Tracking cocrystallization of active pharmaceutical ingredients with Bbenzoic acid coformer using Broadband Acoustic resonance Dissolution Spectroscopy (BARDS)

This study investigates the use of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) as a detection method for the formation of cocrystals. BARDS is a novel approach that uses reproducible changes in the compressibility of a solvent as a sample dissolves to characterize and differentiate between materials and in this case cocrystallization. Two cocrystal systems with a 1:1 stoichiometry were examined, which used benzoic acid as a coformer with isonicotinamide and with theophylline. Cocrystals were prepared using dry and wet milling for periods from 1 to 40 min, and samples were analyzed using infrared spectroscopy, powder X-ray diffraction, and BARDS. Comparison of the BARDS data with the IR and PXRD data cross-validated the BARDS results. This study shows that BARDS can be used to rapidly assess the formation of these cocrystals at-line when milling or as a relatively low cost tool in preformulation product development. The data can also be used to gauge the unique entrained gas and gas volume generation of the cocrystal samples during dissolution and their dissolution kinetics

Approaches to suicide prevention: Ideas and models presented by Japanese and international early career psychiatrists

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146308/1/pcn12737.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146308/2/pcn12737_am.pd

The Inner-Shelf Dynamics Experiment

17 USC 105 interim-entered record; under review.The article of record as published may be found at http://dx.doi.org/10.1175/BAMS-D-19-0281.1The inner shelf, the transition zone between the surfzone and the midshelf, is a dynamically complex region with the evolution of circulation and stratification driven by multiple physical processes. Cross-shelf exchange through the inner shelf has important implications for coastal water quality, ecological connectivity, and lateral movement of sediment and heat. The Inner-Shelf Dynamics Experiment (ISDE) was an intensive, coordinated, multi-institution field experiment from September–October 2017, conducted from the midshelf, through the inner shelf, and into the surfzone near Point Sal, California. Satellite, airborne, shore- and ship-based remote sensing, in-water moorings and ship-based sampling, and numerical ocean circulation models forced by winds, waves, and tides were used to investigate the dynamics governing the circulation and transport in the inner shelf and the role of coastline variability on regional circulation dynamics. Here, the following physical processes are highlighted: internal wave dynamics from the midshelf to the inner shelf; flow separation and eddy shedding off Point Sal; offshore ejection of surfzone waters from rip currents; and wind-driven subtidal circulation dynamics. The extensive dataset from ISDE allows for unprecedented investigations into the role of physical processes in creating spatial heterogeneity, and nonlinear interactions between various inner-shelf physical processes. Overall, the highly spatially and temporally resolved oceanographic measurements and numerical simulations of ISDE provide a central framework for studies exploring this complex and fascinating region of the ocean.U.S. Office of Naval Research (ONR)ONR Departmental Research Initiative (DRI)Inner-Shelf Dynamics Experiment (ISDE

Implications of market integration for cardiovascular and metabolic health among an indigenous Amazonian Ecuadorian population

BackgroundMarket integration (MI), the suite of social and cultural changes that occur with economic development, has been associated with negative health outcomes such as cardiovascular disease; however, key questions remain about how this transition manifests at the local level.AimThe present paper investigates the effects of MI on health among Shuar, an indigenous lowland Ecuadorian population, with the goal of better understanding the mechanisms responsible for this health transition.Subjects and methodsThis study examines associations between measures of MI and several dimensions of cardiovascular and metabolic health (fasting glucose, lipids [LDL, HDL and total cholesterol; triglycerides] and blood pressure) among 348 adults.ResultsOverall, Shuar males and females have relatively favourable cardiovascular and metabolic health. Shuar who live closer to town have higher total (p < 0.001) and HDL cholesterol (p < 0.001), while Shuar in more remote regions have higher diastolic blood pressure (p = 0.007). HDL cholesterol is positively associated with consumption of market foods (r = 0.140; p = 0.045) and ownership of consumer products (r = 0.184; p = 0.029).ConclusionsThis study provides evidence that MI among Shuar is not a uniformly negative process but instead produces complex cardiovascular and metabolic health outcomes

Intermediate flortaucipir uptake is associated with beta-amyloid PET, & cerebrospinal fluid tau in cognitively normal older adults

Hyperphosphorylated tau protein in the form of neurofibrillary tangles is one of the major pathological hallmarks of Alzheimer’s disease (AD). This thesis explores early tau accumulation, as measured with the positron emission tomography (PET) imaging radiotracer [18F]flortaucipir, and its associations with Alzheimer’s disease-related biological and cognitive markers in cognitively intact older adults with a familial history of sporadic Alzheimer’s disease. We show that flortaucipir binding in cognitively normal older adults is associated with three key markers of Alzheimer’s disease: amyloid-beta PET tracer retention, phosphorylated tau in the cerebrospinal fluid, and cognitive performance. Moreover, the associations of flortaucipir with Aβ and cerebrospinal fluid phosphorylated tau are evident at subthreshold levels of flortaucipir binding. These results suggest that intermediate levels of flortaucipir retention can indicate meaningful pathological changes associated with Alzheimer’s disease before the onset of clinical symptoms, while higher levels of flortaucipir retention may be necessary to observe associations with worse cognitive performance on a group level.Les enchevêtrements neurofibrillaires composés de protéines tau hyperphosphorylées sont l’un des principaux signes pathologiques de la maladie d’Alzheimer (MA). Cette thèse explore l’accumulation précoce de tau, mesurée en tomographie par émission de positrons (TEP) à l’aide du radiotraceur [18F]flortaucipir, et ses associations avec les marqueurs biologiques et cognitifs liés à la maladie d’Alzheimer chez des personnes âgées sans trouble cognitif avec antécédents familiaux de la forme sporadique de la MA. Nous montrons que la rétention du traceur flortaucipir chez les personnes âgées cognitivement normales est associée à trois marqueurs clés de la MA: la rétention du traceur bêta-amyloïde (Aβ) TEP, la tau phosphorylée dans le liquide cérébro-spinal et les performances cognitives. De plus, les associations de flortaucipir avec Aβ et la protéine tau phosphorylée dans le liquide cérébro-spinal sont évidentes même à des niveaux faibles de rétention du flortaucipir. Ces résultats suggèrent que même de faibles quantités de rétention du flortaucipir peuvent indiquer des modifications pathologiques significatives associées à la MA avant l’apparition de symptômes cliniques. En revanche, des quantités plus élevées de rétention du flortaucipir sont nécessaires pour observer des associations avec des performances cognitives

Failure to tolerate continuous subcutaneous treprostinil in pediatric pulmonary hypertension patients

Abstract Continuous subcutaneous (SubQ) treprostinil is an effective therapy for pediatric patients diagnosed with pulmonary hypertension (PH). To date, the clinical characteristics and factors associated with failure to tolerate this therapy have not been described. The purpose was to describe patient‐reported factors contributing to SubQ treprostinil intolerance in pediatric patients with PH. A retrospective descriptive study was performed at 11 participating sites in the United States and Canada for patients younger than 21 years of age diagnosed with PH who failed treatment to tolerate SubQ treprostinil between January 1, 2009, and December 31, 2019. All data were summarized using descriptive statistics. Forty‐one patients met the inclusion criteria. The average age at SQ treprostinil initiation, and length of treatment, was 8.6 years and 22.6 months, respectively. The average maximum dose, concentration, and rate were 95.8 ng/kg/min, 6.06 mg/mL, and 0.040 mL/h, respectively. The reasons for failure to tolerate SubQ treprostinil included intractable site pain (73.2%), frequent site changes (56.1%), severe site reactions (53.7%), infections (26.8%), and noncompliance/depression/anxiety (17.1%). Thirty‐nine (95.1%) patients transitioned to a prostacyclin therapy with 23 patients transitioning to intravenous prostacyclin, 5 to inhaled prostacyclin, 5 to oral prostacyclin, and 7 to a prostacyclin receptor agonist. A subset of pediatric PH patients failed to tolerate SubQ treprostinil infusions despite advances in SubQ site maintenance and pain management strategies. Intractable site pain, frequent SubQ site changes, and severe localized skin reactions were the most common reasons for failure

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery