Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

The number of individuals suffering from neuropsychiatric disorders (NPDs) has increased worldwide, with 3 million disability-adjusted life-years calculated in 2019. Though research using various approaches including genetics, imaging, clinical and animal models has advanced our knowledge regarding NPDs, we still lack basic knowledge regarding the underlying pathophysiological mechanisms. Moreover, there is an urgent need for highly effective therapeutics for NPDs. Human induced pluripotent stem cells (hiPSCs) generated from somatic cells enabled scientists to create brain cells in a patient-specific manner. However, there are challenges to the use of hiPSCs that need to be addressed. In the current paper, consideration of best practices for neuropharmacological and neuropsychiatric research using hiPSCs will be discussed. Specifically, we provide recommendations for best practice in patient recruitment, including collecting demographic, clinical, medical (before and after treatment and response), diagnostic (including scales) and genetic data from the donors. We highlight considerations regarding donor genetics and sex, in addition to discussing biological and technical replicates. Furthermore, we present our views on selecting control groups/lines, experimental designs, and considerations for conducting neuropharmacological studies using hiPSC-based models in the context of NPDs. In doing so, we explore key issues in the field concerning reproducibility, statistical analysis, and how to translate in vitro studies into clinically relevant observations. The aim of this article is to provide a key resource for hiPSC researchers to perform robust and reproducible neuropharmacological studies, with the ultimate aim of improving identification and clinical translation of novel therapeutic drugs for NPDs

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition

Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders

The number of individuals suffering from neuropsychiatric disorders (NPDs) has increased worldwide, with 3 million disability-adjusted life-years calculated in 2019. Though research using various approaches including genetics, imaging, clinical and animal models has advanced our knowledge regarding NPDs, we still lack basic knowledge regarding the underlying pathophysiological mechanisms. Moreover, there is an urgent need for highly effective therapeutics for NPDs i. Human induced pluripotent stem cells (hiPSCs) generated from somatic cells enabled scientists to create brain cells in a patient-specific manner. However, there are challenges to the use of hiPSCs that need to be addressed. In the current paper, consideration of best practices for neuropharmacological and neuropsychiatric research using hiPSCs will be discussed. Specifically, we provide recommendations for best practice in patient recruitment, including collecting demographic, clinical, medical (before and after treatment and response), diagnostic (incl. scales) and genetic data from the donors. We highlight considerations regarding donor genetics and sex, in addition to discussing biological and technical replicates. Furthermore, we present our views on selecting control groups/lines, experimental designs, and considerations for conducting neuropharmacological studies using hiPSC-based models in the context of NPDs. In doing so, we explore key issues in the field concerning reproducibility, statistical analysis, and how to translate in vitro studies into clinically relevant observations. The aim of this article is to provide a key resource for hiPSC researchers to perform robust and reproducible neuropharmacological studies, with the ultimate aim of improving identification and clinical translation of novel therapeutic drugs for NPDs

Implementation of a Urinary Tract Infection Treatment Protocol to Improve Prescribing Practices in the Long-Term Care Facility of a Veteran’s Healthcare System

Urinary tract infections (UTIs) are a commonly diagnosed problem in long-term care facilities (LTCFs), but antimicrobial treatment is often incorrectly prescribed. Although bacterial resistance to antimicrobials commonly used for UTIs, such as trimethoprim/sulfamethoxazole and fluoroquinolones, has been dramatically increasing, they are still commonly prescribed. The purpose of this project was to determine if implementation of a standard treatment protocol for UTIs, which emphasized correct UTI diagnosis and use of nitrofurantoin and cefpodoxime/ceftriaxone as empiric therapy per the institutional antibiogram, changed clinician prescribing practices. This quasi-experimental model utilized two years of pre-intervention and two years of post-intervention data. Three hundred patient encounters were included. Antibiotics prescribed in the pre-intervention period included: trimethoprim/sulfamethoxazole (32%), ciprofloxacin (14%), amoxicillin (13%), levofloxacin (9%), cefpodoxime (9%), ceftriaxone (8%), amoxicillin/clavulanate (5%), nitrofurantoin (4%), and other (6%). By contrast, antibiotics prescribed in the post-intervention period included: cefpodoxime (46%), nitrofurantoin (30%), ceftriaxone (10%), trimethoprim/sulfamethoxazole (8%), amoxicillin/clavulanate (1%), and other (5%). These differences in prescribed drug between the pre-intervention and post-intervention encounters were statistically significant (p < 0.001). Overall, appropriate empiric treatment was prescribed in only 48/217 encounters (22%) during the pre-intervention period, but this increased to 73/83 encounters (88%) in the post-intervention period (p < 0.001). The results indicate that the treatment protocol was successful in changing prescribing practices and decreasing the use of inappropriate antimicrobials at the LTCF