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In this study, we first analyzed data from 147 patients with solitary plasmacytomas treated at the Mayo Clinic between 2005 and 2022 and then expanded our investigation through a systematic review and meta-analysis of 62 studies, encompassing 3,487 patients from the years 1960 to 2022. Our findings reveal that patients with up to 10% clonal plasma cells in their bone marrow (BM), denoted as plasmacytoma +, had a significantly reduced median disease-free survival (DFS) of 15.7 months vs. 79 months, p<0.05, observed in patients with true solitary plasmacytomas, with no clonal cells in the BM. Risk factors identified for shorter DFS included the presence of clonal plasma cells in the marrow and a DFLC > 5 mg/dl. The meta-analysis portion of our study highlighted a male predominance among patients, with a median age of 58, and confirmed radiation therapy as the predominant treatment modality. We also found that DFS rates at 3, 5, and 10 years were 66.9%, 55%, and 42.1%, respectively, and noted a significant difference in outcomes between patients with bone and extramedullary plasmacytomas, with the latter group exhibiting better survival rates. This dual-faceted approach provides a thorough overview of survival rates and critical risk factors for plasmacytoma patients, underscoring the vital role of accurate disease staging at diagnosis and the impact of tumor location on patient prognosis., (Copyright © 2025 American Society of Hematology.)

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations., Competing Interests: Competing interests: LJC: Honoraria (Amgen, Bristol-Myers-Squibb, AbbVie, Pfizer, Johnson & Johnson, Adaptive Biotechnologies, Sanofi, Genentech/Roche), Research Funding (Amgen, Bristol-Myers-Squibb, Johnson & Johnson, AbbVie, Caribou, Gracell, Genentech/Roche); RB: Honoraria (Bristol-Myers-Squibb, Pfizer, Adaptive Biotechnologies, Caribou, Genentech/Roche, GSK, Karyopharm, Legend Biotech, Johnson & Johnson, SparkCures), Research Funding (AbbVie, Bristol-Myers-Squibb, Johnson & Johnson, Novartis, Pack Health, Prothena, Sanofi); HM: Honoraria (Bristol-Myers-Squibb, Pfizer, GSK, Karyopharm, AbbVie) Research Funding (Pfizer); SB: Honoraria (AbbVie, Adaptive Biotechnologies, Bristol-Myers-Squibb, Johnson & Johnson, MJH Lifesciences); BD: Honoraria (Sanofi, Johnson & Johnson, Canopy, COTA, Bristol-Myers-Squibb) Research Funding (Amgen, GSK); CN: Honoraria (Johnson & Johnson); JR: Honoraria (Janssen, Bristol-Myers-Squibb, Pfizer, Karyopharm, Sanofi, Takeda, Genentech, AbbVie, Regeneron, Forus, Menarini, Adaptive Biotechnologies); KW:Honoraria (Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, Takeda) Research Funding (Amgen, BMS/Celgene, Janssen, Sanofi; GSK, Abbvie) Consultancy (Abbvie, Amgen, Adaptive Biotech, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Takeda); MJF: Honoraria (Kite/Gilead, CMS, Novartis, Janssen, Legend, Cytoagents, SITC); JCY: Honoraria (Janssen, Sanofi, Bristol-Myers-Squibb, Regeneron, GSK, Pfizer, Menarini); NWCJvdD: Honoraria (Janssen, Amgen, Celgene, Novartis, Cellectis, Bristol-Myers-Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, Servier) Research Funding (Janssen, Amgen, Bristol-Myers-Squibb/Celgene, Novartis, Cellectis); NB: Honoraria (AbbVie, Amgen, Bristol-Myers-Squibb, Forus, Genentech, GlaxoSmithKline, Janssen, Pfizer, Sanofi, Takeda) Research Funding (Pfizer); RP: Honoraria (GSK, Pfizer, Janssen, Bristol-Myers-Squibb, Abbvie, Roche) Research Funding (GSK, Pfizer); W-JC: Honoraria (AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, Novartis) Research Funding (Bristol-Myers-Squibb, Janssen, Novartis); PJH: Advisory Board without honoraria (Antengene, Gilead, iTeos Therapeutics, GSK, Janssen, Pfizer), Research Funding: Novartis; GK: Honoraria (Janssen, Bristol-Myers-Squibb, Sanofi, Kite, Arcellx, Pfizer, Kedrion, Cellectar); PK: Research Funding (Takeda Pharmaceuticals, Celgene, Sanofi, AbbVie, Karyopharm Therapeutics, Sorrento Therapeutics, Ichnos Sciences, Amgen); FS: Honoraria (AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, Bristol-Myers-Squibb, Novartis, SkyliteDX, Pfizer, Daiki-Sankyo,); JB: Honoraria (AstraZeneca, Bristol-Myers-Squibb, Caribou Biosciences, Galapagos, Janssen, K36 Therapeutics, Kite Pharma, Legend Biotech, Pfizer, Regeneron, Roche, Sanofi, Sebia, Takeda) Research Funding (2 Seventy Bio, Abbvie, Amgen, Bristol-Myers-Squibb, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Celularity, CRISPR Therapeutics, Fate Therapeutics, Genentech, GSK, Ichnos Sciences, Incyte, Janssen, Juno Therapeutics, K36 Therapeutics. Karyopharm, Lilly, Novartis, Poseida, Roche, Takeda); HE: Honoraria (Bristol-Myers-Squibb, Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis, Roche), Research Funding (BMS/Celgene, Janssen, Sanofi; GSK, Amgen) Consultancy (Amgen, BMS, Celgene, Janssen, GSK, Novartis, Roche, Sanofi, Takeda); ADC: Honoraria (GSK; Bristol-Myers-Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, Legend; Genentech/Roche, Novartis, AstraZeneca, Kite); Research Funding (GSK, Genentech, Janssen, BMS); Patent (Novartis); JM: Honoraria (Amgen, Sanofi, Bristol-Myers-Squibb, Janssen, Takeda); YL: Honoraria (Janssen, Sanofi, NexImmune, Caribou, Bristol-Myers-Squibb, Pfizer, Regeneron, Genentech; Sanofi, Regeneron) Research Funding (Janssen, Bristol-Myers-Squibb); TGM: Honoraria (GSK, Sanofi, Amgen, Janssen); AC: Honoraria (AbbVie, Adaptive biotechnologies, Amgen, Angengene, Bristol-Myers-Squibb, Forus, Genentech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, Sanofi). The remaining authors declare no conflict of interest. The work presented in this manuscript did not receive any financial or material support., (© 2025. The Author(s).)

Abstract: As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Cause of death (COD) in POEMS (polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and skin changes) syndrome is not well described. We investigated COD in patients with POEMS syndrome treated at Mayo Clinic between 2000 and 2022. Of the 89 deaths, 49 patients had known COD and were the subject of this study. Seventeen patients died of unrelated causes, while 32 patients (65%) died from causes related to POEMS syndrome including secondary malignancies like myelodysplastic syndrome and acute leukemia (n = 5) and complications from active therapy (n = 5). Notably, 19 patients died with a stereotypic syndrome we termed capillary leak phenotype (CLP), which was characterized by refractory ascites, effusions and/or anasarca that ultimately resulted in hypotension, renal failure and cardiopulmonary arrest. Alternate causes for these symptoms, such as cardiac and hepatic etiologies, were excluded. CLP as a COD was an earlier event with a median time from diagnosis to death of 2.5 years compared to 12.0 years for all other deceased patients (p = <0.0001). By definition, treatment of terminal CLP was unsuccessful with median survival of only 4 months after CLP onset. The driver of CLP is unknown, but recognition as an entity should allow for systematic study., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study complies with all relevant ethical guidelines and regulations according to the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board (ID: 19-011683). All patients included had provided consent for participation in research studies., (© 2024. The Author(s).)

Patient-reported outcomes (PROs) are associated with treatment outcomes in multiple myeloma (MM) in the clinical trial setting. However, most PRO tools are time consuming, which hinders use in routine practice. Our institution incorporated a "Hematology Patient-Reported Symptom Screen" (HPRSS), a 3-item questionnaire for fatigue, pain, and quality of life (QOL). The main objective of this study was to evaluate the impact of these symptoms on progression-free (PFS) and overall survival (OS) in real-world cohort patients with newly diagnosed MM. This retrospective study included MM patients diagnosed between April 2011-December 2017, seen at Mayo Clinic (Rochester MN), who completed the HPRSS. Patients rated their symptoms on a scale from 0-10. Clinically relevant symptoms were defined as scores ≥5 for pain and fatigue, and ≤5 for QOL. At diagnosis, 735 patients had scores for all domains. The median follow-up was 8.1 years. Age was associated with increased odds of fatigue and decreased QOL. Female sex and comorbidities were associated with fatigue and pain. Higher disease stage, anemia, lytic lesions, and plasma cell burden were associated with fatigue, pain, and decreased QOL. Clinically relevant fatigue, pain, and decreased QOL were associated with decreased PFS and OS. On multivariate analysis including age, ISS III, high-risk cytogenetics, and post-induction transplantation, fatigue and decreased QOL were independently associated with decreased OS. A composite HPRSS score stratified patients into three groups with distinct OS. Patient-reported symptoms are prognostic in newly diagnosed MM patients. The prognostic values of fatigue and QOL are independent of age, stage, and transplant., (Copyright © 2024 American Society of Hematology.)

Background: The credibility of nutritional research is dependent on the rigor with which studies are conducted and the ability for independent assessment to be performed. Despite the importance of these, more work is needed in the field of nutrition to buttress the trustworthiness of nutrition research., Objective: To develop and apply a process for evaluating the rigor, reproducibility, and verifiability of nutritional research, using the relationship between potato consumption and Colorectal cancer (CRC) as a case study., Methods: We updated existing systematic reviews to include studies on potatoes and CRC, assessing their design, execution, and reporting quality. We attempted to reproduce and verify the results of included studies by requesting raw data from authors and following statistical methods as described in the publications. Rigor was evaluated using four different tools: ROBINS-E, STROBE-Nut, Newcastle-Ottawa scale, and additional criteria related to transparency., Results: Eighteen studies were included, none of which publicly share data. We managed to access data for only two studies, successfully reproducing and verifying the results for one. The majority of studies exhibited a high risk of bias, with significant limitations in reporting quality and methodological rigor., Conclusions: Research on the relationship between potato consumption and CRC risk is insufficiently reproducible and verifiable, undermining the trustworthiness of its findings. This study highlights the need for improving transparency, data sharing, and methodological rigor in nutritional research. Our approach provides a model for assessing the credibility of research in other areas of nutrition.

Laccase is an extracellular enzyme that is widely used in the decolonization of textile dyes in waste water. The aim of our study was to isolate, purify, characterize and immobilize the laccase enzyme produced by Trametes versicolor HBB 7328. Purified laccase enzyme was immobilized in polyacrylamide gel to explore its ability in decolonization of textile dyes. Laccase purification process was carried out by fractionation using ammonium sulphate (80%) followed by DEAE Sepharose column (30 × 3 cm) chromatography method. Recovery and fold purification in this step were 27.35 and 16.23%. Purified laccase (named as LAC1) revealed its optimum activity at pH 5.0 and 35 °C temperature, and displayed remarkable stability in the range of 30-40 °C and in the pH range (pH 3.0-7.0). The single bands on SDS-PAGE represent the purity of LAC1 with molecular weight of 60 kDa. Both free and immobilized laccase assessed for their ability to decolorize textile dyes. Free laccase decolorized Methyl red to 72.705%, Reactive orange to 57.851%, Reactive blue to 37.231%, Bromophenol blue to 24.412% however Immobilized laccase decolorized Methyl red to 89.823%, Reactive orange to 63.151%, Reactive blue to 59.548%, Bromophenol blue to 49.421% respectively. This study proposes the role of laccase from Trametes versicolor HBB 7328 in decolonization of textile dyes., Competing Interests: Conflict of interestsThe authors declare that they have no known competing financial interests or personal relationship that could have appeared to influence the work reported in this paper., (© Association of Microbiologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Study Objectives: To (1) estimate the prevalence and trajectory of functional disability exceeding patient-acceptable and clinically significant levels in older surgical patients preoperatively and at 30, 90, and 180 days postoperatively, (2) identify risk factors associated with postoperative functional disability, and (3) compare adverse clinical outcomes between participants with and without functional disability., Design: Multicenter prospective study., Setting: Remote preoperative and postoperative assessments., Patients: 307 older patients aged ≥65 years undergoing non-cardiac surgery., Measurements: Functional disability was assessed using the 12-item World Health Organization Disability Assessment Schedule 2.0 on an online survey, with a score ≥ 16 % exceeding a patient-acceptable symptom state and ≥ 35 % indicating significant, or at least moderate, severity., Main Results: We found that 133 (43 %) patients exhibited preoperative functional disability exceeding a patient-acceptable level, with 42 (14 %) experiencing clinically significant, or at least moderate, functional disability. The Functional Disability group showed greater improvement in function than the No-disability group. Specifically, over 60 % of participants in the Functional Disability group showed significant improvement at 90 and 180 days postoperatively, with 40 % being disability-free. However, 12 % of the Functional Disability group and 9 % of the No-disability group experienced a clinically important worsening in functional disability at 180 days postoperatively. Preoperative functional disability and depression were associated with nearly 6- and 4-fold higher odds of functional disability at 180 days, respectively., Conclusions: Patients with preoperative functional disability experienced greater postoperative improvement in functional disability than the No-disability group. Preoperative evaluation of functional disability informs perioperative care and recovery for patients and clinicians., Competing Interests: Declaration of competing interest EY reports research support from the Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarships Doctoral Award (funding reference number: 195197). JW reports research support from the Ontario Ministry of Health and Long-Term CareInnovation Fund, Merck Inc. and is supported by a Merit Research Award from the Department of Anesthesiology and Pain Medicine, University of Toronto. LM reports grant funding from Brain Canada, Centre for Aging and Brain Health Innovation, and MOHLTC AFP Innovation Fund. FC reports research support from the Ontario Ministry of Health and Long-Term Care Innovation Grant, ResMed Foundation, University Health Network Foundation, Consultant to Takeda and Hasico Pharma, and STOP-Bang Questionnaire proprietary to University Health Network., (Copyright © 2024. Published by Elsevier Inc.)

Waldenström macroglobulinaemia (WM) is a unique, cluster of differentiation (CD) 20+ B-cell malignancy, with a characteristic immunoglobulin M-secreting lymphoplasmacytic bone marrow infiltrate that is bolstered by a highly supportive microenvironment, including upregulated programmed death 1 expression. However, the impact of checkpoint inhibition in WM is unclear. Commentary on: Kothari et al. PembroWM: A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström's macroglobulinaemia. Br J Haematol 2024; 205:2273-2281., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

This report chronicles the case of an adolescent female with cleft palate associated severe hypoplastic maxillary Class III deformity. Treatment involved anterior maxillary segmental distraction osteogenesis (AMSDO) in conjunction with pre-distraction and post-distraction orthodontics. Following pre-distraction orthodontics, AMSDO was performed using a customized Hyrax distractor assembly. Post-distraction orthodontics helped stabilize distraction outcomes and finalize occlusion. Post-treatment, midface deficiency and prognathic profile improved dramatically with establishment of acceptable interincisal relationship and well-balanced functionally interdigitated occlusion. Three-year follow-up showed excellent morphologic and functional stability. AMSDO is a viable modality that contributes to effective stomatological rehabilitation of patients with cleft maxillary hypoplasia., (Copyright © 2024. Published by Elsevier Masson SAS.)

Importance: Lipodermatosclerosis (LDS) stems from vascular dysfunction and dermal inflammation and thereby is mechanistically similar to systemic sclerosis (SSc). The association of LDS with SSc in the clinical setting has not been well characterized in the literature., Objective: To evaluate the prevalence of LDS in SSc and the association of LDS with vascular complications, particularly pulmonary hypertension, in patients with SSc., Design, Setting, and Participants: This retrospective cohort study used prospectively collected longitudinal data from a cohort of patients from the multidisciplinary rheumatology and dermatology clinic at a single tertiary care center from November 2004 to November 2022. Adult patients (aged ≥18 years at the time of cohort entry) with SSc were included., Exposure: Clinical diagnosis of LDS based on expert opinion or histopathologic findings., Main Outcomes and Measures: The main outcomes included prevalence of LDS, the association of LDS with the macrovascular complications, including pulmonary hypertension, digital gangrene and/or scleroderma renal crisis. Disease complications, including cardiac arrhythmias and heart failure, were compared among patients with and without LDS., Results: Among 567 patients with SSc (494 [87.1%] female; mean [SD] age, 53.4 [14.4] years), 25 (4.4%) had LDS and 542 (95.6%) did not have LDS. Skin ulceration occurred in 8 patients with LDS (32.0%). Patients with LDS had higher frequencies of cardiac arrhythmia (11 of 24 [45.8%] vs 145 of 539 [26.9%]), heart failure (7 [28.0%] vs 55 [10.1%]), and pulmonary hypertension (12 [48.0%] vs 137 of 541 [25.3%]) compared with patients without LDS. Frequency of scleroderma renal crisis and digital gangrene did not differ significantly between patients with and without LDS (0 vs 37 [6.8%] and 4 [16.0%] vs 69 of 538 [12.8%], respectively). Among patients with LDS, 9 (36.0%) were either discharged to hospice or died during follow-up compared with 115 patients without LDS (21.2%). Lipodermatosclerosis was associated with pulmonary hypertension (adjusted prevalence odds ratio, 3.10; 95% CI, 1.33-7.25)., Conclusions and Relevance: In this cohort study, LDS was a rare clinical manifestation in patients with SSc but was associated with pulmonary hypertension. Therefore, patients with LDS should be closely monitored and screened for pulmonary hypertension.

In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma-defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36-month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%-97.42%), with a trend towards longer OS in the SLiM cohort (p = 0.065). The 36-month progression-free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%-97.87%) and 65.95% in the control group (95% CI 52.31%-76.53%). There was no difference in the PFS between the cohorts (p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM., Methods: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D)., Results: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively., Conclusions: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

For an effective control of tuberculosis (TB), there is a persistent need for biomarkers that can report true estimates of TB infection (TBI) and predict its progression towards active TB disease. We investigated whether the cell-mediated immune responses to Mycobacterium tuberculosis (Mtb) antigens could provide such biomarkers. The study subjects (n = 174) comprised a cohort of smear-positive, drug-sensitive, HIV-negative pulmonary TB patients (n = 54) and their household contacts (HC, n = 120). Whole blood cultures, in the presence or absence of Mtb antigens- membrane (MtM), purified protein derivative (PPD) and alpha-crystallin (Acr), or the mitogen PHA were subjected to determinations, by flow cytometry, for T cell proliferative and, by ELISA, for IFN-γ, TNF-α, and IL-6 cytokine responses. Additionally, serum levels of the three cytokines were also estimated. The strongest cell-proliferative and cytokine responses were induced by MtM and IL-6 was the most abundantly produced cytokine. While none of the responses induced by Mtb antigens or the serum cytokines levels could discriminate between TB and HC, the ex vivo cytokine responses induced by PHA or 'spontaneously' could apparently do so. The concentrations of IFN-γ induced by PHA in TB blood cultures were significantly lower than in HC cultures (AUC = 0.72). Conversely, the spontaneous IFN-γ or TNF-α secretions in TB cultures were significantly higher than in HC cultures (AUC = 0.66). Our results suggest that IL-6 responses to MtM could be a sensitive indicator of TBI, and low levels of PHA-induced or high levels of spontaneous IFN-γ secretions in HC blood cultures may indicate a progressive infection., (© 2024 The Scandinavian Foundation for Immunology.)

G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development. Here, we use Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) to explore the structural dynamics of the turkey β1-adrenergic receptor (tβ1AR) bound with nine different ligands, including agonists, partial agonists, and antagonists. We find that these ligands induce distinct dynamic patterns across the receptor, which can be grouped by compound modality. Notably, full agonist binding destabilises the intracellular loop 1 (ICL1), while antagonist binding stabilises it, highlighting ICL1's role in G protein recruitment. Our findings indicate that the conserved L72 residue in ICL1 is crucial for maintaining receptor structural integrity and stabilising the GDP-bound state. Overall, our results provide a platform for determining drug modality and highlight how HDX-MS can be used to dissect receptor ligand interaction properties and GPCR mechanism., (© 2024. The Author(s).)

Study Objectives: To determine the prevalence of suspected cognitive impairment using the Centers for Disease Control and Prevention (CDC) cognitive question, Ascertain Dementia Eight-item Questionnaire (AD8), Modified Telephone Interview for Cognitive Status (TICS-M), and Telephone Montreal Cognitive Assessment (T-MoCA), the agreement between each tool beyond chance, and the risk factors associated with a positive screen., Design: Multicenter prospective study., Setting: Remote preoperative assessments., Patients: 307 non-cardiac surgical patients aged ≥65 years., Measurements: Prevalence, Cohen's kappa (κ)., Main Results: The T-MoCA detected the highest prevalence of suspected cognitive impairment (28%), followed by the AD8 (17%), CDC cognitive question (9%), and TICS-M (6%). The four screening tools showed poor agreement beyond chance with one another, with the CDC cognitive question and AD8 approaching the threshold for weak agreement (κ = 0.39). Depression was associated with screening positive on the CDC cognitive question (OR: 2.81; 95% CI: 1.04, 7.68). Obstructive sleep apnea (OSA) (OR: 3.10; 95% CI: 1.26, 7.71) and functional disability (OR: 3.74; 95% CI: 1.34, 11.11) were associated with a positive AD8 screen. Older age (OR: 1.56; 95% CI: 1.01, 2.41), male sex (OR: 3.08; 95% CI: 1.09, 9.40), and higher pain level (OR: 1.21; 95% CI: 1.01, 1.47) were associated with a positive TICS-M screen. Similarly, older age (OR: 1.33; 95% CI: 1.03, 1.73), male sex (OR: 2.02; 95% CI: 1.09, 3.83), and higher pain level (OR: 1.15; 95% CI: 1.02, 1.30) were associated with a positive T-MoCA screen., Conclusions: The CDC cognitive question, AD8, TICS-M, and T-MoCA were easily implemented during preoperative assessment among older surgical patients. OSA, functional disability, and depression were associated with complaints on the CDC cognitive question and AD8. Older age, male sex, and higher pain level were associated with screening positive on the TICS-M and T-MoCA. Early remote cognitive screening may enhance risk stratification of vulnerable patients., Competing Interests: Declaration of competing interest EY reports research support from the Canadian Institute of Health Research (CIHR) Canada Graduate Scholarships Doctoral Award (funding reference number: FBD-195197). JW reports research support from the Ontario Ministry of Health and Long-Term CareInnovation Fund, Merck Inc. and is supported by a Merit Research Award from the Department of Anesthesiology and Pain Medicine, University of Toronto. LM reports grant funding from Brain Canada, Centre for Aging and Brain Health Innovation, and MOHLTC AFP Innovation Fund. MCT reports funding from NIH Clinical trials in AD: Janssen, Roche, Avanex, Merck, Green Valley, Biogen. FC reports research support from the Ontario Ministry of Health Innovation Grant, ResMed Foundation, University Health Network Foundation, Consultant to Takeda and Hasico Pharma, and STOP-Bang Questionnaire proprietary to University Health Network., (Copyright © 2024. Published by Elsevier Inc.)

Background: The effect of thrombocytopenia has not been studied in the era of novel treatments in multiple myeloma (MM)., Objective: To evaluate the clinical characteristics and outcomes in MM patients presenting with thrombocytopenia., Materials: Newly diagnosed MM patients between 2008 and 2018 who received at least 2 novel agents at induction. Thrombocytopenia was defined as a platelet count of less than < 150,000/mm 3 ., Results: A total of 648 patients were identified. Thrombocytopenia was found in 120 patients (18.5%). Baseline disease characteristics associated with higher rates of thrombocytopenia at baseline included IgA myeloma, P < .01, ISS 3 versus 1 or 2, P < .01, R-ISS 3 versus 1 or 2, P < .01, renal failure (CrCl < 30 mL/min), P < .01, hypercalcemia (Ca > 11.5 mg/dL), P < .01, elevated LDH, P < .03, anemia (Hb < 10 g/dL), P < .01, higher serum monoclonal protein, P < .02, and > 60% plasma cells in the bone marrow, P < .01. Thrombocytopenia was more prevalent across patients with t(4;14) and t(14;16), but was not associated with an overall high-risk fluorescence in situ hybridization (FISH) classification. Median OS was significantly lower among patients with thrombocytopenia (64.4 vs. 145.0 months, P < .01). In multivariable Cox regression, thrombocytopenia was associated with mortality (HR = 2.45, 95% CI, 1.7-3.6) independently of age, sex, high-risk FISH, ISS stage, response at induction, percentage of plasma cells in the BM, and anemia., Conclusion: We found that thrombocytopenia was seen among one-fifth of MM patients and was more common in patients with (t[4; 14] and t[14; 16]). Thrombocytopenia had an independent association with worse survival., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Waldenström macroglobulinemia (WM) is a B-cell lymphoma characterized by the presence of bone marrow lymphoplasmacytic infiltration and circulating monoclonal immunoglobulin M protein. The clinical presentation of WM is variable, ranging from gradually progressive cytopenias, organomegaly, fatigue, B symptoms, and peripheral neuropathy to the more emergent presentation with symptomatic hyperviscosity, cryoglobulinemia, hemolytic anemia-associated symptoms, acquired von Willebrand disease or acquired hemophilia-associated bleeding. Approximately 1 in 5 patients with WM are asymptomatic at diagnosis and classified as having smoldering WM, not requiring WM-directed therapy. Although WM typically has an indolent, relapsing-remitting course, the outcomes are heterogeneous. The prognosis of patients with WM is known to be impacted by certain clinical and laboratory features at initial presentation, with advanced age, elevated serum lactate dehydrogenase, and low serum albumin unfavorably affecting the outcome. Although complications such as histologic transformation or light and/or heavy chain (AL/ALH) amyloidosis are infrequent, their occurrence adversely influences the disease course. The International Prognostic Staging System for WM (IPSS-WM) is a validated model, often used in clinical practice, but needs to be reexamined in the current era. The discovery of the recurrent MYD88L265P gain-of-function point mutation and the subclonal CXCR4 mutations has helped improve our understanding of the WM biology, and the prognostic impact of these mutations is under evaluation, with somewhat inconsistent findings thus far across studies. This review discusses the clinical presentation, diagnostic criteria, and prognostic markers of WM.

In plants, nitric oxide (NO) has become a versatile signaling molecule essential for mediating a wide range of physiological processes under various biotic and abiotic stress conditions. The fundamental function of NO under various stress scenarios has led to a paradigm shift in which NO is now seen as both a free radical liberated from the toxic product of oxidative metabolism and an agent that aids in plant sustenance. Numerous studies on NO biology have shown that NO is an important signal for germination, leaf senescence, photosynthesis, plant growth, pollen growth, and other processes. It is implicated in defense responses against pathogensas well as adaptation of plants in response to environmental cues like salinity, drought, and temperature extremes which demonstrates its multifaceted role. NO can carry out its biological action in a variety of ways, including interaction with protein kinases, modifying gene expression, and releasing secondary messengers. In addition to these signaling events, NO may also be in charge of the chromatin modifications, nitration, and S-nitrosylation-induced posttranslational modifications (PTM) of target proteins. Deciphering the molecular mechanism behind its essential function is essential to unravel the regulatory networks controlling the responses of plants to various environmental stimuli. Taking into consideration the versatile role of NO, an effort has been made to interpret its mode of action based on the post-translational modifications and to cover shreds of evidence for increased growth parameters along with an altered gene expression., Competing Interests: Declaration of competing interest Authors do not have any kind of financial or non-financial conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Skeletal class III malocclusion is a therapeutic challenge in orthodontic practice. Reverse functional appliances such as reverse twin block (RTB) are used to correct class III skeletal and occlusal disharmonies associated with functional anterior shift in growing patients. However, treatment options become limited with increasing age, especially when patients desire nonsurgical and nonextraction camouflage treatment. This report illustrates the successful nonsurgical treatment of class III malocclusion during adolescence and adulthood, exacerbated by a functional anterior shift that resulted in overclosure of the mandible. A modified fixed RTB was utilized to posture the mandible backwards, thereby inducing active clockwise rotation of the mandible. After treatment, patients demonstrated significantly improved maxillomandibular relationships, well-maintained stable occlusion, and facial esthetics. Satisfactory occlusal, esthetic, and functional outcomes achieved in the present cases underline the fact that dentoalveolar changes induced by fixed RTB can be utilized even past a patient's peak pubertal growth period to obtain changes that aid in correcting a class III malocclusion. A synergistic combination of modified fixed RTB therapy accompanied by comprehensive fixed mechanotherapy is a viable treatment alternative for the correction of aptly selected mild to moderate skeletal class III malocclusions associated with functional anterior shift, anterior crossbites, and mandibular overclosure., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Camels play a crucial socio-economic role in sustaining the livelihoods of millions in arid and semi-arid regions. They possess remarkable physiological attributes which enable them to thrive in extreme environments, and provide a source of meat, milk and transportation. With their unique traits, camels embody an irreplaceable source of untapped genomic knowledge. This study introduces Axiom-MaruPri, a medium-density SNP chip meticulously designed and validated for both Camelus bactrianus and Camelus dromedarius. Comprising of 182,122 SNP markers, derived from the re-sequenced data of nine Indian dromedary breeds and the double-humped Bactrian camel, this SNP chip offers 34,894 markers that display polymorphism in both species. It achieves an estimated inter-marker distance of 14 Kb, significantly enhancing the coverage of the camel genome. The medium-density chip has been successfully genotyped using 480 camel samples, achieving an impressive 99 % call rate, with 96 % of the 182,122 SNPs being highly reliable for genotyping. Phylogenetic analysis and Discriminant Analysis of Principal Components yield clear distinctions between Bactrian camels and dromedaries. Moreover, the discriminant functions substantially enhance the classification of dromedary camels into different breeds. The clustering of various camel breeds reveals an apparent correlation between geographical and genetic distances. The results affirm the efficacy of this SNP array, demonstrating high genotyping precision and clear differentiation between Bactrian and dromedary camels. With an enhanced genome coverage, accuracy and economic efficiency the Axiom&#95;MaruPri SNP chip is poised to advance genomic breeding research in camels. It holds the potential to serve as an invaluable genetic resource for investigating population structure, genome-wide association studies and implementing genomic selection in domesticated camelid species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents., Recent Findings: Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20-0.43) and TCEs (aHR = 0.62, 95%CI = 0.43-0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18-0.44) and TCEs (aHR = 0.60, 95%CI = 0.39-0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable., (© 2024. The Author(s).)

Purpose: Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters., Patients and Methods: We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort., Results: In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001)., Conclusion: Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.

Background: Implicit bias can influence behavior and decision-making. In clinical settings, implicit bias may influence treatment decisions and contribute to health disparities. Given documented Black-White disparities in vascular care, the purpose of this study was to examine the prevalence and degree of unconscious bias and awareness of bias among vascular surgeons treating peripheral artery disease (PAD)., Methods: The sampling frame included all vascular surgeons who participate in the Vascular Quality Initiative (VQI). Participants completed a survey which included demographic questions, the race implicit association test (IAT) to measure magnitude of unconscious bias, and six bias awareness questions to measure conscious bias. The magnitude of unconscious bias was no preference; or slight, moderate, or strong in the direction of pro-White or pro-Black. Data from participants were weighted to account for nonresponse bias and known differences in the characteristics of surgeons who chose to participate compared to the full registry. We stratified unconscious and conscious findings by physician race/ethnicity, physician sex, and years of experience. Finally, we examined the relationship between unconscious and conscious bias., Results: There were 2,512 surgeons in the VQI registry, 304 of whom completed the survey, including getting IAT results. Most participants (71.6%) showed a pro-White bias with 73.0% of this group in the moderate and strong categories. While 77.5% of respondents showed conscious awareness of bias, of those whose conscious results showed lack of awareness, 67.8% had moderate or strong bias, compared to 55.7% for those with awareness. Bias magnitude varied based on physician race/ethnicity and years of experience. Women were more likely than men to report awareness of biases and potential impact of bias on decision-making., Conclusions: Most people have some level of unconscious bias, developed from early life reinforcements, social stereotypes, and learned experiences. Regarding health disparities, however, these are important findings in a profession that takes care of patients with PAD due to heavy burden of comorbid conditions and high proportion of individuals from structurally vulnerable groups. Given the lack of association between unconscious and conscious awareness of biases, awareness may be an important first step in mitigation to minimize racial disparities in healthcare.

Purpose of Review: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM., Recent Findings: Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4 WHIM mutation or MYD88 WT genotype. The development of BTK C481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88 L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Evidence-based prescribing is essential to optimize patient outcomes in cystitis. This requires knowledge of local antibiotic resistance rates. Diagnostic and Antimicrobial Stewardship (DASH) to Protect Antibiotics (https://dashuti.com/) is a multicentric mentorship program guiding centers in preparing, analyzing and disseminating local antibiograms to promote antimicrobial stewardship in community urinary tract infection. Here, we mapped the susceptibility profile of Escherichia coli from 22 Indian centers., Methods: These centers spanned 10 Indian states and three union territories. Antibiograms for urinary E. coli from the outpatient departments were collated. Standardization was achieved by regional online training; anomalies were resolved via consultation with study experts. Data were collated and analyzed., Results: Nationally, fosfomycin, with 94% susceptibility (inter-center range 83-97%), and nitrofurantoin, with 85% susceptibility (61-97%), retained the widest activity. The susceptibility rates were lower for co-trimoxazole (49%), fluoroquinolones (31%), and oral cephalosporins (26%). The rates for third- and fourth-generation cephalosporins were 46% and 52%, respectively, with 54% (33-58%) extended-spectrum β-lactamase prevalence. Piperacillin-tazobactam (81%), amikacin (88%), and meropenem (88%) retained better activity; however, one center in Delhi recorded only 42% meropenem susceptibility. Susceptibility rates were mostly higher in South, West, and Northeast India; centers in the heavily populated Gangetic plains, across north and northwest India, had greater resistance. These findings highlight the importance of local antibiograms in guiding appropriate antimicrobial choices., Conclusions: Fosfomycin and nitrofurantoin are the preferred oral empirical choices for uncomplicated E. coli cystitis in India, although elevated resistance in some areas is concerning. Empiric use of fluoroquinolones and third-generation cephalosporins is discouraged, whereas piperacillin/tazobactam and aminoglycosides remain carbapenem-sparing parenteral agents., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Background: The use of an artificial intelligence electrocardiography (AI-ECG) algorithm has demonstrated its reliability in predicting the risk of atrial fibrillation (AF) within the general population., Objectives: This study aimed to determine the effectiveness of the AI-ECG score in identifying patients with chronic lymphocytic leukemia (CLL) who are at high risk of developing AF., Methods: We estimated the probability of AF based on AI-ECG among patients with CLL extracted from the Mayo Clinic CLL database. Additionally, we computed the Mayo Clinic CLL AF risk score and determined its ability to predict AF., Results: Among 754 newly diagnosed patients with CLL, 71.4% were male (median age = 69 years). The median baseline AI-ECG score was 0.02 (range = 0-0.93), with a value ≥0.1 indicating high risk. Over a median follow-up of 5.8 years, the estimated 10-year cumulative risk of AF was 26.1%. Patients with an AI-ECG score of ≥0.1 had a significantly higher risk of AF (HR: 3.9; 95% CI: 2.6-5.7; P < 0.001). This heightened risk remained significant (HR: 2.5; 95% CI: 1.6-3.9; P < 0.001) even after adjusting for the Mayo CLL AF risk score, heart failure, chronic kidney disease, and CLL therapy. In a second cohort of CLL patients treated with a Bruton tyrosine kinase inhibitor (n = 220), a pretreatment AI-ECG score ≥0.1 showed a nonsignificant increase in the risk of AF (HR: 1.7; 95% CI: 0.8-3.6; P = 0.19)., Conclusions: An AI-ECG algorithm, in conjunction with the Mayo CLL AF risk score, can predict the risk of AF in patients with newly diagnosed CLL. Additional studies are needed to determine the role of AI-ECG in predicting AF risk in CLL patients treated with a Bruton tyrosine kinase inhibitor., Competing Interests: Dr Herrmann was supported National Institutes of Health/NCI (RO1 CA233610), Miami Heart Research Institute, and Mayo Clinic Department of Cardiovascular Medicine. This research was supported in part by the Henry J. Predolin Foundation. IP related to AI-ECG algorithm for AF risk has been licensed to Anumana (potential equity/royalty relationship). Dr Ding has received research funding from Merck and DTRM; and has served on the Advisory Boards of Merck and Octapharma (no personal compensation). Dr Kenderian is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between Mayo Clinic, University of Pennsylvania, and Novartis), Humanigen (through Mayo Clinic), Morphosys (through Mayo Clinic), Tolero (through Mayo Clinic), and Mettaforge (through Mayo Clinic); has received research funding from Kite, Gilead, Juno, Celgene, Novartis, Humanigen, MorphoSys, Tolero, Sunesis, Leahlabs; and Lentigen; has participated in consultancy with Torque, Leahlabs, and Kiniksa; has participated in scientific advisory board meetings of Juno, Kite, and Humanigen; and has participated in data safety monitoring board meetings of Humanigen. Dr Wang has received research funding (to the institution) from Incyte, InnoCare, Novartis, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, and Genmab; has served on the Advisory Boards (compensation to institution) of Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene; has served as a consultant (compensation to institution) to Innocare and AbbVie; and has received honorarium (to institution) from Kite. Dr Kay has served on the Advisory Boards for AbbVie, AstraZeneca, BeiGene, Behring, Boehringer Ingelheim Pharmaceuticals Inc, Dava Oncology, Janssen, Juno Therapeutics, and Pharmacyclics; has served on the Data Safety Monitoring Committee for Agios Pharm, AstraZeneca, Bristol-Myers Squibb Celgene, and Dren Bio Janssen; and has received research funding from: AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, Pharmacyclics, Sunesis, and Vincerx. Dr Kappor has served as a consultant for Sanofi and Cellectar; has received research funding from Sanofi, Janssen, Amgen, GlaxoSmithKline, Takeda, and AbbVie; and has received honoraria from Celgene, Janssen, Takeda, Karyopharm, Beigene, and AbbVie. Dr Shanafelt has received research support to his institution from Genentech, AbbVie, and Pharmacyclics. Dr Herrmann has served on the Advisory Board for AstraZenca, Astellas, and Pfizer; and has received royalties from Elsevier, Inc. Dr Parikh has received research funding to his institution from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which Dr Parikh is a principal investigator; and has received honoraria to his institution from Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, NovalGen Limited, Kite Pharma, and AbbVie for his participation in consulting activities/advisory board meetings. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. This research was previously presented as an abstract at the American Society of Hematology Scientific Sessions in 2020, December 7, 2020, virtual poster session., (© 2024 The Authors.)

In this study, we employed two multiple criteria decision-making (MCDM) methods, namely the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) and the Analytic Hierarchic Process (AHP), to determine the best management choice for the cultivation of wheat with a regime of conservation agriculture (CA) practices. By combining alternative tillage approaches, such as reduced tillage and zero tillage, with the quantity of crop residues and fertilizer application, we were able to develop the regime of CA practices. The performance of the regimes compared to the conventional ones was then evaluated using conflicting parameters relating to energy use, economics, agronomy, plant protection, and soil science. TOPSIS assigned a grade to each alternative based on how close it was to the ideal solution and how far away it was from the negative ideal solution. However, employing AHP, we determined the weights of each of the main and sub-parameters used for this study using pairwise comparison. With TOPSIS, we found ZERO1 (0% residue + 100% NPK) followed by ZERO4 (50%residue + 100% NPK), and ZERO2 (100% residue + 50% NPK) were the best performing tillage-based alternatives. To best optimize the performance of wheat crops under various CA regimes, TOPSIS assisted the decision-makers in distinguishing the effects of the parameters on the outcome and identifying the potential for maneuvering the weak links. The outcomes of this investigation could be used to improve management techniques for wheat production with CA practices for upscaling among the farmers., (© 2024. The Author(s).)

Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory., (© 2024. The Author(s).)

The grain-filling stage in Triticum aestivum (wheat) is highly vulnerable to increasing temperature as terminal heat stress diminishes grain quality and yield. To examine the mechanism of terminal heat tolerance, we performed the biochemical and gene expression analyses using two heat-tolerant (WH730 and WH1218) and two heat-sensitive (WH711 and WH157) wheat genotypes. We observed a significant increase in total soluble sugar (25%-47%), proline (7%-15%), and glycine betaine (GB) (22%-34%) contents in flag leaf, whereas a decrease in grain-filling duration, 1000-kernel weight (8%-25%), and grain yield per plant (11%-23%) was observed under the late-sown compared to the timely sown. The maximum content of osmolytes, including total soluble sugar, proline, and GB, was observed in heat-tolerant genotypes compared to heat-sensitive genotypes. The expression of 10 heat-responsive genes associated with heat shock proteins (sHsp-1, Hsp17, and HsfA4), flavonoid biosynthesis (F3'-1 and PAL), β-glucan synthesis (CslF6 and CslH), and xyloglucan metabolism (XTH1, XTH2, and XTH5) was studied in flag leaf exposed to different heat treatments (34, 36, 38, and 40°C) at 15 days after anthesis by quantitative real-time polymerase chain reaction. A significant increase in the relative fold expression of these genes with increasing temperature indicated their involvement in providing heat-stress tolerance. The high differential expression of most of the genes in heat-tolerant genotype "WH730" followed by "WH1218" indicates the high adaptability of these genotypes to heat stress compared to heat-sensitive wheat genotypes. Based on the previous results, "WH730" performed better in terms of maximum osmolyte accumulation, grain yield, and gene expression under heat stress., (© 2023 CCS Haryana Agricultural University. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

In multiple myeloma (MM) significant variation in progression-free survival (PFS) and overall survival (OS) is observed. We examined the outcomes of 1557 MM patients stratified into short (<2 years), medium (between 2 and 5 years) and long (>5 years) PFS. Short PFS occurred in 758 patients (48.7%), medium in 561 patients (36.2%), and long in 238 patients (15.3%). Median post-progression PFS was 9.2 months (95% CI: 8.1-11.0) in the short PFS and 33.1 months (95% CI: 29.0-42.1; P < .001) in the long PFS group. Median post-progression OS was 26.6 months (95% CI: 23.9-29.8) in the short PFS and 87.8 months (95% CI: 71.3- NR; P < .001) in the long PFS. Worse survival in the short PFS was irrespective of high risk (HR) fluorescence in situ hybridization (FISH) features, defined as deletion 17p and/or translocation t(4;14), t(14;16), t(14;20). In a multivariable analysis short PFS was associated with HR FISH, extramedullary plasmacytoma, plasma cell labeling index ≥2% at diagnosis, nonimmunoglobulin G isotype, treatment without autologous stem cell transplantation and achieving less than very good partial remission. In conclusion, the duration of the PFS significantly influences survival, regardless of HR cytogenetic features. Therefore, it should be considered an important parameter for risk stratification in patients experiencing a relapse., Competing Interests: Disclosure Prashant Kapoor: Research Funding: Takeda, Sanofi, Karyopharm, Glaxo SmithKline, Regeneron Pharmaceuticals, Ichnos Sciences, Amgen. Cosultancy: Sanofi, Pharmacyclics, BeiGene, Cellectar, Karyopharm; Angela Dispenzieri: Consultancy and Research Funding: Janssen. Research Funding: Takeda, Alnylam, Pfizer. Consultancy: Oncopeptides, Sorrento Therapeutics; Morie A. Gertz: Advisory Board: Ionis Pharmaceuticals. Consultancy: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena. Data Safetly & Monitoring: AbbVie Inc, Celgene Corporation. Honoraria: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme. Stock option: Aurora Biopharma; David Dingli: Consultancy: Alexion, Apellis, GSK, Sanofi, Janssen. Research Funding: Novartis; Shaji Kumar: Consultancy and Research Funding: BMS, Amgen, Roche-Genentech. Consultancy, Membership on an entity's Board of Directors or advisory committees and Research Funding: Abbvie, Takeda, Janssen, KITE, Astra-Zeneca. Research Funding: Tenebio, Carsgen, Merck, Novartis, Sanofi. Consultancy: Beigene, Oncopeptides, Bluebird Bio. Consultancy and Honoraria: Antengene. Membership on an entity's Board of Directors or advisory committees and Research Funding: Adaptive, Celgene., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Extracorporeal Life Support Organization (ELSO) maintains the world's largest extracorporeal membrane oxygenation (ECMO) registry by volume, center participation, and international scope. This 2022 ELSO Registry Report describes the program characteristics of ECMO centers, processes of ECMO care, and reported outcomes. Neonates (0-28 days), children (29 days-17 years), and adults (≥18 years) supported with ECMO from 2009 through 2022 and reported to the ELSO Registry were included. This report describes adjunctive therapies, support modes, treatments, complications, and survival outcomes. Data are presented descriptively as counts and percent or median and interquartile range (IQR) by year, group, or level. Missing values were excluded before calculating descriptive statistics. Complications are reported per 1,000 ECMO hours. From 2009 to 2022, 154,568 ECMO runs were entered into the ELSO Registry. Seven hundred and eighty centers submitted data during this time (557 in 2022). Since 2009, the median annual number of adult ECMO runs per center per year increased from 4 to 15, whereas for pediatric and neonatal runs, the rate decreased from 12 to 7. Over 50% of patients were transferred to the reporting ECMO center; 20% of these patients were transported with ECMO. The use of prone positioning before respiratory ECMO increased from 15% (2019) to 44% (2021) for adults during the coronavirus disease-2019 (COVID-19) pandemic. Survival to hospital discharge was greatest at 68.5% for neonatal respiratory support and lowest at 29.5% for ECPR delivered to adults. By 2022, the Registry had enrolled its 200,000th ECMO patient and 100,000th patient discharged alive. Since its inception, the ELSO Registry has helped centers measure and compare outcomes across its member centers and strategies of care. Continued growth and development of the Registry will aim to bolster its utility to patients and centers., Competing Interests: Disclosure: J.E.T. is the Chair of the Registry Committee of the Extracorporeal Life Support Organization (ELSO). P.S.B. receives salary support from ELSO. G.M. is the President of ELSO. M.P. is the Immediate past President of ELSO. D.B. receives research support from and consults for LivaNova. He has been on the medical advisory boards for Abiomed, Xenios, Medtronic, Inspira, and Cellenkos. He is the President-elect of ELSO and the Chair of the Executive Committee of the International ECMO Network (ECMONet), and he writes for UpToDate. M.A., A.H., and K.R. are the Immediate Past Co-Chairs of the Scientific Oversight Committee of ELSO. P.R. is the Executive Director of ELSO. C.S. is the Chief Executive Officer (CEO) of ELSO. N.A.B. is the President of European Chapter of ELSO. N.A.B. has been on the medical advisory boards for Xenios and Baxter. T.M. is on the Board of Directors of ELSO. R.D.G. is the President of the Latin-American Chapter of ELSO. P.M.K. is the President of the South West Asia and Africa Chapter of ELSO. J.F.F. is the President of Asia-Pacific Chapter of ELSO. P.M.A.A. is Treasurer of ELSO Board of Directors. P.M.A.A. is funded by U.S. DoD PRMRP Clinical Trial Award #W81XWH2210301, NIH (R13HD104432) and FDA UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation (U01FD004979/U01FD005978). None of the funding sources were involved in the design or conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. No other conflicts of interest reported. R.P.B. is a member of the Board of Directors for ELSO and receives funding from the National Heart, Lung, And Blood Institute (R01 HL153519)., (Copyright © ASAIO 2024.)

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing., (© 2024. The Author(s).)

Daratumumab is an anti-CD38 mAb, used frequently in combination with lenalidomide and pomalidomide. No studies compared daratumumab plus lenalidomide and dexamethasone (DRd) to daratumumab plus pomalidomide and dexamethasone (DPd) in lenalidomide-exposed multiple myeloma. We identified 504 consecutive multiple myeloma patients who received daratumumab at Mayo Clinic between January 2015 and April 2019. We excluded patients who received daratumumab in the first line, received more than four lines of therapy prior to daratumumab use, did not receive lenalidomide prior to daratumumab, or had an unknown status of lenalidomide exposure, and patients who received daratumumab combinations other than DRd or DPd. We examined the impact of using DRd compared to DPd on progression-free survival (PFS) and overall survival (OS) in patients with relapsed/refractory multiple myeloma. Out of 504 patients, 162 received DRd or DPd and were included; 67 were lenalidomide-exposed and 95 were lenalidomide-refractory. DRd was used in 76 (47%) and DPd in 86 (53%) patients. In lenalidomide-exposed multiple myeloma, there was no difference in median PFS; 34.2 months [95% confidence interval (CI), 22.8-44.6] for DRd compared to 25.2 months (95% CI, 4.9-35.3) for DPd, P  = 0.2. In lenalidomide-refractory multiple myeloma, there was no difference in median PFS; 18.6 months (95% CI, 13-32) for DRd compared to 9 months (95% CI, 5.2-14.6) for DPd, P  = 0.09. No difference in median OS was observed in DRd compared to DPd. Our study shows combining daratumumab with lenalidomide in patients with prior lenalidomide use is a viable and effective treatment option., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010-2019 who had an 18 F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively (P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively (P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics., (© 2023. The Author(s).)