Faculty Bibliography

AIM/UNASSIGNED:To better understand the real-world impact that wearable technologies with vibration feedback are having on the treatment of body focused repetitive behaviours (BFRBs). MATERIALS AND METHODS/UNASSIGNED:A manual content analysis was performed on 173 Amazon, Google Play, and Apple reviews, collected from September 2016 to September 2023, on 3 wearable technologies designed to treat BFRBs: 1. Habit Aware Keen (versions 1 and 2), 2. Slightly Robot, and 3. Face Touch Aware. RESULTS/UNASSIGNED:96 % of all clinical commentary was positive. The most frequent endorsements were 1. symptomatic improvement, 2. increased awareness of BFRBs throughout the day, and 3. rapid symptom reduction. 8 % of clinical commentary reported complete remission of BFRBs. CONCLUSION/UNASSIGNED:Our findings suggest that wearable technologies are being favourably adopted by the public to treat BFRBs. This treatment approach offers a unique advantage over traditional behaviour modification therapies, which have been limited by lack of trained therapists and cost.

MR urography (MRU) is an imaging technique that provides comprehensive evaluation of the kidneys, pelvicalyceal system, ureters, and urinary bladder. Although CT urography (CTU) remains the first-line imaging modality for the urinary tract, incremental improvements in MRU have allowed simultaneous imaging of the kidneys, collecting system, and urinary bladder with superior contrast resolution and tissue characterization, equivalent visualization of the upper tracts, and similar specificity for detection of noncalculous diseases of the collecting system compared with that of CTU. MRU has evolved into an alternative to CTU in the broader patient population and a first-line examination in specific patient populations for which CTU is less preferred. This subgroup includes pediatric patients, pregnant patients, patients needing recurring studies, and patients with poor renal function or severe allergies to iodinated contrast material. The most common techniques encompassing a conventional MRU examination include static-fluid T2-weighted imaging and gadolinium-enhanced urothelial and excretory phase imaging. The addition of dynamic contrast-enhanced MRI and diffusion-weighted imaging results in multiparametric MRU that increases diagnostic accuracy. Newer techniques, such as parallel imaging, compressed sensing, radial k-space sampling, and deep learning-based image reconstruction, can shorten examination times and improve image quality and patient compliance. Successful MRU interpretation relies on technique optimization, knowledge of various urinary tract pathologic conditions, and familiarity with different sequences, potential interpretive pitfalls, and artifacts. ^©RSNA, 2025 Supplemental material is available for this article.

The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.

Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug-drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug-drug interaction between riluzole and fluvoxamine-a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor-in children with obsessive-compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug-drug interaction studies are completed.

BACKGROUND:Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS. METHODS:This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8-33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology. FINDINGS/RESULTS:Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology. INTERPRETATION/CONCLUSIONS:The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial. FUNDING/BACKGROUND:ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.

INTRODUCTION/AIMS/OBJECTIVE:Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS. METHODS:This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years. RESULTS:The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance. DISCUSSION/CONCLUSIONS:The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.

BACKGROUND:Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer and prostate cancer. We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the American Association for Cancer Research Genomics, Evidence, Neoplasia, Information, Exchange database. METHODS:FOXA1 alterations were characterized across more than 87 000 samples from more than 30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the Memorial Sloan Kettering - Metastatic Events and Tropisms (MSK-MET) cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models. RESULTS:FOXA1 was altered in 1869 (2.1%) samples, with distinct patterns across different cancers: prostate cancer enriched with indel-inframe alterations, breast cancer with missense mutations, and lung cancers with copy number amplifications. Of 74 715 samples with FOXA1 copy number profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC; 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by breast cancer (2% primary; 1.6% metastatic) and prostate cancer (2.2% primary; 1.6% metastatic). Copy number amplifications were associated with decreased overall survival in NSCLC (HR = 1.45, 95% confidence interval [CI] = 1.06 to 1.99; P = .02), breast cancer (HR = 3.04, 95% CI = 1.89 to 4.89; P = 4e-6), and prostate cancer (HR = 1.94, 95% CI = 1.03 to 3.68; P = .04). Amplifications were associated with widespread metastases in NSCLC, breast cancer, and prostate cancer. CONCLUSIONS:FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.

Adolescents and young adults with HIV (AYH) are at greater risk for mental health conditions. Provision of mental health services to AYH is limited by an overburdened and untrained workforce, and psychological interventions ill-adapted for adolescent HIV care. Brief, transdiagnostic psychological interventions delivered in the HIV clinics may address some of these challenges. We will evaluate the PRO-ACT intervention in a hybrid type 1 cluster randomized clinical trial (NCT06247527) in 30 HIV clinics in 3 counties in Kenya. PRO-ACT is a cognitive behavioral therapy with 5 modules: Psychoeducation, Relaxation, prOblem-solving, behavioral Activation and Cognitive coping, delivered to AYH by trained health providers without specialist mental health training in 4-6 sessions within 6 months. We performed stratified randomization with matching to balance for county and facility size to assign 5 intervention (PRO-ACT) and 5 control (standard of care) clinics in each of the 3 counties. Screening of AYH ages 16-24 years will be conducted using the 9-item patient health questionnaire (PHQ-9). Up to 300 AYH with psychological distress (PHQ-9 score>4) will be enrolled in each arm. Further assessments will include the 5-item ASK suicide screening questions (ASQ), 7-item Generalized Anxiety Disorder (GAD-7), 20-item Child and Adolescent Trauma Screen (CATS)/PTSD Checklist for DSM-5 (PCL-5), self-reported treatment adherence, and HIV viral loads. Follow-up assessments will be conducted at month 3, 6, 9 and 12. Mixed methods will be used to measure implementation outcomes, cost-effectiveness, and characterize determinants of implementation. Primary analysis of PRO-ACT effectiveness will be conducted at month 6 (near term treatment effect), and month 12 (treatment effect sustainability) comparing PHQ-9 mean scores between treatment and control groups. Secondary analyses will compare GAD-7, CATS/PCL-5, adherence and viral suppression between the groups. The study will inform integration efforts of holistic mental health services in HIV care.

Abnormal JAK/STAT pathway activation is widespread in virtually all T-cell lymphoma (TCL) subtypes. However, activating mutations are insufficient to drive leukemic cell proliferation, which also requires enhanced upstream signaling. We have described that thyroid hormones (THs) contribute to the malignant phenotype of TCL by inducing intracellular transcriptional programs through integrin αvβ3 activation. Here, we evaluate the effect of THs on the JAK/STAT pathway and its implications on TCL therapy. We found that THs induce the activation of STAT1, 3, and 5, including the upregulation of target genes and metalloprotease activity. Furthermore, we observed that the integrin αvβ3 inhibitor, cilengitide, not only reverts these effects but also enhances the antilymphoma activity to a greater extent than the JAK1/2 inhibitor, ruxolitinib, when combined with bexarotene, a synthetic rexinoid clinically used for cutaneous TCL treatment. Furthermore, we explored the mechanisms of action of cilengitide and bexarotene combination using preclinical TCL in vivo models and proteomic analysis. We found that this combinatorial protocol significantly reduced tumor STATs phosphorylation, matrix metalloproteinase activity, and the number of metastatic foci by regulating proteins involved in cell proliferation, angiogenesis, metabolism, and immune response. In addition, we observed that high integrin αvβ3 messenger RNA levels are enriched in pathways associated with lymphoma progression and reduce overall survival in samples from patients with TCL. Our findings support the therapeutic potential of targeting THs signaling through integrin αvβ3 inhibition in combination with bexarotene as a less toxic therapeutic strategy to mitigate aberrant JAK/STAT activation and limit lymphoma dissemination.