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BACKGROUND: Guidelines recommend dual-energy x-ray absorptiometry (DXA) screening to assess fracture risk and benefit from antiresorptive therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) on androgen deprivation therapy (ADT). However,

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen- specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens., Introduction The ability to engender potent neoantigen- or tumor-associated antigen-specific [CD8.sup.+] cytotoxic T cell immunity is indispensable to the long-term therapeutic efficacy of essentially all cancer treatment strategies. Classical methods [...]

Mercury (Hg) is a global atmospheric pollutant. In its oxidized form (HgII), it can readily deposit to ecosystems, where it may bioaccumulate and cause severe health effects. High HgII concentrations are reported in the free troposphere, but spatiotemporal data coverage is limited. Underestimation of HgII by commercially available measurement systems hinders quantification of Hg cycling and fate. During spring–summer 2021 and 2022, we measured elemental (Hg0) and oxidized Hg using a calibrated dual-channel system alongside trace gases, aerosol properties, and meteorology at the high-elevation Storm Peak Laboratory (SPL) above Steamboat Springs, Colorado. Oxidized Hg concentrations displayed diel and episodic behavior similar to previous work at SPL but were approximately 3 times higher in magnitude due to improved measurement accuracy. We identified 18 multi-day events of elevated HgII (mean enhancement of 36 pgm-3) that occurred in dry air (mean ± SD of relative humidity = 32 ± 16 %). Lagrangian particle dispersion model (HYSPLIT–STILT, Hybrid Single-Particle Lagrangian Integrated Trajectory–Stochastic Time-Inverted Lagrangian Transport) 10 d back trajectories showed that the majority of transport prior to events occurred in the low to middle free troposphere. Oxidized Hg was anticorrelated with Hg0 during events, with an average (± SD) slope of - 0.39 ± 0.14. We posit that event HgII resulted from upwind oxidation followed by deposition or cloud uptake during transport. Meanwhile, sulfur dioxide measurements verified that three upwind coal-fired power plants did not influence ambient Hg at SPL. Principal component analysis showed HgII consistently inversely related to Hg0 and generally not associated with combustion tracers, confirming oxidation in the clean, dry free troposphere as its primary origin. [ABSTRACT FROM AUTHOR]

Background Reemergence of human herpesvirus 8 (HHV-8)–induced Kaposi sarcoma (KS) in people living with HIV (PLWH) despite antiretroviral therapy (ART) poses a clinical challenge because they already have favorable CD4 T-cell numbers and undetectable viral loads. We observed that clinical presentation in PLWH on ART resembled classic KS found in older HIV-uninfected patients and hypothesized that immunosenescence may thus play a role in occurrence of KS on ART. We compared viral and immune factors implicated in the development of KS in ART-treated PLWH (HIV KS) and HIV-uninfected classic KS patients (cKS), compared to controls without KS (HIV Control, cControls respectively). Methods Plasma, peripheral blood mononuclear cell, and skin tissues were obtained from 11 HIV KS and 11 cKS patients and 2 groups of age-matched controls. Results HIV KS participants were younger than cKS (aged 53 vs 75 years). HHV-8 genotypes did not differ between groups. Despite the younger age and a lower CD4/CD8 ratio, activated, exhausted, and senescent T-cell frequencies were similar between HIV KS and cKS. Anti–HHV-8 immunoglobulin G levels were higher and circulating HHV-8 DNA lower in HIV KS compared with cKS. Circulating platelet-derived growth factors AA-BB and granulocyte colony-stimulating factors were higher in HIV KS We observed similar levels of HHV-8 DNA and PD-1 expression in skin lesions from HIV KS and cKS patients. Conclusions Altogether, early immune senescence could be involved in the development of KS in ART-treated PLWH. Higher anti–HHV-8 immunoglobulin G levels could be linked with lower circulating viral load. Such insights should help developing therapeutical strategies to prevent development and treat KS in PLWH on ART. [ABSTRACT FROM AUTHOR]

The unexpected spread of the pandemic raised concerns regarding pilots' skill decay resulting from the significant drops in the frequency of flights by about 70%. This research retrieved 4761 Flight Data Monitoring (FDM) occurrences based on the FDM programme containing 123,140 flights operated by an international airline between June 2019 and May 2021. The FDM severity index was analysed by event category, aircraft type, and flight phase. The results demonstrate an increase in severity score from the pre-pandemic level to the pandemic onset on events that occurred on different flight phases. This trend is not present in the third stage, which indicates that pilots and the safety management system of the airline demonstrated resilience to cope with the flight disruptions during the pandemic. Through the analysis of event severity, FDM enables safety managers to recommend measures to increase safety resilience and self-monitoring capabilities of both operators and regulators. Practitioner summary: The onset of the pandemic led to a rise in the severity of flight data monitoring events in a large airline, likely linked to a lack of operational practice and skills decay. This was demonstrated across different flight phases and aircraft types. In the settled pandemic period, the severity index returned to pre-pandemic levels, indicating that the resilience of individual pilots and safety management systems is critical to operational safety. The FDM event severity scores significantly increased following the pandemic onset, especially for event categories involving pilot core competencies. The FDM event severity scores stagnated or decreased during the later pandemic stage indicating resilience among the airline pilots and the airline's safety management system. The airline and pilots demonstrated resilience by effectively mitigating the effects of proficiency decay which took place as the pandemic started. FDM analysis has shown to be effective in establishing a proactive SMS programme to mitigate the negative impacts of the pandemic on aviation safety. [ABSTRACT FROM AUTHOR]

Although research suggests a relationship among personal characteristics, behaviors, and performance, there has been limited examination of these influences in the context of intelligence tests using eye movement techniques. Thus, this study explored the roles of personal characteristics (i.e., visual/verbal cognitive styles, self-efficacy) and reading behaviors in the reasoning performance of Raven's Advanced Progressive Matrices test based on social cognitive perspectives using eye movement techniques, in order to provide more authentic information about individuals' actual behaviors. A total of 53 undergraduate and graduate students participated. Thirty participants were classified as visual style and the others were classified as verbal style learners. Regarding the role of cognitive styles in reading behaviors and reasoning performance, the results indicated a marginal difference in dispersion reading behavior between participants with visual and verbal cognitive style, and a significant relationship between visual style and dispersion reading behavior. However, no difference was found in performance between these two styles. As for the role of self-efficacy, the results showed that it was positively related to horizontal reading and APM-short performance. Mediation analyses revealed that self-efficacy not only directly impacted reasoning performance, but also had an indirect effect on performance through horizontal and tilted reading. On the other hand, cognitive style had no direct or indirect effect on reasoning performance. Moreover, the results showed that horizontal, vertical and tilted reading significantly predicted reasoning performance. The findings suggest that educators could enhance learners' selfefficacy through goal setting, feedback, and strategy instruction, which would help facilitate their learning behaviors and performance. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is a global atmospheric pollutant. In its oxidized form (HgII), atmospheric Hg can readily deposit to ecosystems, where it may bioaccumulate and cause severe health effects. High HgII concentrations are reported in the free troposphere, but spatiotemporal data coverage is limited. Underestimation of HgII by commercially available measurement systems hinders quantification of Hg cycling and fate. During spring-summer 2021 and 2022, we measured elemental (Hg0) and oxidized Hg using a calibrated dual-channel system alongside trace gases, aerosol properties, and meteorology at the high-elevation Storm Peak Laboratory (SPL) above Steamboat Springs, Colorado. Oxidized Hg concentrations displayed temporal behavior similar to previous work at SPL, but were approximately three times higher in magnitude due to improved measurement accuracy. We identified 18 multi-day events of elevated HgII (mean enhancement: 36 pg m-3) that occurred in dry air (mean ± s.d. RH = 32 ± 16 %). Lagrangian particle dispersion model (HYSPLIT-STILT) 10-day back-trajectories showed that the majority of transport prior to events occurred in the low to mid-free troposphere. Oxidized Hg was anticorrelated with Hg0 during events, with an average (± s.d.) slope of -0.39 ± 0.14, suggestive of upwind oxidation followed by deposition during transport. Concurrent sulfur dioxide measurements verified that three upwind coal-fired power plants did not measurably contribute ambient Hg at SPL. Principal Components Analysis revealed HgII consistently inversely related with Hg0 and was generally not associated with combustion tracers, confirming oxidation in the clean, dry free troposphere as its primary origin. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal Membrane Oxygenation (ECMO) may be used as a bridge to lung transplantation in selected patients with end‐stage respiratory failure. Historically, ECMO use in this setting has been associated with poor outcomes Puri V et.al, J Thorac Cardiovasc Surg, 140:427. More recently, technical advances and the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO have led to improved surgical and post‐transplant outcomes Kirkby S et.al, J Thorac Dis, 6:1024. Methods: We illustrate the case of a 6‐year‐old child who received prolonged ECMO support as a bridge to lung re‐transplantation secondary to Chronic Lung Allograft Dysfunction (CLAD). Results: Early rehabilitation was key in improving the overall pre‐transplant conditioning during ECMO. Conclusions: Despite challenges associated with awake/ambulatory ECMO, the use of this strategy as a bridge to lung transplantation is feasible and has resulted in improved pre‐transplant conditioning and post‐transplant outcomes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We estimate the economic impact of applying risk assessment tools to identify very low-risk patients with upper gastrointestinal bleeding who can be safely discharged from the emergency department using a cost minimization analysis. METHODS: We compare triage strategies (Glasgow-Blatchford score = 0/0-1 or validated machine learning model) with usual care using a Markov chain model from a US health care payer perspective. RESULTS: Over 5 years, the Glasgow-Blatchford score triage strategy produced national cumulative savings over usual care of more than $2.7 billion and the machine learning strategy of more than $3.4 billion. DISCUSSION: Implementing risk assessment models for upper gastrointestinal bleeding reduces costs, thereby increasing value. [ABSTRACT FROM AUTHOR]

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens. [ABSTRACT FROM AUTHOR]

Background: Sepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a non-selective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis., Methods: 326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact., Results: Pooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), p-value = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, p-value = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4., Conclusion: This study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. While exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants., Competing Interests: The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Shock Society.)

Optogenetic techniques provide genetically targeted, spatially and temporally precise approaches to correlate cellular activities and physiological outcomes. In the nervous system, G protein-coupled receptors (GPCRs) have essential neuromodulatory functions through binding extracellular ligands to induce intracellular signaling cascades. In this work, we develop and validate an optogenetic tool that disrupts Gα q signaling through membrane recruitment of a minimal regulator of G protein signaling (RGS) domain. This approach, Photo-induced Gα Modulator-Inhibition of Gα q (PiGM-Iq), exhibited potent and selective inhibition of Gα q signaling. Using PiGM-Iq we alter the behavior of Caenorhabditis elegans and Drosophila with outcomes consistent with GPCR-Gα q disruption. PiGM-Iq changes axon guidance in cultured dorsal root ganglia neurons in response to serotonin. PiGM-Iq activation leads to developmental deficits in zebrafish embryos and larvae resulting in altered neuronal wiring and behavior. Furthermore, by altering the minimal RGS domain, we show that this approach is amenable to Gα i signaling. Our unique and robust optogenetic Gα inhibiting approaches complement existing neurobiological tools and can be used to investigate the functional effects neuromodulators that signal through GPCR and trimeric G proteins., Competing Interests: Competing interests statement:The authors declare no competing interest.

The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTβR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments.

Background: We assessed human papillomavirus (HPV) vaccine effectiveness (VE) against anal HPV among men who have sex with men (MSM) in 2018-2023., Methods: Residual anal specimens from MSM without HIV ages 18-45 years were tested for HPV. We calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between vaccination (≥1 dose) and quadrivalent vaccine (4vHPV)-type prevalence adjusting for city, race/ethnicity, and non-vaccine-type HPV prevalence, stratified by age group (18-26, 27-45). VE was calculated as (1-aPR)x100., Results: Among 2802 persons aged 18-26, 4vHPV-type prevalence was lower in those vaccinated at age <18 (aPR=0.13, CI: 0.08-0.22, VE=87%) and those vaccinated ≥2 years before specimen collection (aPR=0.52, CI: 0.42-0.64, VE=48%), compared with unvaccinated persons. Among 3548 persons aged 27-45, 4vHPV-type prevalence was lower in those vaccinated at ages 18-26 (aPR=0.68, CI: 0.57-0.82, VE=32%) and those vaccinated ≥2 years before specimen collection (aPR=0.66, CI: 0.57-0.77, VE=33%), compared with unvaccinated persons. While we observed no VE in persons vaccinated at age >26 overall, 4vHPV-type prevalence was lower in the subgroup vaccinated ≥2 years before specimen collection (aPR=0.71, CI: 0.56-0.89, VE=29%)., Conclusions: We found high VE against anal 4vHPV-type prevalence among MSM aged 18-26 who were vaccinated at age <18. Lower VE was observed among MSM ages 27-45 who were vaccinated at age 18-26 or ≥2 years before specimen collection. While ideally vaccination should be given at younger ages, vaccination can prevent some future infections in this population., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca 2+  sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Access to care is associated with cancer survival. The US Military Health System (MHS) provides universal health care to all beneficiaries. However, it is unknown whether survival among patients with bone sarcoma in a health system providing universal care is better than that in the general population. The aim of the study was to compare survival of patients with bone sarcoma in the US MHS with that of the US general population., Methods: The MHS data were obtained from the Department of Defense Automated Central Tumor Registry (ACTUR). The US general population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. Adult patients were defined as those aged 25 years or older with a histologically confirmed musculoskeletal bone sarcoma diagnosed from January 1, 1987, to December 31, 2013. Kaplan-Meier survival curves and multivariable Cox proportional hazards models were used to compare the overall survival of the two populations., Results: The final analysis included 2,273 bone sarcoma cases from ACTUR and 9,092 bone sarcoma cases from SEER. ACTUR patients had significant lower 5-year all-cause death (hazard ratio = 0.72; 95% CI, 0.66 to 0.78) after adjustment for the potential confounders. ACTUR patients with bone sarcoma also exhibited significantly lower risk of all-cause death during the entire follow-up period than the SEER patients (hazard ratio = 0.75; 95% CI, 0.6 to 0.81)., Conclusions: MHS beneficiaries with bone sarcoma may have longer survival than SEER patients. Our findings support the role of universal access to high-quality care in improving bone sarcoma outcomes., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)