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.

Abstract Background: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT. Methods: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12–36 h post-MT. Results: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes. Conclusions: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy.

AbstractBackgroundComplications associated with cardiovascular implantable electronic devices may necessitate device and lead removal. An open approach to removal may be electively chosen in cases with high risk of complications or those requiring additional concomitant cardiac surgery. This study aimed to investigate outcomes of patients who underwent elective open lead extractions (OLE) at two large tertiary care centers.MethodsThe records of 29 patients undergoing elective OLE were analyzed through retrospective chart review.Results69 total leads were extracted from 29 patients (77% completely, 23% partially). The average age of the oldest leads was 13.3 ± 11.3 years. Infective endocarditis with severe valvular insufficiency requiring valvular intervention (41%)—an infectious etiology, and tricuspid valve intervention to correct RV lead‐related severe TR (38%)—a noninfectious etiology, were the most common reasons for OLE. 38% of the patients had additional co‐primary or secondary indications for open extraction, such as CABG and pericardiectomies. The rate of major complications and procedural failure was 3% each (1/29). 30‐day survival was 100%, and 1‐year survival was 92%. The average length of hospital stay was 15 days and higher among those undergoing OLE for infectious indications.ConclusionOpen lead extractions offered a similar clinical success rate (97%) to transvenous extractions in this cohort and may be a viable alternative for those necessitating valvular intervention or when the risk of complications from TLE is considered very high.

Abstract Background Sphingolipids play a crucial role in cellular functions and are essential components of cell membranes, signaling molecules, and lipid metabolism. In particular, ceramide is a key intermediate in sphingolipid metabolism and defects in ceramide metabolism can lead to various inborn errors of metabolism, making ceramides important targets for clinical screening and diagnosis. Detecting altered concentration patterns of sphingolipids is desirable for distinguishing related inborn errors of metabolism for diagnosis and treatment monitoring. Methods We developed a liquid chromatography-tandem mass spectrometry method with a pathway-oriented approach to focus on sphingolipids involved in ceramide metabolism. A total of 47 sphingolipids bearing different head groups and side chains were targeted. Precision/reproducibility, linearity, and spike recovery extraction efficiency tests were performed on plasma and serum samples from confirmed cases of sphingolipidosis. Results Linearity of the method showed the coefficient of determination (r2) for all standards to be >0.99 with a slope of 1.00 ± 0.01. Intra- and interday reproducibility of standards spiked into plasma and serum revealed a coefficient of variation <20%. Spike and recovery assessment showed recovery values of 80%–120% for all standards. Altered levels of sphingolipids from patients with hereditary sensory and autonomic neuropathy caused by pathogenic variants in SPTLC2 and hypomyelinating leukodystrophy related to variants in DEGS1 were detected, in agreement with trends reported in earlier studies confirming the utility of this pathway-centric method. Conclusions This method can serve as a useful tool to simultaneously monitor sphingolipids, enabling screening and diagnosis of inborn errors of ceramide metabolism.

AbstractBackgroundCutaneous melanoma (CM) is a significant health concern because of its high metastatic potential. Gene Expression Profile (GEP) testing, particularly the 31‐GEP test (DecisionDx‐Melanoma), has been increasingly used for risk stratification in CM patients. This study aimed to evaluate the clinical utility and performance of the 31‐GEP test in a real‐world setting.MethodsPatients with CM who underwent 31‐GEP testing from August 2014 to August 2022 at our institution were identified through searches of electronic health records. The study analyzed the influence of 31‐GEP testing on clinical decision‐making related to sentinel lymph node biopsy (SLNB), medical oncology referral, and postdiagnosis surveillance. Kaplan–Meier curves and Cox proportional hazard models were used to elucidate the test's performance, focusing on relapse‐free survival (RFS) and melanoma‐specific survival (MSS).ResultsThe study included 65 CM patients. Dermatologists ordered more than 80% of 31‐GEP tests. In 81.5% of cases, 31‐GEP results did not alter standard clinical management. SLNB decisions were unaffected in 92% of patients with pre‐SLNB 31‐GEP results. Among patients with stage I‐IIA melanoma, 25% of those with high‐risk 31‐GEP results were referred to medical oncology. Contrary to expectations, the rate of nodal metastasis was higher in low‐risk than in high‐risk 31‐GEP cases. Survival analysis showed overlapping RFS and MSS curves between different 31‐GEP classes, suggesting limited prognostic value.ConclusionsThe 31‐GEP test has a limited impact on clinical management decisions and shows limited prognostic value.

AbstractEpilepsy associated with high‐titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug‐resistant epilepsy associated with GAD65‐IgG. We retrospectively identified 15 patients with drug‐resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L−1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I–II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure‐free at last follow‐up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Background: Acute ischemic stroke (AIS) from primary medium vessel occlusions (MeVO) is a prevalent condition associated with substantial morbidity and mortality. Despite the common use of mechanical thrombectomy (MT) in AIS, predictors of poor outcomes in MeVO remain poorly characterized. Methods: In this prospectively collected, retrospectively reviewed, multicenter, multinational study, data from the MAD-MT (Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy) registry were analyzed. The study included 1568 patients from 37 academic centers across North America, Asia, and Europe, treated with MT, with or without intravenous tissue plasminogen activator (IVtPA), between September 2017 and July 2021. Results: Among the 1568 patients, 347 (22.2%) experienced very poor outcomes (modified Rankin score (mRS), 5–6). Key predictors of poor outcomes were advanced age (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.02 to 1.04; p < 0.001), higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (OR: 1.07; 95% CI: 1.05 to 1.10; p < 0.001), pre-operative glucose levels (OR: 1.01; 95% CI: 1.00 to 1.02; p < 0.001), and a baseline mRS of 4 (OR: 2.69; 95% CI: 1.25 to 5.82; p = 0.011). The multivariable model demonstrated good predictive accuracy with an area under the receiver-operating characteristic (ROC) curve of 0.76. Conclusions: This study demonstrates that advanced age, higher NIHSS scores, elevated pre-stroke mRS, and pre-operative glucose levels significantly predict very poor outcomes in AIS-MeVO patients who received MT. These findings highlight the importance of a comprehensive risk assessment in primary MeVO patients for personalized treatment strategies. However, they also suggest a need for cautious patient selection for endovascular thrombectomy. Further prospective studies are needed to confirm these findings and explore targeted therapeutic interventions.