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Introduction: Warfighters are exposed to life-threatening injuries daily and according to the Joint Trauma System Military Clinical Practice Guideline-Global Snake Envenomation Management snakebites are a concerning threat in all theaters of operation. Snake venom is a complex mixture of toxins including phospholipases A2 (PLA2) and snake venom metalloproteinases (SVMP) that produce myotoxic, hemotoxic, and cytotoxic injuries. Antibody-based antivenom is the standard of care but new approaches including small-molecule inhibitors have gained attention in recent years. Doxycycline is an effective inhibitor of human metalloproteinases and PLA2. The enzymatic activities of 3 phylogenetically distinct snakes: Agkistrodon piscivorus, Naja kaouthia, and Daboia russelii were tested under inhibitory conditions using doxycycline., Materials and Methods: Enzymatic activity of PLA2 and SVMP was measured in N. kaouthia, D. russelii, and A. piscivorus venom alone and with doxycycline using EnzChek Phospholipase A2 and Gelatinase Assay Kits. A 1-way ANOVA with Tukey's post-hoc test was used to conduct comparative analysis. The median lethal dose of the venoms, the effective dose of doxycycline, and creatine kinase (CK) inhibition levels were measured in a murine model with adult Bagg Albino (BALB/c) mice using intramuscular injections. Median lethal and effective doses were determined using Spearman-Karber's method and a 1-way ANOVA with Tukey's post-hoc test was used to compare CK inhibition levels., Results: Phospholipases A2 activity was reduced to 1.5% to 44.0% in all 3 venoms in a dose-dependent manner using 0.32, 0.16, and 0.08 mg/mL doxycycline when compared to venom-only controls (P < .0001) (Fig. 1A). Snake venom metalloproteinases activity was reduced to 4% to 62% in all 3 venoms in a dose-dependent manner using 0.32, 0.16, and 0.08 mg/mL doxycycline (P < .0001) (Fig. 1B). The lethal dose (LD50) values of the venoms in the murine model were calculated as follows: A. piscivorus = 20.29 mg/kg (Fig. 2A), N. kaouthia = 0.38 mg/kg (Fig. 2B), and D. russelii = 7.92 mg/kg (Fig. 2C). The effective dose (ED50) of doxycycline in A. piscivorus was calculated to be 20.82 mg/kg and 72.07 mg/kg when treating D. russelii venom. No ED50 could be calculated when treating N. kaouthia venom (Fig. 3). Creatine kinase activity was significantly decreased in all 3 venoms treated with doxycycline (P < .0001) (Fig. 4)., Conclusion: Doxycycline reduced PLA2- and SVMP-related lethality, particularly in A. piscivorus envenomings and in a limited capacity with D. russelii revealing its promise as a treatment for snakebites. In addition, CK activity, a common indicator of muscle damage was inhibited in mice that received doxycycline-treated venom. The doxycycline concentrations identified in the ED50 studies correspond to 1,456 to 5,061 mg dosages for a 70 kg human. Factors including venom yield and snake species would affect the actual dosage needed. Studies into high-dose doxycycline safety and its effectiveness against several snake species is needed to fully translate its use into humans. Based on this work, doxycycline could be used as a treatment en route to higher echelons of care, providing protection from muscle damage and reducing lethality in different snake species., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels or hyperglycemia. Diabetes causes a decrease in immune function in the human body. Mytilus edulis has been identified as having anti-inflammatory properties and the ability to improve inflammation. Thus, this study aimed to investigate the function of Matsu M. edulis water extract (MWE) in mediating the regulation of immune responses and dysregulating the intestinal immune system in hyperglycemia mouse models. The mice were treated with MWE for seven weeks. The results showed that treatment with MWE has the ability to decrease triglyceride and total cholesterol concentrations. MWE also increases the interleukin (IL)-10 concentration and natural killer cell activation. It also improves the phagocytic capacity of monocytes in the colon and the proliferative capacity of lymphocytes in the mesentery. Furthermore, MWE also regulates the IL-6 concentration and the ratio of T helper 17 cells to regulatory T cells. Collectively, this extract can improve dyslipidemia, inflammatory responses, and dysregulation of the intestinal immune system. Therefore, M. edulis water extract can be used as an alternative treatment to reduce diabetes complications.

Negative perspectives around advance care planning (ACP) prevent people with heart failure (HF) from preparing their end-of-life (EOL) effectively. A Q methodology study was conducted to identify types of ACP perspectives in Koreans with HF. The Q sample (31 statements representing ACP perspectives) was constructed through an extensive literature review and in-depth qualitative interview. The P sample (individuals with HF) completed each grid with a statement on the Q sorting table. The data were analyzed using the PQ program. Individuals with HF have both different and common perspectives on ACP. Three types of perspectives were identified: " positive acceptance ," " contemplative support ," and " hesitancy in acceptance ." Common perspectives across types indicated that people with HF had positive attitudes toward ACP and emphasized their autonomy in EOL decisions. Clinicians need to consider these different and common perspectives on ACP to facilitate patients' engagement and provide relevant support., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In Hong Kong, newly diagnosed multiple myeloma (NDMM) receives bortezomib-based triplet induction. Upfront autologous stem cell transplant (ASCT) is offered to transplant eligible (TE) patients (NDMM ≤ 65 years of age), unless medically unfit (TE-unfit) or refused (TE-refused). Data was retrieved for 448 patients to assess outcomes. For the entire cohort, multivariate analysis showed that male gender (p = 0.006), international staging system (ISS) 3 (p = 0.003), high lactate dehydrogenase (LDH) (p = 7.6 × 10 -7 ) were adverse predictors for overall survival (OS), while complete response/ near complete response (CR/nCR) post-induction (p = 2.7 × 10 -5 ) and ASCT (p = 4.8 × 10 -4 ) were favorable factors for OS. In TE group, upfront ASCT was conducted in 252 (76.1%). Failure to undergo ASCT in TE patients rendered an inferior OS (TE-unfit p = 1.06 × 10 -8 , TE-refused p = 0.002) and event free survival (EFS) (TE-unfit p = 0.00013, TE-refused p = 0.002). Among TE patients with ASCT, multivariate analysis showed that age ≥ 60 (p = 8.9 × 10 -4 ), ISS 3 (p = 0.019) and high LDH (p = 2.6 × 10 -4 ) were adverse factors for OS. In those with high-risk features (HR cytogenetics, ISS 3, R-ISS 3), ASCT appeared to mitigate their adverse impact. Our data reaffirmed the importance of ASCT. The poor survival inherent with refusal of ASCT should be recognized by clinicians. Finally, improved outcome with ASCT in those with high-risk features warrant further studies., (© 2024. The Author(s).)

Background: Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting β  cells. A comprehensive immune cell phenotype evaluation in T1DM has not been performed thus far at the single-cell level., Methods: In this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (stage 3) cases and 31 matched controls., Results: We surprisingly detected profound alterations in circulatory immune cells (1784 dysregulated genes in 13 immune cell types), far exceeding the count in the comparator systemic autoimmune disease SLE. Genes upregulated in T1DM were involved in WNT signaling, interferon signaling and migration of T/NK cells, antigen presentation by B cells, and monocyte activation. A significant fraction of these differentially expressed genes were also altered in T1DM pancreatic islets. We used the single-cell data to construct a T1DM metagene z-score (TMZ score) that distinguished cases and controls and classified patients into molecular subtypes. This score correlated with known prognostic immune markers of T1DM, as well as with drug response in clinical trials., Conclusions: Our study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes, and has the potential to guide non-invasive test development and patient stratification., (© 2024. The Author(s).)

Introduction: Dental caries are a limiting factor in maintaining dental and medical readiness in the military. Untreated dental caries can lead to dire health consequences. Consistent and comprehensive access to dental care is often limited due to the intensive operational demands on our nation's warfighters. The standard of care for dental caries is a surgical model where diseased tooth tissue is surgically removed and restored with appropriate restorative materials. While effective, it is not practical in the military operational environment, especially under time constraints. Dental restoratives offer military personnel a simple and preventive treatment of dental caries and are suitable as self-applied first aids. The purpose of this study was to measure the shear bond strengths of two dental restorative materials to human teeth paired with two different fluoride treatments and the hardness and biofilm formation on teeth after applying the fluoride varnishes., Materials and Methods: Specimens were made of human molar teeth treated with each of the following four materials: glass ionomer cement GC Fuji II LC Capsules, Filtek Z250, Riva Star steps 1 and 2, or Mark3 NaF varnish. Step 1 of Riva Star consists of silver diamine fluoride and step 2 contains potassium iodide. On human molar slabs, 10 circular specimens of 5 cm in diameter were prepared with restoratives according to manufacturer procedures. Etch-Rite and a proprietary aluminum chloride-based cavity conditioner were used as etchants on tooth surfaces for the Filtek Z250 and glass ionomer cement, respectively. After at least 24 hours underwater, each assembly was removed, and the shear bond strength of the adhesive was measured according to International Organization for Standardization (ISO) 29022.The hardness was measured according to ISO 14233. Hardness measurements were performed before varnish application, then after storage in an incubator at 37 °C for 4 hours in a demineralization solution (pH = 4.5), and after 1 day in a mineralization solution (pH = 7). A crystal violet staining assay was used to measure biofilm formation of Streptococcus mutans bacteria on human molar teeth after the application of fluoride varnish., Results: We report a 16% increase in shear bond strength of the Filtek Z250/Riva Star coupled treatment compared to the Filtek Z250/Mark3 NaF coupled treatment. We also demonstrate a significant 84% decrease in bond strength with a GC Fuji II LC/Mark3 NaF treatment compared to control (P = .0002), while Riva Star remains statistically unchanged. Enamel and dentinal hardness are significantly improved when Riva Star is applied compared to NaF varnish. A 25%-35% (P < .0001) decrease in oral biofilm formation was observed on samples where a Riva Star or NaF varnish was applied., Conclusions: Mechanical and antimicrobial testing indicated Riva Star, compared favorably with and in some cases, performed better in the laboratory than a Mark3 NaF varnish. Hardness measurements indicated Riva Star is more effective in dentin tubule occlusion compared to NaF varnish. Our findings help provide practical suggestions to dental treatment, particularly to the unique dental environments seen in the military. Riva Star may be used as an adjunctive treatment prior to placing a final restoration. This study supports the use of Riva Star in conjunction with GC Fuji II LC or Filtek Z250 restorative materials, making it a promising treatment in military dental applications., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Plastic pollution, including microplastic, has emerged as a severe environmental and public health problem. The health risks, especially in the case of reproductive damage caused by polystyrene microplastic (PS-MP) exposure, are emerging problems that need to be solved. This study aimed to investigate the effects of fucoidan extracted from Cladosiphon okamuranus on the polystyrene microplastic-induced oxidative stress of the Leydig (LC540) cells and reproductive damage in male rats. The oxidative stress of the LC540 cells and reproductive damage in the rats were induced by PS-MP. The fucoidan treatment reduces nitric oxide (NO) and reactive oxygen species generation in the LC540 cells. In the animal study, fucoidan treatment enhanced enzymatic antioxidant activities (glutathione peroxidase, superoxide dismutase, glucose-6-phosphate dehydrogenase, and glutathione reductase) and reduced malondialdehyde and nitric oxide production. Fucoidan supplementation also downregulates tumor necrosis factor-alpha, interleukin-6, and caspase-3 expression. Additionally, fucoidan upregulates testosterone levels, prevents the reduction of epithelium thickness, and reduces the area of the seminiferous tubule lumen. According to these conditions, fucoidan from Cladosiphon okamuranus prevents reproductive damage by downregulating oxidative stress and pro-inflammatory cytokines. Therefore, fucoidan can be used as a source of food supplements or functional food ingredients for reproductive or testicular damage management., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Preclinical models are often used for cancer studies and evaluation of novel therapeutics. The relevance of these models has vastly improved with mice bearing a human immune system, especially in the context of immunotherapy. Nonetheless, cancer is an age-related disease, and studies often overlook the effects of aging. Here we have established a humanized mouse model of human immune aging to investigate the role of this phenomenon on liver tumor dynamics., Methods: Multiple organs and tissues (blood, thymus, lung, liver, spleen and bone marrow) were harvested from NOD-scid IL2rγ -/- (NIKO) mice reconstituted with human immune cells, over a period of 60 weeks post-birth, for immune profiling. Young and aging immune cells were compared for transcriptomic changes and functional differences. Effect of immune aging was investigated in a liver cancer humanized mouse model., Results: Focusing on the T cell population, which is central to cancer immunosurveillance and immunotherapy, we showed that the proportion of naïve T cells declined while memory subsets and senescent-like cells increased with age. RNA-sequencing revealed that downregulated genes were related to immune responses and processes, and this was corroborated by reduced cytokine production in aging T cells. Finally, we showed faster liver tumor growth in aging than younger humanized mice, which could be attributed to specific pathways of aging T cell exhaustion., Conclusion: Our work improves on existing humanized (immune) mouse model and highlights the importance of considering immune aging in liver cancer modeling., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients., Case Presentation: We report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 10 8 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT., Conclusions: Our case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib., (© 2023. The Author(s).)

Background: Rapid and accurate identification of nontuberculous mycobacteria (NTM) species is essential for the diagnosis and treatment of NTM disease. MolecuTech REBA Myco-ID (YD Diagnostics, Yongin, Korea) is a line probe assay for identification of NTM species and can be performed using HybREAD480, an instrument for automating the post-PCR steps. In this study, we assessed the performance of MolecuTech REBA Myco-ID using HybREAD480., Methods: Seventy-four reference strains, including 65 Mycobacterium strains and nine non-Mycobacterium strains within the order Mycobacteriales, were used to determine the analytical specificity of MolecuTech REBA Myco-ID. The clinical performance of this assay was evaluated with 192 clinical Mycobacterium strains, and the assay results were compared to those of multigene sequencing-based typing., Results: The accuracy of MolecuTech REBA Myco-ID for the 74 reference strains and 192 clinical strains was 77.0% (57/74; 95% confidence interval [CI], 65.8 - 86.0%) and 94.3% (181/192; 95% CI, 90.0 - 97.1%), respectively. Although some rarely isolated NTM species are misidentified, the most commonly isolated NTM species, including M. avium complex, M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. fortuitum com-plex, were all correctly identified. Of note, all M. lentiflavum strains tested (reference strain, n = 1; clinical strain, n = 10) were misidentified as M. gordonae., Conclusions: MolecuTech REBA Myco-ID using HybREAD480 was accurate for identifying commonly isolated NTM species and for discriminating between M. abscessus subsp. abscessus and M. abscessus subsp. massiliense. However, the main limitations of this assay, including misidentification of some rarely isolated NTM species and cross-reactivity between M. lentiflavum and M. gordonae, should be considered.

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.

Background: Epstein Barr virus positive (EBV+) immunodeficiency-associated lymphoproliferative disorders (IA-LPD) are heterogeneous diseases with variable treatment strategies that are not well-defined., Case Presentation: A 68-year-old woman with systemic lupus erythematosus developed EBV+ B-cell polymorphic lymphoproliferative disease (LPD). Positron emission tomography computed tomography (PET/CT) showed a large nasopharyngeal mass, multiple pulmonary lesions, splenomegaly and disseminated lymphadenopathy. Plasma EBV DNA was grossly elevated to 1.5 × 10 4 IU/mL. There were three paraproteins. Treatment with O-CHOP (obinutuzumab, cyclophosphamide, adriamycin, vincristine, prednisolone) led to undetectable plasma EBV DNA, suggesting eradiation of the EBV-positive malignant clone. However, radiologic abnormalities were still present on PET/CT, and paraprotein persisted. A nasopharyngeal re-biopsy showed infiltration with EBV-negative plasma cells. On treatment with lenalidomide, she finally achieved complete metabolic response. Molecular analysis showed that the EBV+ B-cell LPD and the EBV- plasma cell lesion exhibited identical immunoglobulin gene rearrangements. Next generation sequencing revealed that the EBV+ B-LPD showed mutation in only one gene ( TP53 ), a profile typical of EBV-driven lymphoid neoplasms. However, the EBV- plasma cell lesion showed mutations in five genes ( TP53 , SF3B1 , STAT5B , CD79B and CRKL ), suggesting that these mutations instead of EBV infection were the oncogenic driver., Conclusion: The presence of both EBV+ and EBV- lesions, which showed different mutational profiles, indicated clonal heterogeneity that might be of biologic and therapeutic significance.

Objectives: Bendamustine is a standard treatment for low-grade B-cell lymphomas, and considered safe in clinical trials. Its safety in routine practice might be different., Methods: We retrospectively analyzed the infection complications in an unselected cohort of patients treated with bendamustine over a nine-year period. Patients were regularly monitored for blood counts and cytomegalovirus (CMV) reactivation by antigen assay and polymerase chain reaction. They received granulocyte colony stimulating factor for neutropenia, and routine anti-pneumocystis and optional anti-fungal prophylaxis., Results: There were 179 men and 127 women at a median age of 61.5 (20-90) years, 52% receiving bendamustine for relapsed/refractory disease. Malignancies included low-grade B-cell lymphomas (54%), myeloma (10%), T-cell lymphomas (11%), Hodgkin lymphoma (2%) and other lymphoid neoplasms (23%). Most patients had good performance status (Eastern Cooperative Oncology Group score: 0-1, 72%). CMV reactivation occurred in 58 patients (19%) at a median age of 68 (39-85) years. Univariate analysis showed CMV reactivation to be significantly associated with elevated lactate dehydrogenase ( P  = 0.045), decreased albumin ( P  = 0.003) and older age (reactivation versus no reactivation: 66.3 ± 11.4 versus 59.4 ± 14.5 years, P  = 0.0016). Age remained the only significant risk on multivariate analysis. CMV reactivation resulted in retinitis ( N  = 4), ependymitis/ventriculitis ( N  = 1) and duodenitis/colitis ( N  = 1). Invasive fungal disease occurred in five patients (candidemia, N  = 2; aspergillosis N  = 1; cryptococcemia, N  = 1; scedosporiosis, N -1). Nineteen patients had culture positive septicaemia., Conclusion: Our observations showed that even with a vigorous anti-infective strategy, bendamustine treatment was still associated with significant risks of bacterial and opportunistic viral and fungal infections.

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [ 18 F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting K V 1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [ 18 F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.

Body composition and muscular strength are important for baseball skills and successful performance. Conditioning training programs have the potential to enhance athletic performance via physiological changes. In this single-group interventional study, we investigated the effect of 8 weeks of Pilates training (PT) on contralateral and regional body composition, and isokinetic muscular strength in knee and trunk flexion/extension in adolescent baseball players. In our results, PT increased both right- and left-sided lean mass in the trunk. Following PT, work per repetition and average power showed significant increases in the flexion and extension of the left knee only. PT significantly decreased the peak torque of the trunk flexor and increased the average power of the trunk extensor. In addition, the ratio of the trunk flexion/extension strength of peak torque showed a decreasing trend, whereas that of work and average power did not change significantly following PT. In conclusion, PT evenly improved lean mass on both the right and left sides of the body. Knee and trunk strength increased after PT. Our findings suggest that PT may be a useful strategy for enhancing athletic performance in regard to the muscular strength of adolescent baseball players.

Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI-chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [ 18 F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (T EM ) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [ 18 F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing T EM cells responsible for durable immunological memory response to combination therapy in vivo.

Despite the high prevalence of nurses' turnover and the turnover intention of new nurses, there are insufficient studies examining turnover intention at the time when job orientation is completed and independent nursing commences. Thus, this study examined turnover intention levels and identified the factors affecting turnover intention of new Generation Z nurses, focusing on job stress and sleep disturbance, at the eighth week after completing job orientation. This was a cross-sectional descriptive correlational study. Using a convenient sampling method, 133 new nurses were recruited. Data were collected using a structured questionnaire consisting of demographic and occupational characteristics, job stress, sleep disturbance, and turnover intention. Descriptive statistics were computed to describe the sample and interest variables. Logistic regression analysis was performed to examine the association of job stress and sleep disturbance with turnover intention. Most nurses were women (91.7%) and approximately two-thirds worked in the surgical ward (n = 61, 45.9%). Turnover intention was 12.8%, average job stress was 40.11 ± 90.7, and average sleep disturbance was 42.39 ± 15.27. New graduate nurses' turnover intention was associated with job stress (OR = 1.07, 95% CI = 1.02-1.12) and sleep disturbance (OR = 1.19, 95% CI = 1.05-1.35), and this model explained 47.7% of the variance. Study findings determine that job stress and sleep disturbance were significant predictors of turnover intention in new nurses at the eighth week after joining the hospital. Therefore, nursing administrators should focus on new nurses' job stress and sleep disturbance, and provide them with timely assessment and management to reduce turnover intention.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Bortezomib has been reported to favourably impact the outcomes of t (4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown., Methods: To address this, 250 patients treated with bortezomib-based induction were analysed. All myeloma samples had fluorescence in situ hybridization (FISH) performed on CD138-sorted bone marrow aspirate, and plasma cells were analysed using DNA probes specific for the following chromosomal aberrations: del(13q14), del(17p), t (14;16), t (4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells., Results: +1q identified in 167 (66.8%) and associated with t (4;14) and high lactate dehydrogenase (LDH). +1q was not associated with response rate but shorter event-free survival (EFS) (median EFS 35 vs 55 months, p  = 0.05) and overall survival (OS) (median OS 74 vs 168 months, p  = 0.00025). Copy number and clone size did not impact survival. Multivariate analysis showed +1q was an independent adverse factor for OS together with International Staging System (ISS)3, high LDH, del(17p) and t (4;14). When a risk score of 1 was assigned to each independent adverse factor, OS was shortened incrementally by a risk score from 0 to 4. Post-relapse/progression survival was inferior in those with +1q (median 60 vs 118 months, p  = 0.000316). Autologous stem cell transplantation (ASCT) improved OS for those with +1q (median OS 96 vs 49 months, p  = 0.000069)., Conclusion: +1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM., Competing Interests: Conflict of interest statement: The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Circulating Ly6C hi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6C hi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes.

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [ 18 F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [ 18 F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [ 18 F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8 + effector memory T cells.

As the demand for rechargeable lithium-ion batteries (LIBs) with higher energy density increases, the interest in lithium-rich oxide (LRO) with extraordinarily high capacities is surging. The capacity of LRO cathodes exceeds that of conventional layered oxides. This has been attributed to the redox contribution from both cations and anions, either sequentially or simultaneously. However, LROs with notable anion redox suffer from capacity loss and voltage decay during cycling. Therefore, a fundamental understanding of their electrochemical behaviors and related structural evolution is a prerequisite for the successful development of high-capacity LRO cathodes with anion redox activity. However, there is still controversy over their electrochemical behavior and principles of operation. In addition, complicated redox mechanisms and the lack of sufficient analytical tools render the basic study difficult. In this review, we aim to introduce theoretical insights into the anion redox mechanism and in situ analytical instruments that can be used to prove the mechanism and behavior of cathodes with anion redox activity. We summarized the anion redox phenomenon, suggested mechanisms, and discussed the history of development for anion redox in cathode materials of LIBs. Finally, we review the recent progress in identification of reaction mechanisms in LROs and validation of engineering strategies to improve cathode performance based on anion redox through various analytical tools, particularly, in situ characterization techniques. Because unexpected phenomena may occur during cycling, it is crucial to study the kinetic properties of materials in situ under operating conditions, especially for this newly investigated anion redox phenomenon. This review provides a comprehensive perspective on the future direction of studies on materials with anion redox activity., (© 2022 IOP Publishing Ltd.)

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [ 18 F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [ 18 F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [ 18 F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.

Graft-versus-host disease (GVHD) is an important complication after allogeneic haematopoietic stem cell transplantation (HSCT). Corticosteroids are the standard first-line treatment. Steroid-resistant/-dependent (SR/D) acute and chronic GVHD (aGVHD, cGVHD) lead to significant morbidity/mortality. The JAK2 inhibitor ruxolitinib has recently been shown in clinical trials to be effective in SR/D aGVHD and cGVHD. We retrospectively analysed the efficacy and safety of ruxolitinib in a cohort of SR/D aGVHD and cGVHD patients treated in a non-trial setting. In the aGVHD cohort, there were 14 men and 12 women, median age at 38 (19-63) years. At day 28 post-ruxolitinib, the overall response rate (ORR) was 86% (complete response, CR, 36%; partial response, PR, 50%). Continued ruxolitinib beyond day 28 resulted in a final CR of 68%. However, 3/15 (20%) of CR patients developed cGVHD. In the cGVHD cohort, there were 16 men and 15 women, median age at 33 (21-64) years. The ORR, CR and PR rates changed with continued ruxolitinib treatment, being 86%, 17% and 69% at 1 month; 79%, 38% and 41% at 3 months; and 83%, 52% and 31% at 6 months. Five patients had overlap GVHD, four of whom achieved CR. Multivariate analysis showed that superior overall survival and failure-free survival were associated with CR at day 28 for aGVHD, and CR at 1 year for cGVHD. Ruxolitinib treatment was efficacious for SR/D aGVHD and cGVHD, and continued treatment for at least 6 months was needed to maximize benefit., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunoglobulin G4-related disease (IgG4-RD) has rarely been associated with lymphoid neoplasms, the spectrum of which remains unclear. B-cell lymphoid neoplasms (LN) associated with IgG4-RD diagnosed in a 4-year period were analysed. There were five men and three women at a median age of 76.5 (52-90) years; three with synchronous IgG4-RD and LN; three with IgG4-RD preceding LN by 2, 3, and 22 years; and two with LN preceding IgG4-RD by 2.5 and 7 years. All patients presented with disseminated lymphadenopathy. Monoclonal gammopathy of undetermined significance (MGUS)/smouldering multiple myeloma (SMM) was found in three patients, all with an IgGκ paraprotein. Levels of IgGκ and IgG4 correlated. Diffuse large B-cell lymphoma (DLBCL) was found in three patients, with one case showing co-existing lymphoma and IgG4-RD in the same lymph node biopsy. The remaining two cases were marginal zone lymphoma (MZL) developing in a lacrimal gland previously involved by IgG4-RD; and nodular lymphocyte predominant Hodgkin lymphoma (NLP-HL) diagnosed in a lymph node with concomitant IgG4-RD. Low-dose continuous prednisolone was given for MGUS/SMM, with both monoclonal IgGκ and IgG4 responding. Combination chemotherapy was given for DLBCL, with two patients achieving complete response and one patient dying from refractory lymphoma. The patient with MZL refused treatment, whereas the case of NLP-HL responded completely to chemotherapy. Our findings together with previous observations suggest that IgG4-RD has an increased risk of B-cell neoplasms. Patients with IgG4-RD presenting with lymphadenopathy require vigorous investigations to exclude lymphoid neoplasms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [ 18 F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [ 18 F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [ 18 F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [ 18 F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Julian L. Goggi et al.)

Purpose: Chemotherapeutic adjuvants, such as oxaliplatin (OXA) and 5-fluorouracil (5-FU), that enhance the immune system, are being assessed as strategies to improve durable response rates when used in combination with immune checkpoint inhibitor (ICI) monotherapy in cancer patients. In this study, we explored granzyme B (GZB), released by tumor-associated immune cells, as a PET imaging-based stratification marker for successful combination therapy using a fluorine-18 ( 18 F)-labelled GZB peptide ([ 18 F]AlF-mNOTA-GZP)., Methods: Using the immunocompetent CT26 syngeneic mouse model of colon cancer, we assessed the potential for [ 18 F]AlF-mNOTA-GZP to stratify OXA/5-FU and ICI combination therapy response via GZB PET. In vivo tumor uptake of [ 18 F]AlF-mNOTA-GZP in different treatment arms was quantified by PET, and linked to differences in tumor-associated immune cell populations defined by using multicolour flow cytometry., Results: [ 18 F]AlF-mNOTA-GZP tumor uptake was able to clearly differentiate treatment responders from non-responders when stratified based on changes in tumor volume. Furthermore, [ 18 F]AlF-mNOTA-GZP showed positive associations with changes in tumor-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells and GZB+ NK+ cells., Conclusions: [ 18 F]AlF-mNOTA-GZP tumor uptake, driven by changes in immune cell populations expressing GZB, is able to stratify tumor response to chemotherapeutics combined with ICIs. Our results show that, while the immunomodulatory mode of action of the chemotherapies may be different, the ultimate mechanism of tumor lysis through release of Granzyme B is an accurate biomarker for treatment response., (© 2021. The Author(s).)

The purpose of this study was to examine practice environment, resilience, and burnout and to identify the impacts of practice environment and resilience on burnout among clinical nurses working at a tertiary hospital. A cross-sectional secondary data analysis was conducted using a convenience sample of 199 nurses. The nurses completed survey questionnaires regarding practice environment, resilience, and burnout. The majority of the nurses were below the age of 30, single, and worked in medical-surgical wards. Approximately, 92% of the nurses reported moderate to high burnout, with a mean practice environment score of 2.54 ± 0.34 and resilience score of 22.01 ± 5.69. Practice environment and resilience were higher in the low level of burnout than in the moderate to high level of burnout. After controlling for demographic and occupational characteristics, resilience and nursing foundations for quality of care were significant predictors of burnout (OR = 0.71, p = 0.001; OR = 0.01, p = 0.036, respectively), explaining 65.7% of the variance. In a mixed practice environment, increased resilience and nursing foundations for quality of care lowered nurses' burnout. Our findings suggest that interventions focused on enhancing individual resilience and practice environment and building better nursing foundations for quality of care should be developed and provided to alleviate burnout in clinical nurses working at tertiary hospitals. Nursing and hospital administrators should consider the importance of practice environment and resilience in nurses in developing interventions to decrease burnout.

The efficacy and safety of low-dose anti-PD1 antibodies in relapsed/refractory classical Hodgkin lymphoma (cHL) require confirmation. Pembrolizumab (100 mg every 3 weeks, Q3W) or nivolumab (40 mg Q2W) were administered to patients with relapsed/refractory cHL. In the pembrolizumab cohort (N = 11), who had failed a median of three (1-6) therapies (brentuximab vedotin [BV]: 91%; autologous hematopoietic stem cell transplantation [auto-HSCT]: 18%), the overall response rate (ORR) by positron emission tomography-computed tomography was 100% (metabolic complete response [mCR]: 73%; partial response [PR]: 27%). Median cumulative dose for achieving best response was 400 (300-800) mg. Median progression-free survival (PFS) was 35 months. Median overall survival (OS) was not reached. Adverse events (AEs) of grade 1-2 were observed in three patients. In the nivolumab cohort (N = 6), who had failed a median of three (2-6) therapies (BV: 50%; auto-HSCT: 17%; allogeneic HSCT: 34%), the ORR was 100% (mCR: 67%; PR: 17%; indeterminate response: 17%). Median cumulative dose for achieving best response was 160 (160-360) mg. Median PFS was 33 months. Median OS was not reached. AEs of grade 1-2 were observed in four patients, two of whom had pre-existing autoimmune conditions. Five patients with Epstein-Barr virus (EBV) positive Reed-Sternberg cells underwent monitoring of plasma EBV DNA, which became negative in four mCR patients but remained positive in one PR patient who died ultimately from refractory lymphoma. Low-dose pembrolizumab and nivolumab were highly efficacious and safe in relapsed/refractory cHL. These observations have significant financial implications in resource-constrained settings., (© 2020 John Wiley & Sons Ltd.)

Purpose: Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes., Procedures: We have assessed the ability of a fluorine-labelled peptide, [ 18 F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [ 18 F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations., Results: [ 18 F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours., Conclusions: [ 18 F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

From a holistic point of view, aging results from the cumulative erosion of the various systems. Among these, the immune system is interconnected to the rest as immune cells are present in all organs and recirculate through bloodstream. Immunosenescence is the term used to define the remodelling of immune changes during aging. Because immune cells-and particularly lymphocytes-can further differentiate after their maturation in response to pathogen recognition, it is therefore unclear when senescence is induced in these cells. Additionally, it is also unclear which signals triggers senescence in immune cells (i) aging per se, (ii) specific response to pathogens, (iii) underlying conditions, or (iv) inflammaging. In this review, we will cover the current knowledge and concepts linked to immunosenescence and we focus this review on lymphocytes and T cells, which represent the typical model for replicative senescence. With the evidence presented, we propose to disentangle the senescence of immune cells from chronological aging.

Snake venoms are inherently complex. They are mixtures of multiple enzymes, peptides, lipids, carbohydrates, nucleosides, and metal ions. Metal ions make up a small portion of a snake's venom but play outsized roles in enzyme function and stability. Unlike enzyme primary structure, which is easily predicted from genomic sequences, a venom's metal ion content must be measured directly. We leveraged the high throughput and sensitivity of inductively coupled plasma mass spectrometry to analyze the metal ion content of seven North American snake venoms. All venoms were collected from snakes reared at one location, so we could discount variation from environmental or geographical factors. We profiled 71 metal isotopes. Selenium isotopes were consistently high across all venoms tested. When each venom's toxicity was graphed as a function of each different metal isotope, the only strong relationships between metal content and toxicity were for magnesium isotopes., (Published by Elsevier Ltd.)

Nursing burnout is associated with reduced nursing performance outcomes. Positive psychological capital is known to play an important role in improving workers' job performance. However, the association among the three variables has rarely been addressed. The purpose of this cross-sectional descriptive study was to explore the association between burnout and nursing performance outcomes among Korean nurses working at a tertiary hospital and the mediating role of psychological capital in this relationship. Recruited through convenience sampling, a total of 285 nurses provided data on their demographic characteristics and completed a structured questionnaire consisting of items from the Professional Quality of Life Scale (burnout), Nursing Performance Scale, and Psychology Capital Questionnaire. Descriptive statistics, student's t-tests, one-way analysis of variance, Pearson's correlation coefficients, and multiple linear regression analyses were used to analyze data. The significance of the mediation effect was obtained using a bootstrap approach with the PROCESS macro. The mean age of participants was 30.51 years, and most participants were females (94.0%) and unmarried (71.6%); more than half (57.5%) experienced a severe workload. The average (±standard deviation) scores of burnout, nursing performance outcomes, and positive psychological capital were 28.77 ± 4.93, 2.98 ± 0.32, and 3.19 ± 0.45, respectively. Burnout was associated with nursing performance among clinical nurses (β = -0.20, p < 0.001). Positive psychological capital mediated the association between burnout and nursing performance outcomes (β = 0.41, p < 0.001). These findings contribute to the understanding that burnout among nurses could be reduced by increased positive psychological capital, which results in improved performance outcomes. The findings also indicate that interventions to improve positive psychological capital should be developed and implemented for nurses' burnout management and improvement in nursing performance outcomes.