Citations

Abstract Background We examined real-world utilization of treat-to-target (TTT) strategies and conducted a quality improvement (QI) project to improve uptake of TTT strategies in a learning health system, IBD Qorus. Methods We implemented a structured QI intervention to increase uptake of TTT in 41 gastroenterology practices in the United States, over a 13-month intervention period (November 2020 to November 2021; modified breakthrough series [BTS] collaborative), and a 10-month post-BTS observation period (December 2021 to October 2022). Through encounter-level surveys, we examined providers’ “intention to TTT” based on discussion of TTT with patients, documentation of inflammation, and intention to change therapy to TTT. We examined changes in rates of “intention to TTT,” and whether improvement in intention to TTT influenced site-level rates of remission. Results Over 13 months, there were 7932 patient visits (55% with Crohn’s disease; 47% in clinical remission); patients in 2160 visits (27%) were not in endoscopic remission. Overall, rates of intention to TTT increased from 31% to 54% (P = .06) with considerable site-to-site variability and was maintained at 49% in the post-BTS observation period. The increased rate was attributable to higher rates of testing for inflammation. Despite an increase in the rate of intention to TTT, there was no significant change in site-level achievement of remission over the same time. Conclusions Through a QI initiative in a learning health system, rates of intention to TTT increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

BACKGROUND Predictive biomarkers to guide chemotherapy decisions for metastatic castration–resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS The CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA 50 response rate were assessed. RESULTS High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52–3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01–2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSION This preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION ClinicalTrials.gov number NCT02485691. FUNDING Funded by Sanofi and Epic Sciences.

Background: Tremor in multiple sclerosis (MS) is often refractory to medications. Deep brain stimulation (DBS) may help, but possible side effects and disease exacerbation limit its use. Objectives: Evaluate outcomes of DBS for MS-associated tremor. Methods: Retrospective review of 18 patients with MS-associated tremor who underwent DBS, analyzing Expanded Disability Status Scale (EDSS) and Fahn–Tolosa–Marin (FTM) tremor scores. Results: Median age at surgery was 49.5 years (range, 28–75), with postoperative follow-up 2.5 years (range, 0–22). No relapses (0/18) or new lesions (0/8) occurred postoperatively. All had ventral intermediate nucleus leads; other targets were not used in programming. EDSS remained stable (median 6 to 6.25; p = 0.2). FTM scores improved (median 14.5 to 10, p = 0.008). Patients with EDSS 3.5–6 had variable outcomes ( p = 0.02). Conclusions: DBS is a potential treatment for severe MS tremor and did not provoke relapse. Targeting VIM alone may optimize tremor control and maintain magnetic resonance imaging (MRI) access.

Purpose Large aneurysms have a higher rupture risk, yet no available in vivo animal model consistently produces large aneurysms for testing endovascular therapies. Recent research suggests that adding calcium chloride (CaCl 2 ) to elastase yields larger aneurysms in a surgical rabbit model. We evaluated whether this effect translates to an endovascular approach by comparing aneurysm sizes created using elastase alone versus a CaCl 2 –elastase combination. Methods Aneurysms were created in the right common carotid artery of New Zealand rabbits. One group received 1 mL porcine elastase; the other received elastase plus 0.055 g CaCl 2 (0.5 M). After four weeks, patency was confirmed via digital subtraction angiography. Two blinded co-authors measured the neck, width, and height of the aneurysms. Aneurysm volumes were estimated using AngioCalc.com. Statistical analyses were performed using either the Mann–Whitney U -test or t -test based on data distribution. Results Twenty-nine (29) New Zealand rabbits were included in the study: six in the CaCl 2 and elastase groups, 23 in the elastase-alone group. All induced aneurysms remained patent at follow-up. Mean neck size was significantly larger in the CaCl 2 + elastase group than in the elastase-alone group (4.4 ± 1.1 mm vs 3.5 ± 0.95 mm; respectively, p = 0.02). Differences in width (4.1 ± 0.92 mm vs 3.4 ± 0.36 mm; p = 0.06), height (9.0 ± 1.1 mm vs 9.1 ± 2.1 mm; p = 0.46), and volume (83.5 ± 38.35 mm ³ vs 53.0 ± 16.94 mm³; p = 0.11) were not significant between CaCl 2 + elastase and elastase-alone, respectively. Conclusions CaCl 2 modestly increased neck size but did not significantly enlarge overall aneurysm dimensions. Further studies are needed to assess its utility in endovascular aneurysm models.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL–not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T H 2)–like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T H 2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase–signal transducer and activator of transcription signaling, promoting T H 2 differentiation while inhibiting T H 1 differentiation. These findings were validated by CRISPR editing of TP53/PTEN loss in human CD4+ T cells and mechanistically evaluated the p53 binding region in intron-3 of GATA3, resulting in transcriptional repression. Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.

Background: Spasticity is common in spinal cord injury (SCI) and multiple sclerosis (MS), and it can manifest as repeated, rhythmic muscle contractions called clonus. The spontaneous nature of clonus can disrupt independent performance of activities of daily living and negatively impact overall health and quality of life. Objectives: To quantify biomarkers of clonus and explore management of clonus in individuals with SCI or progressive MS using epidural spinal cord stimulation (ES) or dorsal root stimulation (DRS). Methods: Four male participants were included in this case series study: 3 with SCI and 1 with MS. All participants underwent temporary percutaneous ES lead placement over the dorsolateral thoracolumbar region of the spinal cord. Participants with SCI were also implanted with DRS leads at the L4 dorsal root. Clonus was elicited mechanically at the ankle while recording electromyography of the soleus muscle synchronized to direct spinal cord field potential recordings from ES and DRS percutaneous leads. Results: Clonus was evident as a prominent band (5-8 Hz) in recordings from ES leads, DRS leads, soleus muscle, and accelerometry. In 4 participants, percutaneous spinal stimulation reduced median clonus duration and cycle count. Clonus was immediately suppressed upon activation of spinal cord stimulation, and the suppression persisted even when clonus was reinitiated after turning off the stimulation. Conclusion: The use of objective biomarkers, including spinal cord potentials, to quantify clonus in real time combined with the immediate and reversible effects of stimulation highlight the potential of neuromodulation as a therapeutic tool for managing clonus. These data demonstrate preliminary efficacy of ES and DRS for clonus monitoring and treatment in 4 participants.

Background Catatonia in medically ill patients is rare but often unrecognized. This monograph summarizes current knowledge on the diagnosis, epidemiology, etiology, and management of catatonia occurring in the medical setting. Methods PubMed searches were used to identify relevant articles from 1962 to present. Results More than 3,000 articles were obtained and reviewed for relevance, including references of articles identified by the initial search. Several areas were identified as important, including: (1) catatonia and delirium; (2) malignant catatonia; (3) pediatric catatonia; (4) catatonia associated with another medical condition (CAMC); (5) drug exposure and withdrawal syndromes associated with catatonia; and (6) treatment of catatonia in the medical setting. Conclusions Catatonia in the medically ill appears to have numerous etiologies, although etiology does not seem to modify the general treatment approach of prompt administration of lorazepam. Delirium and catatonia are commonly comorbid in the medical setting and should not be viewed as mutually exclusive. Electroconvulsive therapy should be offered to patients who do not respond to benzodiazepines or have malignant features. Removing offending agents and treating the underlying medical condition is paramount when treating CAMC. Memantine or amantadine may be helpful adjunctive agents. There is not enough evidence to support the use of antipsychotics or stimulants in treating CAMC.

Background: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. Objective: A GWAS was performed to identify variants associated with TD. Methods: The case–control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p -value threshold of 5 × 10 −8 was GWAS significant and 5 × 10 −6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. Results: Variants on chromosome 14 (rs117797734, p = 2.06 × 10 −11 , odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10 −7 , OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. Conclusion: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.