Evaluating Study Design Rigor in Preclinical Cardiovascular Research: A Replication Study.

Background: Methodological rigor is a major priority in preclinical cardiovascular research to ensure experimental reproducibility and high quality research. Lack of reproducibility results in diminished translation of preclinical discoveries into medical practice and wastes resources. In addition, lack of reproducibility fosters uncertainty in the public's acceptance of reported research results. Methods: We evaluate the reporting of rigorous methodological practices in preclinical cardiovascular research studies published in leading scientific journals by screening articles for the inclusion of the following key study design elements (SDEs): considering sex as a biological variable, randomization, blinding, and sample size power estimation. We have specifically chosen to screen for these SDEs across articles pertaining to preclinical cardiovascular research studies published between 2011 and 2021. Our study replicates and extends a study published in 2017 by Ramirez et al. We hypothesized that there would be higher SDE inclusion across preclinical studies over time, that preclinical studies that also include human and animal substudies within the same study will exhibit greater SDE inclusion than animal-only preclinical studies, and that there will be a difference in SDE usage between large and small animal models. Results: Overall, inclusion of SDEs was low. 15.2% of animal only studies included both sexes as a biological variable, 30.4% included randomization, 32.1% included blinding, and 8.2% included sample size estimation. Incorporation of SDE in preclinical studies did not significantly increase over the ten year time period in the articles we assessed. Although the inclusion of sex as a biological variable increased over the 10 year time frame, that change was not significant (p=0.411, corrected p=8.22). These trends were consistent across journals. Reporting of randomization and sample size estimation differs significantly between animal and human substudies (corrected p=3.690e-06 and corrected p=7.252e-08, respectively.) Large animal studies had a significantly greater percentage of blinding reported when compared to small animal studies (corrected p=0.01.) Additionally, overall, large animal studies tended to have higher SDE usage. Conclusions: In summary, evidence of methodological rigor varies substantially depending on the study type and model organisms used. Over the time period of 2011-2021, the reporting of SDEs within preclinical cardiovascular studies has not improved and suggests extensive evaluation of other SDEs used in cardiovascular research. Limited incorporation of SDEs within research hinders experimental reproducibility that is critical to future research.

Medicine Adherence and Associated Factors in Immigrants and Refugees: A Systematic Review.

Medicine nonadherence is a major contributing factor to morbidity and mortality. Almost half of the chronically ill patients are nonadherent to their medication. Vulnerable groups like immigrants and refugees are at a higher risk of poor medication adherence. This study aims to determine the rate of medicine adherence and the factors associated with medicine nonadherence in a population of immigrants and refugees. A protocol-led (PROSPERO ID: CRD42021285419) systematic review was conducted by searching PubMed, Medline, Embase, Scopus, CINAHL, and Cochrane Library for studies published between 1st January 2000 and 4th November 2021. PRISMA guidelines were followed. The NIH quality assessment tool and CASP checklist were used to quality assess the papers. Data were searched, screened, and extracted. Extracted data were tabulated for descriptive and narrative analyses. 15 studies were conducted across six countries including participants with various medical conditions. The rate of medicine adherence reported ranged from 10.1% to 74.5%. Higher rates of nonadherence were observed in immigrants and refugees compared to migrant and native groups. Socio-economic factors, including language proficiency, level of education, and financial burden, and patient-related factors involving cultural behaviours and beliefs were common themes for nonadherence among immigrants and refugees. Further research is required to address the effect of nonadherence on clinical outcomes. Studies should focus on using a consistent definition of adherence and the same objective methods to measure rates of adherence to allow for meta-analysis of data and definitive results. Healthcare professionals (HCPs) are recommended to target interventions at improving adherence and reducing modifiable risk factors in immigrants and refugees, thus reducing health disparities among the population.

Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol.

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/- mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/- mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/- mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.

DNA damage and neurodegenerative phenotypes in aged Ciz1 null mice.

Cell-cycle dysfunction and faulty DNA repair are closely intertwined pathobiological processes that may contribute to several neurodegenerative disorders. CDKN1A interacting zinc finger protein 1 (CIZ1) plays a critical role in DNA replication and cell-cycle progression at the G1/S checkpoint. Germline or somatic variants in CIZ1 have been linked to several neural and extra-neural diseases. Recently, we showed that germline knockout of Ciz1 is associated with motor and hematological abnormalities in young adult mice. However, the effects of CIZ1 deficiency in much older mice may be more relevant to understanding age-related declines in cognitive and motor functioning and age-related neurologic disorders such as isolated dystonia and Alzheimer disease. Mouse embryonic fibroblasts from Ciz1-/- mice showed abnormal sensitivity to the effects of γ-irradiation with persistent DNA breaks, aberrant cell-cycle progression, and apoptosis. Aged (18-month-old) Ciz1-/- mice exhibited marked deficits in motor and cognitive functioning, and, in brain tissues, overt DNA damage, NF-κB upregulation, oxidative stress, vascular dysfunction, inflammation, and cell death. These findings indicate that the deleterious effects of CIZ1 deficiency become more pronounced with aging and suggest that defects of cell-cycle control and associated DNA repair pathways in postmitotic neurons could contribute to global neurologic decline in elderly human populations. Accordingly, the G1/S cell-cycle checkpoint and associated DNA repair pathways may be targets for the prevention and treatment of age-related neurodegenerative processes.