The patient-centered medical home (PCMH) was established in part to improve chronic disease management, yet evidence is limited for effects on patients with multimorbidity. To examine the association of Patient-Aligned Care Team (PACT) implementation, the Veterans Health Administration (VA) PCMH model, and care quality for multimorbid patients enrolled in VA primary care from 2012 to 2014. Retrospective cohort. 318,764 multimorbid (> 3 chronic diseases) patients receiving care in 917 clinics. PCMH implementation was measured using the PACT Implementation Progress Index (PI ) for clinics in 2012. The PI is a validated composite measure of administrative and survey data with higher scores associated with greater care quality. Quality outcomes from 2013 to 2014 were assessed from External Peer Review Program (EPRP) metrics. Outcomes included preventative care, chronic disease management, and mental health and substance use metrics. We used generalized estimating equations to model associations adjusting for patient and clinic characteristics. We also examined associations for a subgroup with > 5 chronic diseases. For one-third of metrics (5/15), greater implementation of PACT in 2012 was associated with higher predicted probability of meeting the quality metric in 2013-2014. This association persisted for only two metrics (diabetic glycemic control, P < 0.001; lipid control in ischemic heart disease, P = 0.02) among patients with > 5 chronic diseases. Multimorbid patients engaged in care from clinics with higher PCMH implementation received higher quality care across several quality domains, but this association was reduced in patients with > 5 chronic diseases. 5 chronic diseases.Rivaroxaban (RXB) is a class II drug, according to the Biopharmaceutics Classification System. Since its bioavailability is low at high doses, dose proportionality is not achieved for pharmacokinetic parameters. However, when taken with food, its bioavailability increases at high doses. In this study, nanocrystal technology was used to increase the solubility and, hence, the bioavailability of RXB. Pluronic F127, pharmacoat 603, and PVP K-30 were used as stabilizers to prepare RXB nanosuspension, combining ball mill and high pressure homogenization methods. Particle sizes of RXB in nanosuspension (formulation A348 nm; formulation B403 nm) and nanocrystal formulations (formulation A1167 nm; formulation B606 nm) were significantly reduced (p  less then  0.05) compared to those of bulk RXB. In both formulations, 80% of the drug dissolved in 30 min. For dose proportionality evaluation, 3, 10, and 15 mg/kg of RXB nanosuspensions (formulation B) were administered to rabbits. The dose proportionality for AUC and Cmax of RXB nanocrystals was assessed by the power model, variance analysis of pharmacokinetic parameters, linear regression, and equivalence criterion methods. Dose proportionality for AUC was achieved at doses between 10-15 and 3-15 mg/kg. In conclusion, the preparation of a nanocrystal formulation of RXB improved its dissolution rate and pharmacokinetic profile.Cases of discordance between the US Food and Drug Administration (FDA) and its advisory committees are uncommon. Due to the importance of oncology therapies, we sought to identify and discuss instances of disagreement between the regulatory decision made by FDA, and the recommendation made by its Oncologic Drugs Advisory Committee (ODAC) via committee vote. Public databases (Oncologic Drugs Advisory Committee Meeting Materials, Drugs@FDA) as well as publicly available documents from ODAC meetings were reviewed to discern cases of disagreement between the two bodies. Inflammation activator This review of public data yielded six (6) instances in which FDA's ultimate regulatory decision went against the recommendation of the ODAC. The six cases are briefly discussed and key drivers for or against an approval decision are outlined. In cases where FDA's decision was less conservative than that of the ODAC, the value of therapies with novel mechanisms of action which provide new options for patients, as well as regulatory precedent were observed as key drivers for regulatory decision-making. In cases where FDA took a more conservative approach than the ODAC, the importance of appropriate clinical trial design, clinically relevant trial endpoints, and the integrity of the data collected were stressed as driving the ultimate regulatory decision.Multiple system atrophy (MSA) is a progressive neurodegenerative disease variably associated with motor, nonmotor, and autonomic symptoms, resulting from putaminal and cerebellar degeneration and associated with glial cytoplasmic inclusions enriched with α-synuclein in oligodendrocytes and neurons. Although symptomatic treatment of MSA can provide significant improvements in quality of life, the benefit is often partial, limited by adverse effects, and fails to treat the underlying cause. Consistent with the multisystem nature of the disease and evidence that motor symptoms, autonomic failure, and depression drive patient assessments of quality of life, treatment is best achieved through a coordinated multidisciplinary approach driven by the patient's priorities and goals of care. Research into disease-modifying therapies is ongoing with a particular focus on synuclein-targeted therapies among others. This review focuses on both current management and emerging therapies for this devastating disease.The accumulation of abnormal prion protein (PrPSc) produced by the structure conversion of PrP (PrPC) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the "hot spot," stabilizes the structure of PrPC and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrPSc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrPSc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use.