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Medications for Weight Loss and MASLD: A National Survey of Hepatology and Gastroenterology Provider Practices, Attitudes, and Knowledge Before Resmetirom
No full textGOALS: Our aim was to perform a national survey of provider attitudes, practices, and knowledge regarding weight loss and MASLD medications in patients with MASLD.
BACKGROUND: While weight loss is a cornerstone in the management of metabolic dysfunction-associated steatotic liver disease (MASLD), FDA-approved medications for weight loss remain underutilized.
RESULTS: We conducted a survey before resmetirom approval of hepatology and gastroenterology providers practicing in 44 states. Surveys were sent to 747 providers with 304 complete responses (41%), of whom 260 (86%) work at a liver transplant center. While nearly all respondents (96%) believed that weight loss medications could benefit patients with MASLD, 77% have never/rarely prescribed them due to low comfort (81%). Among weight loss medication prescribers, glucagon-like peptide-1 (GLP-1) receptor agonists were preferred (66%). In contrast, 63% had prescribed off-label medications for MASLD in the past 12 months, most commonly vitamin E (30%) and GLP-1 receptor agonists (25%). The top reported barriers to prescribing weight loss medications were lack of training/unfamiliarity, cost/insurance coverage, and side-effects, which may be explained by low formal obesity education and lack of knowledge (only 33% of FDA-approved medications for weight loss were correctly identified by \u3e50% of providers). Overall, there was reasonable provider-reported adherence to the 2023 AASLD practice guidance for MASLD.
CONCLUSIONS: This nationwide survey of hepatology and gastroenterology providers before resmetirom demonstrates that while off-label prescribing for MASLD was common, weight loss medication prescription rates remain very low due to low comfort possibly from insufficient education despite strong beliefs that they can benefit patients with MASLD
Clinical Scale MSC-Derived Extracellular Vesicles Enhance Poststroke Neuroplasticity in Rodents and Non-Human Primates
No full textStroke is a leading cause of death and disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) has shown considerable promise in rodent models of stroke. However, the therapeutic efficacy and safety of clinical-scale MSC-EVs for ischemic stroke are not well elucidated, especially in non-human primates. We developed a scalable production method for MSC-EVs using a 3D bioprocessing platform. EVs were isolated with a filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, nanoflow cytometry analysis, proteomic and lipidomic analysis using mass spectrometry, and RNA sequencing. We determined the appropriate dosage and frequency of intravenous administration of EVs in a mouse stroke model. A biodistribution study of the selected dose regimen was performed using the internal cargo of EVs, human mitochondrial DNA. We then confirmed the efficacy of EVs in a marmoset stroke model. Improvement in behavioural tests and MRI-based neuroplasticity were compared between the control and EV groups through blinded evaluation. The proteome profiles of the infarcted hemisphere were also evaluated. EV products showed suitable lot-to-lot consistency. In a mouse stroke model, intravenous administration of a dose of 6 × 10(8) EVs for 5 days resulted in the smallest infarct volume and improvement in motor function. A biodistribution study showed that EVs were rapidly distributed into systemic organs and were relatively specifically distributed to the infarcted brain areas. Intravenous administration of an equivalent dose (3.5 × 10(9) EVs for 5 days) in a marmoset stroke model significantly improved motor functions and anatomical connectivity on diffusion MRI, and significantly reduced infarct volume. Proteomics analyses indicated that EV treatment promoted neurogenesis, synapse organization, and vascular development. In conclusion, this study is the first to demonstrate that a clinical-scale EV product is safe and significantly enhances function recovery and neuroplasticity in a non-human primate stroke model, offering a promising treatment for human stroke
Vascular Contribution to Cerebral Waste Clearance Affected by Aging or Diabetes
No full textBackground: The brain\u27s vascular system has recently been shown to provide an important efflux pathway for cerebral waste clearance (CWC). However, little is known about the influence of aging or diabetes on the CWC. The aim of the current study is to investigate the vasculature contribution to CWC under aging and diabetic conditions.
Methods: Male Wistar rats under aging and diabetic conditions were evaluated using dynamic intra-cisterna superparamagnetic iron oxide-enhanced susceptibility-weighted imaging (SPIO-SWI). Theoretical analysis of the expected signal intensity using SPIO-SWI was compared with the corresponding dynamic in vivo images. Quantitative susceptibility mapping (QSM) was used to evaluate the iron-based tracer concentration in the venous system.
Results: Our data demonstrated that the theoretical analysis predicted the dynamic changes in the signal intensity after SPIO infusion. The distinct hyperintense signals due to the lower concentration of the SPIO over time in cerebrospinal fluid (CSF) and meningeal lymphatic (ML) vessels likely represented the CWC through various efflux pathways, including cerebral vascular and ML vessels. The QSM analysis further revealed reduced CWC from the vasculature in both the aged and diabetic groups compared to the younger group.
Conclusions: Our results demonstrated that SPIO-SWI can quantitatively evaluate the CWC efflux contributions from cerebral vascular vessels under aging or diabetic conditions
Differences in brain development and need for CSF diversion based on MMC level: Comparison between prenatal and postnatal repair
No full textPURPOSE: How myelomeningocele (MMC) level affects early brain development and hydrocephalus rates after prenatal repair is not well understood. This study aimed to determine differences in brain development and need for cerebrospinal (CSF) diversion in MMC patients according to lesion level and timing of repair.
METHODS: We retrospectively identified patients from Barnes-Jewish/St. Louis Children\u27s Hospitals from 2016 to 2021 who were treated for lumbosacral MMC. CSF diversion need and prenatal and postnatal imaging characteristics were compared between lesion levels L1-L3 and L4-sacrum in the overall, prenatal surgery, and postnatal surgery cohorts.
RESULTS: Twenty-four patients underwent prenatal surgery and 35 underwent postnatal surgery. Overall, prenatal third ventricular diameter (p = 0.029) and postnatal frontal horn diameter (p = 0.022) were larger in L1-L3 than L4-sacral MMC. In the prenatal surgery cohort, prenatal third ventricle (p = 0.011), and postnatal frontal (p = 0.018) and occipital (p = 0.035) horn diameters were greater with L1-L3 vs. L4-sacral MMC. Minimal differences in parenchymal anatomy were observed except for increased massa intermedia size with higher lesion level on postnatal imaging after postnatal MMC repair (p = 0.045). MMC level was not associated with CSF diversion in the overall or prenatal surgery cohorts but was in the postnatal surgery cohort (L1-L3 MMC: 82% vs. L4-sacral MMC: 50%, p = 0.044).
CONCLUSION: Differences in ventricle size were observed based on MMC level. Higher MMC level was associated with increased massa intermedia size and more CSF diversion in those treated postnatally but not those treated prenatally. Prenatal surgery may be associated with greater hydrocephalus risk reduction in patients with higher MMC levels
Multicenter evaluation of the safety and efficacy of varying doses of cangrelor used in acute cerebrovascular stenting in patients with acute ischemic stroke
No full textBACKGROUND: Acute ischemic stroke often necessitates neuroendovascular interventions such as thrombectomy and, occasionally, stenting for large vessel occlusions or intracranial atherosclerotic disease. Effective antiplatelet therapy is essential during stenting to mitigate thrombosis risks, but consensus on optimal cangrelor dosing remains elusive. This study evaluates the safety and efficacy of various cangrelor doses used in acute cerebrovascular stenting.
METHODS: A multicenter, retrospective cohort study was conducted across 11 comprehensive stroke centers. Patients aged 18-85 with ischemic stroke who underwent emergent cerebrovascular stenting with cangrelor were included. Patients were categorized into low-dose cangrelor (\u3c 2 mcg/kg/min; LDC) and high-dose cangrelor (≥2 mcg/kg/min; HDC) cangrelor groups. Outcomes included thrombotic and bleeding complications both intra-procedurally and within 48 hours post-procedure.
RESULTS: A total of 230 patients were included in the analysis (LDC: 68; HDC: 162). Baseline characteristics were similar between groups. Thrombotic outcomes, including intraprocedural thrombosis (13% LDC vs 6% HDC; P=0.078) and thrombosis within 48 hours of the procedure (9% LDC vs 4% HDC; P=0.093), showed no statistical differences. Similarly, intraprocedural bleeding (6% LDC vs 5% HDC; P=0.753) and intracranial hemorrhage within 48 hours of the procedure (19% LDC vs 25% HDC; P=0.360) were not statistically different.
CONCLUSION: Different cangrelor dosing regimens demonstrated no significant differences in thrombotic or bleeding complications during acute neuroendovascular stenting for ischemic stroke. Larger, prospective studies are warranted to refine optimal dosing strategies for cangrelor in this population
Direct delivery of gene- and cell-based therapies to the nervous system. Image-Guided Biologic Therapies: Neurosurgeons Innovating Treatment Excellence Summit summary
No full textRobotic-assisted hysterectomy for endometrial cancer
No full textRobotic-assisted surgery (RAS) has revolutionized the treatment of endometrial cancer (EC), providing a less invasive alternative to traditional open methods. In early-stage EC, RAS has shown similar oncological results compared to conventional techniques while offering notable improvements in perioperative outcomes, such as shorter hospital stays, less post-operative pain, and faster recovery times. Additionally, the robotic platform has seen widespread adoption in gynecologic oncology due to its ability to address the limitations of conventional laparoscopy, especially reduced conversion rate from minimally invasive surgery (MIS) to open/laparotomy. This approach is particularly beneficial for high-risk groups, including obese and elderly patients, where it has proven to be both safe and effective, presenting a favorable risk-benefit profile. Furthermore, robotic-assisted sentinel lymph node (SLN) mapping, utilizing the FireFly(®) fluorescence imaging system with indocyanine green (ICG) dye, offers exceptional accuracy in detecting SLNs, enhancing the precision of nodal mapping, thereby decreasing the need for more invasive lymphadenectomy and reducing associated morbidity. It is essential to recognize physiological challenges that can arise during RAS, particularly when steep Trendelenburg position combined with pneumoperitoneum (increased intra-abdominal pressure due to CO2 insufflation), can significantly affect both cardiovascular and respiratory systems. Although the upfront costs of robotic surgery are relatively higher, the long-term benefits, such as fewer complications and faster recoveries, make it a cost-effective solution. This review examines current evidence supporting the use of RAS as a standard option for managing patients with EC and its positive impact on their outcomes across diverse risk categories
Karyotypic clonal fraction predicts adverse outcome in TP53-mutated myeloid neoplasms: an International TP53 investigators Network (iTiN) study
No full textWe investigated the prognostic impact of blast counts, TP53 allelic state determinants (number of hits, del(17p), variant allele frequency, complex karyotype),and a novel karyotypic clonal cell fraction (≤50% clonal cells vs \u3e50% clonal cells (termed \u27CK50\u27)) in 495 individuals with TP53-mutated (TP53(MUT) ) myeloid neoplasms. Outcome examined was 24-month survival (OS24). The cohort (median age 71) included 29% (144/495) myelodysplastic syndromes (MDS)/MDS-acute myeloid leukaemia (AML) (1%-19% blasts) and 71% (351/495) AML (≥ 20% blasts), with 18% (81/460) having low CK50. Overall, 83% received front-line hypomethylating agents. Higher blast counts (\u3c 20% vs ≥ 20%) were marginally associated with CK50 (p=0.08). In the OS24 analysis, blast count showed a marginal association with OS24 (HR 1.3 (95% CI 1.0 to 1.6); p=0.07), while CK50 predicted significantly inferior outcomes (HR=1.7 (95% CI 1.2 to 2.3); p=0.002). In a multivariable model including all TP53 allelic state determinants, only CK50 and complex karyotype remained relevant for predicting adverse outcomes
Clinical Outcomes of Eravacycline in Patients Treated for Stenotrophomonas maltophilia Infections
No full textINTRODUCTION: Stenotrophomonas maltophilia is notable for its rising incidence and multidrug resistance, which complicates treatment. As a result of insufficient clinical studies, the 2024 Infectious Diseases Society of America (IDSA) Guidance on Treating Antimicrobial Resistant Gram-negative Infection advises against using eravacycline (ERV) for S. maltophilia infections. We present real-world data on patients treated with ERV for these infections.
METHODS: This multicenter, retrospective, observational study included adult patients who received ERV for treating S. maltophilia infections for ≥ 72 h between October 2018 and August 2022. The primary outcome was the clinical cure evaluated at the end of ERV therapy. Key secondary outcomes included a 30-day survival rate, absence of infection recurrence counting from the end of ERV therapy, and occurrence of possible ERV-related adverse effects (AE) noted in the patient\u27s records.
RESULTS: Overall, 41 patients were included with a median (interquartile range [IQR]) age of 63 years (46.0-74.5). Most patients were male (63.4%) and white (51.2%). The primary source of infection was pulmonary (56.1%), and most patients received ERV for regimen consolidation (65.9%). Combination therapy was used in about 10% of the cases for S. maltophilia treatment. The median (IQR) duration of ERV treatment was 7 days (4.0-11.5). The clinical cure rate was 73.2%, and the 30-day survival rate was 68.3%. Four patients (9.8%) experienced possible AE from ERV.
CONCLUSION: S. maltophilia infections are challenging to treat because of limited options. An analysis of 41 patients indicates ERV may be an acceptable treatment option, but more clinical studies are needed to evaluate its efficacy and safety
The Human Myometrial Transcriptome and the DNA Methylome of Testosterone-treated Patients Resemble the Myometria from Fibroid Patients
No full textUterine fibroids, or leiomyomas, are noncancerous tumors of the myometrium and the most common tumors in women, with a cumulative incidence of approximately 80% by age 50. Currently, hysterectomy is the only definitive cure, and effective non-hormonal therapeutics are lacking. Understanding the etiology of fibroids may lead to alternative, less invasive treatments. Several obstetric disorders, including polycystic ovary syndrome (PCOS), have been linked to uterine fibroids, and women with PCOS often exhibit hormonal imbalances, particularly elevated serum testosterone levels. However, the impact of testosterone on the myometrium remains poorly understood. We hypothesize that elevated testosterone may increase the risk of developing uterine fibroids. Using RNA sequencing and MethylationEPIC array analyses, we compared myometrial tissue from women without fibroids (MyoN, n = 33), with fibroids (MyoF, n = 66), and after testosterone therapy as part of clinical care for gender dysphoria (MyoT, n = 7). The transcriptomic and methylation profiles of MyoT clustered with MyoF and were distinct from MyoN. We identified 1,321 differentially expressed protein-coding genes between MyoT and MyoN, while only 494 were found between MyoT and MyoF. Disease ontology analysis of MyoT vs. MyoN revealed enrichment of the fibroid tumor gene set. Fibroid associated genes including TGFβ3, CCND1, SERPINE1, and FGFR1 were upregulated in MyoT and MyoF samples compared to MyoN samples. The DNA methylation profiles of MyoT were closer to those of MyoF, but no correlation was observed between methylation status and gene expression. Our preliminary data suggest that exogenous testosterone induces transcriptional and methylation changes in the myometrium consistent with those observed in MyoF tissues. These findings suggest that elevated testosterone may be associated with an increased risk of developing uterine fibroids