four for ICD, three for CAD and four for SL by concurrently comparing their performances (e.g., accuracy, specificity, sensitivity, absolute and relative errors). Additionally, the effects of walking bout (WB) speed and duration on algorithm performance were investigated.We identified two cohort-specific top performing algorithms for gait sequence detection and CAD, and a single best for ICD and SL. Best gait sequence detection algorithms showed good performances (sensitivity > 0.73, positive predictive values > 0.75, specificity > 0.95, accuracy > 0.94). ICD and CAD algorithms presented excellent results, with sensitivity > 0.79, positive predictive values > 0.89 and relative errors < 11% for ICD and < 8.5% for CAD. The best identified SL algorithm showed lower performances than other DMOs (absolute error < 0.21 m). Lower performances across all DMOs were found for the cohort with most severe gait impairments (proximal femoral fracture). Algorithms' performances were lower for short walking bouts; slower gait speeds (< 0.5 m/s) resulted in reduced performance of the CAD and SL algorithms.Overall, the identified algorithms enabled a robust estimation of key DMOs. Our findings showed that the choice of algorithm for estimation of gait sequence detection and CAD should be cohort-specific (e.g., slow walkers and with gait impairments). Short walking bout length and slow walking speed worsened algorithms' performances. Trial registration ISRCTN - 12246987
Recent progress in Sonogashira-Hagihara cross-couplings in water
No full textThe coupling of terminal acetylenes for the construction of alkyne motives is a frequently required reaction type in the synthesis of pharmaceuticals and natural products. While traditional procedures rely on the use of organic, usually hazardous, solvents with significant impact on the environment and humans, more sustainable and safer approaches have been developed in academia and industry during the last few years. The following account sheds light on the recent progress on copper-free Sonogashira-Hagihara cross-couplings in water
Aerosol technology to mimic dry powder inhalation in vitro using pulmonary cell models.
No full textInhaled therapy confers key advantages for the treatment of topical pulmonary diseases and offers potential for systemic delivery of medicines. Dry powder inhalers (DPIs) are generally the preferred devices for pulmonary delivery due to improved stability and satisfactory patient compliance. However, the mechanisms governing drug powder dissolution and availability in the lung and poorly understood. Here, we report a new in vitro system to study epithelial absorption of inhaled dry powders in lung barrier models of the upper and lower airway. The system is based on a CULTEX® RFS (Radial Flow System) cell exposure module joined to a Vilnius aerosol generator and allows the coupling of drug dissolution and permeability assessments. The cellular models recapitulate the barrier morphology and function of healthy and diseased pulmonary epithelium and incorporate the mucosal barrier to enable the investigation of drug powder dissolution in biorelevant conditions. With this system, we found differences in permeability across the airway tree and pinpointed the impact of diseased barriers in paracellular drug transport. Furthermore, we identified a different rank order of permeability for compounds tested in solution or powder form. These results highlight the value of this in vitro drug aerosolization setup for use in research and development of inhaled medicines
Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.
No full textRenal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment.A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed.Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady‑state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady‑state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile.From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment.Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260
Benchmarking tools for in silico cysteine pKa prediction
No full textAccurate estimation of the pKa’s of cysteine residues in proteins could inform targeted approaches in hit discovery. The pKa of a targetable cysteine residue in a disease-related protein is an important physiochemical parameter in covalent drug discovery, as it influences the fraction of nucleophilic thiolate amenable to chemical protein modification. Traditional structure-based in silico tools are limited in their predictive accuracy of cysteine pKa’s relative to other titratable residues. Additionally, there are limited comprehensive benchmark assessments for cysteine pKa predictive tools. This raises the need for exten-sive assessment and evaluation of methods for cysteine pKa prediction. Here, we report the performance of several computa-tional pKa methods, including structure-based and ensemble-based sampling approaches, on a diverse test set of experimental cysteine pKa’s retrieved from the PKAD database. The dataset consisted of 16 wildtype and 10 mutant proteins with experimentally measured cysteine pKa values. Our results highlight that these methods are varied in their overall predictive accura-cies. Among the test set of wildtype proteins evaluated, the best method yielded a mean absolute error of 2.3 pK units — highlighting the need for improvement of existing pKa methods for accurate cysteine pKa estimation. Given the limited accuracy of these methods, further development is needed before these approaches can be routinely employed to drive design decisions in early drug discovery efforts
CRISPR for neuroscientists
No full textGenome engineering technologies provide an entry point into understanding and controlling the function of genetic elements in health and disease. The discovery and development of the microbial defense system CRISPR-Cas yielded a treasure trove of genome engineering technologies and revolutionized the biomedical sciences. Comprising diverse RNA-guided enzymes and effector proteins that evolved or were engineered to manipulate nucleic acids and cellular processes, the CRISPR toolbox provides precise control over biology. Virtually all biological systems are amenable to genome engineering—from cancer cells to the brains of model organisms to human patients—galvanizing research and innovation and giving rise to fundamental insights into health and powerful strategies for detecting and correcting disease. In the field of neuroscience, these tools are being leveraged across a wide range of applications, including engineering traditional and non-traditional transgenic animal models, modeling disease, testing genomic therapies, unbiased screening, programming cell states, and recording cellular lineages and other biological processes. In this primer, we describe the development and applications of CRISPR technologies while highlighting outstanding limitations and opportunities
Benchmarking Enrichment Efforts in the US & Canada Across Species and Enrichment Categories
No full textEnrichment is important for animal welfare and data quality. Provision of enrichment opportunities varies between species
and enrichment category. However, data benchmarking these differences does not exist. Our objective was to characterize enrichment
provision and associated factors across species in the US and Canada. Personnel who work with research animals (n
= 1098) in the US and Canada voluntarily responded to online promotions and completed a survey about enrichment used for
the species they worked with most, their control of and wish for more enrichment, stress or pain in the animals they worked
the most with, and demographics. All participants (except those working with rats) received the same questionnaire regardless
of species to allow objectivity, as the effects of many enrichment items on some species have not yet been determined.
The questionnaire asked about enrichments that were beneficial to at least one species. The provision of enrichment was
allocated into 2 outcome variables: diversity and frequency per enrichment category. Results showed a significant interaction
between enrichment category and species. Generally, physical, nutritional, and sensory enrichments were provided less often
than social enrichment. In addition, nonhuman primates received more diverse and more frequent enrichment than did other
species (twice as much as rats and mice). Enrichment was provided less frequently by personnel who wished they could do
more than the status quo. Both enrichment frequency and diversity were higher in respondents from Canada, those who had
more control over provision, and those who had been in the field longer. While our results cannot be used to determine the
quality of enrichment provided to various species, they do provide information on current enrichment practices in the US
and Canada and identify differences in implementation by species and enrichment category. The data also indicate provision
of enrichment is influenced by factors such as country and individual control over enrichment. This information can also be
used to identify areas for greater enrichment efforts for some species (for example, rats and mice) and categories, with the
ultimate goal of improving animal welfare
Glycoproteomics of a Single Protein: Revealing Tens of Thousands of Myozyme Glycoforms by Hybrid HPLC-MS Approaches.
No full textCharacterization of highly glycosylated biopharma-ceuticals by mass spectrometry is challenging because of the huge chemical space of coexistent glycoforms present. Here, we report the use of an array of HPLC-mass spectrometry-based approaches at different structural levels of released glycan, glycopeptide, and hitherto unexplored intact glycoforms to scrutinize the biopharmaceutical Myozyme, containing the highly complex lysosomal enzyme recombinant acid α-glucosidase. The intrinsic heterogeneity of recombinant acid α-glucosidase glycoforms was unraveled using a novel strong anion exchange HPLC-mass spectrometry approach involving a pH-gradient of volatile buffers to facilitate chromatographic separation of glycoforms based on their degree of sialylation, followed by the acquisition of native mass spectra in an Orbitrap mass spectrometer. Upon considering the structures of 60 different glycans attached to seven glycosylation sites in the intact protein, the large set of interdependent data acquired at different structural levels was integrated using a set of bioinformatic tools and allowed the annotation of intact glycoforms unraveling more than 1,000,000 putative intact glycoforms. Detectable isoforms also included several mannose-6-phosphate variants, which are essential for directing the drug toward its target, the lysosomes. Finally, for the first time, we sought to validate the intact glycoform annotations by integrating experimental data on the enzymatically dissected proteoforms, which reduced the number of glycoforms supported by experimental evidence to 42,104. The latter verification clearly revealed the strengths but also intrinsic limitations of this approach for fully characterizing such highly complex glycoproteins by mass spectrometry
Central and Peripheral Inflammation in Mild Cognitive Impairment in the Context of Alzheimer's Disease.
No full textMild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD. Understanding the mechanism underlying inflammatory processes involved in the early onset of the disease could help find a safe and effective way to diagnose and treat patients. In this article, we assessed over twenty different blood and cerebrospinal fluid (CSF) inflammatory biomarker concentrations with immunoassay methods in patients with MCI (mild cognitive impairment), non-impaired control (NIC), and serum healthy control (HC). We performed group comparisons and analyzed in-group correlations between the biomarkers. We included 107 participants (mean age: 64.7 ± 7.8, women: 58.9%). CSF osteopontin and YKL-40 were significantly increased in the MCI group, whereas serum C-reactive protein and interleukin-6 were significantly higher (p < 0.001) in the NIC group compared with the MCI and HC groups. Stronger correlations between interleukin-1β and inflammasome markers were observed in the serum of the MCI group. We confirmed specific inflammatory activation in the central nervous system and interleukin-1β pathway upregulation in the serum of the MCI cohort