Citations

Abstract Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich’s ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occurring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters alongside the repeat length to improve diagnostic precision of repeat analysis.

Abstract Bispecific T-cell engagers (TCEs) targeting B-cell maturation antigen (BCMA) and CD3, induce deep hematologic responses in ∼60% of heavily pretreated patients with multiple myeloma (MM). We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs), represent logical partners for TCEs due to their direct anti-MM effects and additional immune-stimulatory activity; however, it is unclear how to optimally combine them with TCEs. Taking advantage of the immunocompetent IMiD-sensitive Vk∗MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCEs and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti–programmed cell death protein 1 (PD1) and pomalidomide reduced the T-cell exhaustion that occurs in response to TCEs in high tumor burden settings. This allowed for a higher degree of T-cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros degraders and dexamethasone (DEX) with step-up–dosed TCEs. Pretreatment with iberdomide and DEX reshaped the bone marrow T-cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T-cell profiling, with limited expansion of regulatory T cells and exhaustion. Overall, administering a TCE after DEX and iberdomide treatments provided deeper and more durable responses with a reduced risk of CRS.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

OBJECTIVE The formation and propagation of intraneural ganglion cysts (INGCs) is being elucidated by the unified articular theory. Its principles include a connection for joint fluid to egress from a synovial joint via an articular branch to a parent nerve and cyst following the path of least resistance, dependent on pressures and pressure fluxes. The occurrence of so-called extreme peroneal or tibial INGCs in the popliteal fossa extending to the sciatic nerve has been reported. One rarely described variant with a circumferential cyst within the subparaneurial compartment outside the epineurium of nerve(s) has been previously illustrated, but its mechanism and morphology have not been clarified. In this study, the authors aimed to investigate this type of cyst to challenge the principles of the unified articular theory. METHODS Four novel cases of patients with peroneal INGCs and "extreme subparaneurial cyst(s)" of the sciatic nerve and its distal branches were investigated: 3 arose from the superior tibiofibular joint (STFJ) and 1 from the knee joint. Three other cases of recognized extreme subparaneurial cyst (2 peroneal and 1 tibial from the STFJ) and 1 case of a peroneal subparaneurial cyst in the literature were reinterpreted. Data on clinical presentation, MR images, and surgical results were analyzed. RESULTS In all 8 cases, subparaneurial extension was observed to different degrees along the sciatic, tibial, common peroneal, sural, and deep and superficial peroneal nerves, as was subparaneurial-to-subparaneurial communication at the sciatic nerve bifurcation (i.e., crossover). Sequential MRI performed in 7 patients showed variable dynamic changes, including extreme ascent and descent. Extraneural rupture of the subparaneurial cyst, with spread into the surrounding tissue, was present at the sciatic nerve bifurcation in 6 cases. CONCLUSIONS The authors provide pathoanatomical and pathophysiological evidence supporting that extreme subparaneurial cysts follow the principles of the articular theory. They propose a distribution pattern that explains the occurrence and evolution of extreme subparaneurial cysts along the sciatic nerve and its distal branches in patients with peroneal or tibial INGCs and subepineurial cysts. Crossover in the subparaneurial compartment allows potentially extensive circumferential distribution within connected nerves. Also, dynamic factors can lead to dramatic changes in cyst size and appearance from reabsorption or extraneural rupture. In Part 2 of this study, the authors provide evidence showing that a fenestration in the epineurium allows cysts to pass from the subepineurial-to-subparaneurial, subparaneurial-to-subparaneurial, and subparaneurial-to-subepimyseal compartments.

Objectives This study identified the prevalence of second victim experience (SVE) in a multidisciplinary sample of healthcare learners and explored personal experiences of trauma and desired forms of support following traumatic patient care events or situations. Method We used the validated SVE Support Tool-Revised and the Physician Well-Being Index (PWBI) to query healthcare learners at a large academic health system across the institution's medical, graduate medical education, and health sciences schools. The survey was open to all healthcare learners from April 8th, 2022 to May 30th, 2022. Here, we report on an analysis of respondents’ fixed responses describing the prevalence and characteristics of SVE. Results Of 2298 potential respondents, 206 answered at least one question (9.0% response rate). Of the 206 respondents, 205 answered questions inquiring if they had been a part of a stressful or traumatic patient care event or situation and 54.1% (111/205) answered in the affirmative. Of this group, 49.5% (51/103) reported feeling like a second victim (SV). The average PWBI of the exposed group was significantly higher (worse well-being) than the nonexposed group (3.4 vs 2.6, P = .0009). The most common forms of desired support for those exposed to a traumatic event and felt like an SV was conversation with peers 95.3% (41/43), family 81.4% (35/43), and a supervisor or manager 67.4% (29/43). Conclusion Findings suggest that many healthcare learners experience SVE and would benefit from connection to desired support strategies. Strategies to mitigate the impact of SVE on professional self-efficacy should be considered by education administrators. We present strategies from the literature and our institution that may be replicated for early identification and support of learners with SVE.

Objectives: The delirium course of critically ill adults can be classified into trajectories based on the severity and duration of delirium as shown by a recent study. It is unknown whether these trajectories and associated outcomes are reproducible. We aimed to define delirium severity trajectories using the Intensive Care Delirium Screening Checklist (ICDSC) and delirium duration and evaluate the association of trajectory membership with clinical characteristics and 30-day post-discharge mortality. Design: Population-based retrospective cohort. Setting: Fourteen medical-surgical ICUs in Alberta, Canada from January 1, 2014, to December 21, 2019. Patients: We included adult patients (≥ 18 yr old) with an ICU length of stay of greater than or equal to 24 hours, an ICDSC score indicating delirium (≥ 4), and 30-day follow-up data were included. Group-based trajectory modeling identified trajectories over a 7-day period with SAS v9.4 (SAS Institute, Cary, NC). Interventions: None. Measurements and Main Results: Demographic (age, sex) and clinical data (2 × d ICDSC score, comorbidities, illness severity, admission reason, procedures, length of stay, in-hospital, and 30-d post-discharge mortality) were captured from electronic medical records. In total, 21,071 patients were included, with a median age of 59 years (interquartile range, 46–70 yr), 59% male (n = 12,547), and 3% died at 30 days (n = 541). The five-trajectory model was selected. These trajectories followed previously defined patterns: 1) Mild-Brief (19.4%); 2); Severe-Rapid Recovers (18.5%); 3) Severe-Slow Recovers (31%); 4) Mild-Accelerating (14.1%); and 5) Severe-Nonrecovers (16.9%). Trajectory membership was not significantly associated with 30-day post-discharge mortality; however, clinically relevant trends were observed. Conclusions: The current study substantiates the proof-of-concept model of five delirium severity trajectories. Trajectory membership did not predict 30-day post-discharge mortality. Further research is needed to understand the associations between trajectory membership, biological-based biomarkers, and patient-relevant outcomes.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

ABSTRACT The lower infrastructure requirements of portable ultra‐low field MRI (ULF‐MRI) systems have enabled their use in diverse settings such as intensive care units and remote medical facilities. The UNITY Project is an international neuroimaging network harnessing this technology, deploying portable ULF‐MRI systems globally to expand access to MRI for studies into brain development. Given the wide range of environments where ULF‐MRI systems may operate, there are external factors that might influence image quality. This work aims to introduce the quality control (QC) framework used by the UNITY Project to investigate how robust the systems are and how QC metrics compare between sites and over time. We present a QC framework using a commercially available phantom, scanned with 64 mT portable MRI systems at 17 sites across 12 countries on four continents. Using automated, open‐source analysis tools, we quantify signal‐to‐noise, image contrast, and geometric distortions. Our results demonstrated that the image quality is robust to the varying operational environment, for example, electromagnetic noise interference and temperature. The Larmor frequency was significantly correlated to room temperature, as was image noise and contrast. Image distortions were less than 2.5 mm, with high robustness over time. Similar to studies at higher field, we found that changes in pulse sequence parameters from software updates had an impact on QC metrics. This study demonstrates that portable ULF‐MRI systems can be deployed in a variety of environments for multi‐center neuroimaging studies and produce robust results.