The Indiana Learning Health System Initiative: Early experience developing a collaborative, regional learning health system

Introduction Learning health systems (LHSs) are usually created and maintained by single institutions or healthcare systems. The Indiana Learning Health System Initiative (ILHSI) is a new multi-institutional, collaborative regional LHS initiative led by the Regenstrief Institute (RI) and developed in partnership with five additional organizations: two Indiana-based health systems, two schools at Indiana University, and our state-wide health information exchange. We report our experiences and lessons learned during the initial 2-year phase of developing and implementing the ILHSI. Methods The initial goals of the ILHSI were to instantiate the concept, establish partnerships, and perform LHS pilot projects to inform expansion. We established shared governance and technical capabilities, conducted a literature review-based and regional environmental scan, and convened key stakeholders to iteratively identify focus areas, and select and implement six initial joint projects. Results The ILHSI successfully collaborated with its partner organizations to establish a foundational governance structure, set goals and strategies, and prioritize projects and training activities. We developed and deployed strategies to effectively use health system and regional HIE infrastructure and minimize information silos, a frequent challenge for multi-organizational LHSs. Successful projects were diverse and included deploying a Fast Healthcare Interoperability Standards (FHIR)-based tool across emergency departments state-wide, analyzing free-text elements of cross-hospital surveys, and developing models to provide clinical decision support based on clinical and social determinants of health. We also experienced organizational challenges, including changes in key leadership personnel and varying levels of engagement with health system partners, which impacted initial ILHSI efforts and structures. Reflecting on these early experiences, we identified lessons learned and next steps. Conclusions Multi-organizational LHSs can be challenging to develop but present the opportunity to leverage learning across multiple organizations and systems to benefit the general population. Attention to governance decisions, shared goal setting and monitoring, and careful selection of projects are important for early success

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

High-resolution esophageal manometry: A time motion study

INTRODUCTION: High-resolution manometry (HRM) of the esophagus is a new technique that provides a more precise assessment of esophageal motility than conventional techniques. Because HRM measures pressure events along the entire length of the esophagus simultaneously, clinical procedure time should be shorter because less catheter manipulation is required. According to manufacturer advertising, the new HRM system is more accurate and up to 50% faster than conventional methods

Predicting the solubility of pharmaceutical cocrystals in solvent/anti-solvent mixtures

In this work, the solubilities of pharmaceutical cocrystals in solvent/anti-solvent systems were predicted using PC-SAFT in order to increase the efficiency of cocrystal formation processes. Modeling results and experimental data were compared for the cocrystal system nicotinamide/succinic acid (2:1) in the solvent/anti-solvent mixtures ethanol/water, ethanol/acetonitrile and ethanol/ethyl acetate at 298.15 K and in the ethanol/ethyl acetate mixture also at 310.15 K. The solubility of the investigated cocrystal slightly increased when adding small amounts of anti-solvent to the solvent, but drastically decreased for high anti-solvent amounts. Furthermore, the solubilities of nicotinamide, succinic acid and the cocrystal in the considered solvent/anti-solvent mixtures showed strong deviations from ideal-solution behavior. However, by accounting for the thermodynamic non-ideality of the components, PC-SAFT is able to predict the solubilities in all above-mentioned solvent/anti-solvent systems in good agreement with the experimental data

Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

Cocrystal formation processes from aqueous solutions are often affected by pH-dependent dissociation, polymorphic transitions, and formation of hydrates and salts. To enhance the efficiency of those processes, the aqueous stability and solubility of pharmaceutical cocrystals were predicted in this study using the perturbed-chain statistical associating fluid theory (PC-SAFT). The solubilities in the binary systems caffeine/water and oxalic acid/water were modeled including hydrate formation and polymorphic transitions between the corresponding anhydrate forms I and II. Moreover, pH-dependent solubilities of these hydrate-forming components, their 2:1 cocrystal, and all appearing salts were measured and modeled at 298.15 K. It was found that the pH-dependent acid–base equilibria of caffeine and oxalic acid directly influence the stability and solubility of their cocrystal, their hydrates, and salts. In consideration of the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT enables solubility predictions of the before-mentioned components as well as if any cocrystal is formed at given conditions of pH and temperature

Predicting the Aqueous Solubility of Pharmaceutical Cocrystals As a Function of pH and Temperature

The solubility of pharmaceutical cocrystals in aqueous solution is influenced by pH-dependent dissociation and salt formation which complicates the design of cocrystal formation and purification processes. To increase the efficiency of those processes, the aqueous solubility of pharmaceutical cocrystals was predicted in this work using perturbed-chain statistical associating fluid theory (PC-SAFT). Modeling results and experimental data of pH-dependent solubilities were compared for the weak base nicotinamide, the weak acid succinic acid, their 2:1 cocrystal, as well as for all occurring salts at 298.15 and 310.15 K. It was found that the pH-dependent acid–base equilibria of nicotinamide and succinic acid directly influence the solubility of their cocrystal and their salts. By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to predict the solubility behavior of all above-mentioned components in good agreement with the experimental data