"Protecting the Future of Medical Innovation: Balancing Fiscal Responsibility with the Need for National Institutes of Health and Federal Health Funding." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.

BACKGROUND:Our previous study demonstrated that alcohol induced the expression of the α4 subunit of nicotinic acetylcholine receptors (nAChRs) in the livers of wild type mice (WT), and that whole-body α4 nAChR knockout mice (α4KO) showed protection against alcohol-induced steatosis, inflammation, and injury. Based on these findings, we hypothesized that hepatocyte-specific α4 nAChRs may directly contribute to the detrimental effects of alcohol on the liver. METHODS:Hepatocyte-specific α4 knockout mice (α4HepKO) were generated, and the absence of α4 nAChR was confirmed through PCR of genomic DNA. Female WT and α4HepKO mice were exposed to alcohol in the NIAAA chronic + binge model. After 10 days on the Lieber-DeCarli liquid diet containing 5% (vol/vol) alcohol or isocaloric maltose-dextrin, the mice were gavaged with a single dose of alcohol or isocaloric maltose-dextrin. The mice were euthanized 9 h later and their organs harvested. Additionally, hepatocytes were isolated from WT, α4HepKO, α4floxed, and α4KO mice and exposed to 80 mM alcohol in vitro for 24 h. Steatosis, inflammation, and cell injury were assessed in both liver and isolated hepatocytes. RESULTS:In WT mice, alcohol exposure resulted in hepatic steatosis, inflammation, and injury as evidenced by increased liver triglycerides, neutrophil infiltration, and serum concentrations of liver enzymes. All of these responses were markedly lower in α4HepKO mice. mRNA expression of genes involved in lipogenesis (Srebf1, Fasn, and Dgat2) and inflammation (TNFα, Cxcl5, Cxcl1, and Serpine1) were increased in the livers of WT mice exposed to alcohol in vivo and in WT hepatocytes exposed to alcohol in vitro. These changes were not observed in liver or hepatocytes from mice lacking α4 nAChRs. CONCLUSIONS:α4 nAChRs expressed in hepatocytes mediate alcohol-associated hepatoxicity. Therefore, the development of therapeutic strategies targeting hepatocyte α4-containing nAChRs could help reduce the burden of ALD.

Oxidative stress has been implicated in lung injury and repair. We seek to understand how alterations in the plasma redox potential (Eh) of the thiol disulfide couple cysteine (Cys) and cystine (CySS) (Eh Cys/CySS) affect this process. Previously, we reported that Eh Cys/CySS oxidation promotes a pro-fibrotic phenotype in lung fibroblasts and identified the cystine/glutamate exchanger solute carrier family 7, member 11 (Slc7a11) as a regulator of Eh Cys/CySS. We also observed that pharmacological agents capable of altering Slc7a11 expression affect lung fibroblast phenotype in vitro. We hypothesized that alterations in Slc7a11 expression would affect lung injury in vivo and set out to test this in C57Bl6 mice exposed to bleomycin. However, we did not observe changes in bleomycin-induced lung injury in animals treated with pharmacological alterations in Slc7a11 expression or when Slc7a11 knockout animals were tested. Thus, the role of Slc7a11 in lung injury remains uncertain.

Rationale: Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive condition caused by mutations that disrupt the trafficking of essential proteins within cells. It is characterized by oculocutaneous albinism, bleeding diathesis, and involvement of other organs. Some HPS mutations are associated with a severe form of pulmonary fibrosis for which there is currently no effective treatment. As a rare condition, the true burden of HPS on the U.S. healthcare system has yet to be determined. Methods We analyzed the TriNetX and Epic Cosmos databases that contain de-identified information on over 250 million subjects in hospitals, ambulatory clinics, and emergency department settings in the U.S. Results The analysis revealed a prevalence of 3 affected individuals per 1,000,000 persons, consistent with prior global estimates, though most HPS-affected individuals are located on the East Coast. The average age of those affected ranged from 27-34, with a predominance of females. The majority of HPS subjects were White (68%), followed by Blacks (6%), Asian (4%), and Native American (2%). Forty-five percent were Hispanics. Consistent between databases, a significant percentage of patients were diagnosed with albinism, qualitative platelet defects, unspecified abdominal pain and diarrhea, and nystagmus. Respiratory conditions and symptoms were also relatively common including shortness of breath, cough, asthma, and upper respiratory infection. Interestingly, in addition to common entities such as hypertension, gastroesophageal reflux, and headaches, HPS subjects showed a relatively high prevalence of anxiety disorders, chronic pain, and fatigue which affected 16% to 22%. Conclusion Our findings suggest that even though the prevalence of HPS in the U.S. is similar to that previously reported worldwide, it is not evenly distributed amongst states. Furthermore, we found that HPS subjects have associated comorbidities that are likely to have a significant impact on quality of life and healthcare resources.

BACKGROUND:Sarcoidosis is a multisystem inflammatory disease in which management and outcomes can vary widely. The renin-angiotensin-aldosterone system (RAAS) has been implicated in its pathogenesis, yet the impact of RAAS modulators on health outcomes in sarcoidosis remains poorly understood. RESEARCH QUESTION:How do pharmacologic modulators of RAAS affect health outcomes in patients with a diagnosis of sarcoidosis? STUDY DESIGN AND METHODS:We conducted a large multicenter investigation using the TriNetX Research Network database. Patients included in this study were individuals with a diagnosis of sarcoidosis who were prescribed either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). All cohorts were matched for important covariates, and outcomes measured included mortality, cardiac and respiratory outcomes, and sepsis rates after sarcoidosis diagnosis. RESULTS:We observed an increased mortality risk among patients with sarcoidosis prescribed ACEIs compared with patients prescribed ARB therapies. Furthermore, patients with sarcoidosis prescribed ACEIs showed worse cardiac and respiratory outcomes and increased sepsis rates compared with the ARB cohort. INTERPRETATION:Our findings suggest that ACEIs and ARBs have divergent effects on outcomes in patients with sarcoidosis. These findings highlight the potential pathogenic role of RAAS signaling in this disease and underscore the importance of carefully selecting RAAS modulators for individuals with sarcoidosis.

Cardiac Sarcoidosis (CS) is a potentially life-threatening manifestation of sarcoidosis that presents significant diagnostic and management challenges. While only 2-5 % of patients with sarcoidosis are diagnosed with CS, autopsy studies have demonstrated a prevalence as high as 25 % suggesting the condition is often under recognized likely because of lack of or nonspecific symptoms or diagnostic limitations. Considering the unreliability and invasiveness of endomyocardial biopsy, cardiac magnetic resonance imaging (CMR) and Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) have become useful diagnostic modalities in suspected cases of CS. However, there is scarce data in support of one imaging modality over the other and each has its limitations. Such limitations are depicted in the case of a patient with complete heart block and newly diagnosed sarcoidosis showing conflicting results on FDG-PET and CMR. A narrative review of current knowledge on this condition and about the imaging modalities available for the workup of CS is provided.

Background The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF. Methods We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF. Results Levels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation. Conclusions IPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers. Trial registration ClinicalTrials.gov; No: NCT01915511; URL: www.clinicaltrials.gov .

Alpha 1 antitrypsin deficiency is a widely under recognized autosomal codominant condition caused by genetic mutations in the SERPINA 1 gene, which encodes for alpha 1 antitrypsin (AAT), a serine protease inhibitor. The SERPINA 1 gene contains 120 variants and mutations in the gene may decrease AAT protein levels or result in dysfunctional proteins. This deficiency leads to unopposed protease activity in tissues, thereby promoting pulmonary and hepatic disease. The most common genotype associated with pulmonary disease is the ZZ genotype, and the most frequent pulmonary manifestation is emphysema. Although its pathophysiology may differ from cigarette smoking related chronic obstructive pulmonary disease, smoking itself can hasten lung decline in alpha 1 antitrypsin deficiency (AATD). The diagnosis of AATD is made through AAT protein testing along with genotyping. AATD patients with obstructive airflow limitation may qualify for intravenous augmentation with AAT. However, there is ongoing research to allow for earlier detection and treatment. This review describes in general terms the genetic mechanisms of AATD; its pathogenesis and the impact of cigarette smoke; and its clinical manifestations, diagnosis, treatment, and prognosis. We hope to stimulate research in the field, but mostly we wish to enhance awareness to promote early diagnosis and treatment in those eligible for intervention.

Academic medicine provides physicians an opportunity for long-term career satisfaction and fulfillment. However, despite the potential for great reward, academic careers can be challenging. To better define approaches to successfully navigate academic medicine, the Southern Society for Clinical Investigation sponsored a workshop titled 'Successful Careers in Academic Medicine' during the 2023 Southern Regional Meeting held in New Orleans; the critical elements of which are highlighted in the following summary. Participants discussed the benefits of an academic career, summarized strategies for negotiating a job, listed critical tools for career development, and discussed key concepts about planning and navigating the academic medicine promotion process. The information provides a roadmap for physicians to develop successful careers in academic medicine.