National Institutes Of Health Grants Research Articles

Federal and foundational research funding trends for cerebrovascular neurosurgeons: the decline of the cerebrovascular surgeon-scientist?

The number of cerebrovascular (CV) surgeons has grown with the rise of endovascular neurosurgery. However, it is unclear whether the number of CV surgeon-scientists has concomitantly increased. With increasing numbers of CV neurosurgeons in the US workforce, the authors analyzed associated changes in National Institutes of Health (NIH) and Neurosurgery Research and Education Foundation (NREF) funding trends for CV surgeons over time. Publicly available data were collected on currently practicing academic CV surgeons in the US. Inflation-adjusted NIH funding between 2009 and 2021 was surveyed using NIH RePORTER and Blue Ridge Institute for Medical Research data. The K12 Neurosurgeon Research Career Development Program and NREF grant data were queried for CV-focused grants. Pearson R correlation, chi-square analysis, and the Mann-Whitney U-test were used for statistical analysis. From 2009 to 2021, NIH funding increased: in total (p = 0.0318), to neurosurgeons (p < 0.0001), to CV research projects (p < 0.0001), and to CV surgeons (p = 0.0018). During this time period, there has been an increase in the total number of CV surgeons (p < 0.0001), the number of NIH-funded CV surgeons (p = 0.0034), and the percentage of CV surgeons with NIH funding (p = 0.370). Additionally, active NIH grant dollars per CV surgeon (p = 0.0398) and the number of NIH grants per CV surgeon (p = 0.4257) have increased. Nevertheless, CV surgeons have been awarded a decreasing proportion of the overall pool of neurosurgeon-awarded NIH grants during this time period (p = 0.3095). In addition, there has been a significant decrease in the number of K08, K12, and K23 career development awards granted to CV surgeons during this time period (p = 0.0024). There was also a significant decline in the proportion of K12 (p = 0.0044) and downtrend in early-career NREF (p = 0.8978) grant applications and grants awarded during this time period. Finally, NIH-funded CV surgeons were more likely to have completed residency less recently (p = 0.001) and less likely to have completed an endovascular fellowship (p = 0.044) as compared with non-NIH-funded CV surgeons. The number of CV surgeons is increasing over time. While there has been a concomitant increase in the number of NIH-funded CV surgeons and the number of NIH grants awarded per CV surgeon in the past 12 years, there has also been a significant decrease in CV surgeons with K08, K12, and K23 career development awards and a downtrend in CV-focused K12 and early-career NREF applications and awarded grants. The latter findings suggest that the pipeline for future NIH-funded CV surgeons may be in decline.

Clock and Bmal1 inhibit expression of Sglt1 in mouse Kidneys and glucose reabsorption

Aberrantly elevated sodium/glucose cotransporter 1 (Sglt1) expression and increased glucose reabsorption contribute to obesity or lean-associated metabolic complications, however, the precise mechanisms underlying the high expression of Sglt1 and increased glucose absorption are unclear. Clock (circadian locomotor output cycles kaput protein) is known as the master clock gene; Bmal1 (basic helix-loop-helix arnt like 1) is a known heterodimer of Clock that is a critical regulator of circadian metabolism and has the potential for regulating obesity-related diseases. We examined whether circadian clock genes involving Clock/Bmal1 and the orphan nuclear receptor Shp (the small heterodimer partner) regulate the expression of Sglt1 to maintain glucose reabsorption and glucose homeostasis. Renal Sglt1 levels were increased in Clock-mutant or Bmal1-knockout (KO) mice and were decreased by activation of Bmal1 in an SHP-dependent manner. Mechanistically, the transactivation of Sglt1 by HNF1α (hepatic nuclear factor 1 alpha) was inhibited by SHP. In wild-type mice fed a western diet, activation of Shp by Nobiletin reduced Sglt1 levels and improved glucose reabsorption and glucose handling, but these beneficial effects were not seen in Clock−mutant and Bmal1 KO mice. These results demonstrate that normal inhibition of Sglt1 by Clock/Bmal1-SHP is defective in obesity, resulting in increased Sglt1 levels, glucose reabsorption, and renal steatosis. This Clock/Bmal1-SHP-Sglt1 pathway may present novel targets for treating obesity. This work was supported in part by National Institutes of Health (NIH) grant R56 HL137912 and American Heart Association Scientist Development Grant 2300158 and Grant-in-Aid 16GRNT30960027 to XP; by U.S. NIH grants DK121490, HL137202, HL158054 and HD094778, and VA Merit Award BX004113 to MMH; and NIH grants R01DK112042, R01HL142814, RF1AG061296, the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337, and the Department of Veterans Affairs to V Vallon. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vascular Smooth Muscle Cell Mechanical Stretch Modulates Tissue Transglutaminase Activity and Cytoskeletal Dynamics

Vascular smooth muscle cells (VSMCs) are exposed to a wide range of mechanical stimuli in both physiological and pathological conditions. These mechanical stimuli are converted into biochemical signals that regulate VSMC contractility and cytoskeletal structures in a process known as mechanotransduction. Thus, the ability of VSMCs to sense and respond to mechanical signals is essential for proper regulation of their structural characteristics and the modulation of vascular tone. We had previously shown that increased tissue transglutaminase 2 (TG2) activity modulates actin dynamics via alterations of the phosphorylation state of cofilin leading to VSMC stiffening and remodeling of the vascular wall. However, whether mechanical forces act through TG2 to modulate VSMC stiffness remains unknown. Herein, we tested the hypothesis that mechanical stretch increases VSMC stiffness by increasing TG2 activity, reducing cofilin activity, and increasing actin cytoskeletal stress fiber formation. To this end, immortalized human aortic vascular smooth muscle cells (HAoSMCs) were cultured and seeded on Uniflex culture plates. HAoSMCs were left unstretched or exposed to cyclic uniaxial stretch using a Flexcell tension system with 11% elongation at 1 Hz for 6 hrs. HAoSMCs were treated without or with the nitric oxide (NO) donor s-nitrosoglutathione (400μmol/L) or cystamine (200μmol/L) under stretched and unstretched conditions, as NO and cystamine are known inhibitors of TG2. All differences reported herein are significant at p&lt;0.05. Our results show that cyclic uniaxial stretch for 6 hrs increases VSMC TG2 content and activity, actin stress fibers (polymerization), and phospho-cofilin/cofilin ratios (cofilin inactivation), relative to the unstretched condition. Notably, the increase in TG2 activity and F-actin content occurring in response to stretch was inhibited by the NO donor or cystamine. As it has been previously shown that cellular stiffness is associated with stress fiber formation, this work suggests that stretch-induced cellular stiffening is potentially mediated by TG2 activity in VSMC. National Institutes of Health grant: R01HL153264 to LM-L and JP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neuraminidase-3 Inhibition Improves Vascular Function in Diabetic Mice

In type 2 diabetes (T2D), endothelial dysfunction and arterial stiffening play a significant role in the development of cardiovascular disease. A central mediator of vascular dysfunction is degradation of the endothelial glycocalyx, a semipermeable mechanosensitive structure that separates the endothelium from the flow of blood and shear forces associated with it. Neuraminidase, a sialidase that cleaves sialic acid from the terminal branches of glycoproteins and glycolipids, is implicated in glycocalyx degradation. However, its role in mediating vascular dysfunction in the setting of T2D remains relatively unexplored. Herein, we tested the hypothesis that pharmacological inhibition of neuraminidase-3 (Neu3i) improves glycocalyx integrity, ameliorates endothelial dysfunction, and reduces arterial stiffness in diabetes. In support of this hypothesis, we report that, relative to vehicle-treated cells, endothelial cells exposed to Neu3i for 24hr have increased glycocalyx components including sialic acid and N-acetylglucosamine (GlcNAc), one of the amino sugars comprising the N-acetyllactosaminoglycans chains within the glycocalyx, as assessed with fluorescent lectin staining using MAA/Mal I+2 and WGA, respectively. We further show that treatment of diabetic ( i.e., db/db) mice with Neu3i for 28 days reduced aortic pulse wave velocity, with no change in blood pressure, when compared to vehicle-treated mice. Neu3i also reduced the stiffness of aortic explants, as assessed via atomic force microscopy. Excised arteries were also assessed for flow-mediated dilation and vascular stiffness using pressure myography. Diabetic mice treated with Neu3i had increased flow-mediated dilation and reduced incremental modulus of elasticity, indicative of improved endothelial function and reduced arterial stiffness. Collectively, these data support the hypothesis that Neu3 is a potential therapeutic target for the amelioration of vascular dysfunction in T2D. National Institutes of Health grant: R01HL153264 to LM-L and JP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Partially Differentiated Ileal and Rectal Human CFTR-F508del Enteroids Secrete Fluid in Response to cAMP and cGMP: Targeted Preclinical Studies of Pharmaco-Therapy of CF Constipation

Introduction: Treatment of Cystic Fibrosis (CF) patients with Trikafta is prolonging life. This has allowed the importance of other causes of morbidity in these patients to become clearer and to emphasize the need to improve their quality of life by developing additional treatments. Chronic constipation is one such continuing unsolved medical issue for patients with CF even on Trikafta. In general, approaches to treat chronic constipation include increasing intestinal fluid secretion that involves inhibiting intestinal NaCl absorption and/or stimulating intestinal Cl secretion, with inhibition of the latter being the primary defect in CF. Drug development efforts have mostly aimed to improve CFTR function and control pancreatic insuffciency. We have recently reported an enterocyte population in the human ileal and colon that is present between the crypt Cl− secretory cells and the mature small intestinal villus or colonic surface Na+ absorptive cells that contain both DRA and CFTR. This population is called partially differentiated enterocytes. This study was undertaken to derive a strategy to stimulate intestinal fluid secretion from partially differentiated enterocytes in the F508del-CF-patient population by enhancing residual CFTR F508del activity using drugs that stimulate cAMP and cGMP. Methods: Ileal and rectal enteroids from F508del CF patients and healthy subjects (HS/normal) were studied. Enteroids were maintained in growth media containing Wnt3A, R-spondin, and Noggin (undifferentiated/UD); induced to partially differentiate (3d-DF) or fully differentiate (6d-DF) by removal of growth factors (Wnt3A and R-spondin) for 3 or 6 days, respectively. Forskolin-induced swelling (FIS) assay and live cell microscopy were used to determine fluid secretion in enteroids. A relative increase in organoid surface area over a time series of 60 min was measured to quantify FIS response. mRNA expression was determined using qRT-PCR. Results: Compared to HS enteroids, F508del enteroids had significantly higher mRNA expression of LGR5, and Ki67 in the UD state. Expression of goblet cell marker MUC2 and enteroendocrine (EEC) marker ChgA increased with differentiation in both HS and F508del, while 6d-DF F508del enteroids had a significantly higher ChgA compared to 6d-DF enteroids from HS. UD F508del enteroids had significantly higher expression of phosphodiesterase-3a (PDE3a) than HS enteroids, which further increased with differentiation, but did not change in HS. While UD and 6d-DF F508del rectal and ileal enteroids did not swell when exposed to cAMP (forskolin) and cGMP (linaclotide), 3d-DF F508del enteroids showed a swelling response when exposed to cAMP (forskolin) and cGMP (linaclotide). Fluid secretion from 3d-DF F508del enteroids was ~50% (cAMP) and ~67% (cGMP) of the response of intestinal enteroids from HS enteroids. Combinations of CFTR correctors and potentiators mimicking the makeup of Trikafta only partially enhanced fluid secretion in F508del CF enteroids as compared to HS. However, cGMP (linaclotide) additively enhanced Trikafta-induced fluid secretion from 3d-DF F508del enteroids. Conclusions: CFTR F508del can be stimulated by cAMP and cGMP in partially differentiated enterocyte populations. Our findings identify a novel role of the partially differentiated ileal and rectal enterocyte populations which behave in a way that offers the potential to improve treatment for CF constipation. Funding: This study is partly supported by Cystic Fibrosis Foundation grant CF-SINGH20G0, National Institutes of Health grants R01-DK-116352 and P30-DK-89502 (the Hopkins Basic and Translational Research Digestive Diseases Research Core Center). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of Renal Medullary Bilirubin and Biliverdin Reductase in Ang II Induced Hypertension

Previous studies have demonstrated the importance of renal medullary heme oxygenase-1 (HO-1) in blood pressure response to angiotensin II. However, the role of the HO metabolite, bilirubin, in this response remains unknown. The goal of the present study was to test the hypothesis that generation of bilirubin in the renal medulla plays an important role in the regulation of blood pressure in response to angiotensin II. Twenty-week-old male C57Bl/6J mice were implanted with intrarenal medullary interstitial (IRMI) catheters following unilateral nephrectomy. After this time, biliverdin IXα was specifically infused into the kidney (3.6 mg/day) for 3 days prior to implantation with an osmotic minipump delivering angiotensin II (1000 ng/kg/min). Blood pressure was recorded for 3 days, 1 week after minipump infusion, in conscious mice. IRMI infusion of biliverdin significantly decreased blood pressure as compared to mice infused with vehicle (118 ± 4 vs. 158 ± 2 mmHg, p&lt;0.05). To further explore the antihypertensive role of renal medullary bilirubin generation, mice with specific deletion of biliverdin reductase-A (BVRA) in the thick ascending loop of Henle (TALH) were generated by crossing BVRAflox/flox mice with Tamm-Horsfall Cre (THP-Cre) mice. THP-Cre/BVRAflox/flox mice exhibited specific deletion of BVRA in the TALH by co-immunostaining with endogenous THP protein. THP-Cre/BVRAflox/flox mice did not exhibit any differences in baseline blood pressure as compared to BVRAflox/flox mice (108 ± 2 vs. 108 ± 2 mmHg). However, angiotensin-II infusion resulted in significantly higher blood pressure measured in conscious mice 7 days after implantation in THP-Cre/BVRAflox/flox as compared to BVRAflox/flox mice (152 ± 2 vs. 140 ± 3 mmHg, p&lt;0.05). These results demonstrate an important role for renal medullary bilirubin and biliverdin reductase in the blood pressure response to angiotensin II. Strategies which increase renal medullary bilirubin/biliverdin reductase levels could be novel antihypertensive therapies. Future studies will examine the mechanistic link between bilirubin and electrolyte transporters in the kidney, specifically, the Na+-K+-2Cl2 cotransporter (NKCC2), which is a major transporter of electrolyte in the thick ascending limb and is known to play a role in Ang II-induced hypertension. This work was supported by National Institutes of Health grants (RO1-HL088421 to DS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice

Increased circulating levels of the soluble prorenin receptor (sPRR), a component of the renin angiotensin system (RAS), plays a role in obesity, glucose, and insulin balance. Additionally, studies show that elevated plasma sPRR in diabetic patients is correlated with hyperglycemia in women but not men. Hence, the current study sought to understand the functional role of circulating human sPRR (HsPRR) produced by the adipose tissue (Adi) on adipogenesis and obesity, glucose homeostasis and insulin sensitivity. Adi-HsPRR mice were generated by breeding human sPRR-Myc-tag transgenic mice with mice expressing Adiponectin/Cre. The mouse model was validated by detecting myc-tagged HsPRR in western blot at 28kD. Adi-HsPRR male and female mice were kept on a low-fat (10% kcal from fat; n=4-9/group) or high-fat diet (60% kcal from fat; n=8-13/group) for 20 weeks. Body weight was recorded weekly and body composition (EchoMRI) was assessed monthly. Intraperitoneal glucose tolerance test (ipGTT) was performed at 12 weeks and insulin tolerance test (ITT) at 14 weeks. At 16 weeks, mice were implanted with radio telemeter to measure blood for 5 consecutive days. At the end of the study, tissues and plasma were collected for biochemical analysis and vascular studies. Adipose HsPRR expression did not change circulating sPRR between groups in mice fed a low-fat diet mouse (M: 3.5±0.5 vs 3.9±0.2 ng/ml, F: 2.3±0.2 vs 3.0±0.2 ng/ml) and high fat-fed females (4.3±0.3 vs 5.4±0.5 ng/ml) but increased plasma sPRR in HFD Adi-HsPRR male mice compared to HFD CTL (5.3±0.4 vs 8.7±0.7 ng/ml p&lt;0.05). Yet, Adi-HsPRR expression did not change body weight and composition, glucose, and insulin balance, nor blood pressure and vascular function in male mice regardless the diet. However, Adi-HsPRR improved insulin sensitivity (438±22 vs 360±14 AUC p&lt;0.05) and endothelium-dependent vascular relaxation (11.7±2.6 vs 19.4±2.5 % p&lt;0.05) in Adi-HsPRR female mice fed an HFD. Blood pressure was similar between groups in males and females on both LFD and HFD. Further analysis showed that Adi-HsPRR increased vasodilator agent, Ang 1-7 (5.1±1.6 vs 16.2±3.0 pmol/L p&lt;0.05) in HFD females which was unchanged in HFD males (10.2±2.4 vs 5.2±1.7 pmol/L). Moreover, Adi-HsPRR reduced gene expression of SREBP1C (1.3±0.2 vs 0.7±0.1 2−ΔΔCT p&lt;0.05) and CD36 (1.5±0.3 vs 0.6±0.1 2−ΔΔCT p&lt;0.05), in gonadal white adipose of HFD females but not in males. Additionally, PPAR gamma mRNA was reduced in HFD Adi-HsPRR females (1.1±0.1 vs 0.6±0.1 2−ΔΔCT p&lt;0.05). Our findings suggest that HsPRR in adipose tissue exerts sex-specific protective effects on insulin sensitivity and endothelial function during obesity, despite similar plasma sPRR levels between control and Adi-HsPRR mice. Thus, our model could be a useful tool to investigate potential antidiabetic effect of adipose sPRR in obese women. This work was supported by National Institutes of Health grants (R01-HL-142969 and R01-HL-1647 to ASL); the National Institute of General Medical Sciences (P30 GM127211); and the University of Kentucky, Center for Clinical and Translational Sciences (UL1TR001998). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Single-Nuclei RNA-Sequencing Uncovers Alterations in the Transcriptional Profile of Skeletal Muscle in Peripheral Artery Disease

BACKGROUND: Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic occlusion of lower limb blood vessels, impacting &gt;200 million people worldwide. PAD causes life-altering symptomatology such as claudication, ischemic rest pain, and gangrene, with limited effective treatment options. Herein, we performed single-nuclei RNA-sequencing (snRNAseq) to facilitate a better understanding of the complex pathobiological environment within the PAD limb and intercellular communication. METHODS: Gastrocnemius muscle specimens were collected from 20 patients with PAD and 12 non-PAD controls. Patients with PAD were classified as Rutherford category 3 (severe claudication). Non-PAD participants were of similar age, body mass index and medication usage as patients with PAD. Nuclei were isolated and snRNAseq was performed. Bioinformatic analysis was conducted to determine differences in gene expression between PAD and non-PAD nuclei, as well as analysis of intercellular signaling networks. Histological analysis of muscle specimens assessed the following: myosin heavy chain fiber distributions, myofiber cross-sectional area and myofiber denervation. RESULTS: 57,364 high-quality nuclei were captured (21,417 PAD; 35,947 non-PAD) and unsupervised clustering revealed 12 distinct nuclei populations based on their transcriptional profile. Quantification of the relative abundance of nuclei populations identified several differences, including PAD muscles having a lower percentage of type I myonuclei, muscle stem cells, and endothelial cells but a higher proportion of type II and regenerating myonuclei. Differentially expressed gene analysis of myonuclei populations uncovered upregulation of genes involved in stress response, autophagy, and atrophy in patients with PAD. Ligand-receptor interactions were used to determine how PAD alters the communication between identified nuclei populations. The inferred strength of interactions was greater in non-PAD compared to PAD patients. Further, intercellular communication network analysis revealed fibro-adipogenic progenitors as a primary signaling hub in PAD muscle. CONCLUSION: snRNAseq uncovered novel transcriptional differences and intercellular communication pathways unique to PAD muscle. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T. Ryan). K. Kim supported by the American Heart Association grant POST903198. T. Thome supported by NIH grant F31-DK128920. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AI-Powered Web Applications for Enhanced Clinical, Research, and Professional Development

Introduction: The rapid growth of technology in the field of anesthesiology offers unique opportunities to leverage artificial intelligence (AI) for enhancing clinical, research, and administrative operations. Our team, consisting of anesthesiologists and data scientists, sought to develop a suite of web applications using generative AI to address specific challenges faced by anesthesiology departments. Objective: To design, develop, and evaluate the feasibility of a range of AI-powered web applications tailored for anesthesiologists to streamline research feasibility, literature searches, protocol drafting, text simplification, work promotion, grant writing, professional advancement, and secure communication. AI Tools developed: Data Feasibility Analysis: AI-assisted search of descriptions and schemas of multiple data warehouses to assess the feasibility of various clinical and research ideas. AI-Powered PubMed Search: AI-assisted search to effciently navigate and extract relevant publications from PubMed, including summarizing the literature found. IRB Protocol Generation: Automated drafting process for Institutional Review Board (IRB) protocol forms, ensuring adherence to regulatory standards. Text Simplification: Tool to distill complex clinical, research, or regulatory text to an 8th-grade reading level, enhancing accessibility — e.g., for patient consent forms. Work Promotion and Amplification: drafts blog posts, “tweets,” and layperson summaries of research abstracts. NIH Grant Drafting: Drafts Specific Aims page and Research Strategy sections for National Institutes of Health (NIH) style applications, ensuring compliance and coherence. Professional Advancement Assistance: Drafts Promotion &amp; Tenure portfolios and letters of recommendations Secure AI Conversations: Integrated generative AI technology in an encrypted and secured platform, safeguarding sensitive information. Conclusions: The suite of AI-powered web applications, developed in collaboration between anesthesiologists and data scientists, showcases potential in enhancing the effciency and impact of various processes integral to anesthesiology research. The integration of these tools into daily operations can potentially revolutionize how anesthesiologists engage with research, patient care, professional development, and communication. Future endeavors will focus on rigorous validation and widespread deployment to harness the full potential of these innovations. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Loss of FAM210A in Satellite Cell Drives Mitochondrial Dysfunction and Muscle Weakness in Experimental Peripheral Artery Disease

Introduction: Peripheral artery disease (PAD) affects approximately 200 million people globally. Chronic limb-threatening ischemia (CLTI) represents the most advanced clinical phenotype of PAD. Mitochondrial metabolism defects are apparent in the satellite cells of CLTI patients, and the muscle regeneration process demands increased energy, with satellite cell mitochondrial metabolism and dynamics playing a crucial role. However, our current understanding of the role of satellite cells and muscle regeneration in PAD pathology is notably inadequate. Recent studies have shown that the absence of FAM210A, a newly identified mitochondrial protein, can trigger morphological and energetic abnormalities in mitochondria, resulting in muscle function deterioration and promoting muscle wasting. Given the impaired mitochondrial function in satellite cells in CLTI patients and the heightened energy demand regulated by mitochondrial dynamics during muscle regeneration in satellite cell, it is therefore essential to exploring the role of FAM210A in satellite cells in CLTI limb pathology. The objective of this study was to investigate the impact of the loss of FAM210A in satellite cells in mice with experimental PAD. Methods: Male and female conditional FAM210A satellite cell knock out (FAM210ASCKO) and FAM210A floxed (FAM210Afl/fl) mice (N=3-5) were used for this project. Femoral artery ligation surgery was performed to induce PAD. Tamoxifen was administered for 5 days intraperitoneally one week prior to the surgery. Mice were euthanized twenty-eight days after surgery. Outcome measures included limb perfusion assessment, muscle weight, muscle force production, and mitochondrial respiration. Results: FAM210ASCKO mice had significantly decreased muscle mass of the tibialis anterior and extensor digitorum longus ( p&lt;0.0001 and p=0.0004 respectively). More importantly, maximal muscle force with in-situ contraction in tibialis anterior was significantly lower in FAM210ASCKO mice compared to FAM210Afl/fl mice (FAM210Afl/fl mice: 1085.16 ± 331.08 mN; FAM210ASCKO mice: 430.77 ± 467.91 mN; p=0.0139). Furthermore, analysis of mitochondrial oxidative phosphorylation (OXPHOS) revealed that FAM210ASCKO mice had a significant reduction compared to FAM210Afl/fl mice (48%) in skeletal muscle mitochondrial bioenergetic function at various levels of energy demand mimicking from resting to maximal exercise when carbohydrate was used to energize mitochondria ( p=0.034). Importantly, the analysis of mitochondrial membrane potential consistently reveals a substantial reduction in FAM210ASCKO mice compared to FAM210Afl/fl mice, which can partially explain the diminished mitochondrial bioenergetic function observed in ischemic FAM210ASCKO mice. Conclusion: The results of this study indicate that the loss of FAM210A in satellite cells exacerbates ischemic muscle pathology evidenced by muscle weakness and mitochondrial failure in FAM210ASCKO mice with PAD. Future work is needed to elucidate the mechanisms by which FAM210A regulate ischemic satellite cell function and the therapeutic potential of preventing ischemia-induced loss of FAM210A in PAD. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (to Dr Ryan). Mr Thome was supported by NIH grant F31-DK128920. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of Sociogenomics on Chronic Wounds

Background and Objective: &#x0D; Chronic wounds affect almost 2.5% of the United States population. Along with substantial healthcare costs, other factors like reduced employment opportunities and social isolation further complicate the patient’s quality of life. Socioeconomic status (SES) has been shown to influence gene expression that can increase susceptibility and deterioration of chronic wounds. Our study looks to identify genes that have been impacted by SES in chronic wound patients. Exploring this association can enhance understanding of the relationship between SES and chronic wound outcomes. &#x0D; Experimental Design: &#x0D; A cohort of 72 chronic wound patients were recruited. Patient demographics and socioeconomic backgrounds were collected. Blood DNA isolation was performed and allotted for genetic analysis by Axiom™ Precision Medicine Diversity Array (PMDA). DNA genotyping data was obtained, and single nucleotide polymorphisms (SNP) markers pertaining to wound healing were studied. P &lt; 0.05 were used to designate significant SNP marker mutations in the cohort. &#x0D; Results: &#x0D; To add strength to our project, we have chosen to further study the results obtained by our group (https://doi.org/10.18060/27205), which has previously found significant SNPs associations of the vitamin D receptor (VDR) and the methylenetetrahydrofolate reductase (MTHFR) genes in chronic wound patients. Using PMDA, our analysis showed polymorphisms in CYP24A1 (p = 0.0072), a gene involved in vitamin D metabolism, and MTHFR (p = 0.00625), a gene involved in folate and homocysteine metabolism. Modifications of these genes have been associated with pathogenesis to impaired wound healing. &#x0D; Conclusion: &#x0D; There is a need for further investigation into health outcomes and their association with SES. Our study aims to address the knowledge gap in this field by focusing on chronic wound healing in relation to socioeconomic status. With our results, we hope to emphasize the importance of sociogenomics, and how it can be utilized to advocate for improved patient outcomes across all socioeconomic backgrounds. &#x0D; &#x0D; Acknowledgements: &#x0D; This project was funded, in part, with support from the Indiana Clinical and Translational Sciences Institute funded, in part by UL1TR002529 from the National Institutes of Health (NIH). The presented work is also supported by NIH grants R01DK135447 and R01DK128845 to CKS. The laboratory of KS is supported by DoD grant W81XWH-22-1-0146. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding for Refugee Health Research From the National Institutes of Health Between 2000 and 2020

The US has historically resettled more refugees than any other country, with over 3.5 million refugees since 1980. The National Institutes of Health (NIH) is the largest public funder of biomedical research and development, but its role in mitigating many health disparities refugees experience through its funded research remains unknown. To examine the NIH's research funding patterns on refugee health research over the last 2 decades. Secondary analysis of NIH-funded grants between 2000 and 2020 using a cross-sectional study design. The NIH Research Portfolio Online Reporting Tools database was used to find relevant grants. Data were analyzed from November 2021 to September 2022. NIH grants awarded by year, state, grant type, research area, funding institute, grant duration, and amount funded. Of 1.7 million NIH grants funded over the 20-year study period, only 78 addressed refugee health. Funded grants were mostly training grants (23 grants [29%]), followed by hypothesis-driven research (R01 grants; 22 grants [28%]), pilot or preliminary investigation proposals (13 grants [17%]), and other types of grants (20 grants [26%]). The most studied research domain was mental health (36 grants [46%]), followed by refugee family dynamics and women's and children's health (14 grants [18%]). A total of 26 grants (33%) were funded by the National Institute of Mental Health and 15 (19%) were funded by the National Institute of Child Health and Human Development. Most grants were US-based (60 grants [76%]) and the state of Massachusetts received the greatest amount of funding ($14 825 852 [18%]). In 2020, the NIH allocated about $2.3 million to refugee health research, or less than 0.01% of its $42 billion budget that year. The number of grants funded in each time period did not always reflect changes in the number of refugees resettled in the US over the years. This cross-sectional study found that there remain significant gaps in the understanding of and interventions in the health research needs of refugees locally and along the migratory route. To close these gaps, the NIH should increase its investments in comprehensive studies assessing the physical, mental, and social well-being of this expanding population. This can be achieved by ensuring that all NIH institutes allocate budgets specifically for refugee health research and extend support for the training of refugee researchers.

Impact of vaccination and high-risk group awareness on the mpox epidemic in the United States, 2022–2023: a modelling study

The unprecedented global outbreak of mpox in 2022 posed a public health challenge. In addition to the mpox vaccine campaign in the United States (US), community organisations and public health agencies initiated educational efforts to promote sexual risk reduction. This modelling study estimated the impact of the two-dose vaccination campaign and sexual behaviour changes coincident with high-risk group awareness on the mpox epidemic in the US. We fitted a deterministic, risk-structured SEIARV model to the epidemic curve of reported mpox cases in the US between May 22, 2022 and December 22, 2022. We evaluated the putative effects of the two preventive responses in the US -- vaccination and sexual risk reduction -- at the population-level, by calculating the prevention percentages of cumulative cases compared to the counterfactual scenario without interventions. We performed sensitivity analyses with four parameters: case reporting fidelity, vaccine effectiveness, proportion of asymptomatic cases, and assortative mixing. Model fitting revealed a basic reproduction number of 3.88 and 0.39 for the high-risk and low-risk populations, respectively, with 71.8% of mpox cases estimated from the high-risk population. A two-dose vaccination campaign, solely, could prevent 21.2% (10.2%-24.1%) of cases, while behaviour changes due to high-risk group awareness alone could prevent 15.4% (14.3%-20.6%). The combination of both measures were synergistic, with the model suggesting that 64.0% (43.8%-69.0%) of US cases were averted that would have otherwise occurred. Our models suggest that the 2022-2023 mpox epidemic in the US was controlled by a combination of two-dose mpox vaccination campaign and high-risk group awareness and sexual risk reduction. Taiwan Ministry of Education grant #NTU-112L9004, Taiwan National Science and Technology Council grant #MOST-109-2314-B-002-147-MY3 and grant #NSC-112-2314-B-002-216-MY3. SHV was supported, in part, by US National Institutes of Health grant #P30MH062294.

THE ROLE OF MECHANOSENSORY NEURONS IN MUSCULOSKELETAL DISEASES

Distal arthrogryposis (DA) is a collection of rare developmental disorders characterized by congenital joint contractures. Most arthrogryposis mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal tissues. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Surprisingly, overactive PIEZO2 is likely to cause joint abnormalities via increased exocytosis from sensory neuron endings without involving motor circuitry. This reveals a role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development. We also present proof-of-concept that Botox injection or dietary treatment can counteract the effect of overactive PIEZO2 function to evade DA-like phenotypes in mice when applied during a developmental critical period. These approaches might have clinical applications. Beyond this, our findings call attention to the importance of considering sensory mechanotransduction when diagnosing and treating other musculoskeletal disorders.Acknowledgements: Our work is supported by National Institutes of Health grant (R35 NS105067, R01 DE022358, R25 SC3GM127195, R25 GM07138, R01GM133845, intramural) and Howard Hughes Medical Institute.

Number of completed exercise sessions is associated with slower brain atrophy in MCI over 12 months in the EXERT trial

AbstractBackgroundMid‐ and late‐life exercise has been associated with lower dementia risk. The EXERT trial tested whether aerobic training (AX), compared to stretching/balance/range‐of‐motion training (SBR), could slow cognitive decline in MCI. While no difference was detected between exercise arms, EXERT participants overall showed little cognitive change over 12 months. It is possible that the amount of exercise, rather than the type, may be protective against decline. In this exploratory, post‐hoc analysis of EXERT data, we assessed whether intervention adherence, operationalized as the number of supervised exercise sessions completed, was associated with slower brain atrophy over 12 months.Method194 EXERT participants with baseline and follow‐up MRI were included in this analysis. For each participant, the number of supervised exercise sessions of at least 40 minutes in duration completed during the first 12 months was determined. MRI data were processed using FreeSurfer. Repeated measures ANOVAs were conducted using regional volume or thickness as the dependent variable, and the interaction between number of sessions (continuous scale) and study visit as the independent variable. Baseline age and sex, as well as their interactions with time were included in the model. FDR‐adjusted p‐values &lt;0.05 were considered significant.ResultGreater number of sessions completed was associated with less brain atrophy over 12 months in the hippocampus and parahippocampus, and less ventricular expansion in the lateral and inferior lateral ventricles (Table 1, Figure 1; FDR‐corrected p&lt;0.05 for interaction term). Results remained unchanged when including exercise type (AX vs. SBR), baseline CDR‐SB, or baseline plasma Aβ42/40 in the model. Findings were similar when analyses were restricted to participants who completed the study prior to the onset of the COVID‐19 pandemic.ConclusionOur results show that higher adherence to a supervised exercise intervention over 12 months was associated with reduced brain atrophy in adults with amnestic MCI. These findings were obtained in post‐hoc, exploratory analyses, so causality should be interpreted with caution. EXERT was supported by the Alzheimer’s Disease Cooperative Study and funded by the National Institutes of Health grant U19‐AG010483.

A 10 Year Analysis of Gender Distribution in National Institutes of Health Funding for Non-Malignant Hematology

Introduction: Historically, there has been an underrepresentation of women in the field of hematology. Consequently, this makes them less likely to receive academic research grants. Here, we present a ten year retrospective analysis of the Research Project Grants (R01) awarded by the National Institutes of Health (NIH) through the fiscal years of 2012-2022. The grants were categorized by various NIH agencies. This temporal analysis examines gender disparities under the field of non-malignant hematology research. Methods:Data was extracted for the fiscal years 2012-2022 focusing exclusively on R01 grants awarded and categorized by the various NIH agencies. Data was leveraged using the NIH RePORTER tool, Tidyverse, and janitor packages in R. The dataset incorporated key grant parameters such as grant ID, agency code, activity code, abstract text, project title, fiscal year, activity status, award amount, organization, and principal investigator's(PI) name. In order to distinguish a PI's gender, PI's first names were processed using the gender package in R, which provided a gender-wise distribution of recipients. For statistical analyses, proportions of females with accepted R01 grants were compared between 2012 to 2022; this proportion analysis was also done among each NIH agency. Further, linear regression and associated statistical tests were used to identify whether there was significant change in grants received by either gender over this time period. Results: A total of 250,031 R01 grants were awarded by the NIH during the fiscal years of 2012 to 2022. Females (n=82,152: 32.9% (95% CI 0.41-0.43) received fewer grants than males (n=167,879: 67.1%, (95% CI 0.50-0.55). Across 2012 to 2022, there was no significant change in R01 grants awarded among men (16,221 to 15,601, p-value= 0.52). In contrast, there was a significant difference for females in the R01 grants awarded across 2012 to 2022 (6,865 to 9,339, p-value &amp;lt;0.001). In 2012, the National Institute of General Medical Sciences (NIGMS), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB) awarded less than 25% of the total grants to females. By 2022, of all the agencies, the NBIB remained the agency with the most extensive gender gap with females being awarded only 23% of grants. In contrast, the National Institute of Minority Health and Disparities (NIMHD) and the National Institute of Nursing Research (NINR) were the only agencies in 2012 to award more grants to females with approximately 52% and 74% of grants respectively. In 2022, the NINR and NIHMD continued to show more grants awarded to females versus males. In addition to those agencies, by 2022, the National Institute of Child Health and Human Development(NICHD) and National Center for Complementary and Integrative Health (NCCIH) joined the NINR and NIHMD in awarding more than 50% of grants awarded to females that year. Conclusion: This analysis highlights continued gender disparity as only 33% of total R01 NIH grants were awarded to females during the fiscal years 2012-2022 in non-malignant hematologic research. Although, it is noted that while some agencies have made strides towards gender parity, others continue to have a significant gap. While this remains a systemic and multifaceted issue, identifying these areas of gender disparity will enable targeted efforts to bridge this gap and advance gender equality.

Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk

Although per- and polyfluoroalkyl substances (PFAS) exposure is a potential contributor to the increasing thyroid cancer trend, limited studies have investigated the association between PFAS exposure and thyroid cancer in human populations. We therefore investigated associations between plasma PFAS levels and thyroid cancer diagnosis using a nested case-control study of patients with thyroid cancer with plasma samples collected at/before cancer diagnosis. 88 patients with thyroid cancer using diagnosis codes and 88 healthy (non-cancer) controls pair-matched on sex, age (±5 years), race/ethnicity, body mass index, smoking status, and year of sample collection were identified in the BioMe population (a medical record-linked biobank at the Icahn School of Medicine at Mount Sinai in New York); 74 patients had papillary thyroid cancer. Eight plasma PFAS were measured using untargeted analysis with liquid chromatography-high resolution mass spectrometry and suspect screening. Associations between individual PFAS levels and thyroid cancer were evaluated using unconditional logistic regression models to estimate adjusted odds ratios (ORadj) and 95% confidence intervals (CI). There was a 56% increased rate of thyroid cancer diagnosis per doubling of linear perfluorooctanesulfonic acid (n-PFOS) intensity (ORadj, 1.56, 95% CI: 1.17-2.15, P=0.004); results were similar when including patients with papillary thyroid cancer only (ORadj, 1.56, 95% CI: 1.13-2.21, P=0.009). This positive association remained in subset analysis investigating exposure timing including 31 thyroid cancer cases diagnosed ≥1 year after plasma sample collection (ORadj, 2.67, 95% CI: 1.59-4.88, P<0.001). This study reports associations between exposure to PFAS and increased rate of (papillary) thyroid cancer. Thyroid cancer risk from PFAS exposure is a global concern given the prevalence of PFAS exposure. Individual PFAS studied here are a small proportion of the total number of PFAS supporting additional large-scale prospective studies investigating thyroid cancer risk associated with exposure to PFAS chemicals. National Institutes of Health grants and The Andrea and Charles Bronfman Philanthropies.

The national institute on drug abuse diversity scholars network: success for a diverse addiction science workforce.

There is a well-known lack of diversity in many Science, Technology, Engineering, and Mathematics (STEM) fields. The gap in awarded National Institutes of Health (NIH) grants for scientists from underrepresented populations at the early stages of their careers contributes significantly to this lack of diversity. The National Institute on Drug Abuse (NIDA) Diversity Scholars Network (NDSN) program implemented a new model in 2016 to provide support to underrepresented early-career investigators (ECIs) by equipping them to navigate the competitive NIH grant process. NDSN has a demonstrable track record of providing equity through educational opportunities by enhancing the grant funding success of participants. Of 59 participants from 2016 through 2021, 53% received funding within the first two years after completing the program and 69% by four years. NDSN scholars surmount systemic funding barriers by building relationships with scientific coaches, mentors, NIDA Program Officials and intentionally engaging in network building, which all contribute to the funding success of ECIs. NIDA's NDSN program provides a model for retaining underrepresented ECIs that not only benefits individual scholars, but also the institutions they serve and society as a whole.

Orthopedic surgeon-scientist representation is low among National Institutes of Health grants for rotator cuff research

The purpose of this study is to characterize National Institutes of Health (NIH) funding for rotator cuff research and evaluate the impact of orthopedic surgeons on this portfolio. The NIH's Research Portfolio Online Reporting Tools Expenditures and Results database was queried for "rotator cuff repair" or "rotator cuff tear" from the 2011 to 2021 fiscal years. Compound annual growth rates were calculated and grants were categorized by basic, clinical, or translational research. Funding totals were compared by Principal Investigator (PI) and grant characteristics. A total of 52 grants were awarded to 38 PIs between 2011 and 2021, totaling $40,156,859. Annual NIH funding for rotator cuff tear and rotator cuff repair increased by a Compound annual growth rate of 11.0% from 2011 to 2021, compared to 3.4% for the total NIH budget. Orthopedic surgeon-scientists received $9,208,212 (22.9%), most commonly through R01 (80.5%) and K08 (7.1%) mechanisms. No significant difference in funding was found by PI sex (P=.332), degree (P=.460), academic rank (P=.118), or researcher type (P=.227). Professors had a higher h-index than associate and assistant professors (P=.001). Orthopedic surgeon-scientists had a higher h-index (mean 36.3±9.4) compared to clinician-scientists (mean 8.0±1.4) and research-scientists (35.5±40.7) (P=.044). Clinical topics receiving the highest funding were rehabilitation (23.9%), diagnosis, (22.3%) and surgical technique (14.8%). Orthopedic surgeon-scientists acquired funding for diagnosis (57.1%), rehabilitation (17.0%), and surgical technique (14.5%). While NIH funding for rotator cuff research is growing, orthopedic surgeon representation is low. Future studies should evaluate barriers to obtaining funding for orthopedic surgeon-scientists.

Academic productivity and NIH funding for anesthesiology departmental chairs: A 15-year comparison

Study objectiveThis study evaluated whether there were improvements in the number of departmental National Institutes of Health (NIH) training grants and the academic productivity of departmental chairs in terms of NIH research funding and PubMed-cited publications when compared to chairs of the same departments in 2006. DesignEach chair was identified from the Society of Academic Associations of Academic Anesthesiology & Perioperative Medicine's Association of Academic Anesthesiology Chairs and entered into the NIH Research Portfolio Online Reporting Tools (RePORTER), PubMed, SCOPUS, and the National Provider Identifier Registry. MeasurementsThe number and funding amounts of training grants awarded to the department in 2010, 2015, and 2020 were obtained as well as the department's national ranking and total dollar amount for NIH funding in 2020. For the current chair cohort, total publications and m-quotient (h-index corrected for active research years) were recorded along with each chair's history of NIH grant funding. These data were compared to a previous study of anesthesiology chairs that reviewed funding and publications through 2006. Main resultsWe analyzed data from 100 academic departments of anesthesiology and compared their scholarly activity relative to data gathered in 2006. In 2020, 52 of 100 departments of anesthesiology had evidence of NIH funding. There were not statistically significant (P > 0.05) differences in grants funding obtained by chairs between 2006 and 2020 with the exception that more chairs in 2006 had program or center grants. Median publications for chairs significantly increased from 35 in 2006 to 55 in 2021 (IRR = 1.5, 95% CI = 1.2–2.0, P = 0.003). Nineteen percent of chairs were female, which did not significantly differ from the proportion of women in the 2006 paper (15%, χ2 = 0.57, df = 1, P = 0.452). Of the male chairs, 90% were professors whereas 63% of female chairs were professors (χ2 = 8.8, df = 1, P = 0.003). Female chairs had fewer publications than male chairs (IRR = 1.8, 95% CI = 1.2–1.8, P = 0.002); however, m-quotients were not significantly different between men and women (P = 0.602). ConclusionsWhen compared to 2006, department of anesthesiology chairs had more publications in 2021; however, NIH funding rates remained unchanged. The specialty had 19% female chairs, and those chairs had fewer publications than their male counterparts, though sex differences were attenuated using metrics that account for disparities in career length.