Citations

Abstract Maturation of the secondary antibody repertoire requires class‐switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high‐affinity antibodies. Following immune response or infection within the body, activation of T cell‐dependent and T cell‐independent antigens triggers the activation of activation‐induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper‐IgM syndrome, Waldenström macroglobulinemia, hyper‐IgD syndrome, selective IgA deficiency, hyper‐IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Précis: This study reports 12-month outcomes of combined phacoemulsification and Hydrus Microstent implantation in Asian eyes with moderate-to-severe normal tension glaucoma (NTG), demonstrating a significant reduction in glaucoma medications with an excellent intra and postoperative safety profile. Objective: To evaluate the 12-month safety and efficacy outcomes of combined phacoemulsification and Hydrus Microstent (Ivantis Inc.) implantation in Asian eyes with moderate to severe NTG. Methods: Retrospective study of consecutive surgeries performed from August 2019 to August 2021 in a single tertiary eye centre in Singapore. Outcome measures included a reduction in intraocular pressure (IOP), number of glaucoma medications, and intra and postoperative complications. Results: Data from 21 eyes of 21 subjects were analyzed. All subjects were ethnic Chinese, and the majority were males (14, 66.7%). At baseline, the mean IOP was 13.3 (2.3) mm Hg, all eyes had a Humphrey visual field mean deviation of ≥−6 dB [mean: −13.9 (4.3) dB], and all eyes were on at least one glaucoma medication. There was no statistically significant reduction in IOP at all time points compared with baseline (all P > 0.05). However, the median number of medications was reduced from 2 to 0 at all time points, up to postoperative month (POM) 12 (all P < 0.001). There were no intraoperative complications. No eyes underwent secondary glaucoma procedures nor lost any Snellen line of visual acuity by POM12. One (4.8%) eye experienced numerical hypotony at postoperative day 1, which resolved conservatively. Two (9.5%) eyes underwent laser iridoplasty for stent occlusion by iris. There was no deterioration in Humphrey visual field mean deviation at POM12 compared with baseline (n = 20, P > 0.05). Conclusion: Combined phacoemulsification and Hydrus Microstent implantation were effective in reducing medication burden in Asian eyes with moderate to severe NTG, up to 12 months postoperatively.

OBJECTIVE Fibrin deposition represents a key step in aneurysm occlusion, promoting endothelization of implants and connective tissue organization as part of the aneurysm-healing mechanism. In this study, the authors introduce a novel in vitro testing platform for flow diverters based on human fibrinogen. METHODS A flow diverter was deployed in 4 different glass models. The glass models had the same internal parent artery (4 mm) and aneurysm (8 mm) diameters with varying parent artery angulations (paraophthalmic, sidewall, bifurcation, and slightly curved models). The neck size and area were 4 mm and 25 mm 2 , respectively. Human fibrinogen (330 mg/dl) was circulated within the glass models at varying flow rates (0, 3, 4, and 5 ml/sec) with or without heparin, calcium chloride, and thrombin for as long as 6 hours or until complete fibrin coverage of the flow diverter’s neck was achieved. Aneurysm neck coverage was defined as macroscopic fibrin deposition occluding the flow diverters’ pores. Flow characteristics after flow diverter deployment were assessed with computational fluid dynamics analysis. The effects of flow rates, heparin, calcium chloride, and thrombin on fibrin deposition rates were tested using 1-way ANOVA and the Tukey test. RESULTS A total of 84 replicates were performed. Human fibrin did not accumulate on the flow diverter stents under static conditions. The fibrin deposition rate on the aneurysm neck was significantly greater with the 5 ml/sec flow rate as compared to 3 ml/sec for all models. The paraophthalmic model had the highest inflow velocity of 48.7 cm/sec. The bifurcation model had the highest maximum shear stress (SS) and maximum normalized shear stress values at the device cells at 843.3 dyne/cm 2 and 35.1 SS/SS inflow , respectively. The fibrin deposition rates of the paraophthalmic and bifurcation models were significantly higher than those of sidewall and slightly curved models for all additive or flow rate comparisons (p = 0.001 for all comparisons). The incorporation of thrombin significantly increased the fibrin deposition rates across all models (p = 0.001 for all models). CONCLUSIONS Rates of fibrin deposition varied widely across different configurations and additive conditions in this novel in vitro model system. Fibrin accumulation started at the aneurysm inflow zone where flow velocity and shear stress were the highest. The primary factors influencing fibrin deposition included flow velocities, shear stress, and the addition of thrombin at a physiological concentration. Further research is needed to test the clinical utility of fibrinogen-based models for patient-specific aneurysms.

BackgroundMR elastography (MRE) at 60 Hz is widely used for staging liver fibrosis. MRE with lower frequencies may provide inflammation biomarkers.PurposeTo establish a practical simultaneous dual‐frequency liver MRE protocol at both 30 Hz and 60 Hz during a single examination and validate the occurrence of second harmonic waves at 30 Hz.Study TypeRetrospective.SubjectsOne hundred six patients (48 females, age: 50.0 ± 13.4 years) were divided as follows: Cohort One (15 patients with chronic liver disease [CLD] and 25 healthy volunteers) with simultaneous dual‐frequency MRE. Cohort Two (66 patients with CLD) with second harmonic MRE.Field Strength/Sequence3‐T, single‐ or dual‐frequency MRE at 30 Hz and 60 Hz.AssessmentLiver stiffness (LS) in both cohorts was evaluated with manually placed volumetric ROIs by two independent analyzers. Image quality was assessed by three independent readers on a 4‐point scale (0–3: none/failed, fair, moderate, excellent) based on the depth of wave propagation with 1/3 incremental penetration. The success rate was derived from the percentage of nonzero quality scores.Statistical TestsMeasurement agreement, bias, and repeatability of LS were assessed using intraclass correlation coefficients (ICCs), Bland–Altman plots, and repeatability coefficient (RC). Mann–Whitney U tests were used to evaluate the differences in image quality between different methods. A P‐value <0.05 was considered statistically significant.ResultsSuccess rate was 97.5% in Cohort One and 91% success rate for the second harmonic MRE in Cohort Two. The second harmonic and conventional MRE showed excellent agreement in LS (all ICCs >0.90). The quality scores for the second harmonic wave images were lower than those from the conventional MRE (Z = −4.523).Data ConclusionCompared with conventional and second harmonic methods, simultaneous dual‐frequency had better image quality, high success rate and the advantage of intrinsic co‐registration, while the second harmonic method can be an alternative if custom waveform is not available.Evidence Level3Technical EfficacyStage 1

Introduction Difficult or impossible femoral access remains a significant burden for mechanical thrombectomy (MT) in stroke, affecting between 4.4% (impossible) to ∼10% of cases (time to first angiography [T1A] > 30 min) [1]. Visualization of CT angiography (CTA) or MR angiography are the only available diagnostic tools for neurointerventionalists (NIs) to qualitatively assess catheterization difficulty ahead of intervention. Visualization of 3D segmentation of the head‐and‐neck arteries from CTA may provide enhanced spatial information for catheter access difficulty assessment to the occlusion site, as well as large vessel occlusion (LVO) localization or carotid stenosis detection. Methods Three observers (2 expert NIs and 1 medical image engineer) assessed a sample of patients with anterior circulation stroke rating LVO location, femoral access difficulty according to a Likert scale (0 to 5) and assessment of radial access compared to femoral (easier or not). Raters were asked to answer the same form for each case twice, once after visualizing only the CTA and again after visualizing a deep‐learning, automated 3D segmentation of the head‐and‐neck arteries from CTA [2]. Cases were randomly sampled and blind to raters for both assessments. Likert scale values were normalized and averaged across observers, and correlation to T1A was studied. LVO localization accuracy and time needed for the analysis was also assessed. Results The final sample included N = 117 cases, where 22.98% presented difficult or impossible access. LVO location prevalence was 13/15/45/27% for extracranial ICA (eICA)/TICA/M1/M2, and 49/51% for right/left. Averaged Likert values presented significant linear correlation for both segmentation and CTA visualization, but this was much stronger in the former (R: 0.58 vs 0.30, p<0.001). Three‐dimensional visualization of segmented vessels allowed for an enhanced detection of difficult or impossible femoral access (ROC‐AUC: 0.85 vs 0.66). LVO detection was also superior after segmentation visualization (mean accuracy across observers: 0.81 vs 0.72) and time needed for assessment was on average 2.3 times shorter (44 s vs 100 s). In difficult or impossible patients, radial access was considered easier in 74% (63‐89%) of cases when visualizing the segmentation compared to 42% (35‐48%) when inspecting the CTA. Conclusion Visualization of deep‐learning 3D arterial segmentation resulted in enhanced difficult or impossible femoral access for MT, LVO detection and faster analysis over traditional pre‐procedural CTA inspection. Adding this visualization to the current workflow could enhance difficult access detection ahead of intervention.

Background: Deeper depth of response (DpR) after induction therapy, especially gain of negative minimal residual disease (MRD), has been linked to prolonged survival in multiple myeloma (MM). However, flow-MRD examination focuses on the numbers but not on the biological characteristics of residual plasma cells (PCs). Objectives: To explore whether the genetic features of residual tumor cells affect the survival time of patients with MM. Design: A retrospective cohort study. Methods: We investigated the clonality of cytogenetic abnormalities (CAs) of the residual PCs using interphase fluorescence in situ hybridization (iFISH) in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Here, a longitudinal cohort of 269 patients with patient-paired diagnostic and post-induction iFISH results was analyzed. Results: Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those with genetically detectable MRD [median progression-free survival (mPFS): 59.7 versus 35.7 months, p < 0.001; median overall survival (mOS): 97.1 versus 68.8 months, p = 0.011]. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. Patients who maintained at a high risk during follow-up had the worst survival (mPFS: 30.5 months; mOS: 54.4 months), while those who returned to lower risk or had iFISH− at both time points had the best survival (mPFS: 62.0 months, mOS: not reached). Conclusion: These findings highlighted the prognostic value of genetic testing in residual tumor cells, which may provide a deep understanding of clonal evolution and guide clinical therapeutic strategies.

Background Although direct contact aspiration has emerged as one of the leading techniques for mechanical thrombectomy (MT), there is still ongoing debate about the aspiration/suction pump devices that can optimize recanalization rates. To address this gap, we conducted a meta-analysis comparing the aspiration efficacy of 60 ml syringe and pump devices in benchtop MT models. Methods Systematic literature review was conducted using Medline, Embase, Web of Science, and Scopus in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Outcomes of interest included flow rate and vacuum pressure delivered by a 60 ml syringe and several aspiration pumps. We used a random effects model to calculate the mean difference (MD) with 95% confidence intervals (CIs) and a statistically significant difference was considered as a two-sided p -value of less than 0.05. Results We included six benchtop studies comparing 60 ml syringes and vacuum pumps. Our meta-analysis showed that there were no significant differences in vacuum pressure (MD:0.71inHg, 95% CI: [−0.81;2.23], p = 0.359) and flow rate (MD:0.27 mL/s, 95% CI: [−3,07; 3.61], p = 0.873) between 60 ml syringes and vacuum pumps groups. Conclusions Our study demonstrated comparable performance in terms of vacuum pressure and flow rates between a 60 ml syringe and a heterogeneous combination of commercially available aspiration pumps.

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.