Ammonium bicarbonate buffers combined with hybrid surface technology columns improve the peak shape of strongly tailing lipids.

BACKGROUND: Lipids such as phosphatidic acids (PAs) and cardiolipins (CLs) present strongly tailing peaks in reversed phase liquid chromatography, which entails low detectability. They are usually analyzed by hydrophilic interaction liquid chromatography (HILIC), which hampers high-throughput lipidomics. Thus, there is a great need for improved analytical methods in order to obtain a broader coverage of the lipidome in a single chromatographic method. We investigated the effect of ammonium bicarbonate (ABC) on peak asymmetry and detectability, in comparison with ammonium formate (AFO) on both a conventional BEH C18 column and an HST-CSH C18 column. RESULTS: The combination of 2.5 mM ABC buffer pH 8 with an HST-CSH C18 column produced significantly improved results, reducing the asymmetry factor at 10 % peak height of PA 16:0/18:1 from 8.4 to 1.6. Furthermore, on average, there was up to a 54-fold enhancement in the peak height of its [M - H]- ion compared to AFO and the BEH C18 column. We confirmed this beneficial effect on other strongly tailing lipids, with accessible phosphate moieties e.g., cardiolipins, phosphatidylinositol phosphate, phosphatidylinositol bisphosphate, phosphorylated ceramide and phosphorylated sphingosine. Furthermore, we found an increased detectability of phospho- and sphingolipids up to 28 times in negative mode when using an HST-CSH C18 column. The method was successfully applied to mouse liver samples, where previously undetected endogenous phospholipids could be analyzed with improved chromatographic separation. SIGNIFICANCE: In conclusion, the use of 2.5 mM ABC substantially improved the peak shape of PAs and enhanced the detectability of the lipidome in negative mode on an RPLC-ESI-Q-TOF-MS system on both BEH C18 and HST-CSH C18 columns. This method provides a wider coverage of the lipidome with one single injection for future lipidomic applications in negative mode.

Isolation and characterization of a native strain of the entomopathogenic fungus Beauveria bassiana for the control of the palm weevil Dynamis borassi (Coleoptera: Curculionidae) in the neotropics.

This study aimed to isolate and characterize a native strain of Beauveria bassiana, coded as Bv065, showcasing its potential as a biological control agent targeting the palm weevil Dynamis borassi. Originating from a naturally infected D. borassi specimen collected in southwestern Colombia, the fungus underwent molecular identification and was identified as B. bassiana, exhibiting high sequence similarity with known reference strains. The physiological characterization revealed that Bv065 thrived within a temperature range of 25 to 30 °C and a pH range of 6 to 9. Moreover, the key carbon sources that allow optimal growth of the strain were identified through metabolic profiling, including sucrose, D-mannose, and γ-amino-butyric acid. These findings offer strategic insights for scalability and formulation methodologies. Additionally, enzymatic analyses unveiled robust protease activity within Bv065, crucial for catalysing insect cuticle degradation and facilitating host penetration, thus accentuating its entomopathogenic potential. Subsequent evaluations exposed Bv065's pathogenicity against D. borassi, causing significant mortality within nine days of exposure, albeit exhibiting limited effectiveness against Rhynchophorus palmarum. This study underscores the importance of understanding optimal growth conditions and metabolic preferences of B. bassiana strains for developing effective biopesticides. The findings suggest Bv065 as a promising candidate for integrated pest management strategies in neotropical regions, particularly for controlling palm weevil infestations in coconut and peach palm cultivation. Future research avenues include refining mass production methodologies, formulating novel delivery systems, and conducting comprehensive field efficacy trials to unlock the full potential of Bv065 in fostering sustainable pest management practices. Overall, this study contributes to the growing body of knowledge on entomopathogenic fungi and their pivotal role in biological control, offering nuanced perspectives on eco-friendly alternatives to conventional insecticidal interventions.

Follow-up imaging and surgical costs associated with different guidelines for management of incidentally detected gallbladder polyps.

RATIONALE AND OBJECTIVES: To compare follow-up imaging and surgical cost implications of the Society of Radiologists in Ultrasound (SRU) guidelines, 2017 and 2022 European (EUR) guidelines, 2020 Canadian Association of Radiologists (CAR) recommendations, and 2013 American College of Radiology (ACR) White Paper for managing incidentally detected gallbladder polyps. MATERIALS AND METHODS: 253 consecutive patients with gallbladder polyps identified on ultrasound were independently reviewed by three radiologists for polyp size and morphology. Electronic medical records were reviewed for patient demographics, cholecystectomy (if performed) pathological findings, or any subsequent diagnosis of gallbladder cancer. For each patient, the following were calculated for each of the 5 guidelines studied: 1) number of recommended follow-up ultrasounds based on initial presentation, 2) number of surgical consultations recommended based on initial presentation, 3) number of surgical consultations recommended based on growth, and 4) associated imaging and surgical costs. Interrater agreement was calculated. RESULTS: The SRU 2022 guidelines suggested significantly fewer follow-up ultrasounds and surgical consultations, leading to a cost reduction of 96.5 % and 96.7 % compared to European 2022 and 2017, respectively; 86.5 % compared to CAR; and 86.2 % compared to ACR guidelines. With SRU Recommendations, the majority of gallbladder polyps would be classified as extremely low risk (68.4 %), 30.8 % low risk, and 0.8 % indeterminate risk. In our cohort, a single case of gallbladder cancer was identified (26 mm) which would be recommended for surgical consult by all guidelines. CONCLUSION: The SRU 2022 guidelines can lead to significant savings for patients, health systems, and society, while reducing unnecessary medical interventions for managing incidentally detected gallbladder polyps.

Health-related quality of life in patients with generalized pustular psoriasis - a Swedish register study.

BACKGROUND: Real-world data on health-related quality of life (HRQoL) in generalized pustular psoriasis (GPP) are scarce and studies have been restricted in terms of instruments used for assessments. OBJECTIVE: To assess generic and dermatology-specific HRQoL of patients with GPP compared with patients with plaque psoriasis using real-world data from the Swedish National Register for Systemic Treatment of Psoriasis. METHODS: Cross-sectional data from 2006 to 2021 including 7041 individuals with plaque psoriasis without GPP and 80 patients with GPP, of which 19% also had plaque psoriasis. Total scores for the EuroQol-5 Dimensions (EQ-5D) and Dermatology Life Quality Index (DLQI), as well as degree of severity within the instruments' dimensions/questions, were compared between patient groups. RESULTS: EQ-5D scores were significantly (p < .01) lower (worse) in patients with GPP (mean [standard deviation (SD)] 0.613 [0.346]) vs. patients with plaque psoriasis (mean [SD] 0.715 [0.274]), indicating lower generic HRQoL of patients with GPP. Significantly (p < .01) higher (worse) total DLQI scores were observed for patients with GPP (mean [SD] 10.6 [8.9]) compared with patients with plaque psoriasis (mean [SD] 7.7 [7.1]), with proportionally more patients with GPP having severe (20% vs. 16%) and very severe (17% vs. 8%) problems. The worsened scores for GPP vs. plaque psoriasis were consistent across EQ-5D dimensions and DLQI questions. CONCLUSIONS: Individuals with GPP have a considerable impairment in both generic and dermatology-specific HRQoL. The HRQoL was significantly worse in individuals with GPP compared to individuals with plaque psoriasis. The significant HRQoL impairment of GPP shows the potential value of better healthcare interventions for this multisystem disease.

The study assessed health-related quality of life (HRQoL) in patients with generalized pustular psoriasis (GPP) compared to patients with plaque psoriasis using real-world data from the Swedish National Register for Systemic Treatment of Psoriasis.The results showed significantly worse HRQoL scores by two different HRQoL instruments (EuroQol-5 Dimensions [EQ-5D] and Dermatology Life Quality Index [DLQI]) in patients with GPP compared to patients with plaque psoriasis.The study indicates that individuals with GPP have a considerable impairment in both generic and dermatology-specific HRQoL.

RAG suppresses group 2 innate lymphoid cells.

Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Further, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.

MRI radiomics captures early treatment response in patient-derived organoid endometrial cancer mouse models.

Background: Radiomics can capture microscale information in medical images beyond what is visible to the naked human eye. Using a clinically relevant mouse model for endometrial cancer, the objective of this study was to develop and validate a radiomic signature (RS) predicting response to standard chemotherapy. Methods: Mice orthotopically implanted with a patient-derived grade 3 endometrioid endometrial cancer organoid model (O-PDX) were allocated to chemotherapy (combined paclitaxel/carboplatin, n=11) or saline/control (n=13). During tumor progression, the mice underwent weekly T2-weighted (T2w) magnetic resonance imaging (MRI). Segmentation of primary tumor volume (vMRI) allowed extraction of radiomic features from whole-volume tumor masks. A radiomic model for predicting treatment response was derived employing least absolute shrinkage and selection operator (LASSO) statistics at endpoint images in the orthotopic O-PDX (RS_O), and subsequently applied on the earlier study timepoints (RS_O at baseline, and week 1-3). For external validation, the radiomic model was tested in a separate T2w-MRI dataset on segmented whole-volume subcutaneous tumors (RS_S) from the same O-PDX model, imaged at three timepoints (baseline, day 3 and day 10/endpoint) after start of chemotherapy (n=8 tumors) or saline/control (n=8 tumors). Results: The RS_O yielded rapidly increasing area under the receiver operating characteristic (ROC) curves (AUCs) for predicting treatment response from baseline until endpoint; AUC=0.38 (baseline); 0.80 (week 1), 0.85 (week 2), 0.96 (week 3) and 1.0 (endpoint). In comparison, vMRI yielded AUCs of 0.37 (baseline); 0.69 (w1); 0.83 (week 2); 0.92 (week 3) and 0.97 (endpoint). When tested in the external validation dataset, RS_S yielded high accuracy for predicting treatment response at day10/endpoint (AUC=0.85) and tended to yield higher AUC than vMRI (AUC=0.78, p=0.18). Neither RS_S nor vMRI predicted response at day 3 in the external validation set (AUC=0.56 for both). Conclusions: We have developed and validated a radiomic signature that was able to capture chemotherapeutic treatment response both in an O-PDX and in a subcutaneous endometrial cancer mouse model. This study supports the promising role of preclinical imaging including radiomic tumor profiling to assess early treatment response in endometrial cancer models.

Paraesophageal hernia recurrence following repair: making the case for reoperative surgery in a propensity-matched cohort.

BACKGROUND: Paraesophageal hernia repairs (PEHRs) have high rates of radiographic recurrence, with some patients requiring repeat operation. This study characterizes patients who underwent PEHR to identify the factors associated with postoperative symptom improvement and radiographic recurrence. We furthermore use propensity score matching to compare patients undergoing initial and reoperative PEHR to identify the factors predictive of recurrence or need for reoperation. METHODS: After IRB approval, patients who underwent PEHR at a tertiary care center between January 2018 and December 2022 were identified. Patient characteristics, preoperative imaging, operative findings, and postoperative outcomes were recorded. A computational generalization of inverse propensity score weight was then used to construct populations of initial and redo PEHR patients with similar covariate distributions. RESULTS: A total of 244 patients underwent PEHR (78.7% female, mean age 65.4 ± 12.3 years). Most repairs were performed with crural closure (81.4%) and fundoplication (71.7%) with 14.2% utilizing mesh. Postoperatively, 76.5% of patients had subjective symptom improvement and of 157 patients with postoperative imaging, 52.9% had evidence of radiographic recurrence at a mean follow-up of 10.4 ± 13.6 months. Only 4.9% of patients required a redo operation. Hernia type, crural closure, fundoplication, and mesh usage were not predictors of radiographic recurrence or symptom improvement (P > 0.05). Propensity weight score analysis of 50 redo PEHRs compared to a matched cohort of 194 initial operations revealed lower rates of postoperative symptom improvement (P < 0.05) but no differences in need for revision, complication rates, ED visits, or readmissions. CONCLUSIONS: Most PEHR patients have symptomatic improvement with minimal complications and reoperations despite frequent radiographic recurrence. Hernia type, crural closure, fundoplication, and mesh usage were not significantly associated with recurrence or symptom improvement. Compared to initial PEHR, reoperative PEHRs had lower rates of symptom improvement but similar rates of recurrence, complications, and need for reoperation.

Maternal Sleep Health, Social Support, and Distress: A Mixed-Methods Analysis of Mothers of Infants and Young Children in Rural US.

OBJECTIVES: The purpose of this study was to explore sleep health in rural maternal populations through a social-ecological framework and identify risk and protective factors for this population. METHODS: 39 individuals who are mothers of infants or children under the age of 5 years completed an online survey, 35 of which completed a subsequent semi-structured interview. Recruitment was limited to one rural community and was in partnership with community healthcare providers. Results were integrated using a convergent, parallel mixed-methods design. RESULTS: Poor sleep health and high prevalence of insomnia symptoms in rural mothers were evident and associated with social support and maternal distress. Qualitative content from interviews indicated that well-established precipitating and perpetuating factors for insomnia may contribute to poor maternal sleep health. Results also revealed a gap in knowledge and language surrounding sleep health among rural mothers. CONCLUSIONS: Sleep health is challenged during the transition to motherhood and rural mothers have less access to specialized perinatal and behavioral health care than their urban counterparts. In this sample, poor sleep was attributable to distress in addition to nocturnal infant and child sleep patterns which has implications for psychoeducation and promotion of sleep health in mothers. Sleep is a modifiable health indicator that is associated with several other maternal health outcomes and should be considered an element of a comprehensive maternal health for prevention and intervention across individual, interpersonal, and societal domains of the social-ecological model of sleep health.

SAGES White Paper on the importance of diversity in surgical leadership: creating the fundamentals of leadership development (FLD) curriculum.

BACKGROUND: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has long recognized and championed increasing diversity within the surgical workplace. SAGES initiated the Fundamentals of Leadership Development (FLD) Curriculum to address these needs and to provide surgeon leaders with the necessary tools and skills to promote diversity, equity, and inclusion (DEI) in surgical practice. In 2019, the American College of Surgeons issued a request for anti-racism initiatives which lead to the partnering of the two societies. The primary goal of FLD was to create the first surgeon-focused leadership curriculum dedicated to DEI. The rationale/development of this curriculum and its evaluation/feedback methods are detailed in this White Paper. METHODS: The FLD curriculum was developed by a multidisciplinary task force that included surgeons, education experts, and diversity consultants. The curriculum development followed the Analysis, Design, Development, Implementation and Evaluation (ADDIE) instructional design model and utilized a problem-based learning approach. Competencies were identified, and specific learning objectives and assessments were developed. The implementation of the curriculum was designed to be completed in short intervals (virtual and in-person). Post-course surveys used the Kirkpatrick's model to evaluate the curriculum and provide valuable feedback. RESULTS: The curriculum consisted of interactive online modules, an online discussion forum, and small group interactive sessions focused in three key areas: (1) increasing pipeline of underrepresented individuals in surgical leadership, (2) healthcare equity, and (3) conflict negotiation. By focusing on positive action items and utilizing a problem-solving approach, the curriculum aimed to provide a framework for surgical leaders to make meaningful changes in their institutions and organizations. CONCLUSION: The FLD curriculum is a novel leadership curriculum that provided surgeon leaders with the knowledge and tools to improve diversity in three areas: pipeline improvement, healthcare equity, and conflict negotiation. Future directions include using pilot course feedback to enhance curricular effectiveness and delivery.

Myelodysplastic Neoplasms (MDS) with Ring Sideroblasts or SF3B1 Mutations: The Improved Clinical Utility of World Health Organization and International Consensus Classification 2022 Definitions, a Single-Centre Retrospective Chart Review.

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Total IgE as a biomarker of omalizumab response in chronic spontaneous urticaria: A meta-analysis.

Background: Omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) that is refractory to antihistamines. Total immunoglobulin E (IgE) levels have emerged as a possible biomarker to predict response to omalizumab. However, the existing literature is heterogenous, with conflicting conclusions with regard to the role of total IgE levels. Objective: We sought to clarify the role of evaluating total IgE levels in patients with CSU by performing a meta-analysis on the existing literature to determine if meaningful changes exist between responders and nonresponders to omalizumab. Methods: A total of 68 unique citations were returned and screened by two independent reviewers. Editorials, reviews, and case reports were excluded, and a total of 33 original articles were identified and underwent secondary evaluation. Studies that present mean ± standard deviation total IgE levels and/or 95% confidence intervals (CI) were included, whereas studies with < 25 subjects were excluded. Three studies ultimately met these criteria. Results: We found a mean difference in total IgE levels between those who responded to omalizumab versus those without a response of 49.76 (95% CI, 7.13-92.38; p = 0.02), which demonstrated higher mean IgE values in responders compared with nonresponders. Conclusion: This study presents additional evidence that supports evaluation of total IgE levels as it pertains to response to omalizumab therapy in CSU. When considering the current evidence, it seems reasonable to consider the baseline total IgE level as a biomarker to predict the treatment response to omalizumab. Based on the existing literature, we cannot conclude at what threshold nonresponse is more likely to occur.

Hoarseness due to subcutaneous emphysema: a rare presentation of diverticular perforation.

Pneumomediastinum and subcutaneous emphysema usually result from alveolar rupture and rarely from colonic perforation. Although steroid use has been shown to increase the risk of complicated diverticulitis, there is limited data on the role Addison's disease may play in the development of colonic perforation. We present a rare case of a patient with Addison's disease who presented with hoarseness and was found to have massive subcutaneous emphysema, pneumomediastinum, and pneumoretroperitoneum secondary to complicated diverticulitis.

Astrobiological implications of the organic and inorganic cyanide utilization by a novel Antarctic hyperthermophilic Pyrococcus strain.

Organic and inorganic cyanides are widely distributed in nature, yet not much is known about the ability of microorganisms to use these compounds as a source of nitrogen and/or carbon at high temperatures (>80 °C). Here we studied the capacity of organic and inorganic cyanides to support growth of an hyperthermophilic Pyrococcus strain isolated from Deception Island, Antarctica. This microorganism was capable of growing with aromatic nitriles, aliphatic nitriles, heterocyclic nitriles, amino aromatic nitriles and inorganic cyanides as nitrogen and/or carbon source. This is the first report of an hyperthermophilic microorganism able to incorporate these compounds in its nitrogen and carbon metabolism. Based on enzymatic activity and genomic information, it is possibly that cells of this Pyrococcus strain growing with nitriles or cyanide, might use the carboxylic acid and/or the ammonia generated through the nitrilase enzymatic activity, as a carbon and/or nitrogen source respectively. This work expands the temperature range at which microorganisms can use organic and inorganic cyanides to growth, having important implications to understand microbial metabolisms that can support life on Earth and the possibility to support life elsewhere.

Evaluation of Antibiotic Biodegradation by a Versatile and Highly Active Recombinant Laccase from the Thermoalkaliphilic Bacterium Bacillus sp. FNT.

Laccases are industrially relevant enzymes that have gained great biotechnological importance. To date, most are of fungal and mesophilic origin; however, enzymes from extremophiles possess an even greater potential to withstand industrial conditions. In this study, we evaluate the potential of a recombinant spore-coat laccase from the thermoalkaliphilic bacterium Bacillus sp. FNT (FNTL) to biodegrade antibiotics from the tetracycline, ß-lactams, and fluoroquinolone families. This extremozyme was previously characterized as being thermostable and highly active in a wide range of temperatures (20-90 °C) and very versatile towards several structurally different substrates, including recalcitrant environmental pollutants such as PAHs and synthetic dyes. First, molecular docking analyses were employed for initial ligand affinity screening in the modeled active site of FNTL. Then, the in silico findings were experimentally tested with four highly consumed antibiotics, representatives of each family: tetracycline, oxytetracycline, amoxicillin, and ciprofloxacin. HPLC results indicate that FNTL with help of the natural redox mediator acetosyringone, can efficiently biodegrade 91, 90, and 82% of tetracycline (0.5 mg mL-1) in 24 h at 40, 30, and 20 °C, respectively, with no apparent ecotoxicity of the products on E. coli and B. subtilis. These results complement our previous studies, highlighting the potential of this extremozyme for application in wastewater bioremediation.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Predicted effectiveness of EnChroma multi-notch filters for enhancing color perception in anomalous trichromats.

EnChroma filters are aids designed to improve color vision for anomalous trichromats. Their use is controversial because the results of lab-based assessments of their effectiveness have so far largely failed to agree with positive anecdotal reports. However, the effectiveness of EnChroma filters will vary depending on the conditions of viewing, including whether the stimuli are broadband reflective surfaces or colors presented on RGB displays, whether illumination spectra are broadband or narrowband, the transmission spectra of particular filters, and the cone spectral sensitivity functions of the observer. We created a model of anomalous trichromatic color vision to predict the effects of EnChroma filters on the color signals impaired in anomalous trichromacy. Using the model we varied illumination, filter type and observer cone sensitivity functions, and tested the effect of presenting colors as broadband reflective surfaces or on RGB displays. We also used hyperspectral images to assess the impact of the filters on anomalous trichromats' color vision for natural scenes. Model results predicted that the filters should be broadly effective at enhancing anomalous trichromats' equivalent to L/(L + M) chromatic contrasts under a range of viewing conditions, but are substantially more effective for deuteranomals than for protanomals. The filters are predicted to be more effective for broadband reflective surfaces presented under broadband illuminants than for surfaces presented under narrowband illuminants or for colors presented on RGB displays. Since the potential impacts of contrast adaptation and perceptual learning are not considered in the model, it needs to be empirically validated. Results of empirical tests of the effects of EnChroma filters on deuteranomalous color vision in comparison with model predictions are presented in an accompanying paper (Somers et al., in prep.).

Empirical tests of the effectiveness of EnChroma multi-notch filters for enhancing color vision in deuteranomaly.

Manufacturers of notch filter-based aids for color vision claim that their products can enhance color perception for people with anomalous trichromacy, a form of color vision deficiency (CVD). Anecdotal reports imply that people with CVD can have radically enhanced color vision when using the filters. However, existing empirical research largely focussed on the effect of notch filters on performance on diagnostic tests for CVD has not found that they have any substantial effect. Informed by a model of anomalous trichromatic color vision, we selected stimuli predicted to reveal the effects of EnChroma filters. Using these stimuli, we tested the ability of EnChroma filters to enhance color vision for 10 deuteranomalous trichromats in three experiments: 1. asymmetric color matching between test and control filter conditions, 2. color discrimination measured using four alternative forced-choice, and 3. color appearance measured using dissimilarity ratings to reconstruct subjective color spaces using multidimensional scaling. To investigate potential effects of long-term adaptation or perceptual learning, participants completed all three experiments at two time points, on first exposure to the filters, and after a week of regular use. We found a significant effect of the filters on color matches in the direction predicted by the model at both time points, implying that the filters can enhance the anomalous trichromatic color gamut. However, we found minimal effect of the filters on color discrimination at threshold. We found a significant effect of the filters in enhancing the appearance of colors along the red-green axis at the first time point, and a trend in the same direction at the second time point. Our results provide the first quantitative experimental evidence that notch filters can enhance color perception for anomalous trichromats.