An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.     

Seronegative autoimmune diseases: A challenging diagnosis

Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren’s syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases.     

The impact of different step rate threshold methods on physical activity intensity in older adults

BackgroundOlder adults benefit most from engaging in higher-intensity physical activity, which is often determined using step rate thresholds. Fixed step rate thresholds that correspond to moderate (MPA) and vigorous-intensity physical activity (VPA) have been developed for heuristic activity promotion. The activPAL monitor uses step rate thresholds to determine activity intensity. Stepping thresholds may also vary based on body mass index (BMI) or aerobic fitness level in older adults. Despite the various thresholds used in the literature, it is unclear whether they produce similar outcomes.Research QuestionHow does time spent in physical activity intensities compare between different step rate thresholds in older adults?MethodsThirty-eight participants (24♀; 67 ± 4 years; BMI: 26.6 ± 4.4 kg/m²) wore an activPAL monitor 24-hr/day for up to 7-d (total: 205-d). Aerobic fitness (V̇O₂max: 23 ± 8 ml/kg/min) was determined via indirect calorimetry during a maximal, graded cycling test. Time spent in each intensity category (light-physical-activity [LPA], MPA, VPA) was determined using the fixed (MPA/VPA) 100/130, 110/130, and activPAL step rate thresholds (74/212), as well as BMI-adjusted absolute (108.5 ± 2.5/134.0 ± 4.8) and BMI-adjusted relative (40%/60% V̇O₂max; 111.4 ± 14.7/132.0 ± 19.0) cut-offs. Times spent in each intensity category were compared between methods.ResultsThe activPAL and 100/130 thresholds yielded less LPA and more MPA than all other methods. The activPAL had no time spent in VPA at all. The BMI-adjusted absolute and relative thresholds produced statistically equivalent time in LPA and MPA (via equivalence testing), but not VPA. No two methods yielded similar time spent in LPA, MPA, or VPA.SignificanceThe choice of step rate threshold has a major impact on physical activity intensity outcomes in older adults. Inherently, strategies that adjust for older adults’ body size and/or aerobic fitness level provide a more individualized data processing strategy than fixed thresholds that assume the same threshold for all older adults     

Aqueous outflow channels and its lymphatic association: A review

The human eye has a unique immune architecture and behavior. While the conjunctiva is known to have a well-defined lymphatic drainage system, the cornea, sclera, and uveal tissues were historically considered “alymphatic” and thought to be immune privileged. The very fact that the aqueous outflow channels carry a clear fluid (aqueous humor) along the outflow pathway makes it hard to ignore its lymphatic-like characteristics. The development of novel lymphatic lineage markers and expression of these markers in aqueous outflow channels and improved imaging capabilities has sparked a renewed interest in the study of ocular lymphatics. Ophthalmic lymphatic research has had a directional shift over the last decade, offering an exciting new physiological platform that needs further in-depth understanding. The evidence of a presence of distinct lymphatic channels in the human ciliary body is gaining significant traction. The uveolymphatic pathway is an alternative new route for aqueous outflow and adds a new dimension to pathophysiology and management of glaucoma. Developing novel animal models, markers, and non-invasive imaging tools to delineate the core anatomical structure and physiological functions may help pave some crucial pathways to understand disease pathophysiology and help develop novel targeted therapeutic approaches for glaucoma.     

Evaluation of unsupervised 30-second chair stand test performance assessed by wearable sensors to predict fall status in multiple sclerosis

BackgroundOne in two people with multiple sclerosis (PwMS) will fall in a three-month period. Predicting which patients will fall remains a challenge for clinicians. Standardized functional assessments provide insight into balance deficits and fall risk but their use has been limited to supervised visits.Research questionThe study aim was to characterize unsupervised 30-second chair stand test (30CST) performance using accelerometer-derived metrics and assess its ability to classify fall status in PwMS compared to supervised 30CST.MethodsThirty-seven PwMS (21 fallers) performed instrumented supervised and unsupervised 30CSTs with a single wearable sensor on the thigh. In unsupervised conditions, participants performed bi-hourly 30CSTs and rated their balance confidence and fatigue over 48-hours. ROC analysis was used to classify fall status for 30CST performance.ResultsNon-fallers (p = 0.02) but not fallers (p = 0.23) differed in their average unsupervised 30CST performance (repetitions) compared to their supervised performance. The unsupervised maximum number of 30CST repetitions performed optimized ROC classification AUC (0.79), accuracy (78.4%) and specificity (90.0%) for fall status with an optimal cutoff of 17 repetitions.SignificanceBrief durations of instrumented unsupervised monitoring as an adjunct to routine clinical assessments could improve the ability for predicting fall risk and fluctuations in functional mobility in PwMS.