Primary care diabetes assessment when HbA1c and other measures of glycemia disagree.

AIMS: Although diabetes management decisions in primary care are typically based largely on HbA1c, mismatches between HbA1c and other measures of glycemia that are increasingly more available present challenges to optimal management. This study aimed to assess a systematic approach to identify the frequency of mismatches of potential clinical significance amongst various measures of glycemia in a primary care setting. METHODS: Following screening to exclude conditions known to affect HbA1c interpretation, HbA1c, and fructosamine were obtained and repeated after ∼90 days on 53 adults with prediabetes or type 2 diabetes. A subset of 13 participants with repeat labs wore continuous glucose monitoring (CGM) for 10 days. RESULTS: As expected, HbA1c and fructosamine only modestly correlated (initial R2 = 0.768/repeat R2 = 0.655). The HbA1c/fructosamine mismatch frequency of ± 0.5% (using the following regression HbA1c = 0.015 *fructosamine + 2.994 calculated from the initial sample) was 27.0%. Of the 13 participants with CGM data, HbA1c and CGM-based Glucose Management Indicator correlated at R2 = 0.786 with a mismatch frequency of ± 0.5% at 46.2% compared to a HbA1c/fructosamine mismatch frequency of ± 0.5% at 30.8%. CONCLUSIONS: HbA1c is frequently mismatched with fructosamine and CGM data. As each of the measures has strengths and weaknesses, the utilization of multiple different measures of glycemia may be informative for diabetes assessment in the clinical setting.

Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells.

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry TSC1/TSC2 mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy. Although the genetic basis of LAM is known, mechanisms underlying LAM pathogenesis remain elusive. We integrated single-cell RNA sequencing and single-nuclei ATAC-seq of LAM lungs to construct a gene regulatory network controlling the transcriptional program of LAM cells. We identified activation of uterine-specific HOX-PBX transcriptional programs in pulmonary LAMCORE cells as regulators of cell survival depending upon HOXD11-PBX1 dimerization. Accordingly, blockage of HOXD11-PBX1 dimerization by HXR9 suppressed LAM cell survival in vitro and in vivo. PBX1 regulated STAT1/3, increased the expression of antiapoptotic genes, and promoted LAM cell survival in vitro. The HOX-PBX gene network provides promising targets for treatment of LAM/TSC mTORC1-hyperactive cancers.

Research Initiative Supporting Excellence at the University of Cincinnati (RISE-UC): A Program to Develop and Support Research-Active Faculty Members.

A combination of forces have markedly increased challenges to research-active faculty achieving sustained success. This article describes how one department at the University of Cincinnati College of Medicine (UCCOM) implemented a strategic plan, the Research Initiative Supporting Excellence at the University of Cincinnati (RISE-UC), to promote the research activity of its research-active faculty, fiscal year (FY) 2011-FY 2021. RISE-UC was implemented and regularly updated to address evolving needs. RISE-UC supported faculty members pursuing research via fiscal and administrative services to grow a critical mass of investigators; establish a shared governance model; create pathways for developing physician-scientists; develop discrete and targeted internal research funding; establish an Academic Research Service (ARS) unit (as infrastructure to support research); enhance faculty member mentorship; and recognize, celebrate, and reward research success. RISE-UC was informed by shared governance and resulted in substantial increases in total size of the faculty and external funding. More than 50% of Physician-Scientist Training Program graduates are active researchers at UCCOM. The internal awards program realized a return on investment of ~16.4-fold, and total external direct cost research funds increased from ~$55,400,000 (FY 2015) to ~$114,500,000 (FY 2021). The ARS assisted in the submission of 57 grant proposals and provided services faculty members generally found very helpful or helpful. The peer-mentoring group for early-career faculty members resulted in 12 of 23 participants receiving major grant funding (≥ $100,000; spring 2017-spring 2021) from sources including National Institutes of Health awards, Department of Defense funding, Veterans Affairs funding, and foundation awards. Research recognition included ~$77,000/year in incentive payments to faculty members for grant submissions and grants awarded. RISE-UC is an example of a comprehensive approach to promote research faculty member success and may serve as a model for other institutions with similar aspirations.

Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell-derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2+/- mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1-hyperactive neoplasms, including TSC and LAM.

Head Impact Exposure in Youth and Collegiate American Football.

The relationship between head impact and subsequent brain injury for American football players is not well-defined, especially for youth. The objective of this study is to quantify and assess Head Impact Exposure (HIE) metrics among youth and collegiate football players. This multi-season study enrolled 639 unique athletes (354 collegiate; 285 youth, ages 9-14), recording 476,209 head impacts (367,337 collegiate; 108,872 youth) over 971 sessions (480 collegiate; 491 youth). Youth players experienced 43 and 65% fewer impacts per competition and practice, respectively, and lower impact magnitudes compared to collegiate players (95th percentile peak linear acceleration (PLA, g) competition: 45.6 vs 61.9; 95th percentile PLA practice: 42.6 vs 58.8; 95th percentile peak rotational acceleration (PRA, rad·s-2) competition: 2262 vs 4422; 95th percentile PRA practice: 2081 vs 4052; 95th percentile HITsp competition: 25.4 vs 32.8; 95th percentile HITsp practice: 23.9 vs 30.2). Impacts during competition were more frequent and of greater magnitude than during practice at both levels. Quantified comparisons of head impact frequency and magnitude between youth and collegiate athletes reveal HIE differences as a function of age, and expanded insight better informs the development of age-appropriate guidelines for helmet design, prevention measures, standardized testing, brain injury diagnosis, and recovery management.

SI-MOIRAI: a new method to identify and quantify the metabolic fate of nucleotides.

Since the discovery of nucleotides over 100 years ago, extensive studies have revealed the importance of nucleotides for homeostasis, health and disease. However, there remains no established method to investigate quantitatively and accurately intact nucleotide incorporation into RNA and DNA. Herein, we report a new method, Stable-Isotope Measure Of Influxed Ribonucleic Acid Index (SI-MOIRAI), for the identification and quantification of the metabolic fate of ribonucleotides and their precursors. SI-MOIRAI, named after Greek goddesses of fate, combines a stable isotope-labelling flux assay with mass spectrometry to enable quantification of the newly synthesized ribonucleotides into r/m/tRNA under a metabolic stationary state. Using glioblastoma (GBM) U87MG cells and a patient-derived xenograft (PDX) GBM mouse model, SI-MOIRAI analyses showed that newly synthesized GTP was particularly and disproportionally highly utilized for rRNA and tRNA synthesis but not for mRNA synthesis in GBM in vitro and in vivo. Furthermore, newly synthesized pyrimidine nucleotides exhibited a significantly lower utilization rate for RNA synthesis than newly synthesized purine nucleotides. The results reveal the existence of discrete pathways and compartmentalization of purine and pyrimidine metabolism designated for RNA synthesis, demonstrating the capacity of SI-MOIRAI to reveal previously unknown aspects of nucleotide biology.

In-Season Concussion Symptom Reporting in Male and Female Collegiate Rugby Athletes.

Symptom inventories are generally only collected after a suspected concussion, but regular in-season monitoring may allude to clinical symptoms associated with repetitive subconcussive impacts and potential undiagnosed concussions. Despite sex-specific differences in symptom presentation and outcome of concussion, no return-to-play protocol takes sex into account. The objective of this study was to monitor a cohort of contact-sport athletes and compare the frequency and severity of in-season concussion-like symptom reporting between sexes. Graded symptom checklists from 144 female and 104 male athlete-seasons were administered weekly to quantify the effect of subconcussive impacts on frequency and severity of in-season symptom reporting. In-season, mean symptom severity score (SSS) (p = 0.026, mean difference of 1.8), mean number of symptoms (p = 0.044, mean difference of 0.9), max SSS (p < 0.001, mean difference of 19.2), and max number of symptoms (p < 0.001, mean difference of 6.8) were higher in the females. The females' survey results showed differences between elevated and concussed SSS (p < 0.005, mean difference of 28.1) and number of symptoms reported (p = 0.001, mean difference of 6.6). The males did not have a difference in SSS (p = 0.97, mean difference of 1.12) nor in number of symptoms (p = 0.35, mean difference of 1.96) from elevated to concussed athletes. Rugby players report concussion-like symptoms in the absence of a diagnosed concussion in-season. Female athletes reported elevated symptom frequencies with greater severities than the males, but both sexes reported considerable levels throughout the season.

Ultraviolet-assisted oiling assessment improves detection of oiled birds experiencing clinical signs of hemolytic anemia after exposure to the Deepwater Horizon oil spill.

While large-scale oil spills can cause acute mortality events in birds, there is increasing evidence that sublethal oil exposure can trigger physiological changes that have implications for individual performance and survival. Therefore, improved methods for identifying small amounts of oil on birds are needed. Because ultraviolet (UV) light can be used to identify thin crude oil films in water and on substrate that are not visually apparent under normal lighting conditions, we hypothesized that UV light could be useful for detecting small amounts of oil present on the plumage of birds. We evaluated black skimmers (Rynchops niger), brown pelicans (Pelecanus occidentalis), clapper rails (Rallus crepitans), great egrets (Ardea alba), and seaside sparrows (Ammodramus maritimus) exposed to areas affected by the Deepwater Horizon oil spill in the Gulf of Mexico as well as from reference areas from 20 June, 2010 to 23 February, 2011. When visually assessed without UV light, 19.6% of birds evaluated from areas affected by the spill were determined to be oiled (previously published data), whereas when examined under UV light, 56.3% of the same birds were determined to have oil exposure. Of 705 individuals examined in areas potentially impacted by the spill, we found that fluorescence under UV light assessment identified 259 oiled birds that appeared to be oil-free on visual exam, supporting its utility as a simple tool for improving detection of modestly oiled birds in the field. Further, UV assessment revealed an increase in qualitative severity of oiling (approximate % of body surface oiled) in 40% of birds compared to what was determined on visual exam. Additionally, black skimmers, brown pelicans, and great egrets exposed to oil as determined using UV light experienced oxidative injury to erythrocytes, had decreased numbers of circulating erythrocytes, and showed evidence of a regenerative hematological response in the form of increased reticulocytes. This evidence of adverse effects was similar to changes identified in birds with oil exposure as determined by visual examination without UV light, and is consistent with hemolytic anemia likely caused by oil exposure. Thus, UV assessment proved useful for enhancing detection of birds exposed to oil, but did not increase detection of birds experiencing clinical signs of anemia compared to standard visual oiling assessment. We conclude that UV light evaluation can help identify oil exposure in many birds that would otherwise be identified visually as unexposed during oil spill events.

Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells.

Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either TSC1 or TSC2 that result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). As LAM occurs predominantly in women during their reproductive age and is exacerbated by pregnancy, the female hormonal environment, and in particular estrogen, is implicated in LAM pathogenesis and progression. However, detailed underlying molecular mechanisms are not well understood. In this study, utilizing human pulmonary LAM specimens and cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we tested the hypothesis that estrogen promotes the growth of mTORC1-hyperactive cells through pyruvate kinase M2 (PKM2). Estrogen increased the phosphorylation of PKM2 at Ser37 and induced the nuclear translocation of phospho-PKM2. The estrogen receptor antagonist Faslodex reversed these effects. Restoration of TSC2 inhibited the phosphorylation of PKM2 in an mTORC1 inhibitor-insensitive manner. Finally, accumulation of phosphorylated PKM2 was evident in pulmonary nodule from LAM patients. Together, our data suggest that female predominance of LAM might be at least in part attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. Targeting metabolic regulators of PKM2 might have therapeutic benefits for women with LAM and other female-specific neoplasms.

The impact of sleeve gastrectomy on renal function in patients with chronic kidney disease varies with severity of renal insufficiency.

BACKGROUND: Although laparoscopic sleeve gastrectomy is known, in general, to improve renal function in patients with obesity and chronic kidney disease (CKD), its effect on estimated glomerular filtration rate (eGFR) stratified by the stage of CKD is less clear. OBJECTIVES: We aimed to evaluate the impact of sleeve gastrectomy on renal function in a stratified cohort of patients with CKD. SETTING: University Hospital. METHODS: We performed a retrospective review of 1932 patients who met National Institutes of Health's guidelines for metabolic surgery and underwent laparoscopic sleeve gastrectomy performed by 1 of 3 surgeons. One hundred sixty-four patients with CKD stages 1 through 4 were identified. RESULTS: Mean follow-up period was 1.57 ± 1.0 years. Mean age was 56.4 ± 9.9 years with a preoperative body mass index of 47 ± 9 kg/m2, which decreased to 38.9 ± 8.7 kg/m2 at most recent follow-up (P < .001). In the cohort of patients with diabetes, significant decreases were observed in mean glycated hemoglobin level, daily number of oral hypoglycemics, and daily long acting insulin use (P < .001 each). Of 67 patients with diabetes, 34.3% (n = 24) achieved complete remission. In patients with hypertension, average daily number of antihypertensives decreased (P < .001) and 22.3% (n = 31) of 133 patients with hypertension discontinued all antihypertensives. Patients with CKD stages 2, 3a, and 3b showed significant improvement in eGFR. Reinforcing this evidence of improvement, patients with CKD 3a and 3b were more likely to downstage disease compared with those with CKD 4 (58.1% versus 73.1% versus 22.7%, respectively) (P < .001). CONCLUSION: Renal function, as measured by eGFR, in patients with stages 1 and 4 CKD did not improve after laparoscopic sleeve gastrectomy; in contrast, eGFR in patients with CKD stages 2 and 3 significantly improved. Early surgical referral and intervention may be important in achieving the greatest improvement in eGFR and possibly delaying or reversing progression to end-stage renal disease.

Long-term outcomes in patients with obesity and renal disease after sleeve gastrectomy.

Morbid obesity is a barrier to kidney transplant in patients with end-stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (SG) is an increasingly considered intervention, but the safety and long-term outcomes are uncertain. We reviewed prospectively collected data on patients with ESRD and chronic kidney disease (CKD) undergoing SG from 2011 to 2018. There were 198 patients with ESRD and 45 patients with CKD (stages 1-4) who met National Institutes of Health guidelines for bariatric surgery and underwent SG; 72% and 48% achieved a body mass index of ≤ 40 and ≤ 35 kg/m2 , respectively. The mean percentages of total weight loss and excess weight loss were 18.9 ± 10.8% and 38.2 ± 20.3%, respectively. SG reduced hypertension (85.8% vs 52.1%), decreased antihypertensive medication use (1.6 vs 1.0) (P < .01 each), and reduced incidence of diabetes (59.6% vs 32.5%, P < .01). Of the 71 patients with ESRD who achieved a body mass index of ≤ 40 kg/m2 , 45 were waitlisted and received a kidney transplant, whereas 10 remain on the waitlist. Mortality rate after SG was 1.8 per 100 patient-years, compared with 7.3 for non-SG. Patients with stage 3a or 3b CKD exhibited improved glomerular filtration rate (43.5 vs 58.4 mL/min, P = .01). In conclusion, SG safely improves transplant candidacy while providing significant, sustainable effects on weight loss, reducing medical comorbidities, and possibly improving renal function in stage 3 patients.

Development of a Concussion Risk Function for a Youth Population Using Head Linear and Rotational Acceleration.

Physical differences between youth and adults, which include incomplete myelination, limited neck muscle development, and a higher head-body ratio in the youth population, likely contribute towards the increased susceptibility of youth to concussion. Previous research efforts have considered the biomechanics of concussion for adult populations, but these known age-related differences highlight the necessity of quantifying the risk of concussion for a youth population. This study adapted the previously developed Generalized Acceleration Model for Brian Injury Threshold (GAMBIT) that combines linear and rotational head acceleration to model the risk of concussion for a youth population with the Generalized Acceleration Model for Concussion in Youth (GAM-CY). Survival analysis was used in conjunction with head impact data collected during participation in youth football to model risk between individuals who sustained medically-diagnosed concussions (n = 15). Receiver operator characteristic curves were generated for peak linear acceleration, peak rotational acceleration, and GAM-CY, all of which were observed to be better injury predictors than random guessing. GAM-CY was associated with an area under the curve of 0.89 (95% confidence interval: 0.82-0.95) when all head impacts experienced by the concussed players were considered. Concussion tolerance was observed to be lower for youth athletes, with average peak linear head acceleration of 62.4 ± 29.7 g compared to 102.5 ± 32.7 g for adults and average peak rotational head acceleration of 2609 ± 1591 rad/s2 compared to 4412 ± 2326 rad/s2. These data provide further evidence of age-related differences in concussion tolerance and may be used for the development of youth-specific protective designs.

Quantifying the Efficacy of an Assessment-Based Pest Management (APM) Program for German Cockroach (L.) (Blattodea: Blattellidae) Control in Low-Income Public Housing Units.

Over the last several decades, low-income public housing facilities have been known to be infested with particularly large German cockroach populations. These populations persist even though the housing pest control contracts often require, and pay for, IPM practices to be used in their facilities. When Virginia Tech researchers began reviewing public housing contracts in Virginia and North Carolina, it was easy to see why these 'IPM programs' were not successful. Many of these 'low-bidder' contracts do not allow the technician enough time in each apartment to assess the size of the pest population. In addition, these pest management contracts did not require German cockroach population monitoring, even though all IPM programs are based on assessments of the pest population. There was a clear need for an effective, easy to apply cockroach management program in U.S. public housing authorities. This study determined the long-term efficacy of an Assessment-based Pest Management (APM) program for German cockroach control in U.S. public housing facilities. Specifically, we evaluated an APM program where the residents were not asked to clean or prepare for treatment, and where overnight cockroach trap counts were used to determine the volume of gel bait that would be applied. The APM baiting program was conducted for 15 mo in three housing authorities. In all three housing authorities, cockroach populations in test units were typically reduced by >90%. German cockroach infestations were even eliminated from 49 of the 65 (75%) test units during this study.

Delayed Sleeve Gastrectomy Following Liver Transplantation: A 5-Year Experience.

Obesity has become an epidemic in the United States over the past decade, and recent studies have shown this trend in the liver transplantation (LT) population. These patients may be candidates for laparoscopic sleeve gastrectomy (LSG) to promote significant and sustained weight loss to prevent recurrence of nonalcoholic steatohepatitis. However, safety remains a concern, and efficacy in this setting is uncertain. A single-institution database from 2014 to 2018 was queried for patients undergoing LSG following LT. The selection criteria for surgery were consistent with National Institutes of Health guidelines, and patients were at least 6 months after LT. A total of 15 patients (median age, 59.0 years; Caucasian, 86.7%; and female, 60%) underwent LSG following LT. Median time from LT to LSG was 2.2 years with a median follow-up period of 2.6 years. The median hospital length of stay (LOS) was 2 days after LSG. Mortality and rate of liver allograft rejection was 0, and there was 1 postoperative complication (a surgical site infection). Following LSG, body mass index (BMI) decreased from 42.7 to 35.9 kg/m2 (P < 0.01), and in 12 patients with at least 1 year of follow-up, the total body weight loss was 20.6%. Following LSG in patients with diabetes, the median daily insulin requirements decreased from 98 (49-118) to 0 (0-29) units/day (P = 0.02), and 60% discontinued insulin. Post-LT patients had a similar decrease in BMI and reduction in comorbidities at 1 year compared with a matched non-LT patient cohort. In the largest patient series to date, we show that LSG following LT is safe, effective, and does not increase the incidence of liver allograft rejection. Larger longer-term studies are needed to confirm underlying metabolic changes following LSG.

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story.

The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

Are specific players more likely to be involved in high-magnitude head impacts in youth football?

OBJECTIVE: Youth football attracts approximately 3.5 million participants every year, but concern has recently arisen about the long-term effects of experiencing repetitive head accelerations from a young age due to participation in football. The objective of this study was to quantify total involvement in high-magnitude impacts among individual players in youth football practices. The authors explored the relationship between the total number of high-magnitude accelerations in which players were involved (experienced either by themselves or by other players) during practices and the number of high-magnitude accelerations players experienced. METHODS: A local cohort of 94 youth football players (mean age 11.9 ± 1.5, mean body mass 50.3 ± 16.4 kg) from 4 different teams were recruited and outfitted with helmet-mounted accelerometer arrays. The teams were followed for one season each for a total of 128 sessions (practices, games, and scrimmages). All players involved in high-magnitude (greater than 40g) head accelerations were subsequently identified through analysis of practice film. RESULTS: Players who experienced more high-magnitude accelerations were more likely to be involved in impacts associated with high-magnitude accelerations in other players. A small subset of 6 players (6%) were collectively involved in 230 (53%) high-magnitude impacts during practice, were involved in but did not experience a high-magnitude acceleration 78 times (21% of the 370 one-sided high-magnitude impacts), and experienced 152 (30%) of the 502 high-magnitude accelerations measured. Quarterbacks/running backs/linebackers were involved in the greatest number of high-magnitude impacts in practice and experienced the greatest number of high-magnitude accelerations. Which team a player was on was an important factor, as one team showed much greater head impact exposure than all others. CONCLUSIONS: This study showed that targeting the most impact-prone players for individualized interventions could reduce high-magnitude acceleration exposure for entire teams. These data will help to further quantify elevated head acceleration exposure and enable data-driven interventions that modify exposure for individual players and entire teams.

Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a ß-Cell Glucagon-Like Peptide 1 Receptor.

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct ß-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of ß-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, ß-cell-specific Glp1r knockdown (Glp1rß-cell-ko). Mice with VSG lost ∼20% of body weight over 30 days compared with sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in ß-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1rß-cell-ko and Glp1rWT mice. Therefore, even though the ß-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of ß-cell GLP-1 signaling in obesity.

Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice.

Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop-floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal-regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety-related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent.