Integrative regulation of hLMR1 by dietary and genetic factors in nonalcoholic fatty liver disease and hyperlipidemia.

Long non-coding RNA (lncRNA) genes represent a large class of transcripts that are widely expressed across species. As most human lncRNAs are non-conserved, we recently employed a unique humanized liver mouse model to study lncRNAs expressed in human livers. We identified a human hepatocyte-specific lncRNA, hLMR1 (human lncRNA metabolic regulator 1), which is induced by feeding and promotes hepatic cholesterol synthesis. Recent genome-wide association studies (GWAS) found that several single-nucleotide polymorphisms (SNPs) from the hLMR1 gene locus are associated with blood lipids and markers of liver damage. These results suggest that dietary and genetic factors may regulate hLMR1 to affect disease progression. In this study, we first screened for nutritional/hormonal factors and found that hLMR1 was robustly induced by insulin/glucose in cultured human hepatocytes, and this induction is dependent on the transcription factor SREBP1. We then tested if GWAS SNPs genetically linked to hLMR1 could regulate hLMR1 expression. We found that DNA sequences flanking rs9653945, a SNP from the last exon of the hLMR1 gene, functions as an enhancer that can be robustly activated by SREBP1c depending on the presence of rs9653945 major allele (G). We further performed CRISPR base editing in human HepG2 cells and found that rs9653945 major (G) to minor (A) allele modification resulted in blunted insulin/glucose-induced expression of hLMR1. Finally, we performed genotyping and gene expression analyses using a published human NAFLD RNA-seq dataset and found that individuals homozygous for rs9653945-G have a higher expression of hLMR1 and risk of NAFLD. Taken together, our data support a model that rs9653945-G predisposes individuals to insulin/glucose-induced hLMR1, contributing to the development of hyperlipidemia and NAFLD.

Survey of barriers and opportunities for prescribing buprenorphine for opioid use disorder in Alabama.

Opioid-related overdose deaths have significantly increased in the USA and in Alabama. Despite this, medications for opioid use disorder (MOUD) remains significantly underutilized. Thus, this study aims to gain a better understanding of clinicians' viewpoints on potential barriers and opportunities that are likely to impact and improve the access to MOUD, especially buprenorphine prescribing. A cross-sectional survey study was conducted with Alabama's clinicians (n = 492). The survey containing a QR code was mailed to clinicians throughout the state and was asked about their viewpoints and thoughts on prescribing buprenorphine. Multivariable linear regression was used to examine associations between OUD self-efficacy, beliefs about the effectiveness of MOUD, attitudes regarding whether or not MOUD is addictive, and positive affect surrounding the treatment of OUD patients. A minority of respondents (39.8%) reported that they have an active X-waiver for MOUD. Results showed that beliefs that MOUD is addictive were significantly inversely correlated with beliefs about MOUD being effective. Furthermore, both self-efficacy and positive affect were significantly and positively associated with beliefs that MOUD is effective. Furthermore, nurse practitioners were more likely than physicians to have higher scores on the "MAT is Addictive" construct. Self-efficacy with OUD patients was positively associated with the "MOUD is Effective" construct. Finally, results showed that X-waivered providers expressed greater positive affect toward OUD patients than providers who were not X-waivered (b = 2.9, p < 0.001). Belief that MOUD is effective was also positively associated with higher scores on the positive affect construct (b = 0.5, p < 0.001). Several barriers and opportunities were identified in our survey data which could be used to explore MOUD expansion, especially buprenorphine prescribing. Strategic plans in expanding MOUD access may include educational trainings on MOUD, motivating clinicians to utilize their capacity by implementing incentive plans, increasing provider self-efficacy, reducing stigma around MOUD, and providing more financial support to uninsured patients.

Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer.

Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for advanced NSCLC. ctDNA technologies have also shown the ability to detect the emerging mechanisms of acquired resistance that evolve after targeted therapy. Furthermore, the detection of minimal residual disease (MRD) by ctDNA for patients with NSCLC after curative-intent treatment may serve as a prognostic and potentially predictive biomarker for recurrence and response to therapy, respectively. Finally, ctDNA analysis via mutational, methylation, and/or fragmentation multi-omic profiling offers the potential for improving early lung cancer detection. In this review, we discuss the role of ctDNA in each of these capacities, namely, for molecular profiling, treatment response monitoring, MRD detection, and early cancer detection of NSCLC.

Disparities in naloxone prescriptions in a University Hospital during the COVID-19 pandemic.

BACKGROUND: Per the CDC, it is estimated that 69,710 opioid overdose deaths occurred in the United States from September 2019 to September 2020. However, it is unclear whether naloxone prescribing also increased or otherwise fluctuated in this time. The objective of this study was to characterize the naloxone prescribing rate in patients with opioid use disorder (OUD) at the University of Alabama at Birmingham Hospital in 2019 and 2020. METHODS: A cross-sectional, retrospective medical record review was performed on patients with OUD from January 2019 through December 2020. Naloxone prescribing, defined as either a written prescription or a provided take-home kit, was assessed for all patients with OUD. RESULTS: In 2019, 11,959 visits were made by 2962 unique patients with OUD, compared to 11,661 visits from 2,641 unique patients in 2020; 609 naloxone prescriptions were provided in 2019 (5.1%) and 619 in 2020 (5.3%). In both years, most OUD-related visits and naloxone prescriptions were from and to male, white, individuals. Compared with 2019, more naloxone prescriptions were given to uninsured patients in 2020 (33.2% vs 44.3%, p < 0.05), and more OUD patients were admitted to inpatient settings (26.0% vs 31.2%, p < 0.05) and received more naloxone prescriptions in the inpatient setting (46.3% vs 62.0%, p < 0.05) in 2020. The proportion of frequent users (i.e., visits ≥ 4 times/year) increased in 2020 for the emergency department (21.5% vs 26.4%, p < 0.001) and inpatient setting (24.9% vs 28.6%, p = 0.03). CONCLUSIONS: Our findings indicate the need for improving naloxone awareness in providers and prescribing for patients with OUD, particularly in emergency department and outpatient settings. Our results also demonstrated a disparity in naloxone prescribing; a disproportionate number of opioid-related emergency department visits and overdose deaths were noted in Black people and frequent users.

Immune Checkpoint Inhibitors and Chemoradiation for Limited-Stage Small Cell Lung Cancer.

OPINION STATEMENT: Limited-stage small cell lung cancer (LS-SCLC) is a potentially curable disease. However, most patients develop disease relapse shortly after definitive treatment. The landmark trials IMpower133 and CASPIAN demonstrated a survival benefit with the addition of immunotherapy to first-line platinum/etoposide for extensive-stage small cell lung cancer. Therefore, it is critical to determine whether advancements in overall survival with immunotherapy can be translated earlier into the treatment paradigm for LS-SCLC. Decades of robust preclinical research into the synergism of radiation therapy and immunotherapy set the stage for the combination of these treatment modalities. Recently published data suggests tolerability of single agent immunotherapy concurrent with chemoradiation in LS-SCLC, along with promising efficacy. However, combination immunotherapy in the consolidation setting appears too toxic, although this may be reflective of the dosing schedule rather than inherent to any combination immune checkpoint blockade. Here, we review underlying mechanisms of synergy with the combination of radiation and immunotherapy, the safety and efficacy of respective treatment modalities, and the ongoing trials that are exploring novel therapeutic approaches for LS-SCLC. Pivotal trials in LS-SCLC are ongoing and anticipated to aid in understanding efficacy and safety of immunotherapy with concurrent platinum-based chemoradiotherapy.

Opioid overdose crises during the COVID-19 pandemic: implication of health disparities.

BACKGROUND: Recent data suggest a disproportionate impact of opioid overdoses on Black Americans. The study aims to describe emergency department (ED) visits at a Southern, urban ED pertaining to opioid overdose and associated health disparities. METHODS: Patients presenting to the ED at the University of Alabama at Birmingham Hospital with opioid overdoses from January 1 to October 31, 2019, and from January 1 to October 31, 2020, were identified from electronic medical records. RESULTS: The total number of opioid overdose visits increased 9.7% (556 to 611) between January and October 2020 compared with 2019. Among patients who presented with opioid overdose, the mean ages were 50.3 years and 48.3 years, in 2019 and 2020, respectively. In both 2019 and 2020, more Blacks than whites were treated for opioid overdose in the ED (284 vs. 258 in 2019, and 306 vs. 271 in 2020) although 28 patients did not record their race in 2020. Consistently, more overdose deaths were observed in Blacks than in whites in 2020. More individuals seeking opioid overdose treatment were single in both years. CONCLUSIONS: The study reported a greater number of visits for opioid overdoses from January to October of 2020 in an ED of a southeastern region, as well as higher overdose deaths in Blacks. Our findings highlight the importance of substance use treatment, harm reduction, and overdose prevention efforts that should be immediately present to reduce opioid overdose, especially for vulnerable populations in the South, i.e., Black community, and individuals experiencing singlehood.