"Trend" Statement Use in the Orthopaedic Literature.

INTRODUCTION: For research to effectively guide clinical decision making, appropriate interpretation of data is paramount. The P-value is a useful tool for guiding the interpretation of data. However, despite its utility, the P-value is not without limitations. Of particular concern is the use of "trend statements" to describe non-statistically significant findings, a practice which introduces subjectivity and variability into data interpretation and can lead to the drawing of undue conclusions. METHODS: An audit of original research articles published from January 2022 to December 2022 in four high-impact orthopaedic journals was conducted. The selected journals were queried to identify instances in which a non-statistically significant result was labeled as a "trend." The use of trend statements and associated information was recorded and analyzed. RESULTS: One thousand two hundred sixty articles were included in the analysis. 81 articles (6.4%) included a trend statement to describe a non-statistically significant result. Only two articles (2.5%) formally defined what constituted a trend. In 28.8% of cases, the associated P-value was > 0.10. DISCUSSION: Trend statements are used to describe non-statistically significant findings with moderate frequency in the orthopaedic literature. Given the potentially misleading effects of trend statements, efforts should be made to mitigate their use. If trend statements are to be used, attention should be paid to defining what constitutes a "trend", explicitly acknowledging the lack of statistical significance of the finding to which the trend statement refers, and avoiding drawing undue conclusions from non-statistically significant data.

Outcomes of Image-Free Robotic Assisted Total Knee Arthroplasty in Patients Who Have Valgus Knee Deformities.

BACKGROUND: Valgus knee deformities pose a unique challenge in total knee arthroplasty (TKA) due to the complexity of achieving ligamentous balance and satisfactory alignment compared to varus or neutral deformities. Robotic-assisted (RA) TKA could aid in achieving improved component alignment and balance. METHODS: We retrospectively evaluated a matched cohort of patients to compare image-free RA-TKA (n = 44) versus conventional manual (CM) TKA (n = 30) techniques in patients who have valgus deformity of 5 to 15 degrees, including radiographic and patient-reported outcomes measures (PROMs) over a 3-year period. The patient reported outcome measures (PROMs) studied to determine outcomes were: Western Ontario McMaster University Arthritis Index, Knee Society Score-Function Score, and Short Form 12-item Survey. RESULTS: Overall, the RA-TKA cohort showed faster improvement in PROMs (37.16 ± 1 8.8 versus 25.74 ± 17.7, P = .02), shorter length of stay (1.41 versus 2.29 days, P = .02), and shorter operating room times (120.79 versus 123.67 minutes, P = .02) than CM-TK). Additionally, there was no difference in the use of primary versus varus-valgus constrained polyethylene liners between the cohorts. CONCLUSIONS: In this investigation, RA-TKA yielded a slightly faster patient recovery, more objective measurements of ligamentous balance, and proved noninferior PROMs compared to CM-TKA for preoperative valgus knee deformities.

Patient-reported outcomes measurement information system instruments in knee arthroplasty patients: a systematic review of the literature.

BACKGROUND: The purpose of this study is to provide a systematic review of the literature pertaining to Patient-Reported Outcome Measurement Information System (PROMIS) validation and utilization as an outcomes metric in total knee arthroplasty (TKA) patients. This is the first systematic review on PROMIS use in total knee arthroplasty patients. METHODS: A systematic search of the Pubmed/MEDLINE and Embase databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Study characteristics, patient demographics, psychometric properties (Pearson and Spearman correlation) with legacy patient-reported outcome measurement (PROM) instruments, floor and ceiling effects, responsiveness, and minimum clinically important difference (MCID) and PROMIS outcomes were recorded and analyzed. RESULTS: Fifteen studies investigating PROMIS in 11,140 patients were included. The weighted-average Pearson correlation coefficient comparing PROMIS domains with legacy patient-reported outcome measurements in total knee arthroplasty patients was 0.62 [standard error (SE) = 0.06] and the weighted-average Spearman correlation comparing PROMIS domains with legacy patient-reported outcome measurements in total knee arthroplasty patients was 0.59 (SE = 0.06), demonstrating moderate-to-strong correlation and validity. There were no differences in weighted average floor [0.03% (SE = 3.1) versus 0% (SE = 0.1) versus 0.01% (SE = 1.1); p = 0.25] or ceiling effects [0.01% (SE = 0.7) versus 0.02% (SE = 1.4) versus 0.04% (SE = 3.5); p = 0.36] between PROMIS and legacy instruments. The weighted average for percentage of patients achieving MCID was 59.1% for global physical health (GPH), 26.0% for global mental health (GMH), 52.7% for physical function (PF), 67.2% for pain interference (PI), and 37.2% for depression. CONCLUSION: Notably, PROMIS global physical health, physical function, and pain interference were found to be significantly responsive, with PROMIS pain interference most effectively capturing clinical improvement as evidenced by the achievement of MCID.

The Quality of YouTube Content on Ulnar Collateral Ligament Injuries Is Low: A Systematic Review of Video Content.

Purpose: To provide an evaluation of the quality of diagnostic and treatment information regarding ulnar collateral ligament injuries on YouTube. Methods: YouTube was searched using the terms "ulnar collateral ligament," "Tommy John surgery," and "UCL surgery." The first 100 results for each 3 terms were screened for inclusion. Each included video was graded based on its diagnostic and treatment content and assigned a quality assessment rating. Video characteristics such as duration, views, and "likes" were recorded and compared between video sources and quality assessment ratings. Results: A total of 120 videos were included in the final analysis. Only 17.5% provided very useful to excellent quality content. Only 3 videos (2.5%) provided excellent quality content; these were all physician-sponsored videos. These 3 videos only achieved an excellent score for diagnostic content; no video achieved an excellent score for treatment content. Most videos were scored as somewhat useful for both diagnostic (40%) and treatment (56.7%) content. Videos classified as somewhat useful had the highest number of average views (27,197), with a mean duration of 7 minutes 40 seconds. The most common video source was physician sponsored (32%), followed by educational (26%). Physician videos had the lowest number of views (5,842 views). Conclusions: The quality of ulnar collateral ligament-related information on YouTube is low. Differential diagnoses for related symptoms, accurate surgical indications, and thorough discussions of adverse outcomes were the most lacking information. Physician-sponsored and educational videos provided the highest-quality information but had the lowest number of average views. Clinical Relevance: Because most Internet users in the United States search for information regarding their medical issues online, it is important to understand the quality of available online medical information. Knowing this can help inform the necessary next steps to improve the quality and comprehensibility of online medical information.

Clavicle Nonunion and Malunion: Surgical Interventions for Functional Improvement.

Clavicle nonunion and malunion are relatively uncommon but, when symptomatic, can result in pain and dysfunction that requires surgical intervention. Various reconstructive and grafting techniques are available to achieve stable fixation and union. In the setting of persistent nonunion, vascularized bone grafting may be necessary. A thorough understanding of the patient's type of nonunion and potential for healing is crucial for achieving satisfactory results because is thoughtful preoperative planning and surgical fixation.

The Thoracolumbar Inflection Point in a Population of Asymptomatic Volunteers: A Multi-Ethnic Alignment Normative Study Cohort Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To show population variance in the Inflection Point (IP) and its role in defining maximum Thoracic Kyphosis (TK) and Lumbar Lordosis (LL). METHODS: 468 asymptomatic adult volunteers were included in the Multi-Ethnic Normative Alignment Study (MEANS). To find parameters correlating with IP, the vertebrae and discs were numbered such that C7 was 0, T1 was 1, with T1-T2 disc being 1.5, etc. Statistical analysis was performed by a correlation matrix for IP and the 9 other selected parameters along with linear regressions. RESULTS: The overall mean IP was 12.44 approximately corresponding to T12-L1 disc with the median being 12.50, range was T8-L4. The cohort was then stratified by sex and ethnicity, but there was no significant difference in IP between groups. IP in younger subjects was 13 (L1), compared to 12.5 (T12-L1 disc) in older subjects (P < .05). IP was moderately correlated with the TK apex (r = .66). No strong correlation was found between IP and LL magnitude or apex, TK magnitude, sacral slope, or Pelvic Incidence (PI). In terms of other sagittal parameters, PI and LL demonstrated a significant positive correlation. PI and TK did not have a strong association. CONCLUSIONS: The mean IP was at the T12-L1 disc, however IP ranged from T8 to L4. Older subjects tended to have a relatively more cephalad IP. No radiographic variable was found to be a strong predictor of the IP. TK apex was found to have a moderate correlation.

Publication and Career Trends of Ruth Jackson Orthopaedic Society Grant Winners Over the Past Decade.

Background: The Ruth Jackson Orthopaedic Society awards the Jacquelin Perry, MD Resident Research Grant and RJOS/Zimmer Biomet Clinical/Basic Science Research Grant to female orthopedic surgeons, intending to aid women in the progression and completion of their orthopedic research and bolster their pursuit or current career in academic orthopedic surgery. The impact of these grants has not yet been studied. The purpose of this study is to determine the percentage of scholarship/grant-winners who went on to publish the findings of their research, pursue academic positions, and currently hold positions of leadership in the field of orthopedic surgery. Methods: The titles of the winning research projects were searched in PubMed, Embase, and/or Web of Science to ascertain publication status. For each award recipient, the number of publications prior to the award year, number of publications after the award year, total number of publications, and H-index were calculated. Each award recipient was searched online through the websites of their employment and social media pages to determine their residency institution, whether they pursued a fellowship, the number of fellowships they pursued, their subspecialty within orthopedics, their current job, and whether they are in academic or private practice. Results: Of the fifteen Jacquelin Perry, MD Resident Research Grant winners, 73.3% of awarded research projects have since been published. 76.9% of award winners currently work in an academic setting and are affiliated with a residency program, and 0% currently hold leadership positions in orthopedic surgery. Of the eight winners of the RJOS/Zimmer Biomet Clinical/Basic Science Research Grant, 25% have published the findings of their awarded grant. 87.5% of award winners currently work in academics, and 75% hold leadership positions in orthopedic surgery. Conclusion: Our results show that many of the winners of the Jacquelin Perry, MD Resident Research Grant and RJOS/Zimmer Biomet Clinical/ Basic Science Research Grant have published their research findings, continued research within the field of orthopedic surgery, and pursued academic careers and leadership positions. Many of the barriers to career progression and entry into orthopedic surgery that women and underrepresented groups face could be overcome through more grant opportunities and mentorship. Level of Evidence: V.

Contemporary Review: An Overview of the Utility of Patient-Reported Outcome Measurement Information System (PROMIS) in Foot and Ankle Surgery.

Patient-Reported Outcome Measurement Information System (PROMIS) has favorable psychometric and administrative properties in orthopaedic clinical research. It facilitates clinically meaningful data collection while minimizing administration time and survey fatigue and improving compliance. PROMIS is a critical component of patient-centered care and shared decision making, as it provides enhanced communication and engagement between patients and providers. As a validated instrument, it may also aid in measuring value-based health care quality. The goal of the current work is to provide an overview of PROMIS metrics used in orthopaedic foot and ankle, including advantages and disadvantages compared to legacy scales and PROMIS's applicability in specific foot and ankle conditions based on psychometric properties. We provide a review of the literature regarding the utilization of PROMIS as an outcome measure for specific foot and ankle procedures and conditions.

A systematic review of the patient reported outcome measures utilized in level 1 randomized controlled trials involving achilles tendon ruptures.

BACKGROUND: Patient Reported Outcome Measures (PROMs) are utilized in level 1 randomized controlled trials involving Achilles tendon ruptures. However, the characteristics of these PROMs and current practices has not yet been reported. We hypothesize that there will be heterogeneous PROM usage in this context. METHODS: A PubMed and Embase systematic review was performed including all dates up to July 27th, 2022, assessing Achilles tendon ruptures in level 1 studies using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines where applicable. Inclusion criteria were all randomized controlled clinical studies involving Achilles tendon injuries. Studies that: (1) were not level 1 evidence (including editorial, commentary, review, or technique articles), (2) omitted outcome data or PROMs, (3) included injuries aside from Achilles tendon ruptures, (4) involved non-human or cadaveric subjects, (5) were not written in English, and (6) were duplicates were excluded. Demographics and outcome measures were assessed in the studies included for final review. RESULTS: Out of 18,980 initial results, 46 studies were included for final review. The average number of patients per study was 65.5. Mean follow up was 25 months. The most common study design involved comparing two different rehabilitation interventions (48 %). Twenty different outcome measures were reported including the Achilles tendon rupture score (ATRS) (48 %), followed by the American Orthopedic Foot and Ankle score Ankle-Hindfoot score (AOFAS-AH) (46 %), the Leppilahti score (20 %), and the RAND-36/Short Form (SF) - 36/SF-12 scores (20 %). An average of 1.4 measures were reported per study. CONCLUSION: Significant heterogeneity exists in PROM usage among level 1 studies involving Achilles tendon ruptures, which prevents meaningful interpretation of these data across multiple studies. We advocate for usage of at least the disease-specific Achilles Tendon Rupture score and a global, quality of life (QOL) survey such as the SF-36/12/RAND-36. Future literature should provide more evidence-based guidelines for PROM usage in this context. LEVEL OF EVIDENCE: Level IV; Systematic Review.

The current utilization of the patient-reported outcome measurement information system (PROMIS) in isolated or combined total knee arthroplasty populations.

Patient reported outcome measures (PROMs) are essential for clinical research and patient-centric care because they allow us to capture patient perspectives on their health condition. In knee arthroplasty, PROMs are frequently used to assess the risks and benefits of new interventions, surgical approaches, and other management strategies. A few examples of PROMs used in total knee arthroplasty (TKA) include the Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Forgotten Joint Score (FJS) (collectively referred to as "legacy" PROMs). More recently, attention has been brought to another PROM called the Patient-Reported Outcomes Measurement Information System (PROMIS). PROMIS was developed by the National Institute of Health (NIH) and has over 300 domains assessing various aspects of patient health, including pain, physical function, and mental health. With the use of PROMIS increasing in TKA literature, there is a need to review the advancements being made in understanding and applying PROMIS for this population. Thus, the purpose of this study is to provide insight on the utilization, advantages, and disadvantages of PROMIS within the field of knee arthroplasty and to provide a comparison to legacy PROMs.

Anatomic Structures at Risk During Posterior to Anterior Percutaneous Screw Fixation of Posterior Malleolar Fractures: A Cadaveric Study.

Background. There are no established guidelines for fixation of posterior malleolus fractures (PMFs). However, fixation of PMFs appears to be increasing with growing evidence demonstrating benefits for stability, alignment, and early functional outcomes. The purpose of this study was to determine the risk to anatomic structures utilizing a percutaneous technique for posterior to anterior (PA) screw fixation of PMFs. Methods. Percutaneous PA screw placement was carried out on 10 fresh frozen cadaveric ankles followed by dissection to identify soft tissue and neurovascular structures at risk. The distance from the guidewire to each anatomic structure of interest was measured. The correlation between the mean distances from the guidewire to each structure was calculated. Results. The sural nerve was directly transected in 1/10 specimens (10%) and in contact with the wire in a second specimen (10%). There was a significant correlation between the proximity of the guidewire to the apex of Volkmann's tubercle and its proximity to the sural nerve. The flexor hallucis longus (FHL) muscle belly was perforated by the guidewire 40% of the time but was not tethered or entrapped by the screw. Conclusions. Percutaneous PA screw placement is a safe technique which can be improved with several modifications. A mini-open technique is recommended to protect the sural nerve. There may be potential for tethering of the FHL with use of a washer or large screw head. Risk to the anterior and posterior neurovascular bundles is minimal.Levels of Evidence: Level V.

Diagnosis and Treatment of Neuropathic Ankle Fractures.

¼: Standard 3-view ankle radiographs are the first-line imaging modality for suspected neuropathic ankle fractures. Computed tomography is helpful to evaluate for concomitant osseous changes and soft-tissue infection. ¼: Nonoperative management may be considered for low-demand, elderly, or comorbid patients for whom surgery and anesthesia are contraindicated. However, the presence of comorbidities alone should not necessarily preclude operative intervention. Given the overall poor results of nonoperative treatment in the neuropathic ankle fracture population, operative intervention may in fact be less risky to the patient. ¼: The authors have 2 preferred treatment techniques. For cases in which the vascular supply and bone stock are adequate, open reduction and internal fixation (ORIF) with locking fixation for the fibula, a medial buttress/hook plate with lag screws for the medial malleolus, multiple syndesmotic screws for additional fixation even in the absence of a syndesmotic injury, and temporary transfixation Steinmann pins from the calcaneus into the tibia are used. For cases in which there is a concern for wound healing or previously failed ORIF, minimally invasive surgical tibiotalocalcaneal arthrodesis with a retrograde locked intramedullary nail is used.

Addressing Common Questions About Traveling by Air After Orthopedic Surgery.

Many patients have questions about traveling by air after orthopedic surgery. The goal of this review was to provide a guide to addressing these issues to better prepare patients for air travel. A comprehensive literature review was conducted to address patient questions regarding metal detectors, as well as deep venous thrombosis risk with flying. Further, patient questions pertaining to specific airlines, airports, and Transportation Security Administration policies were answered through direct discussion with representatives, website review, and internet research. Ultimately, providers should be aware of the many challenges that orthopedic patients face during air travel, and patients should consult their providers before making travel plans. Airline passengers are likewise encouraged to equip themselves with the information presented in this article, to best advocate for themselves. This guide should be used as a reference tool, providing up-to-date information about air travel after orthopedic surgery to both patients and providers alike. [Orthopedics. 2021;44(6):e719-e723.].

Contamination of the Mini C-Arm During Foot and Ankle Surgery.

BACKGROUND: Many orthopedic surgeries utilize intraoperative fluoroscopy. The mini C-arm is an advantageous device as it can be easily used without the need for a dedicated radiology technician. However, there are concerns that the mini C-arm may represent a potential source of contamination and subsequent postoperative infection. Previous investigations of standard C-arm drapes have shown high rates of contamination. Similar contamination rates would be even more concerning for the mini C-arm as it requires physically maneuvering the machine. This study aimed to determine the rate of mini C-arm drape contamination and identify high-risk areas. METHODS: Fifty foot and ankle surgeries requiring the use of mini C-arm fluoroscopy were included. Eight locations on the mini C-arm drape were sampled at the conclusion of each procedure. Culture Q-swabs were used for sampling defined locations. Swab samples were then assessed for bacterial growth on a 5% blood agar plate using a semiquantitative technique. RESULTS: In 70% of surgical cases, contamination was observed in at least 1 location. Six of the 8 evaluated locations were found to have significantly higher contamination in comparison with their corresponding negative controls (Mann-Whitney U test, P < .05). The "outer portion of the upper arm" (location 1) exhibited bacteria growth in 26% (P < .0001) of cases. The "superior portion of the x-ray source" (location 2) exhibited growth in 30% (P < .0001) of cases. These were the highest-risk areas for contamination and were both significantly more likely to be involved than the "inferior portion of the x-ray source" and "superior portion of the beam receiver," locations 4 and 5, respectively. Fourteen percent (7/50) C-arm cases and 1.72% (1/58) Achilles tendon surgery control cases developed surgical site infection (P = .0234; OR, 9.27). CONCLUSION: Bacterial contamination of the mini C-arm drape was found to be common after foot and ankle procedures. Contamination was more prevalent on the outer ring areas of the C-arm, both at the emitter and receiver. LEVEL OF EVIDENCE: Level III, prospective cohort study.

Effects of Pitavastatin on Insulin Sensitivity and Liver Fat: A Randomized Clinical Trial.

Context: 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are widely prescribed. Statins may have important metabolic effects on insulin sensitivity and liver fat, but limited studies have assessed these effects by using euglycemic hyperinsulinemic clamp, stable isotopes, and 1H magnetic resonance spectroscopy (MRS) for liver fat quantification. Objective: To study the effects of pitavastatin on hepatic fat and insulin sensitivity. Design: Six-month, double-blind, randomized, placebo-controlled trial. Setting: Academic clinical research center in Boston, Massachusetts. Participants: Overweight, insulin-resistant men aged 40 to 65 years who had not received statin therapy for ≥1 year. Interventions: Pitavastatin 4 mg or placebo daily. Outcome: The primary endpoints were changes in insulin sensitivity measured by euglycemic hyperinsulinemic clamp and liver fat measured by 1H MRS. Results: Pitavastatin showed no effect on endogenous glucose production (ΔRa glucose 0.07 ± 0.07 vs 0.04 ± 0.07 mg/kg/min, pitavastatin vs placebo, P = 0.76) or insulin-stimulated glucose uptake during "low dose" (ΔM 0.1 ± 0.1 vs -0.3 ± 0.2 mg/kg/min, P = 0.11) and "high dose" (ΔM -0.5 ± 0.3 vs -0.7 ± 0.4 mg/kg/min, P = 0.70) euglycemic hyperinsulinemic clamps. There was also no effect of pitavastatin on fasting glucose, HbA1c, and 2-hour glucose after 75-g glucose challenge. There was also no change in liver fat fraction (-1 ± 1 vs -0 ± 1%, P = 0.56). Conclusion: Compared with placebo, pitavastatin did not affect hepatic or whole-body insulin sensitivity, and it did not reduce liver fat.

Insulin-like growth factor 1 inversely relates to monocyte/macrophage activation markers in HIV.

OBJECTIVE: Monocyte/macrophage activation is increased among people with HIV, and may contribute to the heightened risk of atherosclerosis and neurocognitive dysfunction in this population. Insulin-like growth factor 1 (IGF-1) has been shown to attenuate the innate immune response in animal models of atherosclerosis and inflammatory bowel disease. We investigated, for the first time, relationships of circulating IGF-1 with monocyte/macrophage-specific indices among HIV-infected individuals and uninfected controls. DESIGN: Observational. METHODS: One hundred and thirty-one HIV-infected patients and 65 well matched controls without known cardiac disease or viral hepatitis were recruited previously. IGF-1, expressed as a z-score relative to the age-adjusted and sex-adjusted population mean, was related to log-transformed inflammatory markers within HIV and non-HIV groups. RESULTS: In HIV, IGF-1 inversely related to sCD163 (r = -0.28, P = 0.002), sCD14 (r = -0.29, P = 0.002), and high-sensitivity IL-6 (r = -0.27, P = 0.006). There was no association of IGF-1 with high-sensitivity CRP, MCP-1, IL-18, or LPS in HIV, or between IGF-1 and any inflammatory marker in controls. Relationships of IGF-1 with sCD163 and sCD14 remained significant in HIV after controlling for age, sex, smoking, BMI, visceral fat, statin use, viral load, and antiretroviral therapy. For every one-unit decline in IGF-1 z-score, sCD163 and sCD14 increased by 14% (95% CI, 0.23-29%) and 29% (95% CI, 1.4-63%), respectively. CONCLUSION: Low IGF-1 was robustly associated with high sCD163 and sCD14 in HIV. Prospective studies are needed to investigate augmentation of IGF-1 as a novel strategy to reduce monocyte/macrophage activation in this population.

Differential relationships of hepatic and epicardial fat to body composition in HIV.

HIV-infected patients commonly experience changes in central and peripheral fat content as well as ectopic fat accumulation. However, whether hepatic and epicardial fat stores relate differentially to body composition or how these associations are modified by HIV status has not been well explored. A previously recruited sample of 124 HIV-infected patients and 58 healthy controls had undergone dual energy X-ray absorptiometry (DEXA) and computed tomography (CT) from which body composition measures, liver-spleen ratio, and epicardial fat volume were obtained. Unique to the HIV-infected group, there was a parabolic association between abdominal subcutaneous adipose tissue (SAT) area and liver-spleen ratio (P = 0.03, inflection point 324 cm2) such that hepatic fat content was greatest at the extremes of low and high SAT A quadratic model also closely described the relationship between mean leg fat and liver-spleen ratio among patients with HIV (P = 0.02, inflection point 4.7 kg), again suggesting greater liver fat content with both low and high leg fat. Notably, an analogous relationship of epicardial fat with SAT was not evident among HIV-infected individuals or healthy controls. In contrast, visceral adipose tissue (VAT) linearly related to both liver-spleen ratio in HIV and epicardial fat volume irrespective of HIV status in multivariable models. In conclusion, our analyses implicate both low and high SAT as risk factors for hepatic fat accumulation in HIV These findings add to growing evidence of SAT dysfunction in the setting of HIV infection, and highlight key physiologic differences between hepatic and epicardial fat depots.

Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans. METHODS: 50 HIV-infected men and women with increased abdominal adiposity participated in this randomized, placebo-controlled trial of tesamorelin, 2mg vs. identical placebo daily for six months. Fasting laboratory measures, liver fat by 1H-magnetic resonance spectroscopy, and visceral adipose tissue (VAT) by computed tomography were obtained. Euglycemic hyperinsulinemic clamp was performed in a randomly selected subset. RESULTS: At baseline, serum log10 FGF21 was significantly associated with log10 liver fat (r=0.32, p=0.03). Log10 FGF21 tended to decrease in the tesamorelin group compared to placebo (p=0.06). Among the entire cohort, reductions in FGF21 were significantly associated with reductions in liver fat (ρ=0.41, p=0.01), log10 gamma glutamyl tran speptidase (GGT, r=0.40, p=0.009), and FIB4 index (r=0.37, p=0.02). CONCLUSIONS: In HIV-infected individuals, FGF21 is significantly positively associated with liver fat. FGF21 decreases in association with reductions in liver fat, GGT, and FIB4, suggesting that FGF21 is upregulated in the context of steatosis and steatohepatitis and is reduced when these conditions improve. Moreover, these data suggest that tesamorelin improves liver fat via pathways other than increasing serum FGF21. TRIAL REGISTRATION: clinicaltrials.govNCT01263717.

Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV.

OBJECTIVE: Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS: We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS: At baseline, VAT was positively associated with ALT (P = 0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30 U/l, VAT responders experienced greater reductions in ALT (-8.9 ±â€Š22.6 vs. 1.4 ±â€Š34.7 U/l, P = 0.004) and AST (-3.8 ±â€Š12.9 vs. 0.4 ±â€Š22.4 U/l, P = 0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION: A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.