Citations

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.

Background Low back pain is the leading cause of disability worldwide. Multidisciplinary approaches to chronic pain can support resilience in recovery of functioning. The ancient arts of t’ai chi and qigong have been touted for centuries as multimodal approaches to health and healing. An RCT of an on-line t’ai chi and qigong program for individuals with chronic low back pain found clinically significant improvements in pain, physical function, and quality of life. The program consisted of the integrated practice of t’ai chi movement and the stillness of qigong practice. Meditations in the program focused on developing positive mental attitudes to support resilience in managing the emotional challenges of pain and disease. Objective The purpose of the current qualitative study aimed to better understand participants’ experiences during the online Heal and Strengthen the Spine with T’ai Chi and Qigong (HSSTQ) program. Methods Written feedback was received from 96 program participants, and semi-structured interviews were completed with 20 participants. Interviews were transcribed and coded based upon the written feedback and interview questions. A thematic narrative was developed from the coded segments of texts and reviewed by participants in a member check. Results Three interlocking themes characterized the experiences of participants in the program: (1) participants learned skills to relieve back pain including moderation in movement; (2) the holistic nature of the program enabled a range of benefits for participants beyond pain reduction; and (3) personal healing experience, the enthusiasm of the instructor, the program itself, and available staff resources motivated individuals to participate. Conclusion The conclusion from this study and the initial RCT is that a virtually delivered integrated tai chi, qigong, and meditation program may be a viable treatment option for adults with low back pain.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

Objective: To evaluate the function and safety of the SteadiSet™ infusion set over a continuous 7-day wear period in adults with type 1 diabetes. Research Design and Methods: Participants used a SteadiSet infusion set with a t:slim X2™ insulin pump with Control-IQ™ technology, and either insulin aspart or insulin lispro, for a target of 7 days for 12 consecutive wear periods. Each set removed before 7 days was adjudicated by an independent committee to assess the cause of early removal and to determine whether criteria for primary or key secondary endpoints were met. Results: There were 260 participants who inserted 3028 infusion sets. For the primary endpoint, the Kaplan–Meier 7-day survival estimate was 95% (95% CI 94% to 96%). For the key secondary endpoint, which expanded the reasons for a failed infusion set, the Kaplan–Meier 7-day survival estimate was 84% (95% CI 82% to 86%). For both endpoints, the P value was <0.001 compared with a prespecified survival rate of 75%. Time-in-range 70–180 mg/dL (TIR) increased through day 3 of set wear and then decreased through day 7, with the average TIR being 70.6% over the entire wear period across all infusion sets, including those that failed. An increase in total daily insulin was observed from day 4 through day 7. Conclusions: The 7-day survival of the SteadiSet infusion set was very high for the primary endpoint and at an acceptable level with respect to early removal for any reason related to the device.

It is unknown how many children with obesity are offered treatments aligned with clinical practice guidelines. This study examined electronic medical record data from a Midwest, USA, health system to quantify referrals to obesity treatment among patients 2–17 years old with obesity presenting for well-child visits in 2022 and/or 2023. Mixed-effects logistic regression models tested associations of referral placement with child characteristics, the Area Deprivation Index, and distance to specialty care. Of 14,893 patients, 591 (4.0%) received a referral. Referrals were associated with severe obesity ( p < 0.001), older age ( p < 0.001), proximity to specialty care ( p < 0.001), number of well-visits ( p ≤ 0.001), and identification with a minoritized race or ethnicity ( p < 0.05–0.001). Findings indicate a large gap from the current state of referrals to alignment with practice guidelines for pediatric obesity. Furthermore, research needs to explore and address barriers to referrals and treatment access.

Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM-targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM and nonfailing donor hearts. High-resolution mass spectrometry–based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1 , FBLN1 , and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFB signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.

Abstract Objectives γ‐Aminobutyric acid B receptor (GABA B R)‐IgG (immunoglobulin G) is an intermediate‐risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA B R‐IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing. Methods Patients testing positive for GABA B R‐IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell‐based assay (CBA) at 1:100 and 1:200 dilutions. A live‐cell flow cytometry–based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA B R‐IgG AE or oncological explanations for antibody presence. Results Eighty‐six patients (median age 63 years; 43 female) presented with classic presentations of GABA B R‐IgG AE: encephalopathy with prominent seizures ( n = 55), status epilepticus ( n = 23), and rapidly progressive dementia ( n = 8). In addition, 44 patients (33%) had a false‐positive result for GABA B R‐IgG characterized by non‐specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true‐positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true‐positive patients ( p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA ( p = 0.031). An in‐house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA ( p = 0.125) in CSF, but better than tissue IFA ( p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA ( p = 0.022) and tissue IFA ( p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution. Significance GABA B R‐IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.