FIB-4 Reliability in Patients With Severe Obesity: Lower Cutoffs Needed?

BACKGROUND: Liver biopsy is the gold standard to evaluate hepatic fibrosis; however, it has many drawbacks, especially in patients with severe obesity. Noninvasive testing such as the FIB-4 score is increasingly being used as the initial screening tool to identify patients at risk for advanced fibrosis. The broader applicability of FIB-4 and the precision of its cutoff values remain uncertain in metabolic dysfunction-associated steatotic liver disease and patients with severe obesity. Our study explored the correlation between FIB-4 scores and intraoperative liver biopsy in patients with severe obesity undergoing bariatric surgery. METHODS: A total of 632 patients with severe obesity underwent preoperative vibration-controlled transient elastography and intraoperative liver biopsy during bariatric surgery from January 2020 to August 2021. Variables collected included patient demographics, laboratory values, abdominal ultrasound, vibration-controlled transient elastography, and liver biopsy results. ANOVA 1-way test, χ2 tests, and Fisher exact tests were used for quantitative and qualitative variables, respectively. The 95% CIs for the mean FIB-4 scores were used to generate surrogate cutoff values. The proposed FIB-4 cutoffs for F0-1, F2, F3, and F4 were 0.62 (CI: 0.59, 0.64), 0.88 (0.74, 1.01), 1.24 (0.94, 1.54), and 1.53 (0.82, 2.24), respectively. Area under the curve (AUC) methods were used to compare traditional to proposed cutoff values. RESULTS: Applying the traditional FIB-4 cutoffs to approximate advanced fibrosis yielded an AUC of 0.5748. Use of the proposed FIB-4 cutoffs increased the AUC to 0.6899. The proposed FIB-4 cutoffs correctly identified 40 patients with biopsy-proven advanced fibrosis (F3-F4), all of which would have been missed using traditional cutoffs. CONCLUSION: Our study revealed that the use of the currently accepted FIB-4 cutoffs as the screening modality for identifying patients with advanced fibrosis due to metabolic dysfunction-associated steatotic liver disease is insufficient and will result in missing patients with histologically confirmed advanced fibrosis. Use of the revised FIB-4 scores should be considered to diagnose patients with severe obesity at high risk of liver disease progression.

The integrated stress response in cancer progression: a force for plasticity and resistance.

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression. Rewiring the cellular proteome shifts the phenotypic balance between growth and adaptation to promote therapeutic resistance and cancer cell survival. The integrated stress response (ISR) is a key translational program activated by oncogenic stress that is utilized to fine-tune protein synthesis and adjust to environmental barriers. Here, we focus on the role of ISR signaling for driving cancer progression. We highlight mechanisms of regulation for distinct mRNA translation downstream of the ISR, expand on oncogenic signaling utilizing the ISR in response to environmental stresses, and pinpoint the impact this has for cancer cell plasticity during resistance to therapy. There is an ongoing need for innovative drug targets in cancer treatment, and modulating ISR activity may provide a unique avenue for clinical benefit.

The Immersive Cleveland Clinic Virtual Reality Shopping Platform for the Assessment of Instrumental Activities of Daily Living.

A decline in the performance of instrumental activities of daily living (IADLs) has been proposed as a prodromal marker of neurological disease. Existing clinical and performance-based IADL assessments are not feasible for integration into clinical medicine. Virtual reality (VR) is a powerful yet underutilized tool that could advance the diagnosis and treatment of neurological disease. An impediment to the adoption and scaling of VR in clinical neurology is VR-related sickness resulting from sensory inconsistencies between the visual and vestibular systems (i.e., locomotion problem). The Cleveland Clinic Virtual Reality Shopping (CC-VRS) platform attempts to solve the locomotion problem by coupling an omnidirectional treadmill with high-resolution VR content, enabling the user to physically navigate a virtual grocery store to simulate shopping. The CC-VRS consists of Basic and Complex shopping experiences; both require walking 150 m and retrieving five items. The Complex experience has additional scenarios that increase the cognitive and motor demands of the task to better represent the continuum of activities associated with real-world shopping. The CC-VRS platform provides objective and quantitative biomechanical and cognitive outcomes related to the user's IADL performance. Initial data indicate that the CC-VRS results in minimal VR-sickness and is feasible and tolerable for older adults and patients with Parkinson's disease (PD). The considerations underlying the development, design, and hardware and software technology are reviewed, and initial models of integration into primary care and neurology are provided.

Galectin-3 Promotes Müller Glia Clearance Phagocytosis via MERTK and Reduces Harmful Müller Glia Activation in Inherited and Induced Retinal Degeneration.

Clearance phagocytosis is a documented function of Müller glia in the retina. However, the molecular mechanisms of Müller glia phagocytosis remain largely undefined. Here, we show that extracellular galectin-3 and protein S promote clearance phagocytosis by immortalized human MIO-M1 Müller cells in an additive, saturable manner. Galectin-3 promotes phagocytosis by primary Müller glia from wild-type (WT) mice but not from mice that lack the engulfment receptor MERTK and therefore develop postnatal photoreceptor degeneration. Probing a possible functional link between Müller galectin-3 and MERTK, we discovered that mertk -/- Müller glia in situ show excess galectin-3 at postnatal day 20 (P20), an age prior to detectable photoreceptor degeneration. Moreover, double knockout (DKO) mice lacking both galectin-3 and MERTK show increased activation of Müller cells (but not of microglia) at P20 and more pronounced photoreceptor loss at P35 compared to mice lacking MERTK alone. Exploring the well-established sodium iodate injury model, we also found more severe activation specifically of Müller glia, and worse retinal damage in mice lacking galectin-3 compared to WT mice. Indeed, galectin-3 deficiency significantly increased sensitivity to injury, yielding Müller activation and retinal damage at a sodium iodate concentration that had no effect on the WT retina. Altogether, our results from both inherited and acutely induced models of retinal degeneration agree that eliminating galectin-3 exacerbates Müller cell activation and retinal degeneration. These data identify an important protective role for the MERTK ligand galectin-3 in the retina in restraining Müller glia activation.

Characterizing Head Impact Exposure in Men and Women During Boxing and Mixed Martial Arts.

BACKGROUND: The accumulation of subconcussive impacts has been implicated in permanent neurological impairment. A gap in understanding the relationship between head impacts and neurological function is the lack of precise characterization and quantification of forces that individuals experience during sports training and competition. PURPOSE: To characterize impact exposure during training and competition among male and female athletes participating in boxing and mixed martial arts (MMA) via an instrumented custom-fit Impact Monitoring Mouthguard (IMM). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Twenty-three athletes (n = 4 women) were provided a custom-fit IMM. The IMM monitored impacts during sparring and competition. All training and competition sessions were videotaped. Video and IMM data were synchronized for post hoc data verification of true positives and substantiation of impact location. IMM data were collected from boxing and MMA athletes at a collaborating site. For each true-positive impact, peak linear acceleration and peak angular acceleration were calculated. Wilcoxon rank sum tests were used to evaluate potential differences in sport, activity type, and sex with respect to each outcome. Differences in impact location were assessed via Kruskal-Wallis tests. RESULTS: IMM data were collected from 53 amateur training sessions and 6 competitions (session range, 5-20 minutes). A total of 896 head impacts (men, n = 786; women, n = 110) were identified using IMM data and video verification: 827 in practice and 69 during competition. MMA and boxers experienced a comparable number of impacts per practice session or competition. In general, MMA impacts produced significantly higher peak angular acceleration than did boxing impacts (P < .001) and were more varied in impact location on the head during competitions. In terms of sex, men experienced a greater number of impacts than women per practice session. However, there was no significant difference between men and women in terms of impact magnitude. CONCLUSION: Characteristic profiles of head impact exposure differed between boxing and MMA athletes; however, the impact magnitudes were not significantly different for male and female athletes.

Military-Specific Normative Data for Cognitive and Motor Single- and Dual-Task Assessments for Use in Mild Traumatic Brain Injury Assessment.

INTRODUCTION: Military personnel and civilian athletes are both at risk for mild traumatic brain injury. However, these groups are unique in their training and typical daily activities. A fundamental gap in the evaluation of military personnel following mild traumatic brain injury is the lack of military-specific normative reference data. This project aimed to determine if a separate normative sample should be used for military personnel on their performance of the Cleveland Clinic Concussion application and a recently developed dual-task module. METHODS: Data were collected from healthy military personnel (n = 305) and civilians (n = 281) 18 to 30 years of age. Participants completed the following assessments: simple and choice reaction time, Trail Making tests A&B, processing speed test, single-task postural stability, single-task cognitive assessment, and dual-task assessment. RESULTS: Civilian participants outperformed military service members on all cognitive tasks under single- and dual-task conditions (P ≤ 0.04). The military group outperformed civilians on all postural stability tasks under single- and dual-task conditions (P ≤ 0.01). CONCLUSION: Differences in cognitive performance and postural stability measures may be influenced by demographic differences between military and civilian cohorts. Thus, military-specific normative datasets must be established to optimize clinical interpretation of Cleveland Clinic Concussion assessments.

Reduction of opioid use after implementation of enhanced recovery after bariatric surgery (ERABS).

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been extensively proven in lower gastrointestinal surgery to decrease postoperative physiologic stress and length of stay (LOS). ERAS in bariatric surgery (ERABS) varies immensely from each program with inconsistent results with a predominant goal of reducing LOS. Our focus in implementing enhanced recovery after bariatric surgery (ERABS) protocols is aimed at reducing postoperative pain and opioid use. METHODS: This is a retrospective review of patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (VSG) at a single high-volume center from June 2016 to October 2017. Patients on previous standard protocol were categorized into "Pre-Liposomal Bupivacaine (LB) group." After routine use of Exparel™, patients were grouped into "LB group." After ERABS protocol was initiated, patients were categorized into "ERABS/LB group." Postoperative opioids were converted to morphine equivalents units (MEU); pain scores, LOS, and 30-day outcomes were analyzed using combination of t test and Mann-Whitney U. RESULTS: A total of 1340 patients were included in the study: 304 patients in pre-LB group; 754 patients in LB group, and 282 patients in ERABS/LB group. Total hospital opioid use was 58.6 MEU in pre-LB, 40.8 MEU in LB, and 23.8 MEU in ERABS/LB (p = 0.01). ERABS/LB group found a 59.5% decline in MEU requirements compared to pre-LB (p < 0.001) and 44.9% of patients did not require any additional narcotics on the floor compared to 0% in pre-LB group (p < 0.001). ERABS/LB LOS was an average of 1.48 days compared to 1.54 days in pre-LB group (p = 0.03) with an overall decrease of 3.74% in readmission rates (p = 0.03). CONCLUSIONS: Implementation of ERABS significantly reduced postoperative opioid use, LOS, and readmissions. With ERABS, a more profound effect was observed than simply adding Exparel™ to preexisting protocols. Almost half of these patients did not require narcotics while recovering on the surgical floor. More studies are required to assess the true effect of ERABS without use of Exparel™.

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP.

This study was designed to evaluate cardiac and respiratory dysfunction in a mouse model of sudden unexpected death in epilepsy i.e., SUDEP. We simultaneously monitored respiration via plethysmography and the electrocardiogram via telemetry before, during, and after an audiogenic seizure. DBA/1 mice responded to an acoustic stimulus with one or two cycles of circling and jumping before entering a clonic/tonic seizure. This was followed by death unless the mice were resuscitated by mechanical ventilation using room air. During the initial clonic phase, respiration declined and cardiac rhythm is slowed. By the tonic phase, respiration had ceased, atrial P-waves were absent or dissociated from the QRS complex, and heart rate had decreased from 771±11 to 252±16 bpm. Heart rate further deteriorated terminating in asystole unless the mice were resuscitated at the end of the tonic phase which resulted in abrupt recovery of P-waves and a return to normal sinus rhythm, associated with gasping. Interestingly, P-waves were preserved in the mice treated with methylatropine during the pre-ictal period (to block parasympathetic stimulation) and heart rate remained unchanged through the end of the tonic phase (765±8 vs. 748±21 bpm), but as in control, methylatropine treated mice died from respiratory arrest. These results demonstrate that a clonic/tonic seizure in the DBA/1 mouse results in abrupt and simultaneous respiratory and cardiac depression. Although death clearly results from respiratory arrest, our results suggest that seizure activates two central nervous system pathways in this model-one inhibits respiratory drive, whereas the other inhibits cardiac function via vagal efferents. The abrupt and simultaneous recovery of both respiration and cardiac function with mechanical ventilation within an early post-ictal timeframe shows that the vagal discharge can be rapidly terminated. Understanding the central mechanism associated with the abrupt cardiorespiratory dysfunction and equally abrupt recovery may provide clues for therapeutic targets for SUDEP.

Efficacy of liposomal bupivacaine versus bupivacaine in port site injections on postoperative pain within enhanced recovery after bariatric surgery program: a randomized clinical trial.

BACKGROUND: Use of liposomal bupivacaine (LB) in surgery is reported with decreased postoperative opioid requirements. The efficacy of LB versus standard bupivacaine injections at laparoscopic port sites during bariatric surgery is unknown. OBJECTIVES: To determine whether there was a difference in postoperative hospital opioid requirements after port site injections of LB versus standard bupivacaine during laparoscopic bariatric surgeries. Primary endpoint was total in hospital opioid use expressed as morphine-equivalent use. Secondary endpoints included home opioid use, pain scores, hospital length of stay, and adverse events. SETTING: Academic-affiliated private practice. METHODS: A 2-group randomized, double-blinded trial from November 2017 to August 2018 with patients randomly assigned to receive either LB or bupivacaine alone at trocar site injections during laparoscopic Roux-en-Y gastric bypass (LRYGB) or vertical sleeve gastrectomy (VSG). All patients underwent enhanced recovery after bariatric surgery protocols. RESULTS: All patients undergoing LRYGB or VSG assessed for eligibility. Of 682 patients undergoing LRYGB or VSG, 231 met inclusion criteria, 52 patients excluded intraoperatively. Among 231 patients (mean age, 39.2 years; 79% women; mean body mass index 45.0), 179 patients (77%) completed the trial. Patients randomly assigned to receive either LB (n = 89) or bupivacaine alone (n = 90) at trocar site injection during LRYGB or VSG. Postoperative morphine-equivalent use were similar (LB 8.3 [standard deviation 4.0-13.9] versus bupivacaine group 7.5 [standard deviation 3.6-13.1] P = .94) with highest requirement in first 4 hours after surgery. There was no significant difference in length of stay, pain scores, or complications. There were more patients in the bupivacaine group that did not take pain medications on postoperative days 2 to 4 (P = .032, P = .23, P = .005, respectively). There were more patients in the bupivacaine group 48.1% (n = 39) compared with the LB group 34.2% (n = 27) that did not consume any narcotic tablets at home but this not found to be statistically significant (P value = .07). CONCLUSIONS: Among patients undergoing primary bariatric surgery under enhanced recovery after bariatric surgery protocol, there was no significant difference in postoperative hospital opioid use in those receiving LB compared with standard bupivacaine. A greater percentage of patients in the standard bupivacaine group did not require any narcotics at home, which was significant on postoperative days 2 to 4. To become completely opioid free after bariatric surgery, resources should be focused on multimodal approaches instead of reliance on type of anesthetic medication used.