Relative Cost and Infectious Days Averted Associated With Rapid Gonorrhea and Chlamydia Testing Among Men Who Have Sex With Men.

BACKGROUND: Standard-of-care nucleic acid amplification tests (routine NAATs) for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can take several days to result and therefore delay treatment. Rapid point-of-care GC/CT NAAT (rapid NAAT) could reduce the time to treatment and therefore onward transmission. This study evaluated the incremental cost per infectious day averted and overall cost of implementation associated with rapid compared with routine NAAT. METHODS: Prospective sexually transmitted infection (STI) treatment data from men who have sex with men and transgender women in San Diego who received rapid NAAT between November 2018 and February 2021 were evaluated. Historical time from testing to treatment for routine NAAT was abstracted from the literature. Costs per test for rapid and routine NAAT were calculated using a micro-costing approach. The incremental cost per infectious day averted comparing rapid to routine NAAT and the costs of rapid GC/CT NAAT implementation in San Diego Public Health STI clinics were calculated. RESULTS: Overall, 2333 individuals underwent rapid NAAT with a median time from sample collection to treatment of 2 days compared with 7 to 14 days for routine NAAT equating to a reduction of 5 to 12 days. The cost of rapid and routine GC/CT NAAT was $57.86 and $18.38 per test, respectively, with a cost-effectiveness of between $2.43 and $5.82 per infectious day averted. The incremental cost of rapid NAAT improved when at least 2000 tests were performed annually. CONCLUSIONS: Although rapid GC/CT NAAT is more expensive than routine testing, the reduction of infectious days between testing and treatment may reduce transmission and provide improved STI treatment services to patients.

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Comparative reproductive ecology of Old and New World Trogons, an order in decline across the world.

Many tropical species show declining populations. The pantropical order Trogoniformes has 76% of its species ranked as declining, reflecting a worldwide problem. Here, we report on the reproductive ecology and life history traits of the declining and near-threatened old world Whitehead's Trogon (Harpactes whiteheadi), the declining new world Collared Trogon (Trogon collaris), and the stable Masked Trogon (T. personatus). We also reviewed the literature on reproductive ecology and life history traits of trogons to assess possible commonalities that might help explain population declines. We found that the declining Whitehead's and Collared Trogons had reasonable nest success (32% and 25%, respectively), while the stable Masked Trogon had poor reproductive success (9%), all contrary to population trends. However, the limited literature data suggested that poor reproductive success may be common among trogons, which may contribute to population declines. Parents fed young at a low rate and had long on-bouts for incubation and nestling warming that reduced activity at the nest, as favored by high nest predation risk over evolutionary time. We found that young fledged from the nest with poorly developed wings, as also favored by high nest predation risk. Evolved nestling periods among trogon species suggests that poor wing development is likely common. Wing development has been shown to affect juvenile survival after leaving the nest. The poor wing development may be an important contributor to population declines that deserves more attention. Evolved life history traits are important to recognize as creating population vulnerabilities in a changing world.

CD4+ CAR-T cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR-T cell therapy.

Multiple myeloma is characterized by frequent clinical relapses following conventional therapy. Recently, chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, while >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune intrinsic mechanisms may contribute to this resistance. While there were no pre-existing T cell features associated with clinical outcomes, we found that patients with a durable response to CAR-T cell treatment had greater persistence of their CAR-T cells compared to patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR-T cells. These cells expand in vivo early after infusion but express exhaustion markers (HAVCR2 and TIGIT) and remain polyclonal. Finally, we demonstrate that non-classical monocytes are enriched in the myeloma niche and may induce CAR-T cell dysfunction through mechanisms that include TGFß. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR-T cell therapy.

BAG3 localizes to mitochondria in cardiac fibroblasts and regulates mitophagy.

The co-chaperone Bcl2-associated athanogene 3 (BAG3) is a central node in protein quality control in the heart. In humans and animal models, decreased BAG3 expression is associated with cardiac dysfunction and dilated cardiomyopathy. Although previous studies focused on BAG3 in cardiomyocytes, cardiac fibroblasts are also critical drivers of pathologic remodeling. Yet, the role of BAG3 in cardiac fibroblasts is almost completely unexplored. Here, we show that BAG3 is expressed in primary rat neonatal cardiac fibroblasts and preferentially localizes to mitochondria. Knockdown of BAG3 reduces mitophagy and enhances fibroblast activation, which is associated with fibrotic remodeling. Heat shock protein 70 (Hsp70) is a critical binding partner for BAG3 and inhibiting this interaction in fibroblasts using the drug JG-98 decreased autophagy, decreased mitofusin-2 expression, and disrupted mitochondrial morphology. Together, these data indicate that BAG3 is expressed in cardiac fibroblasts, where it facilitates mitophagy and promotes fibroblast quiescence. This suggests that depressed BAG3 levels in heart failure may exacerbate fibrotic pathology, thus contributing to myocardial dysfunction through sarcomere-independent pathways.NEW & NOTEWORTHY We report BAG3's localization to mitochondria and its role in mitophagy for the first time in primary ventricular cardiac fibroblasts. We have also collected the first evidence showing that loss of BAG3 increases cardiac fibroblast activation into myofibroblasts, which are major drivers of cardiac fibrosis and pathological remodeling during heart disease.

Enhancing spatial inference of air pollution using machine learning techniques with low-cost monitors in data-limited scenarios.

Ensuring environmental justice necessitates equitable access to air quality data, particularly for vulnerable communities. However, traditional air quality data from reference monitors can be costly and challenging to interpret without in-depth knowledge of local meteorology. Low-cost monitors present an opportunity to enhance data availability in developing countries and enable the establishment of local monitoring networks. While machine learning models have shown promise in atmospheric dispersion modelling, many existing approaches rely on complementary data sources that are inaccessible in low-income areas, such as smartphone tracking and real-time traffic monitoring. This study addresses these limitations by introducing deep learning-based models for particulate matter dispersion at the neighbourhood scale. The models utilize data from low-cost monitors and widely available free datasets, delivering root mean square errors (RMSE) below 2.9 µg m-3 for PM1, PM2.5, and PM10. The sensitivity analysis shows that the most important inputs to the models were the nearby monitors' PM concentrations, boundary layer dissipation and height, and precipitation variables. The models presented different sensitivities to each road type, and an RMSE below the regional differences, evidencing the learning of the spatial dependencies. This breakthrough paves the way for applications in various vulnerable localities, significantly improving air pollution data accessibility and contributing to environmental justice. Moreover, this work sets the stage for future research endeavours in refining the models and expanding data accessibility using alternative sources.

Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma.

ABSTRACT: For patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA-directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

Crafting impactful papers: Expectations and recommendations for Business and management articles.

This paper introduces Heliyon's Business and Management Section, established in 2023 as a platform committed to maintaining rigorous ethical and scientific publishing standards within the field. Prioritizing scientific correctness and technical soundness over mere novelty, it encompasses a wide range of research domains, encouraging contributions from scholars across diverse backgrounds. Within this guide, we provide insights into the process of preparing effective papers and offer constructive guidelines for the reviewing process. Authors will find valuable tools to align their work with the journal's expectations, incorporating current literature to enhance the probability of successful publication. Both aspiring authors and reviewers will benefit from this resource, which emphasizes academic and professional growth. By promoting collaboration and upholding high-quality standards, we aim to fortify the scholarly publishing community and advance knowledge in the field of business and management.

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

Perioperative considerations for patients exposed to hallucinogens.

Hallucinogen exposure in patients in the perioperative period presents challenges for anesthesiologists and other anesthesia providers. Acute and chronic exposure to these substances can cause physiological impacts that can affect the function of anesthetic and analgesic medications used during perioperative care. The objective of this narrative review is to educate readers on the wide array of hallucinogens and psychedelics that may influence the perioperative management of patients exposed to these substances. A narrative review of the literature surrounding hallucinogens and psychedelics was completed. Hallucinogens and psychedelics are quite varied in their mechanisms of action and therefore present a variety of perioperative implications and perioperative considerations. Many of these substances increase serotonin levels or act directly at serotonergic receptors. However, there are other relevant actions that may include varied mechanisms from N-methyl-D-aspartate receptor antagonism to stimulation of muscarinic receptors. With hallucinogen exposure rates on the rise, understanding the effects of hallucinogens is important for optimizing management and reducing risks perioperatively for patients with acute or chronic exposure.

A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1.

The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Trends in kidney transplantation and living donor nephrectomy in Germany: a total population analysis from 2006 to 2021.

PURPOSE: To analyze recent trends of surgical access routes, length of hospital stay (LOS), and mortality in kidney transplantation (KT) and living donor nephrectomy (LDN) in Germany. MATERIALS AND METHODS: We studied the nationwide German hospital billing database and the German hospital quality reports from 2006 to 2021. RESULTS: There were a total of 35.898 KTs. In total, 9044 (25%) were living donor transplantations, while 26.854 (75%) were transplantations after donation after brain death (DBD). The share of open LDN decreased from 82% in 2006 to 22% in 2020 (- 4%/year; p < 0.001). The share of laparoscopic LDN increased from 18% in 2006 to 70% in 2020 (+ 3%/year; p < 0.001). The share of robotic LDN increased from 0% in 2006 to 8% in 2020 (+ 0.6%/year; p < 0.001). Robotic-assisted KT increased from 5 cases in 2016 to 13 procedures in 2019 (p = 0.2). LOS was shorter after living donor KT, i.e., 18 ± 12.1 days versus 21 ± 19.6 days for DBD renal transplantation (p < 0.001). Moreover, LOS differed for open versus laparoscopic versus robotic LDN (9 ± 3.1 vs. 8 ± 2.9 vs. 6 ± 2.6; p = 0.031). The overall in-hospital mortality was 0.16% (n = 5) after LDN, 0.47% (n = 42) after living donor KT and 1.8% (n = 475) after DBD KT. CONCLUSIONS: There is an increasing trend toward minimal-invasive LDN in recent years. Overall, in-hospital mortality was low after KT. However, 5 deceased healthy donors after LKD caution that the risks of this procedure should also be taken very seriously.

Importance of temporary and permanent snow for new second homes.

This study investigates empirically how natural snow depth and permanent snow affect the number of new second homes in Norway. One out of four Norwegian municipalities is partly covered by glaciers and permanent snow. In the winter seasons of 1983-2020, there is a decline in snow depth from 50 to 35 cm on average (based on 41 popular second-home areas in the mountains). Results of the fixed effects Poisson estimator with spatial elements show that there is a significant and positive relationship between natural snow depth in the municipality and the number of second homes started. There is also a significant and negative relationship between the number of new second homes in the municipality and a scarcity of snow in the surrounding municipalities. However, the magnitude of both effects is small. Estimates also show a strong positive relationship between the proportion of surface covered by permanent snow or glaciers in the municipality and new second homes. This implies that a decline in permanent snow and glaciers may make these areas less attractive for the location of second homes.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation.

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Reproductive toxicity in birds predicted by physiologically-based kinetics and bioenergetics modelling.

Effects on the growth and reproduction of birds are important endpoints in the environmental risk assessment (ERA) of pesticides. Toxicokinetic-toxicodynamic models based on dynamic energy budget theory (DEB) are promising tools to predict these effects mechanistically and make extrapolations relevant to ERA. However, before DEB-TKTD models are accepted as part of ERA for birds, ecotoxicological case studies are required so that stakeholders can assess their capabilities. We present such a case-study, modelling the effects of the fluopyram metabolite benzamide on the northern bobwhite quail (Colinus virginianus). We parametrised a DEB-TKTD model for the embryo stage on the basis of an egg injection study, designed to provide data for model development. We found that information on various endpoints, such as survival, growth, and yolk utilisation were needed to clearly distinguish between the performance of model variants with different TKTD assumptions. The calibration data were best explained when it was assumed that chemical uptake occurs via the yolk and that benzamide places stress on energy assimilation and mobilisation. To be able to bridge from the in vitro tests to real-life exposure, we developed a physiologically-based toxicokinetic (PBK) model for the quail and used it to predict benzamide exposure inside the eggs based on dietary exposure in a standard reproductive toxicity study. We then combined the standard DEB model with the TKTD module calibrated to the egg injection studies and used it to predict effects on hatchling and 14-day chick weight based on the exposure predicted by the PBK model. Observed weight reductions, relative to controls, were accurately predicted. Thus, we demonstrate that DEB-TKTD models, in combination with suitable experimental data and, if necessary, with an exposure model, can be used in bird ERA to predict chemical effects on reproduction.