Citations

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Background: Immune checkpoint inhibitors (ICIs) have been successfully used in the previous decade for the treatment of a variety of malignancies. Adverse events (AEs) can cause many symptoms, most notably cardiac. We analyzed the frequency of these adverse events, comparing pembrolizumab and other ICIs. Methods: Using the Food and Drug Administration (FDA) adverse event reporting database (FAERS), we searched for all adverse events of interest reported for every ICI included in this study. After obtaining the data, we conducted a disproportionality analysis using the reporting odds ratio (ROR) and the information component (IC). Results: A total of 6719 ICI-related cardiac adverse events of interest were reported in the database. Serious outcomes were reported in 100% of the cases, with 34.3% of the cases ending fatally. Compared with all other medications in the database, pembrolizumab use was more frequently associated with myocarditis, pericardial disease, heart failure, and atrial fibrillation. No difference was found in cardiotoxicity between different ICIs. Conclusions: Although infrequent, cardiac AEs in pembrolizumab use are associated with serious outcomes and high mortality. Prospective studies are needed to further research the connection between ICI use and cardiotoxicity.

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)’s precise role in these conditions, while providing a summary of its unique molecular characteristics.

OBJECTIVE The Woven EndoBridge (WEB) device was approved to treat wide-necked bifurcation aneurysms. The device is designed as an intrasaccular flow disruptor covering aneurysm widths up to 10 mm. Although prior studies combined all aneurysm sizes, it is known that aneurysms behave differently in response to endovascular treatment based on their size. Therefore, the authors’ objective was to identify ideal middle cerebral artery (MCA) aneurysm width and neck sizes most suitable for WEB treatment. METHODS The WorldWideWEB consortium is a large multicenter retrospective database that analyzes intracranial aneurysms treated with the WEB device. In this study, all unruptured MCA bifurcation aneurysms with available measurements were included. Cutoff values based on aneurysm width and neck in relation to aneurysm occlusion status were measured using the receiver operating characteristic (ROC) curve. Propensity score matching (PSM) was then used to compare treatment outcomes between aneurysms smaller and larger than the cutoff value for both width and neck size. RESULTS The ideal cutoff values for MCA bifurcation aneurysm width and neck were 6.1 mm and 4.6 mm, respectively. On PSM, 87 matched pairs were compared based on width size (≤ 6.1 mm and > 6.1 mm), and 77 matched pairs were compared based on neck size (≤ 4.6 mm and > 4.6 mm). There was a significant difference in adequate aneurysm occlusion between aneurysms smaller and larger than those cutoff values for both widths (93% vs 76%, p = 0.0017) and neck sizes (90% vs 70%, p = 0.0026). The retreatment rate was also significantly higher for larger aneurysms in both parameters. CONCLUSIONS This study shows that MCA bifurcation aneurysms ≤ 6.1 mm in width and ≤ 4.6 mm in neck size are significantly better candidates for WEB treatment, leading to improved occlusion status and reduced retreatment rate, which are important considerations when using WEB devices.

Endotoxemia is closely related to many diseases. As the largest endotoxin reservoir in the human body, the gut microbiota should be a key target for alleviating endotoxemia. The intestinal microbiota is believed to cause endotoxemia directly or indirectly by modifying the intestinal barrier function through dysbiosis, changing intestinal mucosal permeability and bacterial translocation. Diet is known to be the main environmental factor affecting the intestinal microbiota, and different diets and food components have a large impact on the gut microbiota. The Mediterranean diet, which received much attention in recent years, is believed to be able to regulate the gut microbiota, thereby maintaining the function of the intestinal barrier and alleviating endotoxemia. In this review, we focus on the relationship between the gut microbiota and endotoxemia, and how the Mediterranean dietary (MD) pattern can interfere with endotoxemia through the gut microbiota.

Abstract Disclosure: D. Segura Torres: None. K. Raygoza: None. M. Garcia: None. J.P. Brito: None. M.E. McDonnell: None. M. Corrigan: None. C.R. McCartney: None. R. Dhaliwal: None. N.M. Singh Ospina: None. Clinical practice guidelines (CPG) improve healthcare quality by guiding decision making. Recent trends in CPG development emphasize incorporating race/ethnicity terms and health equity considerations. However, the appropriateness of how race/ethnicity is utilized remains uncertain. Objective This study seeks to evaluate the use of race/ethnicity in published Endocrine Society (ES) CPG and elucidate the context in which race and ethnicity terms are used. Methods: We identified 30 active clinical practice guidelines from ES up to January 2023. Two reviewers independently and in duplicate: a) located statements addressing race/ethnicity using an electronic search with 24 keywords, b) determined the statements' location within guidelines, and c) classified them based on content using frameworks by Cerdena and Gilliam. Disagreements were resolved by consensus. Exclusions were made for statements not addressing race and ethnicity terms in the appropriate context (e.g., “minority” of the panel disagreed), as well as for those in references or duplicates. Results: We reviewed 30 clinical practice guidelines, with 19 of them containing statements related to race or ethnicity. After applying exclusion criteria, we identified a final analytic sample of 114 statements. The majority of these statements were found in the body of the clinical guidelines (79%), followed by the evidence-to-decision framework (14%), and clinical recommendations (7%).The predominant classification were statements in which there was biologization of race/ethnicity 55% (n=63). Discussions on racial/ethnic disparities accounted for 23% (n=26) of the statements, with 31% (n=8) of these including explicit considerations of social context. Additionally, there were descriptions of race-specific treatment or diagnosis/screening in 14% (n=16) and 9% (n=10) of the statements, respectively.Less commonly statements of race/ethnicity reflected the consideration of ancestry as a code for race/ethnicity (n=7, 6%), identified ancestry as a risk factor for disease (n=19, 6%), highlighted racial/ethnic groups as understudied n=6, 5%), normalized findings to the majority group (White centeredness) (n=7, 6%), and other categories (7%). None of the statements employed race/ethnicity terms to emphasize cultural humility or the value of inclusivity in guideline committees. Conclusion: We systematically analyzed how race and ethnicity terms are used in ES CPGs. Our findings align with prior assessments made in non-ES CPG, highlighting the prevalent biologization of race and ethnicity constructs. Addressing this trend and incorporating socio-structural context considerations could bolster the impact of clinical guidelines in promoting health equity. Presentation: 6/1/2024

Three multicenter studies have shown that the addition of mycophenolate mofetil (MMF) to an immunosuppressive regime consisting of cyclosporin A (CSA) and prednisone (PRED) decreases the incidence of acute rejection episodes when compared with azathioprine (AZA) or placebo (1–3). In those patients receiving 3 g/d of MMF, the highest dose used in the studies, there was a trend towards an increased incidence of cytomegaloviral sepsis (CMV). We postulated therefore that MMF may represent an independent risk factor for the development of CMV infection in patients receiving renal allografts and MMF at our institution. Having altered the triple drug regime from CSA, AZA (2‐2.5 mg/kg/d) and PRED to CSA. MMF (2 g/d) and PRED in July 1995, we elected to study all patients undergoing kidney transplantation for the 33‐month period January 1994‐September 1996, by undertaking a case control analysis to determine independent risk factors for the development of CMV infection, as defined by CMV viremia or tissue‐invasive CMV. Three CMV disease‐free control patients were matched to each case, these patients having been randomly selected from the entire pool of patients in the observation period. There were 31 CMV case patients and 102 control patients. Univariate analysis indicated that gender, a concomitant pancreas transplant, acute rejection and CMV seropositivity in the donor were risk factors. However, multivariate analysis indicated that only acute rejection and donor CMV seropositivity were independently linked (p<0.05) to CMV disease in this sample. Specifically, the odds ratio (OR) for CMV disease between MMF and AZA was 1.0 (95% confidence interval (CI): 0.46‐2.18). Therefore, in this case control study we find no evidence that MMF at a dose of 2 g/d is an independent risk factor for primary CMV viremia or tissue invasion in renal allograft recipients.

Key Points In patients with cirrhosis and AKI requiring renal replacement therapy (RRT), hepatorenal syndrome-AKI was not associated with an increased 90-day mortality when compared with other AKI etiologies. Etiology of AKI may not be a critical factor regarding decisions to trial RRT in acutely ill patients with cirrhosis and AKI. Although elevated, mortality rates in this study are comparable with those reported in general hospitalized patients with AKI requiring RRT. Background While AKI requiring renal replacement therapy (AKI-RRT) is associated with increased mortality in heterogeneous inpatient populations, the epidemiology of AKI-RRT in hospitalized patients with cirrhosis is not fully known. Herein, we evaluated the association of etiology of AKI with mortality in hospitalized patients with cirrhosis and AKI-RRT in a multicentric contemporary cohort. Methods This is a multicenter retrospective cohort study using data from the HRS-HARMONY consortium, which included 11 US hospital network systems. Consecutive adult patients admitted in 2019 with cirrhosis and AKI-RRT were included. The primary outcome was 90-day mortality, and the main independent variable was AKI etiology, classified as hepatorenal syndrome (HRS-AKI) versus other (non–HRS-AKI). AKI etiology was determined by at least two independent adjudicators. We performed Fine and Gray subdistribution hazard analyses adjusting for relevant clinical variables. Results Of 2063 hospitalized patients with cirrhosis and AKI, 374 (18.1%) had AKI-RRT. Among them, 65 (17.4%) had HRS-AKI and 309 (82.6%) had non–HRS-AKI, which included acute tubular necrosis in most cases (62.6%). Continuous renal replacement therapy was used as the initial modality in 264 (71%) of patients, while intermittent hemodialysis was used in 108 (29%). The HRS-AKI (versus non–HRS-AKI) group received more vasoconstrictors for HRS management (81.5% versus 67.9%), whereas the non–HRS-AKI group received more mechanical ventilation (64.3% versus 50.8%) and more continuous renal replacement therapy (versus intermittent hemodialysis) as the initial RRT modality (73.9% versus 56.9%). In the adjusted model, HRS-AKI (versus non–HRS-AKI) was not independently associated with increased 90-day mortality (subdistribution hazard ratio, 1.36; 95% confidence interval, 0.95 to 1.94). Conclusions In this multicenter contemporary cohort of hospitalized adult patients with cirrhosis and AKI-RRT, HRS-AKI was not independently associated with an increased risk of 90-day mortality when compared with other AKI etiologies. The etiology of AKI appears less relevant than previously considered when evaluating the prognosis of hospitalized adult patients with cirrhosis and AKI requiring RRT.

BACKGROUND AND OBJECTIVES: Awake minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) generates minimal surrounding tissue damage and has been shown to be a safe, time-effective, and cost-reductive technique in single-level procedures. The purpose of this study was to advocate for the utilization of multilevel MIS-TLIF even in challenging cases as it has demonstrated positive outcomes. METHODS: Chart review was conducted for consecutive patients undergoing awake multilevel MIS-TLIF from 2020 to 2023. Various demographic, preoperative, and postoperative variables were collected and descriptively analyzed. RESULTS: Sixteen patients underwent multilevel awake MIS-TLIF at our institution during the specified period. Among them, 87.5% underwent a two-level procedure and 12.5% a three-level procedure. The median age ± IQR was 69.5 ± 11 years, with a slight male predominance (56.25%). Common comorbidities included hypertension (56.25%), obesity (37.5%), sleep apnea (25%), and type 2 diabetes (18.75%). The American Society of Anesthesiologists risk was 2 in 43.75% of patients and 3 in 56.25%. All patients presented pain, and 12.5% showed motor deficit. Intraoperative data showed a median of 196 minutes in the operating room where 156 ± 27.75 minutes corresponded to actual procedure time. The median estimated blood loss was 50 ± 70 cc. In the immediate postoperative period, 1 patient had nausea and emesis, and 1 reported fatigue. The median pain score during this period was 4.6 ± 2.03. Pain control medications were required for various patients, with methocarbamol (50%), hydromorphone (37.5%), and oxycodone (25%) being the most commonly prescribed in the postanesthesia care unit. No patient had new neurological deficits after the surgical intervention. The median length of stay was 2 days ±1.25. All patients were discharged with no complications. CONCLUSION: Multilevel awake MIS-TLIF emerges as a safe and effective technique for complex cases, enhancing patient quality of life with minimal blood loss and postoperative pain.

Background/Objectives: There is evidence of overtreatment in patients with subclinical hypothyroidism (SCH). We aimed to identify the proportion of patients treated for SCH and the determinants of thyroid hormone therapy initiation. Methods: We included a random sample of adult Veterans diagnosed with SCH from 1 January 2016 to 31 December 2018 and conducted univariate and multivariable logistic regression to identify factors associated with levothyroxine initiation. Results: Out of 229 Veterans with SCH [90.0% male, 87.2% White, 99.1% non-Hispanic, median age (interquartile range; IQR) 68 (17) years], 27.5% were treated with levothyroxine. The treated group had a higher proportion of White patients (95.2% vs. 84.2%, p = 0.039), a higher thyrotropin level [median (IQR), 6.98 (2.06) mIU/L vs. 6.14 (1.10) mIU/L, p = 0.0002], a higher proportion of patients with thyrotropin level ≥ 10 mIU/L (11.1% vs. 3.0%, p = 0.021), a lower frequency of confirmatory thyroid testing before initiating levothyroxine (49.2% vs. 97.0%, p < 0.0001), and a similar frequency of thyroid autoimmunity testing (3.2% vs. 0.6%, p = 0.18) compared to the untreated group. In a multivariable logistic regression analysis, White race (OR = 4.50, 95% CI 1.19 to 17.08, p = 0.026) and index thyrotropin level [OR = 1.71, 95% CI 1.24 to 2.35, p = 0.001; for every SD increase (1.6 mIU/L)] were associated with higher odds of treatment. Conclusions: Three in 10 Veterans with SCH received levothyroxine, often based on a single abnormal thyroid test without autoimmunity assessment. White race and higher thyrotropin level were linked to increased odds of starting treatment, indicating potential disparities and the influence of SCH severity on decision-making.