Non-operated Controls Research Articles

In vivo mapping of postprandial hepatic glucose metabolism using dynamic magnetic resonance spectroscopy combined with stable isotope flux analysis in Roux-en-Y gastric bypass adults and non-operated controls: A case-control study.

Roux-en-Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post-bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB-operated patients with PBH compared to non-operated healthy controls (HC). We enrolled RYGB-operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6'-2H2]-glucose (d-glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post-d-glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco-regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models. In RYGB subjects, the hepatic d-glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d-glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between-group differences in peripheral insulin sensitivity. Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose-insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients.

The glucagon-like peptide-1 and other endocrine responses to alcohol ingestion in women with versus without metabolic surgery.

Glucagon-like peptide-1 (GLP-1)-based therapies, effective in treating obesity and type 2 diabetes, hold potential for reducing alcohol-seeking behaviour. However, the understanding of how alcohol consumption affects endogenous GLP-1 responses-important for understanding GLP-1-based therapies' potential in addressing alcohol misuse-is limited, given the absence of placebo-controlled studies examining these effects. This study aimed to determine the acute effects of alcohol ingestion on GLP-1 and other peptides and evaluate whether metabolic surgery, which increases GLP-1 responses, blood alcohol concentrations (BAC) and alcohol misuse risk, influences this effect. Additionally, we assessed the acute effects of alcohol on plasma glucose and insulin concentrations. Using a placebo-controlled crossover study, we examined hormonal and glucose responses after oral alcohol consumption (0.5g/kg of fat-free mass) versus placebo drinks in 18 women who underwent metabolic surgery <5years ago and in 14 non-operated controls (equivalent in age, body mass index [BMI], race and alcohol consumption patterns). Women had a mean (SD) age of 41 (10) years and a BMI of 33 (5) kg/m2. Compared with the control group, the surgery group exhibited a higher peak BAC (0.99 [0.20] g/L vs. 0.75 [0.16] g/L; P < 0.005). Alcohol decreased GLP-1 by 34% (95% CI, 16%-52%) in both groups and decreased ghrelin more in the control (27%) than in the surgery group (13%). Alcohol modestly decreased plasma glucose and transiently increased insulin secretion in both groups (P < 0.05). However, alcohol lowered blood glucose concentrations to the hypoglycaemic range in 28% of the women in the surgery group versus none in the control group. These findings provide compelling evidence that acute alcohol consumption decreases GLP-1, a satiation signal, elucidating alcohol's 'apéritif' effect. This study also highlights the potential increase in alcohol-related hypoglycaemic effects after metabolic surgery.

Impact of Stimulation Frequency on Verbal Fluency Following Bilateral Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

The effects of stimulation frequency on verbal fluency (VF) following subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not well understood. The present study examines the impact stimulation frequency has on VF following bilateral STN-DBS in PD. Prospective study of 38 consecutive patients with PD with low frequency STN-DBS (LFS) (n= 10) and high frequency STN-DBS (HFS) (n= 14), and a non-operated PD control group consisting of patients with fluctuating response to dopaminergic medication (n= 14) homogeneous in age, education, disease duration, and global cognitive function. Patients were evaluated on VF tasks (letter, semantic, action verbs, alternating). A one-way analysis of variance (ANOVA) was conducted to assess distinctions between groups. Pre- and post-surgical comparisons of fluencies were performed for operated groups. A mixed ANOVA was applied to the data to evaluate the interaction between treatment (HFS vs. LFS) and time (pre- vs. post-surgery). Strategy use (clustering and switching) was evaluated. Semantic and letter fluency performance revealed significant differences between HFS and LFS groups. Pre- and post-surgical comparisons revealed HFS negatively affected letter, semantic, and action fluencies, but LFS had no effect on VF. No interaction effect or main effect of treatment was found. Main effect of time was significant for semantic and action fluencies indicating a decrease in postoperative fluency performance. Patients with LFS produced larger average cluster sizes than patients with HFS. LFS may be less detrimental to VF, but these findings suggest that VF decline following STN-DBS is not caused by stimulation frequency alone.

Impact of Spinal Deformity and Surgery on Health-Related Quality of Life in Cerebral Palsy: A Multicenter Prospective Controlled Trial.

Spinal fusion for scoliosis associated with cerebral palsy (CP) is challenging to study because specialized outcome measures are needed. Therefore, evidence in favor of the benefits of surgery has not been firmly established. This study aimed to determine if corrective spinal fusion improves health-related quality of life (HRQoL) in children with CP scoliosis at 2 years. Children with CP and scoliosis who met the criteria for posterior spinal fusion were offered enrollment at 16 US and Canada centers. Participants' families selected either operative intervention (OP) or nonoperative treatment (NON) in discussion with their surgeon with no influence by the decision to participate in the research study. Demographic, clinical data (function level, magnitude of deformity, comorbidities), and HRQoL (CPCHILD Questionnaire) were collected at baseline and 2 years. Change (from baseline) in total CPCHIL scores was the primary outcome. Three hundred one OP and 34 NON subjects had complete baseline and 2-year data. At baseline, both groups were comparable in function level, comorbid status, and CPCHILD scores (52.1 ±15.3 vs. 53.4 ±14.5; P=0.66). The OP group had a larger spinal deformity magnitude (84.5˚ ± 21.8˚ vs. 66.3˚ ± 18.1˚) (P=0.001). The total CPCHILD score improved in the OP group by 6.6 points (P<0.001). NON scores were unchanged (+1.2; P=0.65) during follow-up. There were also significant score increases in the OP group for 5 of 6 CPCHILD domains. The change in CPCHILD scores from enrollment to 2 years was more significant in the OP group (P=0.05). For children with CP who undergo spinal fusion, HRQoL improved over preoperative levels and an unchanged nonoperative control group. Level II.

Continuous Glucose Monitoring Captures Glycemic Variability After Roux-en-Y Gastric Bypass in Patients with and Without Type 2 Diabetes Mellitus: A Prospective Cohort Study.

To evaluate glycemic variability (GV) using continuous glucose monitoring (CGM) in individuals with and without type 2 diabetes mellitus (T2DM) undergoing Roux-en-Y gastric bypass (RYGB). This prospective cohort study compared the CGM data of fourteen patients with T2DM (n = 7) and without T2DM (n = 7) undergoing RYGB. After 6months, these patients were compared to a non-operative control group (n = 7) matched by BMI, sex, and age to the T2DM group. Fourteen patients underwent RYGB, with a mean BMI of 46.9 ± 5.3kg/m2 and an average age of 47.9 ± 8.9years; 85% were female. After 6months post-surgery, the total weight loss (TWL) was 27.1 ± 6.3%, with no significant differences between the groups. Patients without diabetes had lower mean interstitial glucose levels (81 vs. 94 and 98mg/dl, p < 0.01) and lower glucose management indicator (GMI) (5.2 vs. 5.6 and 5.65%, p = 0.01) compared to the control and T2DM groups, respectively. The coefficient of variation (CV) significantly increased only in patients with diabetes (17% vs. 26.7%, p < 0.01). Both groups with (0% vs. 2%, p = 0.03) and without (3% vs. 22%, p = 0.03) T2DM experienced an increased time below range with low glucose (54-69mg/dL). However, patients without T2DM had significantly less time in rage (70-180mg/dL) (97% vs. 78%, p = 0.04). Significant differences in CGM metrics among RYGB patients suggest an increase in glycemic variability after surgery, with a longer duration of hypoglycemia, especially in patients without T2DM.

1569-P: Quantification of Postprandial Hepatic Glucose Disposal in Roux-en-Y Gastric Bypass and Non-operated Controls Using Stable Isotope Labelling and Liver Metabolic Imaging

1569-P: Quantification of Postprandial Hepatic Glucose Disposal in Roux-en-Y Gastric Bypass and Non-operated Controls Using Stable Isotope Labelling and Liver Metabolic Imaging

Target NF-κB p65 for preventing posttraumatic joint contracture in rats.

RelA/p65 is as a crucial component of the nuclear factor κB (NF-κB) signaling pathway that has a significant impact on various fibrotic diseases. However, its role in the fibrosis of tissues surrounding the joint after traumatic injury remains unclear. In this study, rats were divided into three groups: non-operated control (NC) group, p65-siRNA treated (siRNA-p65) group, and negative siRNA treated (siRNA-neg) group. Then, 10 μL (10 nmol) of p65-siRNAwas injected into the joint of the siRNA-p65 group. Meanwhile, 10 μL of negative siRNA was administered to the knee joint of the operated siRNA-neg group for comparison. The rats in the NC group did not receive surgery or drug intervention. After 4 weeks of right knee fixation in each group, X-ray measurements revealed significantly reduced degree of knee flexion contracture following p65-siRNA treatment (siRNA-neg: 77.73° ± 2.799°; siRNA-p65: 105.7° ± 2.629°, p < 0.0001). Histopathological examination revealed that the number of dense fibrous connective tissues decreased following p65-siRNA inhibition. Western blot analysis revealed significantly different expression levels of fibrosis-related proteins between the siRNA-p65 and siRNA-neg groups. Immunohistochemical analysis revealed a reduction in the average number of myofibroblasts in the siRNA-p65 group compared with that in the siRNA-neg group. Thus, intra-articular p65-siRNA injection could attenuate fibroblast activation and fibrosis-related protein production, suppress periarticular tissue fibrosis, and prevent joint contracture by downregulating the NF-κB p65 pathway. Statement of clinical significance: Intra-articular injection of p65-siRNA could reduce myofibroblast proliferation and fibrosis-related protein expressionby downregulating the NF-κB p65 pathway, inhibit periarticular tissue fibrosis, and prevent joint adhesion, which representsa potential therapy in the prevention of joint fibrosis following traumatic injury.

Participant recruitment and attrition in surgical randomised trials with placebo controls versus non-operative controls: a meta-epidemiological study and meta-analysis

ObjectiveTo compare differences in recruitment and attrition between placebo control randomised trials of surgery, and trials of the same surgical interventions and conditions that used non-operative (non-placebo) controls.DesignMeta-epidemiological study.Data sourcesRandomised...

Determination of Serum Arginase-1 Concentrations and Serum Arginase Activity for the Non-Invasive Diagnosis of Endometriosis.

Backgroud: Endometriosis remains a diagnostic challenge, both clinically and economically, affecting 6% to 15% of women of child-bearing potential. We have attempted to determine whether testing serum concentrations and activity of arginase isoenzymes could be useful for the non-invasive diagnosis of endometriosis. Methods: This study involved 180 women (105 endometriosis subjects-study group B; 22 subjects with other benign gynaecological conditions-control group 1-K1, both undergoing surgery; and 53 healthy subjects without features of endometriosis-control group 2-K2). Results: Preoperative and postoperative arginase-1 (Arg-1) concentrations were significantly higher in patients, as compared with the control groups K1 (p < 0.0001 and p = 0.0005, respectively) and K2 (both p < 0.0001). Similarly, arginase activity was significantly higher in patients than in the control group K1 before surgery and higher than in both control groups after surgery. No significant differences in either Arg-1 concentrations or arginase activity were noted between the operated control group K1 and the non-operated control group K2. A significant postoperative decrease in Arg-1 concentration was observed within both patient (p < 0.0001) and control group K1 (p = 0.0043). Diagnostic performance was assessed using the receiver operating characteristic (ROC) method. The threshold for differentiation between endometriosis patients and healthy non-operated controls was 42.3 ng/mL, with a sensitivity of 90% and specificity of 81%. For differentiation of patients and operated controls with benign gynaecological conditions, the threshold was 78.4 ng/mL, with a sensitivity of 61% and specificity of 95%. Conclusions: We, therefore, conclude that Arg-1 serum concentrations and arginase activity could be considered potential biomarkers for endometriosis but require further studies on larger cohorts of patients.

Vagal activation alters prandial bile acid composition and glycemia in patients with hypoglycemia after Roux-en-Y gastric bypass surgery.

Altered prandial glycemic response after Roux-en-Y gastric bypass (RYGB) is exaggerated in patients with post-RYGB hypoglycemia. Increased contribution of glucagon-like peptide 1 (GLP-1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls. Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB-treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal-tolerance test with (MTT-Sham) and without (MTT) preceding modified sham feeding (chew and spit). Meal ingestion raised serum total BAs in RYGB-treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal-induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = -0.75, p < 0.05) and were directly associated with ISR and GLP-1 during MTT-Sham. In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post-RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB.

Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex

BackgroundIn children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. MethodsHearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). ResultsIn the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p < 0.05). Deafened rats showed significantly more play fighting during development (p < 0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p > 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p < 0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p < 0.05). ConclusionsHearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

Taste and odor interactions after metabolic surgery.

Most patients report "taste" changes after undergoing metabolic surgeries. Yet, most studies that used validated sensory evaluation techniques, including ours, found no changes in perceived taste intensity from before to after surgery. However, we assessed participants with pure gustatory stimuli and after an overnight fast, which raises questions about whether patients' self-reported "taste" changes are due to conflating changes in retronasal smell/"flavor" with taste changes or whether they only manifest during the fed state. To investigate this, we conducted a cross-sectional study comparing sensory responses in women who underwent metabolic surgery 2 to 6 yr ago (n = 15) with 2 nonoperated control groups: one with a body mass index (BMI) equivalent (n = 15) and one with a healthy BMI (n = 15). Participants attended 2 sessions, one fed and one fasted. Using a sip-and-spit method, women tasted liquid samples containing gustatory and olfactory stimuli and puddings with varying fat content with and without nose clips. They used separate general labeled magnitude scales to rate their perceived intensity of taste, smell, flavor, and liking. Mixed ANOVAs indicated that the surgery and BMI equivalent groups rated retronasal smell intensity of coffee stronger than the healthy BMI group (P ≤ 0.015). However, there were no differences in taste/flavor intensity or liking ratings among groups. Additionally, feeding conditions did not significantly affect perceived intensity ratings. Our findings suggest that changes in the sensory-discriminatory component of taste or taste-odor interactions are not significant contributors to dietary modifications following metabolic surgery.

Differential effect of gastric bypass versus sleeve gastrectomy on insulinotropic action of endogenous incretins.

Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins. Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg ofsitagliptin. Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased β-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN. After GB, increasing incretin activity augments prandial β-cell response whereas the β-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.

P13.08.A JAKOB V. E. GERSTL, MBBS

Abstract BACKGROUND Pituitary adenomas are benign neoplasms which can have a profound impact on quality of life. In-situ assessments of patient quality of life with pituitary adenomas and recovery from surgery are limited; existing patient reported outcome measures are, moreover, biased by patient recollection. Smartphone-based digital phenotyping may provide a means of monitoring patient recovery and quality of life at a more granular and accurate level. MATERIALS AND METHODS Patients with pituitary adenomas were enrolled during preoperative clinic visits. Included patients installed the Beiwe application, which passively collected GPS data during patient follow-up. Dates of significant clinical events were recorded to assess how they affected mobility. Using a LOESS regression line, aggregate trends amongst patients who underwent transsphenoidal resection were established and compared to baseline values from preoperative patients awaiting surgery and non-operative controls. RESULTS As part of a still ongoing study, 35 Patients with pituitary adenomas were enrolled between October 2022 and February 2023. Of these, 13 underwent transsphenoidal resection, the remaining 22 patients were either waiting for surgery and/or served as non-operative controls. Patients undergoing transsphenoidal resection of pituitary adenomas spent more time at home, spent less time walking, walked fewer steps and traveled shorter distances away from home compared following surgery compared to baseline preoperative data and non-operative controls. CONCLUSION The authors were able to generate initial digital phenotypes for a cohort of pituitary patients based on passively collected smartphone GPS data; the authors also hope that these initial data may help in the establishment of an in-situ tool to monitor recovery following surgery for pituitary adenoma. It is the authors’ contention that such preoperative mobility metrics may be further utilized to predict postoperative outcomes following surgery which has been demonstrated in the general surgery setting. In the case of pituitary disease, these include postoperative CSF leak, infection, dysnatremia and hospital length of stay.

Clinical evaluation of a decision support system for glucose infusion in hypoglycaemic clamp experiments.

To provide a preliminary evaluation of the accuracy and safety of Gluclas decision support system suggestions in a hypoglycaemic clamp study. This analysis was performed using data from 32 participants (four groups with different glucose-insulin regulation: post Roux-en-Y gastric bypass with and without postprandial hypoglycaemia syndrome, postsleeve gastrectomy and non-operated controls) undergoing Gluclas-assisted hypoglycaemic clamps (target: 2.5 mmol/L for 20 minutes at 150 minutes after oral glucose ingestion). Gluclas provided glucose infusion rate suggestions upon manual entry of blood glucose values (every 5 minutes), which were either followed or overruled by investigators after critical review. Accuracy and safety were evaluated by mean absolute error (MAE), mean absolute percentage error (MAPE), average glucose level, coefficient of variation (CV) and minimal glucose level during the 20-minute hypoglycaemic period. Investigators accepted 84% of suggestions, with a mean deviation of 30.33 mg/min. During the hypoglycaemic period, the MAE was 0.16 (0.12-0.24) (median [interquartile range]) mmol/L and the MAPE was 6.12% (4.80%-9.29%). CV was 4.90% (3.58%-7.27%), with 5% considered the threshold for sufficient quality. The minimal glucose level was 2.40 (2.30-2.50) mmol/L. Gluclas achieved sufficiently high accuracy with minimal safety risks in a population with differences in glucose-insulin dynamics, underscoring its applicability to various patient groups.

Bariatric surgery alters mitochondrial function in gut mucosa.

The obesity pandemic has worsened global disease burden, including type 2 diabetes, cardiovascular disease, and cancer. Metabolic/bariatric surgery (MBS) is the most effective and durable obesity treatment, but the mechanisms underlying its long-term weight loss efficacy remain unclear. MBS drives substrate oxidation that has been linked to improvements in metabolic function and improved glycemic control that are potentially mediated by mitochondria-a primary site of energy production. As such, augmentation of intestinal mitochondrial function may drive processes underlying the systemic metabolic benefits of MBS. Herein, we applied a highly sensitive technique to evaluate intestinal mitochondrial function ex vivo in a mouse model of MBS. Mice were randomized to surgery, sham, or non-operative control. A simplified model of MBS, ileal interposition, was performed by interposition of a 2-cm segment of terminal ileum into the proximal bowel 5mm from the ligament of Treitz. After a four-week recovery period, intestinal mucosa of duodenum, jejunum, ileum, and interposed ileum were assayed for determination of mitochondrial respiratory function. Citrate synthase activity was measured as a marker of mitochondrial content. Ileal interposition was well tolerated and associated with modest body weight loss and transient hypophagia relative to controls. Mitochondrial capacity declined in the native duodenum and jejunum of animals following ileal interposition relative to controls, although respiration remained unchanged in these segments. Similarly, ileal interposition lowered citrate synthase activity in the duodenum and jejunum following relative to controls but ileal function remained constant across all groups. Ileal interposition decreases mitochondrial volume in the proximal intestinal mucosa of mice. This change in concentration with preserved respiration suggests a global mucosal response to segment specific nutrition signals in the distal bowel. Future studies are required to understand the causes underlying these mitochondrial changes.

Progression of Osteoarthritis at Long-term Follow-up in Patients Treated for Symptomatic Femoroacetabular Impingement With Hip Arthroscopy Compared With Nonsurgically Treated Patients

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain, especially in young patients. When left untreated, it has been demonstrated to be a risk factor for the onset or progression of osteoarthritis (OA) and has been identified as one of the main contributors leading to the need for total hip arthroplasty (THA) at a young age. While the short-term therapeutic potential of hip arthroscopy is widely recognized, little is known regarding its potential mid- to long-term preventive effect on the progression of hip OA. Purpose: To (1) report clinical outcomes of arthroscopically treated FAI syndrome with a minimum 5-year follow-up and compare the results to a cohort with FAI treated nonsurgically and (2) determine the influence of hip arthroscopy on the onset and progression of hip OA in patients diagnosed with FAI. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who had hip pain and were diagnosed with FAI were included. Exclusion criteria were (1) previous or concomitant hip surgery, (2) <5 years of follow-up, and (3) insufficient radiographs. Patients treated with hip arthroscopy were compared with a cohort of patients with FAI who were treated nonsurgically. Kaplan-Meier estimates of failure (defined as conversion to THA) were performed. Bivariate analysis and Cox regression were used to identify factors associated with inferior clinical and radiographic outcomes. Results: A total of 957 patients (650 female, 307 male; 1114 hips) (mean age, 28.03 ± 8.9 years [range, 6.5-41.0 years]) with FAI were included. A total of 132 hips underwent hip arthroscopy and 982 hips were nonoperatively treated. The mean follow-up was 12.5 ± 4.7 years (range, 5.0-23.4 years). At the final follow-up, the rate of OA progression was 26.5% in the operative group and 35.2% in the nonoperative cohort (P < .01). Conversion to THA was performed in 6.8% of the surgical patients and 10.5% of the initially nonsurgical patients (P = .19). Additionally, there was no significant difference in the risk of failure between the operatively and nonoperatively treated patients. Male sex, increased age at initial diagnosis, presence of cam morphology, and increased initial Tönnis grade were risk factors for failure (male sex: hazard ratio [HR], 2.3; P < .01; per year of increased age: HR, 1.1; P < .01; presence of cam: HR, 3.5; P < .01; per Tönnis grade: HR, 4.0; P < .01). Conclusion: At a mean follow-up of nearly 13 years, 7% of patients of the surgical group experienced progression to THA, compared with 11% of the nonoperative control group. While most of the operative group showed little to no OA at final follow-up, moderate OA (Tönnis grade 2) was present in 12% of the cohort compared with 22% of nonsurgical patients. Increased age at diagnosis, male sex, presence of a cam morphology, and presence of initial arthritic joint changes were found to be risk factors for failure. The results of this study demonstrated evidence for a preventive effect of hip arthroscopy on the development and progression of OA in young patients with FAI at mid- to long-term follow-up.

Bioactive Scaffold With Spatially Embedded Growth Factors Promotes Bone-to-Tendon Interface Healing of Chronic Rotator Cuff Tear in Rabbit Model

Background: Functional restoration of the bone-to-tendon interface (BTI) after rotator cuff repair is a challenge. Therefore, numerous biocompatible biomaterials for promoting BTI healing have been investigated. Purpose: To determine the efficacy of scaffolds with spatiotemporal delivery of growth factors (GFs) to accelerate BTI healing after rotator cuff repair. Study Design: Controlled laboratory study. Methods: An advanced 3-dimensional printing technique was used to fabricate bioactive scaffolds with spatiotemporal delivery of multiple GFs targeting the tendon, fibrocartilage, and bone regions. In total, 50 rabbits were used: 2 nonoperated controls and 48 rabbits with induced chronic rotator cuff tears (RCTs). The animals with RCTs were divided into 3 groups: (A) saline injection, (B) scaffold without GF, and (C) scaffold with GF. To induce chronic models, RCTs were left unrepaired for 6 weeks; then, surgical repairs with or without bioactive scaffolds were performed. For groups B and C, each scaffold was implanted between the bony footprint and the supraspinatus tendon. Four weeks after repair, quantitative real-time polymerase chain reaction and immunofluorescence analyses were performed to evaluate early signs of regenerative healing. Histological, biomechanical, and micro–computed tomography analyses were performed 12 weeks after repair. Results: Group C had the highest mRNA expression of collagen type I alpha 1, collagen type III alpha 1, and aggrecan. Immunofluorescence analysis showed the formation of an aggrecan+/collagen II+ fibrocartilaginous matrix at the BTI when repaired with scaffold with GFs. Histologic analysis revealed greater collagen fiber continuity, denser collagen fibers, and a more mature tendon-to-bone junction in GF-embedded scaffolds than those in the other groups. Group C demonstrated the highest load-to-failure ratio, and modulus mapping showed that the distribution of the micromechanical properties of the BTI repaired with GF-embedded scaffolds was comparable with that of the native BTI. Micro–computed tomography analysis identified the highest bone mineral density and bone volume/total volume ratio in group C. Conclusion: Bioactive scaffolds with spatially embedded GFs have significant potential to promote the BTI healing of chronic RCTs in a rabbit model. Clinical Relevance: The scaffolds with spatiotemporal delivery of GF may serve as an off-the-shelf biomaterial graft to promote the healing of RCTs.

283-LB: The Differential Effect of Gastric Bypass vs. Sleeve Gastrectomy on Prandial Symptoms of Hypoglycemia and Dumping Syndrome

Gastric bypass surgery (GB), and to lesser degree sleeve gastrectomy (SG), predispose to prandial hypoglycemia. Diagnosis is challenging since hypoglycemic symptoms overlap with those of dumping syndrome. Here, we sought to determine whether symptoms distribution after meal challenge differ among GB vs. SG or non-operated controls (CN), and between GB with and without documented hypoglycemia syndrome as per Whipple's triad. Plasma glucose and prandial symptoms were obtained every 15 min during a 3-h mixed-meal test in matched, non-diabetic groups of 11 hypoglycemic-GB (HGB), 18 asymptomatic-GB (AGB), 24 SG and 5 CN. Symptoms were stratified into autonomic (breathlessness, fatigue, sleepiness, palpitation, restlessness, dizziness, shaking, sweating, feeling warm) and neuroglycopenic (fainting or syncope, impaired cognition, irritability, seizure), and gastrointestinal (GI) symptoms. Peak-to-nadir glycemic excursion was higher in GB vs. SG vs. CN (137±8.0 vs. 86.6±6.0 vs. 48.6±9.1 mg/dl, respectively, P &amp;lt; 0.001). GI symptoms were experienced mainly within first 60 minutes of meal study in all 4 groups (P &amp;lt; 0.001 for time factor), and their average score was higher in GB compared with SG (by 2-fold) and CN subjects (by 14-fold, P &amp;lt; 0.01 for group factor). Likewise, autonomic symptoms were most prevalent during the early phase of the meal (P &amp;lt; 0.05), and their average score tended to be higher in GB compared with SG (by 2-fold) and CN subjects (by 5-fold, P = 0.06 for group factor). Neither GI nor autonomic symptom scores differed among HGB and AGB. Given the low rate of chemical hypoglycemia, neuroglycopenic symptoms were rare and not different among the groups. We conclude that the majority of autonomic symptoms, often mistaken for hypoglycemia, occur in early prandial phase and are not different among GB with and without documented hypoglycemia syndrome. Thus, presence of neuroglycopenia is critical in diagnosis of clinical hypoglycemia in this population. Disclosure H. Honka: None. S. Al-rifaie: None. A. Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp &amp; Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp &amp; Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. M. Salehi: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)

Abstract 1245: A novel, immune-competent, Myc-dependent model of rapid metastatic recurrence of pancreatic cancer after resection

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a resistant malignancy with dismal outcomes. Early diagnosis, systemic treatment, and surgical resection are interdependently essential in improving survival. However, 20-30% of patients who undergo primary tumor resection will experience a metastatic recurrence in the liver within six months of surgery, despite no substantial differences in clinical history. This “rapid recurrence” (rrPDAC) is poorly understood. These metastatic lesions have a few possible origins, including occult synchronous metastases and disseminated metachronous lesions. We hypothesize metastases from either origin are affected by systemic and microenvironmental changes due to surgical intervention. RNA-seq of human rrPDAC primary tumors identified increased expression of Myc-targets when compared to long-term non-recurrers. Here, we describe a novel mouse model of immune competent, surgically resected PDAC that models rapid recurrence. Utilizing novel cell lines derived from our lab’s inducible, p48-Cre-recombinase driven LSL-KrasG12D/+ LSL-ROSA-MYC+/+ (KMC) mouse model, we orthotopically implanted KMC tumor cells into the pancreas of immune competent mice and monitored tumor growth and liver metastases weekly for two weeks via ultrasound. Mice taken down at day 14 (pre-surgery) did not demonstrate micrometastases on serial liver sectioning, however circulating tumor cells were present and isolated from venous blood. Experimental mice were randomized into control (n=17), distal pancreatectomy (n=14), and sham laparotomy cohort (n=14) and metastases were tracked via ultrasound twice-weekly. Surgically resected and sham surgery mice developed liver metastases a median 12 days earlier than controls. Additionally, using cell lines derived from the more traditionally studied KPC mouse model of PDAC (Kras activating mutation and p53 loss of function mutation) and the surgical model described above, distal pancreatectomy (n=13) resulted in metastasis to the liver in a median of 9 days earlier than controls (n=12).In the rrPDAC KMC model, RNA-sequencing of liver parenchyma of mice one day after surgery showed significantly elevated levels of Saa1 mRNA compared to nonoperative controls. This is indicative of a systemic inflammatory response after surgery that we hypothesize is having pro-metastatic effects on the liver, which has been previously reported (1).This model will allow for investigation into rrPDAC and the role surgery plays in exacerbation of metastasis in humans. Our goal is to inform changes in pre- and/or post-operative standards of care for pancreatic resection surgery to reduce the risk of rapid liver metastasis following pancreas resection surgery.