Faculty Bibliography

BACKGROUND:The presence of bone marrow edema (BME) on magnetic resonance imaging (MRI) has been used to evaluate for bone stress injuries in athletes. PURPOSE/OBJECTIVE:To examine the prevalence of MRI findings, including BME, in a single male collegiate basketball team before and after a single season and to assess its association with clinically symptomatic metatarsal bone stress injuries. STUDY DESIGN/METHODS:Cohort Study; Level of evidence, 3. METHODS:A total of 16 men on a single collegiate basketball team (mean age, 20.0 ± 1.8 years) underwent 1.5-T MRI focused on both midfeet during the preseason, and 13 underwent repeat MRI during the postseason. MRI findings included the presence of BME and the radiographic classification of the bone stress injury (grades 1-4). Injury surveillance performed by athletic trainers was used to identify metatarsal bone stress injuries over the course of the season. RESULTS:< .10), with the abnormalities persisting on postseason MRI in all players. CONCLUSION/CONCLUSIONS:Collegiate male basketball players may have a high prevalence of BME, often without associated symptoms. The absence of foot pain or a corresponding diagnosis of a metatarsal bone stress injury in this study suggests that MRI findings of BME in asymptomatic athletes should be interpreted with caution.

CONTEXT:Sleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes. OBJECTIVE:To determine mechanisms contributing to impaired bone health in youth following SG. METHODS:12-month longitudinal observational study in a multidisciplinary tertiary-care hospital, including 64 youth 13-25 years old with moderate-to-severe obesity (51 females); 30 underwent SG and 34 were nonsurgical (NS) controls. SG was undertaken after a combined decision-making process between treatment team and patient. The main outcome measures were fasting blood for enteric peptides, sex steroids, sclerostin, and bone turnover markers (N-terminal propeptide of type 1 procollagen [P1NP] and C-terminal cross-linking telopeptide [CTX]); dual-energy X-ray absorptiometry measures of areal bone mineral density (aBMD) and body composition; high resolution peripheral quantitative computed tomography; measures of volumetric BMD (vBMD); microfinite element analysis of strength estimates (distal radius and tibia). RESULTS:SG had greater reductions in body mass index (BMI) z-scores, serum estrone, and the free androgen index (FAI) (P ≤ .046), and greater increases in sclerostin, P1NP, and CTX (P ≤ .010) than NS controls. Fasting ghrelin decreased in SG vs NS (P < .0001); fasting peptide YY did not change. Most changes were driven by female SG participants. Among females (the majority of study participants), after controlling for baseline age and race, reductions in total hip aBMD Z-scores were positively associated with changes in BMI, lean mass, estrone, FAI, and ghrelin, and inversely with changes in sclerostin.. Decreases in total vBMD of the radius and tibia were associated positively with decreases in BMI. Increases in CTX were associated with decreases in BMI, lean mass, and ghrelin, and increases in sclerostin. CONCLUSION:Bone loss after SG in youth is associated with changes in body composition, sex steroids, sclerostin, and enteric peptides. These are potential targets for future preventative or therapeutic strategies.

The Harvard Catalyst KL2/CMeRIT program is a 2-year mentored institutional career award that includes KL2 grants funded by National Institutes of Health (NIH) and CMeRIT grants funded by Harvard Catalyst nonfederal funds. The purpose of this study was to compare outcomes for early-stage investigators funded by the KL2/CMeRIT program to a group of applicants who were not chosen for support to assess the potential impact of the program on early career outcomes. Career data, including academic promotions, subsequent grant funding, and publication rates, from both successful and unsuccessful 2008-2018 KL2/CMeRIT applicants were compiled throughout the year 2020. Data were obtained directly through outreach to both groups and through assessment of online resources. The cohort comprised 487 individuals, 109 awardees, and 378 nonawardees. Awardees were more likely to be subsequently involved in clinical and translational research than nonawardees (92% vs 75%, p < 0.001). A higher proportion of awardees also had achieved academic promotion (81% vs 69%, p = 0.016) and subsequent NIH funding (72% vs 58%, p = 0.047), while there was no difference in publication rates (p = 0.555). Participants in the Harvard Catalyst KL2/CMeRIT program demonstrate greater early career success than nonparticipants though the nonparticipants also fared relatively well.

Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.

BACKGROUND:With the growing prevalence of severe obesity in adolescents, sleeve gastrectomy (SG), a type of metabolic bariatric surgery (MBS), is increasingly being performed at a younger age. Data regarding changes in homeostatic and hedonic appetite following SG are conflicting in adults, with some studies showing no change and others showing a decrease in appetite. Data evaluating the effect of SG on appetite during adolescence, when appetite is more plastic, are currently lacking. OBJECTIVE:To evaluate appetite changes one year after SG in adolescents with obesity vs. in non-surgical controls (NS). METHODS:Thirty-nine subjects 13-21 years old with severe obesity were followed for a year; 19 underwent SG, and 20 were followed without surgery. Subjects had fasting blood tests for appetite-regulating hormones and completed a visual analog scale for appetite assessment (VAS). RESULTS:= 0.011). Appetite changes were not associated with weight loss or final BMI. CONCLUSIONS:There were no changes in appetite measures one-year after SG from pre-surgery levels in adolescents with obesity, and appetite changes were not associated with changes in BMI. It is important to evaluate the impact of long-term appetite changes, if any, on weight loss after SG.

PURPOSE/OBJECTIVE:To assess the perception of equity and respect in the workplace and within the SSR. We hypothesized that responses would differ by gender and minorities underrepresented in medicine (URiM) status. METHODS:An electronic survey was sent to 1,531 SSR members between January 2020 and March 2020 to determine perception of equity and respect. Descriptive statistics were calculated, and analysis of differences in response by gender/minority status was performed using the Fisher's exact test. The study was exempt from IRB approval. RESULTS:There were 176 responses (11.5%). Most respondents (61.9%) were between 30 and 50 years. Members identified as male (M) in 74.4%, as female (F) in 25.0%, and as "other" in 0.6%. URiM comprised 9.1% of members. Women worked more commonly in academia (p = 0.005), had the perception of unequal opportunities for leadership positions within the institution (p = 0.006), and emphasized the importance of having a mentor of the same gender (p = 0.001). URiM members were less likely to hold a leadership position (p = 0.1, trend), had a perception of unequal opportunities for leadership positions within the institution (p = 0.06, trend), and reported the importance of having a mentor of the same race (p = 0.06, trend). There were no significant differences between gender or URiM status and perception of the SSR to provide an inclusive environment and leadership opportunities (p ≥ 0.39). CONCLUSION/CONCLUSIONS:While survey participation was limited and potentially biased, respondents perceived that women and minorities have fewer opportunities and are treated with lower regard in the workplace compared to male, non-minority colleagues.

OBJECTIVE:The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DESIGN:GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1-4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1-3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. RESULTS:IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. CONCLUSIONS:IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.

CONTEXT:Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD. OBJECTIVE:We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. METHODS:This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS). RESULTS:There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8 ± 13.3% vs 2.9 ± 1.1%, P < 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0 ± 6.3 vs 15.4 ± 11.2 ng/mL, P = 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (P = 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores. CONCLUSION:Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.

OBJECTIVE/UNASSIGNED:Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. DESIGN/UNASSIGNED:An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. METHODS/UNASSIGNED:In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. RESULTS/UNASSIGNED:Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. CONCLUSIONS/UNASSIGNED:GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

In addition to restrictions on conducting research, COVID-19-related travel bans and scientific meeting cancellations have negatively affected scholars in the Clinical and Translational Science Award (CTSA) Mentored Career Development Award (KL2) program. In response, a national virtual visiting scholar program was developed to provide opportunity for KL2 scholars to be virtual visiting professors at another CTSA hub, meet faculty and scholars, and expand networks and build collaborations. This article describes the design and short-term outcomes of the virtual CTSA Visiting Scholar Program. In 2020, a working group designed core program elements and developed an application and selection process. Anonymized surveys were sent to scholars post visit and to scholars and program directors 6 months post visit to evaluate their experience and solicit suggestions for improvements. Between November 2020 and May 2021, 56 KL2 scholars and 27 hubs participated. Forty-five (80.4%) participating scholars responded to the initial survey. Nearly all scholars (44, 97.7%) agreed their experience was valuable. All respondents indicated they would recommend the program to other KL2 scholars. For the 6-month survey, the response rate was 87.5% (49/56). Within 6 months of their visit, 36 (73.5%) respondents had contacted at least one person at the host hub and for 17 (34.7%) respondents, new collaborations with the host hub ensued. Twenty-five of 27 (92.6%) host hubs responded to the survey. Most (21, 84.0%) agreed that hearing visiting scholar talks was valuable to their own scholars and 23 (92%) indicated likelihood of their hub participating in future round of the program. The virtual Visiting Scholar Program provided KL2 scholars an opportunity to virtually visit another CTSA hub, present their research, and meet with faculty and other scholars to expand their networks. Although geared to KL2 scholars, this model is potentially generalizable to other nationally coordinated career development programs.