Predicting the Influence of Drug Solubilizing Agents on Cocrystal Solubility, Stability, and Transition Points.

Pharmaceutical cocrystals have emerged as a useful strategy to improve the aqueous solubility of inherently poorly soluble drugs to improve their oral absorption and bioavailability. Aqueous cocrystal solubility can be orders of magnitude higher than that of the constituent drug. Chemical interactions between cocrystal constituents and dissolution media additives are critically important for cocrystals to achieve a wide range of solubility and stability (Scocrystal/Sdrug) behaviors. In the presence of drug solubilizing agents, a cocrystal with high aqueous Scocrystal/Sdrug can display higher, equal, or lower solubility than the drug, depending on the nature and concentration of the additive. This dissertation explores the mechanisms of cocrystal solubilization by solubilizing agents and the impact on cocrystal solubility, Scocrystal/Sdrug, and transition points. The objectives of this work are to (1) understand the effect of solubilization by physiologically relevant solubilizing agents on cocrystal solubility, solubilzation ratio (SRcocrystal), and Scocrystal/Sdrug (2) develop models to describe cocrystal solubility, SRcocrystal, and Scocrystal/Sdrug based on cocrystal dissociation and constituent ionization and micellar solubilization solution equilibria, (3) expand these models to consider the effect of multiple solubilizing agents, and (4) develop simplified models for the facile estimation of cocrystal transition points from commonly reported drug solubility descriptors. Cocrystal solubility, SRcocrystal, and Scocrystal/Sdrug, were investigated in fed state simulated intestinal fluid (FeSSIF) for seven cocrystals comprised of constituents with a range of ionization and micellar solubilization properties. Mathematical models that predicted cocrystal solubility and Scocrystal/Sdrug based on cocrystal dissociation and constituent ionization and micellar solubilization were derived and expanded to consider two ideally mixing solubilizing agents (FeSSIF and Tween 80). The models were found to be in excellent agreement with the experimentally measured values. SRcocrystal was found to be correlated with the log octanol-water distribution coefficient (log D) and models derived to predict SRcocrystal from log D. Cocrystal solubility at the transition point (S*) was found to be independent of solubilizing agent and solely depend on drug and cocrystal aqueous solubility and models derived to predict this behavior. The influence of solubilizing agents on the position of cocrystal solubility relative to the transition point was predicted by comparing SRdrug with S*.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111365/1/mlipert_1.pd

Global Biobank Meta-analysis Initiative:Powering genetic discovery across human disease

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.</p

The application of omics in ruminant production: a review in the tropical and sub-tropical animal production context

The demand for animal products (e.g. dairy and beef) in tropical regions is expected to increase in parallel with the public demand for sustainable practices, due to factors such as population growth and climate change. The necessity to increase animal production output must be achieved with better management and production technologies. For this to happen, novel research methodologies, animal selection and postgenomic tools play a pivotal role. Indeed, improving breeder selection programs, the quality of meat and dairy products as well as animal health will contribute to higher sustainability and productivity. This would surely benefit regions where resource quality and quantity are increasingly unstable, and research is still very incipient, which is the case of many regions in the tropics. The purpose of this review is to demonstrate how omics-based approaches play a major role in animal science, particularly concerning ruminant production systems and research associated to the tropics and developing countriesinfo:eu-repo/semantics/acceptedVersio

Congenital Long QT Syndrome: A Review of Genetic and Pathophysiologic Etiologies, Phenotypic Subtypes, and Clinical Management

Congenital Long QT Syndrome (CLQTS) is the most common inherited arrhythmia. The QT interval, which marks the duration of ventricular depolarization and repolarization in the myocardium, can be prolonged due to mutations in genes coding for the ion channel proteins that govern the cardiac action potential. The lengthening of the QT interval can lead to a wide range of clinical symptoms, including seizures, torsades de pointes, and fatal arrhythmias. There is a growing body of evidence that has revealed the genetic mutations responsible for the pathophysiology of CLQTS, and this has led to hypotheses regarding unique triggers and clinical features associated with specific gene mutations. Epidemiologic evidence has revealed a 1-year mortality rate of approximately 20% in untreated CLQTS patients, and a \u3c1% of 1-year mortality rate in treated patients, underscoring the importance of timely diagnosis and effective clinical management. There are many phenotypic syndromes that constitute CLQTS, including but not limited to, Jervell and Lange-Nielsen syndrome, Romano and Ward syndrome, Andersen-Tawil syndrome, and Timothy syndrome. In this review, we aim to (1) summarize the genetic, epidemiologic, and pathophysiological basis of CLQTS and (2) outline the unique features of the phenotypic subtypes and their clinical management

The need for improved end-of-life care medical education: Causes, consequences, and strategies for enhancement and integration

End-of-life (EOL) care is a unique area of medicine that emphasizes holistic patient-centered care. It requires clinicians to consider a patients\u27 mental, emotional, spiritual, social and physical comforts and engage patients and their families in complex discussions and decisions. It is an area of medicine that requires sensitivity in communication in order to respond to a wide range of emotions from patients and their families. Given these intricacies, it is essential that healthcare professional trainees are exposed early in their careers so they can be better equipped to address EOL situations effectively. While many medical schools have integrated this important element in pre-clinical education, a formalized and standardized curriculum could allow for students to better engage in EOLcare scenarios that they will face as future physicians. In this editorial, we discuss potential strategies to incorporate EOL care didactics and experiential learning earlier in medical education as well as the consequences of inadequate EOL care education, particularly in medical schools, in its current stat

Impact of Chronic Obstructive Pulmonary Disease on Heart Failure Hospitalizations After an Acute Myocardial Infarction

INTRODUCTION: The presence of chronic obstructive pulmonary disease (COPD) can impact the management of acute myocardial infarction (AMI) and is associated with higher mortality. Few studies addressed COPD impact on heart failure hospitalisations (HFHs) in AMI survivors. MATERIAL AND METHODS: Adult survivors of an AMI between January and June 2014 were identified from the US Nationwide Readmissions Database. The impact of COPD on HFH within 6 months, fatal HFH and the composite of in-hospital HF or 6-month HFH was studied. RESULTS: Of 237,549 AMI survivors, patients with COPD (17.5%) were older, more likely female, had a higher prevalence of cardiac comorbidities and a lower coronary revascularization rate. In-hospital HF was more frequent in patients with COPD (47.0% vs. 25.4%; \u3c 0.001). HFH within 6 months occured in 12,934 (5.4%) patients, at a 114% higher rate in patients with COPD (9.4% vs. 4.6%, OR = 2.14, 95% CI : 2.01-2.29; \u3c 0.001), which was attenuated to a 39% higher adjusted risk (OR = 1.39, 95% CI: 1.30-1.49). Findings were consistent across subgroups of age, AMI type, and major HF risk factors. Mortality during a HFH (5.7% vs. 4.2%, \u3c 0.001) and the rate of the composite HF outcome (49.0% vs. 26.9%, \u3c 0.001) were significantly higher in patients with COPD. CONCLUSIONS: COPD was present in 1 of 6 AMI survivors and was associated with worse HF related outcomes. The increased HFH rate in COPD patients was consistent across several clinically relevant subgroups and these findings highlight the need for optimal in-hospital and post-discharge management of these higher-risk patients

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Jotirao Phule (1827-1890) was India’s first systematic theorist of caste, and the most radical 19th-century opponent of it, who desired nothing less than a complete smashing up of its oppressive structure. This volume makes available all his most important prose writings in English. At the centre of Phule’s thought and analysis are Gulamgiri (Slavery) and Shetkaryacha Asud (Cultivator’s Whipcord), both included in this volume in their entirety. Also included are Phule’s deposition to the Hunter Commission on Education; his response to the Parsi social reformer Malabari’s notes on ‘Infant Marriage and Enforced Widowhood’; his letter to M.G. Ranade regarding the Marathi Authors’ Conference; his stirring defence of Pandita Ramabai in two numbers of the journal Satsar; and selections from The Book of the True Faith. All translations have been specially commissioned for this richly annotated volume, and the Editor’s Introduction places Phule’s life, work, and thought, as well as each text included in this volume, in historical perspective. For anyone interested in the question of caste, this volume is an indispensable resource