Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia.

A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated antibiotic treatment during influenza infection causes a fungal dysbiosis that drive lung eosinophilia and impair MRSA clearance. Finally, we evaluated three cohorts of hospitalized patients and found eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs thereby increasing the risk of developing a secondary bacterial infection.

"Synthetic" DSC perfusion MRI with adjustable acquisition parameters in brain tumors using dynamic spin-and-gradient-echo echoplanar imaging.

BACKGROUND AND PURPOSE: Normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) computed from dynamic susceptibility contrast (DSC) perfusion imaging are useful biomarkers for differential diagnosis and treatment response assessment in brain tumors. However, their measurements are dependent on DSC acquisition factors, and CBV-optimized protocols technically differ from PSR-optimized protocols. This study aimed to generate "synthetic" DSC data with adjustable synthetic acquisition parameters using dual-echo gradient-echo (GE) DSC datasets extracted from dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI). Synthetic DSC was aimed at: 1) simultaneously create nrCBV and PSR maps using optimal sequence parameters, 2) compare DSC datasets with heterogeneous external cohorts, and 3) assess the impact of acquisition factors on DSC metrics. MATERIALS AND METHODS: Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection and included in this cross-sectional study. Multiple synthetic DSC curves with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo GE data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation. RESULTS: Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection, while PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman's ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p<0.0001), supporting a role of synthetic DSC for multicenter comparisons. Acquisition factors highly impacted PSR, and nrCBV without leakage correction also showed parameter-dependence, although less pronounced. However, this dependence was remarkably mitigated by post-hoc leakage correction. CONCLUSIONS: Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with one acquisition and a single contrast injection, facilitating the use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion metrics across heterogeneous multicenter datasets, as it facilitates post-hoc harmonization. ABBREVIATIONS: DSC = dynamic susceptibility contrast; FA = flip angle; GBCA = gadolinium-based contrast agent; GBM = glioblastoma; GE = gradient echo; IDH = isocitrate dehydrogenase; IDHm = IDH-mutant; IDHwt = IDH-wild-type; 1p19qcod = 1p19q codeleted; 1p19qint = 1p19q intact; MRI = magnetic resonance imaging; PCNSL = primary CNS lymphoma; PSR = percentage of signal recovery; Rec = recurrent; SAGE-EPI = spin-and-gradient-echo echoplanar imaging; CBV = cerebral blood volume; nrCBV = normalized relative CBV; ROI = region of interest; TE = echo time; TN = treatment-naïve; TR = repetition time.

Impact of healthcare system strain on the implementation of ICU sedation practices and encephalopathy burden during the early COVID-19 pandemic.

The COVID-19 pandemic posed unprecedented challenges to healthcare systems worldwide, particularly in managing critically ill patients requiring mechanical ventilation early in the pandemic. Surging patient volumes strained hospital resources and complicated the implementation of standard-of-care intensive care unit (ICU) practices, including sedation management. The objective of this study was to evaluate the impact of an evidence-based ICU sedation bundle during the early COVID-19 pandemic. The bundle was designed by a multi-disciplinary collaborative to reinforce best clinical practices related to ICU sedation. The bundle was implemented prospectively with retrospective analysis of electronic medical record data. The setting was the ICUs of a single-center tertiary hospital. The patients were the ICU patients requiring mechanical ventilation for confirmed COVID-19 between March and June 2020. A learning health collaborative developed a sedation bundle encouraging goal-directed sedation and use of adjunctive strategies to avoid excessive sedative administration. Implementation strategies included structured in-service training, audit and feedback, and continuous improvement. Sedative utilization and clinical outcomes were compared between patients admitted before and after the sedation bundle implementation. Quasi-experimental interrupted time-series analyses of pre and post intervention sedative utilization, hospital length of stay, and number of days free of delirium, coma, or death in 21 days (as a quantitative measure of encephalopathy burden). The analysis used the time duration between start of the COVID-19 wave and ICU admission to identify a "breakpoint" indicating a change in observed trends. A total of 183 patients (age 59.0 ± 15.9 years) were included, with 83 (45%) admitted before the intervention began. Benzodiazepine utilization increased for patients admitted after the bundle implementation, while agents intended to reduce benzodiazepine use showed no greater utilization. No "breakpoint" was identified to suggest the bundle impacted any endpoint measure. However, increasing time between COVID-19 wave start and ICU admission was associated with fewer delirium, coma, and death-free days (ß = - 0.044 [95% CI - 0.085, - 0.003] days/wave day); more days of benzodiazepine infusion (ß = 0.056 [95% CI 0.025, 0.088] days/wave day); and a higher maximum benzodiazepine infusion rate (ß = 0.079 [95% CI 0.037, 0.120] mg/h/wave day). The evidence-based practice bundle did not significantly alter sedation utilization patterns during the first COVID-19 wave. Sedation practices deteriorated and encephalopathy burden increased over time, highlighting that strategies to reinforce clinical practices may be hindered under conditions of extreme healthcare system strain.

Deep network and multi-atlas segmentation fusion for delineation of thigh muscle groups in three-dimensional water-fat separated MRI.

Purpose: Segmentation is essential for tissue quantification and characterization in studies of aging and age-related and metabolic diseases and the development of imaging biomarkers. We propose a multi-method and multi-atlas methodology for automated segmentation of functional muscle groups in three-dimensional (3D) thigh magnetic resonance images. These groups lie anatomically adjacent to each other, rendering their manual delineation a challenging and time-consuming task. Approach: We introduce a framework for automated segmentation of the four main functional muscle groups of the thigh, gracilis, hamstring, quadriceps femoris, and sartorius, using chemical shift encoded water-fat magnetic resonance imaging (CSE-MRI). We propose fusing anatomical mappings from multiple deformable models with 3D deep learning model-based segmentation. This approach leverages the generalizability of multi-atlas segmentation (MAS) and accuracy of deep networks, hence enabling accurate assessment of volume and fat content of muscle groups. Results: For segmentation performance evaluation, we calculated the Dice similarity coefficient (DSC) and Hausdorff distance 95th percentile (HD-95). We evaluated the proposed framework, its variants, and baseline methods on 15 healthy subjects by threefold cross-validation and tested on four patients. Fusion of multiple atlases, deformable registration models, and deep learning segmentation produced the top performance with an average DSC of 0.859 and HD-95 of 8.34 over all muscles. Conclusions: Fusion of multiple anatomical mappings from multiple MAS techniques enriches the template set and improves the segmentation accuracy. Additional fusion with deep network decisions applied to the subject space offers complementary information. The proposed approach can produce accurate segmentation of individual muscle groups in 3D thigh MRI scans.

Could Knowledge of Borderline Personality Disorder Benefit College Campus Mental Health?

Borderline personality disorder is a common, treatable condition that usually presents in late adolescence or early adulthood. Patients with borderline personality disorder are disproportionately represented in many clinical settings. Early identification and intervention of borderline personality disorder could help address the current mental health affecting young adults. College and university mental health settings have an opportunity to identify borderline personality disorder and to help guide students and families to appropriate treatment. College-based clinicians also have a role in educating campus administrators who may have little or no familiarity with standard borderline personality disorder symptoms or the trajectory of the disorder.

Quantitative metrics commonly derived from diffusion tractography covary with streamline length: a characterization and method of adjustment.

Tractography algorithms are used extensively to delineate white matter structures, by operating on the voxel-wise information generated through the application of diffusion tensor imaging (DTI) or other models to diffusion weighted (DW) magnetic resonance imaging (MRI) data. Through statistical modelling, we demonstrate that these methods commonly yield substantial and systematic associations between streamline length and several tractography derived quantitative metrics, such as fractional anisotropy (FA). These associations may be described as piecewise linear. For streamlines shorter than an inflection point (determined for a group of tracts delineated for each individual brain), estimates of FA exhibit a positive linear relation with streamline length. For streamlines longer than the point of inflection, the association is weaker, with the slope of the relationship between streamline length and FA differing only marginally from zero. As the association is most pronounced for a range of streamline lengths encountered typically in DW imaging of the human brain (less than ~ 100 mm), our results suggest that some quantitative metrics derived from diffusion tractography have the potential to mislead, if variations in streamline length are not considered. A method is described, whereby an Akaike information weighted average of linear, Blackman and piecewise linear model predictions, may be used to compensate effectively for the association of FA (and other quantitative metrics) with streamline length, across the entire range of streamline lengths present in each specimen.

Contribution of ethnicity, area level deprivation and air pollution to paediatric intensive care unit admissions in the United Kingdom 2008-2021.

Background: There is emerging evidence on the impact of social and environmental determinants of health on paediatric intensive care unit (PICU) admissions and outcomes. We analysed UK paediatric intensive care data to explore disparities in the incidence of admission according to a child's ethnicity and the degree of deprivation and pollution in the child's residential area. Methods: Data were extracted on children <16 years admitted to UK PICUs between 1st January 2008 and 31st December 2021 from the Paediatric Intensive Care Audit Network (PICANet) database. Ethnicity was categorised as White, Asian, Black, Mixed or Other. Deprivation was quantified using the 'children in low-income families' measure and outdoor air pollution was characterised using mean annual PM2.5 level at local authority level, both divided into population-weighted quintiles. UK population estimates were used to calculate crude incidence of PICU admission. Incidence rate ratios were calculated using Poisson regression models. Findings: There were 245,099 admissions, of which 60.7% were unplanned. After adjusting for age and sex, Asian and Black children had higher relative incidence of unplanned PICU admission compared to White (IRR 1.29 [95% CI: 1.25-1.33] and 1.50 [95% CI: 1.44-1.56] respectively), but there was no evidence of increased incidence of planned admission. Children living in the most deprived quintile had 1.50 times the incidence of admission in the least deprived quintile (95% CI: 1.46-1.54). There were higher crude admission levels of children living in the most polluted quintile compared to the least (157.8 vs 113.6 admissions per 100,000 child years), but after adjustment for ethnicity, deprivation, age and sex there was no association between pollution and PICU admission (IRR 1.00 [95% CI: 1.00-1.00] per 1 µg/m3 increase). Interpretation: Ethnicity and deprivation impact the incidence of PICU admission. When restricting to unplanned respiratory admissions and ventilated patients only, increasing pollution level was associated with increased incidence of PICU admission. It is essential to act to reduce these observed disparities, further work is needed to understand mechanisms behind these findings and how they relate to outcomes. Funding: There was no direct funding for this project. HM was funded by an NIHR Academic Clinical Fellowship (ACF-2022-18-017).

Pseudomonas aeruginosa population dynamics in a vancomycin-induced murine model of gastrointestinal carriage.

Pseudomonas aeruginosa is a common nosocomial pathogen and a major cause of morbidity and mortality in hospitalized patients. Multiple reports highlight that P. aeruginosa gastrointestinal colonization may precede systemic infections by this pathogen. Gaining a deeper insight into the dynamics of P. aeruginosa gastrointestinal carriage is an essential step in managing gastrointestinal colonization and could contribute to preventing bacterial transmission and progression to systemic infection. Here, we present a clinically relevant mouse model relying on parenteral vancomycin pretreatment and a single orogastric gavage of a controlled dose of P. aeruginosa. Robust carriage was observed with multiple clinical isolates, and carriage persisted for up to 60 days. Histological and microbiological examination of mice indicated that this model indeed represented carriage and not infection. We then used a barcoded P. aeruginosa library along with the sequence tag-based analysis of microbial populations (STAMPR) analytic pipeline to quantify bacterial population dynamics and bottlenecks during the establishment of the gastrointestinal carriage. Analysis indicated that most of the P. aeruginosa population was rapidly eliminated in the stomach, but the few bacteria that moved to the small intestine and the caecum expanded significantly. Hence, the stomach constitutes a significant barrier against gastrointestinal carriage of P. aeruginosa, which may have clinical implications for hospitalized patients.

Differential Pharmacodynamic Effects on Psoriatic Biomarkers by Guselkumab Versus Secukinumab Correlate with Long-Term Efficacy: An ECLIPSE Substudy.

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses. Serum and/or skin biopsies were isolated from patients treated with guselkumab or secukinumab for evaluation of potential biomarkers of pharmacodynamic response to treatment. Guselkumab treatment led to significantly greater reductions of IL-17F and IL-22 serum levels than treatment with secukinumab at weeks 24 and 48, demonstrating sustained regulation of the IL-23/T helper 17 pathway. Analyses of proteomic and transcriptomic profiles of patient sera and skin biopsies demonstrated differential regulation of proteins involved in chemokine, TNF, and relevant immune signaling pathways to a greater degree with guselkumab than with secukinumab treatment. These data provide insights into the differences between the mechanisms and impact of IL-23 and IL-17A blockade in psoriasis, with implications for efficacy observations and treatment paradigms. Trial Registration: The original study was registered at ClinicalTrials.gov (NCT03090100).

Towards Establishing Best Practice in the Analysis of Hydrogen and Deuterium by Atom Probe Tomography.

As hydrogen is touted as a key player in the decarbonization of modern society, it is critical to enable quantitative hydrogen (H) analysis at high spatial resolution and, if possible, at the atomic scale. H has a known deleterious impact on the mechanical properties (strength, ductility, toughness) of most materials that can hinder their use as part of the infrastructure of a hydrogen-based economy. Enabling H mapping including local hydrogen concentration analyses at specific microstructural features is essential for understanding the multiple ways that H affect the properties of materials including embrittlement mechanisms and their synergies. In addition, spatial mapping and quantification of hydrogen isotopes is essential to accurately predict tritium inventory of future fusion power plants thus ensuring their safe and efficient operation. Atom probe tomography (APT) has the intrinsic capability to detect H and deuterium (D), and in principle the capacity for performing quantitative mapping of H within a material's microstructure. Yet, the accuracy and precision of H analysis by APT remain affected by complex field evaporation behavior and the influence of residual hydrogen from the ultrahigh vacuum chamber that can obscure the signal of H from within the material. The present article reports a summary of discussions at a focused workshop held at the Max-Planck Institute for Sustainable Materials in April 2024. The workshop was organized to pave the way to establishing best practices in reporting APT data for the analysis of H. We first summarize the key aspects of the intricacies of H analysis by APT and then propose a path for better reporting of the relevant data to support interpretation of APT-based H analysis in materials.

CDK5-cyclin B1 regulates mitotic fidelity.

CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression1. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p392. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK-cyclin complexes and validation with mutational analysis indicate that CDK5-cyclin B1 can form a functional complex. Disruption of the CDK5-cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5-cyclin B1 functions as a canonical CDK-cyclin complex to ensure mitotic fidelity.

Current immunotherapy techniques in meningioma.

INTRODUCTION: Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier. AREAS COVERED: This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers. EXPERT OPINION: Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.

A cogent technique to circumvent the use of (some) ratio measures in physiology.

Physiologists often express the change in the value of a measurement made on two occasions as a ratio of the initial value. This is usually motivated by an assumption that the absolute change fails to capture the true extent of the alteration that has occurred in attaining the final value - if there is initial variation among individual cases. While it may appear reasonable to use ratios to standardize the magnitude of change in this way, the perils of doing so have been widely documented. Ratios frequently have intractable statistical properties, both when taken in isolation and when analysed using techniques such as regression. A new method of computing a standardized metric of change, based on principal components analysis (PCA), is described. It exploits the collinearity within sets of initial, absolute change and final values. When these sets define variables subjected to PCA, the standardized measure of change is obtained as the product of the loading of absolute change onto the first principal component (PC1) and the eigenvalue of PC1. It is demonstrated that a sample drawn from a population of these standardized measures: approximates a normal distribution (unlike the corresponding ratios); lies within the same range; and preserves the rank order of the ratios. It is also shown that this method can be used to express the magnitude of a physiological response in an experimental condition relative to that obtained in a control condition. KEY POINTS: The intractable statistical properties of ratios and the perils of using ratios to standardize the magnitude of change are well known. A new method of computing a standardized metric, based on principal components analysis (PCA), is described, which exploits the collinearity within sets of initial, absolute change and final values. A sample drawn from a population of these PCA-derived measures: approximates a normal distribution (unlike the corresponding ratios); lies within the same range as the ratios; and preserves the rank order of the ratios. The method can also be applied to express the magnitude of a physiological response in an experimental condition relative to a control condition.

Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification.

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis.

Social anxiety and weight interact with body salience to affect experiences of social exclusion.

BACKGROUND: Individuals at a higher weight experience greater victimization and exclusion by peers, and limited research suggests that the salience of one's body image may increase negative emotional reactions to social rejection. Additionally, social exclusion is related to higher levels of social anxiety (SA). We examined how body salience interacts with SA and weight to predict anxiety, self-esteem, and negative affect following social rejection. METHODS: Participants were undergraduate women (N = 186). We explored the interactive effects of SA, body mass index (BMI), and body salience (i.e., face versus body photo condition) on emotional response to exclusion in a social ostracism paradigm, Cyberball. BMI and self-reported SA were collected at baseline. One week later, participants played Cyberball and reported state affect, anxiety, and self-esteem before and after the game. RESULTS: The 3-way interaction of BMI, SA, and photo condition did not significantly predict post-exclusion state measures. Photo condition moderated the relationship between SA and post-exclusion anxiety and between BMI and post-exclusion anxiety. CONCLUSIONS: Those with higher SA were particularly anxious following exclusion if their bodies were visible to others. Additionally, those with lower BMI experienced greater anxiety after exclusion when their body was visible than those with higher BMI.

Analysis of public records of lobbying practices of the ultra-processed sugary food and drink industries in Chile: a qualitative study.

Background: Given the role of commercial determinants on sugar consumption and health, this study aimed to describe lobbying practices of the ultra-processed sugary food and drinks industries in Chile between 2014 and 2022. Methods: Official meetings between ultra-processed sugary food and drinks industries and related commercial actors and Chilean government officials were obtained from the Chilean Lobby Registry. Relevant commercial names were initially identified based on their market share and expanded iteratively based on information from relevant meetings. Qualitative analysis followed a deductive-inductive approach using the Corporate Political Activity Model to identify and classify objectives, framing and action strategies. Findings: From 237 records identified, the Ministries of Health, Social Development, and Economy were the most frequently lobbied. Industry representatives sought to achieve their short- and long-term objectives by targeting a diverse range of authorities, including Ministers and Under-secretaries, using different strategies. Framing strategies focused on presenting sugary food and drinks industries as socially responsible and legitimate policy actors and criticised public health initiatives as 'bad solutions'. Action strategies aimed to influence policymaking and nurture corporate reputations. Interpretation: Extensive lobbying took place by the sugary food and drinks industries between 2014 and 2022, a period when major public health policies were being discussed in Chile. Lobbying strategies varied to meet industry objectives and targeted a diverse range of government institutions including high-ranking officials. Tighter regulations to stop inappropriate industry influence in public health policymaking are urgently required. Funding: Agencia Nacional de Investigación y Desarrollo (Chile)-PhD Scholarship. University College London-Open Access fees.

Guselkumab Reduces Disease- and Mechanism-Related Biomarkers More Than Adalimumab in Patients with Psoriasis: A VOYAGE 1 Substudy.

Background: Psoriasis is an immune-mediated inflammatory disease characterized by activation of IL-23-driven IL-17-producing T cell and other IL-23 receptor-positive IL-17-producing cell responses. Selective blockade of IL-23p19 with guselkumab was superior to blockade of TNF-α with adalimumab (ADA) in treating moderate-to-severe psoriasis. Objective: Pharmacodynamic responses of guselkumab versus ADA were compared in patients with psoriasis in VOYAGE 1. Design: Inflammatory cytokine serum levels were assessed (n = 118), and lesional and nonlesional skin biopsies were collected (n = 38) in patient subsets at baseline and 4, 24, and 48 weeks after treatment to evaluate pharmacodynamic responses of guselkumab versus those of ADA. Results: Guselkumab provided rapid reductions in serum IL-17A, IL-17F, and IL-22 levels by week 4 versus at baseline, which were maintained through weeks 24 and 48 (P < .001). The magnitude of reduction of IL-17A and IL-22 at week 48 and IL-17F at weeks 4, 24, and 48 were greater with guselkumab than with ADA (all P < .05). In the skin, guselkumab reduced the expression of IL-23/IL-17 pathway-associated and psoriasis-associated genes. Conclusion: These data provide extensive characterization of pharmacodynamic anti-inflammatory responses to IL-23p19 and TNF-α inhibition in human blood and tissue over time with FDA-approved doses of guselkumab and ADA. Trial registration:ClinicalTrials.govClinicalTrials.gov (NCT02207231).

The PI3Kδ inhibitor zandelisib on intermittent dosing in relapsed/refractory follicular lymphoma: Results from a global phase 2 study.

In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2-8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9-80.4), the complete response (CR) rate was 38% (95% CI, 29.3-47.3), and the median DOR was 16.4 months (95% CI, 9.5-not reached). With a median follow-up of 14.3 months (range, 1-30.5), the median progression-free survival was 11.6 months (95% CI, 8.3-not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3-4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.