Alternating magnetic fields (AMF) and linezolid reduce Staphylococcus aureus biofilm in a large animal implant model.

OBJECTIVES: We aimed to evaluate the effectiveness of alternating magnetic fields (AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone. METHODS: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5 or 21 days post-implantation. Blood and tissue samples were collected at various time points post-AMF treatment. RESULTS: In vivo efficacy studies demonstrated significant biofilm reduction on titanium and cobalt-chrome implants with AMF-linezolid combination treatment compared to controls. Significant bacterial reductions were also observed in surrounding tissues and bones. Cytokine analysis showed improved inflammatory responses with combination therapy, and histopathology confirmed reduced inflammation, necrosis, and bacterial presence, especially at 5 days post-implantation. CONCLUSIONS: This study demonstrates that combining AMF with antibiotics significantly reduces biofilm-associated infections on metal implants in a large animal model. Numerical simulations confirmed targeted heating, and in vivo results showed substantial bacterial load reduction and reduced inflammatory response. These findings support the potential of AMF as a non-invasive treatment for prosthetic joint infections.

V-ToCs (Venom Toxin Clustering): A tool for the investigation of sequence and structure similarities in snake venom toxins.

Recently, there has been a major push toward the development of next-generation treatments against snakebite envenoming. However, unlike current antivenoms that rely on animal-derived polyclonal antibodies, most of these novel approaches are reliant on an in-depth understanding of the over 2000 known snake venom toxins. Indeed, by identifying similarities (i.e., conserved epitopes) across these different toxins, it is possible to design cross-reactive treatments, such as broadly-neutralising antibodies, that target these similarities. Therefore, in this project, we built an automated pipeline that generates sequence and structural distance matrices and homology trees across all available snake venom toxin sequences and structures. To facilitate analysis, we also developed a user-friendly and high-throughput visualisation tool, coined "Venom TOxin CluStering" (V-ToCs). This tool allows researchers to easily investigate sequence and structure patterns in snake venom toxins for a wide array of purposes, such as elucidating toxin evolution, and will also hopefully help guide the discovery and development of increasingly broadly-neutralising antivenoms in the near future.

Early Adjuvant Chemotherapy Improves Survival in Muscle Invasive Bladder Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate whether earlier administration of adjuvant chemotherapy (AC) can significantly augment survival rates in muscle-invasive bladder cancer. METHODS: We systematically searched PubMed, Cochrane Central, Scopus, and Web of Science library databases for original articles that looked at timing to AC after radical cystectomy. Heterogeneity was assessed using Higgins I2%, with values over 50% considered heterogeneous and analyzed with a random effects model; otherwise, a fixed effects model was used. Studies were stratified based on the cutoff time used for administering AC. Two primary cutoffs were employed: 45 days and 90 days. Immediate AC was defined as chemotherapy administered before the predefined cutoff, while delayed AC was defined as chemotherapy administered after this cutoff. Comparisons were made between immediate versus delayed. RESULTS: A total of 5 studies were included. Overall survival (OS) was reported in all of the studies. The meta-analysis showed that immediate AC significantly improved OS, with a hazard ratio (HR) of 1.20 [1.06, 1.36], P=.004. When stratifying by the timing of therapy, starting chemotherapy within 45 days resulted in a greater improvement in survival (HR 1.27 [1.02, 1.59], P=.03) compared to starting within 90 days (HR 1.17 [1.00, 1.36], P=.04). CONCLUSION: The findings of this systematic review and meta-analysis emphasize that the timing of AC post-radical cystectomy significantly influences survival outcomes in patients with MIBC. The benefits of early AC initiation underscore its potential in mitigating disease progression and improving long-term survival rates.

Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity.

Loss-of-function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.

Impact of expected blood pressure reduction on patient preferences for pharmaceutical and renal denervation treatment.

BACKGROUND: Effective patient-centered care requires an adequate understanding of patient preferences for different therapeutic options. We modelled patient preference for blood pressure (BP) management by pharmaceutical or interventional treatments such as renal denervation in patients with different profiles of uncontrolled hypertension. METHODS: Modeling was based on the findings from a previously conducted quantitative discrete choice experiment (DCE). The likelihood of selecting either an interventional treatment option or additional antihypertensive medication option was calculated for three patient profiles that represent the range of patients with hypertension commonly encountered in clinical practice: treatment-naive, patients with uncontrolled BP while on one to three antihypertensive medications, and patients with drug-resistant hypertension. Variables in the preference model were treatment attributes from the DCE study: expected reduction in office SBP with each treatment, duration of treatment effect, risk of reversible drug side effects from drugs, and risk of temporary pain and/or bruising or vascular injury from interventions. Values of the variables were derived from published clinical studies or expert opinion. RESULTS: The model predicted that the likelihood of choosing renal denervation over initiating pharmacotherapy was 17.2% for previously untreated patients, 23.7% for patients with moderate hypertension currently on pharmacotherapy, and 41.8% for patients with drug-resistant hypertension. The dominant variable driving preference in these models was the expected BP reduction. Patient preferences for intervention are greater when drug nonadherence or increased SBP reduction at 3 vs. 1 year are included in the model. Baseline BP, drug side effects, or risks of the procedure had little influence on decisions. CONCLUSION: Modeling using patient preference weights predicts that a substantial minority of patients favor an interventional treatment such as renal denervation over initiation or escalation of medications. Awareness of a patient's interest in device-based versus pharmaceutical strategies should inform the shared decision-making process for hypertension treatment.

Influence of Magnesium Ion Binding on the Adenosine Diphosphate Structure and Dynamics, Investigated by 31P NMR and Molecular Dynamics Simulations.

Magnesium (Mg2+) is the most abundant divalent cation in the cell and is essential to nearly every biochemical reaction involving adenosine triphosphate (ATP) and its lower energy counterpart, adenosine diphosphate (ADP). In this work, we examine the solution dynamics of ADP at different concentrations and record the changes thereof due to the presence of Mg2+ ions. Relaxation and diffusion experiments were performed on a range of ADP solutions with increasing magnesium concentration. The most significant changes of both relaxation and diffusion behaviors are observed when adding Mg2+ up to 0.5 ADP equivalent (eq), with most of the changes complete at 1 eq. Molecular dynamics simulations also show a significant structure introduced by Mg2+ with very stable pyramidal coordination with the phosphate oxygens. A more extended structure found in the presence of Mg2+ is consistent with the experimental slowing of diffusion and an increase in the spin-lattice relaxation rate. We do not observe direct evidence of aggregation in solution, although translational diffusion is slowed down significantly at higher concentrations (while solvent diffusion remains constant).

Neuroimaging and biofluid biomarkers across race and ethnicity in older adults across the spectrum of cognition.

Neuroimaging and biofluid biomarkers provide a proxy of pathological changes for Alzheimer's disease (AD) and are useful in improving diagnosis and assessing disease progression. However, it is not clear how race/ethnicity and different prevalence of AD risks impact biomarker levels. In this narrative review, we survey studies focusing on comparing biomarker differences between non-Hispanic White American(s) (NHW), African American(s) (AA), Hispanic/Latino American(s) (HLA), and Asian American(s) with normal cognition, mild cognitive impairment, and dementia. We found no strong evidence of racial and ethnic differences in imaging biomarkers after controlling for cognitive status and cardiovascular risks. For biofluid biomarkers, in AA, higher levels of plasma Aß42/Aß40, and lower levels of CSF total tau and p-tau 181, were observed after controlling for APOE status and comorbidities compared to NHW. Examining the impact of AD risks and comorbidities on biomarkers and their contributions to racial/ethnic differences in cognitive impairment are critical to interpreting biomarkers, understanding their generalizability, and eliminating racial/ethnic health disparities.

Influence of annealing temperature on persistent luminescence in BaAl2O4:Eu2+/Eu3+ nanocrystals and its application for latent fingerprint detection.

The luminescent properties of europium (Eu) doped BaAl2O4 phosphors were strongly influenced by post-annealing temperatures for blue-green persistent luminescence and latent fingerprints (LFPs). The X-ray powder diffraction patterns of the BaAl2O4: 1 mol% Eu nanophosphor, annealed between 1000 and 1300 °C, indicated a hexagonal ferroelectric phase. The X-ray photoelectron spectroscopy (XPS) revealed that the Ba atoms occupied two different sites in the BaAl2O4. The XPS and photoluminescence (PL) results revealed the presence of Eu3+ and Eu2+ states. The Eu-doped BaAl2O4 showed the characteristic red emission of Eu3+ at 251 and 464 nm excitations, while excitations at 340 and 380 nm showed yellowish-green emission. Strong evidence of energy transfer between a charge transfer band and the different energy levels of Eu2+ and Eu3+ ions was obtained. The existence of the Cr ion impurity in the aluminates was confirmed with UV-VIS diffuse reflectance and PL spectroscopy. The present results suggested that and O''i defects have introduced electron and hole traps in the host that acted as luminescent centers for persistent luminescence. LFPs detection using BaAl2O3:Eu2+/Eu3+ phosphor showed an excellent marking agent for applications in forensic science.

Antigenic drift and subtype interference shape A(H3N2) epidemic dynamics in the United States.

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity.

Seasonal influenza (flu) viruses cause outbreaks every winter. People infected with influenza typically develop mild respiratory symptoms. But flu infections can cause serious illness in young children, older adults and people with chronic medical conditions. Infected or vaccinated individuals develop some immunity, but the viruses evolve quickly to evade these defenses in a process called antigenic drift. As the viruses change, they can re-infect previously immune people. Scientists update the flu vaccine yearly to keep up with this antigenic drift. The immune system fights flu infections by recognizing two proteins, known as antigens, on the virus's surface, called hemagglutinin (HA) and neuraminidase (NA). However, mutations in the genes encoding these proteins can make them unrecognizable, letting the virus slip past the immune system. Scientists would like to know how these changes affect the size, severity and timing of annual influenza outbreaks. Perofsky et al. show that tracking genetic changes in HA and NA may help improve flu season predictions. The experiments compared the severity of 22 flu seasons caused by the A(H3N2) subtype in the United States with how much HA and NA had evolved since the previous year. The A(H3N2) subtype experiences the fastest rates of antigenic drift and causes more cases and deaths than other seasonal flu viruses. Genetic changes in HA and NA were a better predictor of A(H3N2) outbreak severity than the blood tests for protective antibodies that epidemiologists traditionally use to track flu evolution. However, the prevalence of another subtype of influenza A circulating in the population, called A(H1N1), was an even better predictor of how severe A(H3N2) outbreaks would be. Perofsky et al. are the first to show that genetic changes in NA contribute to the severity of flu seasons. Previous studies suggested a link between genetic changes in HA and flu season severity, and flu vaccines include the HA protein to help the body recognize new influenza strains. The results suggest that adding the NA protein to flu vaccines may improve their effectiveness. In the future, flu forecasters may want to analyze genetic changes in both NA and HA to make their outbreak predictions. Tracking how much of the A(H1N1) subtype is circulating may also be useful for predicting the severity of A(H3N2) outbreaks.

Management of thoracic aortic graft infections with combined omental and bilateral pectoralis major flaps.

BACKGROUND: Aortic vascular graft/endograft infection (VGEI) has historically been managed through graft removal and re-replacement, but new approaches suggest vascularized tissue transfer is an effective adjunctive treatment. We describe our experience with treating thoracic aortic vascular graft infection with combined omental and bilateral pectoralis major myocutaneous (PMM) advancement flaps. METHODS: Data from all patients undergoing combined flap closure by the senior author at a high-acuity cardiac surgery center from 1995-2023 were reviewed. Patients with clinical and radiographic signs of thoracic aortic vascular graft infection were included. RESULTS: Complete data were available for 598 patients with sternal and mediastinal wounds. Combined PMM and omental flaps were mobilized in 11 thoracic aortic vascular graft infection patients. Indications for flap management included culture-positive infection (8/11; 72.7%), dehiscence (5/11; 45.5%), drainage (7/11; 63.6%), and inability to close the sternotomy due to hemodynamic instability (5/11; 45.5%). During chest exploration, 6/11 (54.5%) underwent complete removal of the infected graft, compared to 5/11 (45.5%) who underwent graft-preserving washout and debridement. Immediate flap closure was performed in 6/11 (54.5%). Postoperative complications included dehiscence (2/11; 18.2%), seroma (1/11; 9.1%), hematoma (1/11, 9.1%), abdominal hernia (1/11; 9.1%), and recurrent infection (1/11; 9.1%). One patient (9.1%) died within 30 days of sternal reconstruction from mitral valve failure tachyarrhythmia. None of the patients underwent reoperation for flap-related complications. CONCLUSIONS: Despite significant comorbidities, low postoperative morbidity and mortality indicate that combined omental and pectoralis major flaps are a safe and effective adjunctive treatment to the antimicrobial and surgical management of select thoracic aortic vascular graft infections.

Walking in a controlled ankle motion (CAM) boot: In-boot measurement of joint kinematics and kinetics.

Research investigating ankle function during walking in a controlled ankle motion (CAM) boot has either placed markers on the outside of the boot or made major alterations to the structure of the CAM boot to uncover key landmarks. The aim of this study was to quantify joint kinematics and kinetics using "in-boot" skin markers whilst making only minimal structural alterations. Seventeen healthy participants walked at their preferred walking speed in two conditions: (1) in standard athletic trainers (ASICS patriot 8, ASICS Oceania Pty Ltd, USA), and (2) using a hard-cased CAM boot (Rebound® Air Walker, Össur, Iceland) fitted on the right foot. Kinematic measurements revealed that CAM boots restrict sagittal plane ankle range of motion to less than 5°, and to ∼3° in the frontal plane, which is a reduction of 85% and 73% compared to standard footwear, respectively (p < 0.001). This ankle restriction resulted in a reduction of ankle joint total limb work contribution from 38 ± 5% in normal footwear to 13 ± 4% in the CAM boot (p < 0.001). This study suggests that CAM boots do restrict the ankle joint's ability to effectively perform work during walking, which leads to compensatory mechanisms at the ipsilateral and contralateral hip and knee joints. Our findings align with previous research that employed "on-boot" kinematic measurements, so we conclude that in-boot approaches do not offer any benefit to the researcher and instead, on-boot measurements are suitable.

MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species.

Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.

Improving Shape-Sensing Robotic-Assisted Bronchoscopy Outcomes with Mobile Cone-Beam Computed Tomography Guidance.

BACKGROUND: Computed tomography to body divergence (CTBD) is one of the main barriers to bronchoscopic techniques for the diagnosis of peripherally located lung nodules. Cone-beam CT (CBCT) guidance is being rapidly adopted to correct for this phenomenon and to potentially increase diagnostic outcomes. In this trial, we hypothesized that the addition of mobile CBCT (m-CBCT) could improve the rate of tool in lesion (TIL) and the diagnostic yield of shape-sensing robotic-assisted bronchoscopy (SS-RAB). METHODS: This was a prospective, single-arm study, which enrolled patients with peripheral lung nodules of 1-3 cm and compared the rate of TIL and the diagnostic yield of SS-RAB alone and combined with mCBCT. RESULTS: A total of 67 subjects were enrolled, the median nodule size was 1.7 cm (range, 0.9-3 cm). TIL was achieved in 23 patients (34.3%) with SS-RAB alone, and 66 patients (98.6%) with the addition of mCBCT (p < 0.0001). The diagnostic yield of SS-RAB alone was 29.9% (95% CI, 29.3-42.3%) and it was 86.6% (95% CI, 76-93.7%) with the addition of mCBCT (p < 0.0001). There were no pneumothoraxes or any bronchoscopy-related complications, and the median total dose-area product (DAP) was 50.5 Gy-cm2. CONCLUSIONS: The addition of mCBCT guidance to SS-RAB allows bronchoscopists to compensate for CTBD, leading to an increase in TIL and diagnostic yield, with acceptable radiation exposure.

Investigating the Obesity Paradox in Colorectal Cancer: An Analysis of Prospectively Collected Data in a Diverse Cohort.

BACKGROUND: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. METHODS: Utilizing the Multiethnic Cohort, we included adults aged 18-75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. RESULTS: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00-2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10-2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31-6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08-3.10], p = 0.026). CONCLUSIONS: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis.

Genomic characterization of highly pathogenic H5 avian influenza viruses from Alaska during 2022 provides evidence for genotype-specific trends of spatiotemporal and interspecies dissemination.

The ongoing panzootic of highly pathogenic H5 clade 2.3.4.4b avian influenza (HPAI) spread to North America in late 2021, with detections of HPAI viruses in Alaska beginning in April 2022. HPAI viruses have since spread across the state, affecting many species of wild birds as well as domestic poultry and wild mammals. To better understand the dissemination of HPAI viruses spatiotemporally and among hosts in Alaska and adjacent regions, we compared the genomes of 177 confirmed HPAI viruses detected in Alaska during April - December 2022. Results suggest multiple viral introductions into Alaska between November 2021 and August or September 2022, as well as dissemination to areas within and outside of the state. Viral genotypes differed in their spatiotemporal spread, likely influenced by timing of introductions relative to population immunity. We found evidence for dissemination of HPAI viruses between wild bird species, wild birds and domestic poultry, as well as wild birds and wild mammals. Continued monitoring for and genomic characterization of HPAI viruses in Alaska can improve our understanding of the evolution and dispersal of these economically costly and ecologically relevant pathogens.

Nuclear dualism without extensive DNA elimination in the ciliate Loxodes magnus.

Most eukaryotes have one nucleus and nuclear genome per cell. Ciliates have instead evolved distinct nuclei that coexist in each cell: a silent germline vs. transcriptionally active somatic nuclei. In the best-studied model species, both nuclei can divide asexually, but only germline nuclei undergo meiosis and karyogamy during sex. Thereafter, thousands of DNA segments, called internally eliminated sequences (IESs), are excised from copies of the germline genomes to produce the streamlined somatic genome. In Loxodes, however, somatic nuclei cannot divide but instead develop from germline copies even during asexual cell division, which would incur a huge overhead cost if genome editing was required. Here, we purified and sequenced both genomes in Loxodes magnus to see whether their nondividing somatic nuclei are associated with differences in genome architecture. Unlike in other ciliates studied to date, we did not find canonical germline-limited IESs, implying Loxodes does not extensively edit its genomes. Instead, both genomes appear large and equivalent, replete with retrotransposons and repetitive sequences, unlike the compact, gene-rich somatic genomes of other ciliates. Two other hallmarks of nuclear development in ciliates-domesticated DDE-family transposases and editing-associated small RNAs-were also not found. Thus, among the ciliates, Loxodes genomes most resemble those of conventional eukaryotes. Nonetheless, base modifications, histone marks, and nucleosome positioning of vegetative Loxodes nuclei are consistent with functional differentiation between actively transcribed somatic vs. inactive germline nuclei. Given their phylogenetic position, it is likely that editing was present in the ancestral ciliate but secondarily lost in the Loxodes lineage.

Pump-driven clinical infusions: laboratory comparison of pump types, fluid composition and flow rates on model drug delivery applying a new quantitative tool, the pharmacokinetic coefficient of short-term variation (PK-CV).

Critically ill or anesthetized patients commonly receive pump-driven intravenous infusions of potent, fast-acting, short half-life medications for managing hemodynamics. Stepwise dosing, e.g. over 3-5 min, adjusts physiologic responses. Flow rates range from < 0.1 to > 30 ml/h, depending on pump type (large volume, syringe) and drug concentration. Most drugs are formulated in aqueous solutions. Hydrophobic drugs are formulated as lipid emulsions. Do the physical and chemical properties of emulsions impact delivery compared to aqueous solutions? Does stepwise dose titration by the pump correlate with predicted plasma concentrations? Precise, gravimetric, flow rate measurement compared delivery of a 20% lipid emulsion (LE) and 0.9% saline (NS) using different pump types and flow rates. We measured stepwise delivery and then computed predicted plasma concentrations following stepwise dose titration. We measured the pharmacokinetic coefficient of short-term variation, (PK-CV), to assess pump performance. LE and NS had similar mean flow rates in stepwise rate increments and decrements between 0.5 and 32 ml/h and continuous flows 0.5 and 5 ml/h. Pharmacokinetic computation predictions suggest delayed achievement of intended plasma levels following dose titrations. Syringe pumps exhibited smaller variations in PK-CV than large volume pumps. Pump-driven deliveries of lipid emulsion and aqueous solution behave similarly. At low flow rates we observed large flow rate variability differences between pump types showing they may not be interchangeable. PK-CV analysis provides a quantitative tool to assess infusion pump performance. Drug plasma concentrations may lag behind intent of pump dose titration.

A B7-H3-targeted CD28 bispecific antibody enhances the activity of anti-PD1 and CD3 T-cell engager immunotherapies.

T-cell activation is a multistep process requiring T-cell receptor engagement by peptide-major histocompatibility complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell-mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells (PBMCs) and cancer cells, and in mice engrafted with human PBMCs and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated interleukin (IL)2 and interferon (IFN)γ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the anti-apoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell-mediated cytotoxicity in vitro. XmAb808 combined with a EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Further, XmAb808 combined with an anti-PD1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti-PD1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.

Redemption or Manipulation? Revisiting the Art of a Serial Killer-A Dialogue.

This article revisits an ongoing dialogue between the co-authors, examining their divergent perspectives on whether the art of serial killers was used to perpetuate their psychopathic cycles after their murderous sprees were interrupted, or whether the art-particularly a piece done by one serial killer, Glen Rogers-reflects remorse and redemption. The two art therapists draw from their own clinical and professional experiences to argue their respective outlooks. After explaining what art therapy is, re-examining the concept of murderabilia, and underscoring psychopathy, this article provides an in-depth evaluation of two art pieces done by the serial killer through both of their viewpoints. Ultimately, while neither author completely changed their overall conclusions, elements from both sides of the argument were found relevant. Ultimately, this article emphasized the chaotic and messy connections between art and violence, yet through new perspectives explored on the complexities and motivations within the mayhem, mutual understandings emerged.