Biology subjects

Shah, A. S.

Publications and source records attributed to Shah, A. S..

4 recordsLinked to original sources

bioRxiv2020

Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes

Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc), and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the BOLD response, and that interhemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional MRI measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.

neuroscience↗

bioRxiv2020

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

We report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated to false discovery rate < 0.01, including 36 regions associated to genome-wide significance for the first time. Credible sets of disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly in CD4+ effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) in CD4+ T cells identified five regions where differences in T1D risk and chromatin accessibility are potentially driven by the same causal variant. Allele-specific chromatin accessibility further refined the set of putative causal variants with functional relevance in CD4+ T cells and integration of whole blood expression QTLs identified candidate T1D genes, providing high-yield targets for mechanistic follow-up. We highlight rs72938038 in BACH2 as a candidate causal T1D variant, where the T1D risk allele leads to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritise potential drug targets by integrating genetic evidence, functional genomic maps, and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D, including proposed genetic regulatory mechanisms of T1D-associated variants and genetic support for therapeutic targets for immune intervention.

genetics↗

bioRxiv2019

A Large-scale Study Reveals 24 hour Operational Rhythms in Hospital Treatment

Hospitals operate 24 hours a day, and it is assumed that critical decisions occur continuously around the clock. However, many aspects of hospital operation occur at particular times of day, including medical team rounding and shift changes. It is unclear if this impacts patient care, as an empirical account of 24 h treatment patterns is lacking. We analyzed the daily distribution of ~120K doses of 12 separate drugs in 1,486 inpatients at a major childrens hospital in the U.S. Treatment orders and administration were strongly time-of-day-dependent, marked by distinct morning time surges and overnight lulls. These 24 h rhythms in treatment were remarkably consistent across drugs, diagnoses, and hospital units. In sum, nearly one-third of all 116,975 orders for treatment were placed between 8 AM and 12 PM. This rhythm in hospital medicine coincided with medical team rounding time, not necessarily immediate medical need. Lastly, we show that the clinical response to hydralazine, an acute antihypertensive, is dosing time-dependent and greatest at night, when the fewest doses were administered. The prevailing dogma is that hospital treatment is administered as needed regardless of time of day. Our findings challenge this notion and reveal a potential operational barrier to best clinical care.\n\nSIGNIFICANCE STATEMENTThe order and administration of hospital treatment was characterized by morning time surges and overnight lulls, regardless of drug type, diagnosis or care unit. As the first large-scale account of 24 h rhythms in hospital medicine, this study identifies a potential operational barrier to best clinical care. Critical clinical decisions should be made around the clock; pain, infection, hypertensive crisis, and other conditions do not occur selectively in the morning. Systemic bias in the timing of medicine is also at odds with circadian biology, which can influence when certain treatments are most effective or safe. Prevailing dogma is that hospital treatment is administered as needed regardless of time of day. Our findings challenge this notion and suggest that time of day in hospital operations deserves further consideration.

epidemiology↗

bioRxiv2018

Global Adoption of High-Sensitivity Cardiac Troponins and the Universal Definition of Myocardial Infarction

ImportanceThe third Universal Definition of Myocardial Infarction aimed to standardize the approach to the diagnosis and management of myocardial infarction. High-sensitivity cardiac troponin testing was recommended, as these assays have improved precision at low concentrations, but concerns over specificity may have limited implementation.\n\nObjectiveTo determine the global adoption of high-sensitivity cardiac troponin assays and key recommendations from the Universal Definition.\n\nDesign, Setting and ParticipantsGlobal survey of 1,902 medical centers across 23 countries evenly distributed across all five continents. Included respondents were involved in the diagnosis and management of patients with suspected acute coronary syndrome at their institutions.\n\nMain Outcomes and MeasuresStructured questionnaire detailing the primary biomarker used for myocardial infarction, diagnostic thresholds and critical elements of clinical pathways for comparison to the third Universal Definition recommendations.\n\nResultsCardiac troponin was the primary diagnostic biomarker for myocardial infarction at 96% of all sites surveyed. Only 41% of centers had adopted high-sensitivity cardiac troponin assays, with wide variation from 7% in North America to 60% in Europe. Sites using high-sensitivity assays more frequently employed serial sampling pathways (91% vs. 78%) and the 99th percentile diagnostic threshold (74% vs. 66%) when compared to sites using the previous generation of troponin assays. Furthermore, sites using high-sensitivity assays more often used earlier serial sampling ([≤]3 hours) and accelerated diagnostic pathways. However, fewer than 1 in 5 sites using high-sensitivity assays had adopted sex-specific thresholds (18%).\n\nConclusions and RelevanceProgress has been made in adopting the recommendations of the Universal Definition of Myocardial Infarction, particularly in the use of the 99th percentile diagnostic threshold and serial sampling. However, high-sensitivity assays are used in a minority of sites and sex-specific thresholds in even fewer. These findings highlight regions where additional efforts are required to improve the risk stratification and diagnosis of patients with myocardial infarction.

biochemistry↗