RESPAN: an accurate, unbiased and automated pipeline for analysis of dendritic morphology and dendritic spine mapping.

Accurate and unbiased reconstructions of neuronal morphology, including quantification of dendritic spine morphology and distribution, are widely used in neuroscience but remain a major roadblock for large-scale analysis. Traditionally, spine analysis has required labor-intensive manual annotation, which is prone to human error and impractical for large 3D datasets. Previous automated tools for reconstructing neuronal morphology and quantitative dendritic spine analysis face challenges in generating accurate results and, following close inspection, often require extensive manual correction. While recent tools leveraging deep learning approaches have substantially increased accuracy, they lack functionality and useful outputs, necessitating additional tools to perform a complete analysis and limiting their utility. In this paper, we describe Restoration Enhanced SPine And Neuron (RESPAN) analysis, a new comprehensive pipeline developed as an open-source, easily deployable solution that harnesses recent advances in deep learning and GPU processing. Our approach demonstrates high accuracy and robustness, validated extensively across a range of imaging modalities for automated dendrite and spine mapping. It also offers extensive visual and tabulated data outputs, including detailed morphological and spatial metrics, dendritic spine classification, and 3D renderings. Additionally, RESPAN includes tools for validating results, ensuring scientific rigor and reproducibility.

Implementation of a Trauma Bay Checklist Improves Antibiotic Prophylaxis Compliance in Open Extremity Fractures.

BACKGROUND: Best practice guidelines from the ACS recommend that patients with open fractures receive antibiotics within 1-hour of presentation. Checklists are effective mechanisms for improving safety and compliance in surgical settings. The current study investigates implementation of a trauma bay checklist, referred to as MARTY, to improve administration of antibiotics in open extremity fractures at a level I trauma center. METHODS: Retrospective pre-post design. Population consisted of trauma alerts from January to December 2021 (pre-MARTY) and 2022 (post-MARTY) with open fractures. Outcome measures included antibiotics administered within 1-hour of presentation and in the trauma bay. Bivariate and multivariate analyses were performed to estimate differences in both measures. RESULTS: Our sample included 339 encounters, 174 pre-MARTY and 165 post-MARTY implementation. In the pre-MARTY period, 57.5% of encounters received antibiotics within 1-hour of presentation with 46.0% occurring in the trauma bay, in comparison to 65.5% and 54.5% in the post-MARTY period. In adjusted models, there were greater odds of antibiotic administration within 1-hour (OR = 1.654, P = .038) and prior to leaving the trauma bay (OR = 1.660, P = .041) than pre-MARTY. Encounters with higher-grade fractures were more likely to receive timely antibiotics (P<=.001). DISCUSSION: Our study estimates improved compliance of antibiotic administration after implementation of MARTY after adjusting for encounter characteristics. Findings from this study demonstrate improved compliance, but this compliance is often still lacking in those with higher injury severity scores. Findings from this study may be used to inform approaches to further improve trauma care.

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study.

OBJECTIVE: Evaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA). METHODS: Post hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data. RESULTS: 442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported. CONCLUSION: In biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets.

Type of Prior Operation Does Not Predict Surgical Intervention for Small Bowel Obstruction.

Background: Patients with prior abdominal surgeries are at higher risk for intra-abdominal adhesive tissue formation and subsequently higher risk for small bowel obstruction (SBO).Purpose: In this study, we investigated whether surgical intervention for SBO was more likely following specific types of abdominal surgeries.Research Design: With retrospective chart review, we pooled data from 799 patients, ages 18 to 89, admitted with SBO between 2012 and 2019. Patients were evaluated based on whether they underwent surgery or were managed conservatively. They were further compared with regard to past surgical history by way of type of abdominal surgery (or surgeries) undergone prior to admission.Results: Of the 799 patients admitted for SBO, 206 underwent surgical intervention while 593 were managed nonoperatively. There was no significant difference in number of prior surgeries (2.07 ± 1.56 vs 2.36 ± 2.11, P = .07) or in number of comorbidities (2.39 ± 1.97 vs 2.65 ± 1.93, P = .09) for surgical vs non-surgical intervention. Additionally, of the operations evaluated, no specific type of abdominal surgery predicted need for surgical intervention in the setting of SBO. However, for both surgical and non-surgical intervention following SBO, pelvic surgery was the most common type of prior abdominal surgery (45% vs 43%). There are significantly more female pelvic surgeries in both the operative (91.4% vs 8.6%, P < .0001) and nonoperative groups (89.9% vs 10.2%, P < .0001).Conclusion: Ultimately, no specific type of prior operation predicted the need for surgical intervention in the setting of SBO.

Indications for Readmission for Small Bowel Obstruction: A Comparison of Medical vs Surgical Service Admission.

Small bowel obstruction (SBO) impacts the health care system and patient quality of life. Previously, we evaluated differences between medical and surgical admissions in the management of SBO. This study investigates indications for readmission based on original admission to medical (MS) or surgical services (SS). A retrospective chart review was performed for 799 patients aged 18 to 89 admitted between 2012 and 2019 with a diagnosis of SBO. Patient characteristics examined included length of stay (LOS), prior abdominal operations, prior SBO, use of small bowel follow through imaging, operative intervention, mortality, and 30-day readmission. There was no difference in readmission rates in patients originally admitted to MS or SS (13.2% vs 12.7%, P = .86). Patients admitted to SS were more likely to be readmitted for recurrent SBO (39% vs 8.6%, P = .006). Patients admitted to MS were more likely to be readmitted for other reasons (73.9% v. 40.2%, P = .004). In the MS cohort, 30.4% (7 patients) had surgery during their initial admission for SBO, and none of those patients were readmitted for recurrent SBO (rSBO). In the SS cohort, 23% had surgery during their initial admission and 31.6% were readmitted for rSBO (P = .002). Patients admitted to SS were more likely to be readmitted for rSBO and to require surgery. Patients admitted to MS were more likely to be readmitted for other reasons. None of the MS patients who had surgery were readmitted for SBO. 31.6% of SS patients who had surgery were readmitted for SBO.

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis.

OBJECTIVES: To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. METHODS: Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0-6) and Dactylitis Severity Score (range, 0-60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0-100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. RESULTS: Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). CONCLUSION: In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT03158285; Registered: May 16, 2017. Key Points • At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR). • Achieving ER was associated with achieving DR and vice versa through the end of study. • Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes.

Work Productivity and General Health Through 2 Years of Guselkumab Treatment in a Phase 3 Randomized Trial of Patients With Active Psoriatic Arthritis.

INTRODUCTION: To evaluate the effect of guselkumab on work productivity and nonwork daily activity impairment and general health status through 2 years in patients who were biologic-naïve with active psoriatic arthritis (PsA) in the phase 3 DISCOVER-2 clinical trial. METHODS: Adult patients with PsA were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W); at weeks 0, 4, then every 8 weeks (Q8W); or placebo (through week 24 with crossover to guselkumab Q4W). Work productivity and nonwork daily activity impairment were assessed using the Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) and patient-reported general health status using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index and EQ-Visual Analog Scale (EQ-VAS). Least-squares (LS) mean changes from baseline in WPAI-PsA domains and EQ-5D-5L/EQ-VAS were assessed through week 100. Changes in employment status were utilized to estimate potential indirect savings from improved work productivity. RESULTS: Of 739 randomized patients, 738 had available baseline data for the analyses (Q4W 245; Q8W 248; placebo 245). At week 24, greater improvements in work productivity, nonwork daily activity, and EQ-5D-5L/EQ-VAS were observed in the Q4W and Q8W groups versus the placebo group. At week 100, LS mean reductions in work productivity impairment (- 23.8% to - 28.0%) and nonwork daily activity impairment (- 26.6% to - 29.2%) and improvements in EQ-5D-5L/EQ-VAS (0.14 to 0.15/21.2 to 25.0) were maintained in patients receiving guselkumab. Among patients employed at baseline, 12.1-16.4% were not employed at week 100, and 20.0-25.3% shifted from not employed at baseline to employed at week 100. Potential yearly indirect cost savings (USD) from improved work productivity at week 100 ranged from $16,529 to $19,409. CONCLUSION: Patients with active PsA treated with guselkumab demonstrated reduced impairment in work productivity and nonwork daily activity, together with improvement in general health status and substantial potential cost savings, over a 2-year period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03158285.

Continuous improvement through differential trajectories of individual minimal disease activity criteria with guselkumab in active psoriatic arthritis: post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study.

BACKGROUND: To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. METHODS: The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. RESULTS: Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p < 0.0001), with SJC ≤ 1 (20 weeks), PASI ≤ 1 (16 weeks), and ≤ 1 tender entheses (16 weeks) being faster than patient-reported criteria (pain ≤ 15 mm, patient global assessment of arthritis and psoriasis ≤ 20 mm, Health Assessment Questionnaire-Disability Index ≤ 0.5) and tender joint count ≤ 1. Higher baseline domain scores, older age, worse fatigue, and increased body mass index were significant predictors of longer time to achieve minimal levels of disease activity assessed via patient-reported criteria. CONCLUSIONS: Substantial proportions of guselkumab-treated patients achieved individual MDA criteria, each showing continuous improvement through week 100, although with distinct trajectories. Median times to achieve physician-assessed MDA criteria were significantly faster compared with patient-driven criteria. Identification of modifiable factors affecting the time to achieve patient-reported criteria has the potential to optimize the achievement and sustainability of MDA in the clinic via a multidisciplinary approach to managing PsA, involving both medical and lifestyle interventions. TRIAL REGISTRATION NUMBER: NCT03158285. TRIAL REGISTRATION DATE: May 16, 2017.

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

OBJECTIVE: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

Long-Term Safety of Guselkumab in Patients with Psoriatic Disease: An Integrated Analysis of Eleven Phase II/III Clinical Studies in Psoriasis and Psoriatic Arthritis.

INTRODUCTION: The benefit/risk profiles of biologics can be affected by comorbidities, certain demographic characteristics, and concomitant medications; therefore, it is important to evaluate the long-term safety profiles of biologics across broad patient populations. Guselkumab was well tolerated and efficacious across individual pivotal clinical studies in adults with moderate-to-severe psoriasis and/or active psoriatic arthritis (PsA). OBJECTIVES: The objective of the current analysis was to evaluate guselkumab safety in a large population of patients with psoriatic disease by pooling adverse event (AE) data from 11 phase II/III studies (seven in psoriasis; four in PsA). METHODS: Guselkumab was generally administered as 100 mg subcutaneous injections at Week 0, Week 4, then every 8 weeks (Q8W) in psoriasis studies and at Week 0, Week 4, then every 4 weeks (Q4W) or Q8W in PsA studies. Safety data were summarized for the placebo-controlled period (Weeks 0-16 in psoriasis; Weeks 0-24 in PsA) and through the end of the reporting period (up to 5 years in psoriasis; up to 2 years in PsA). Using the integrated data, incidence rates of key AEs were determined post hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PYs). AE rates were also determined in subgroups of patients defined by sex, age, body mass index (BMI), and prior biologic use. RESULTS: During the placebo-controlled period, 1061 patients received placebo (395 PYs) and 2257 received guselkumab (856 PYs). Through the end of the reporting period, 4399 guselkumab-treated patients contributed 10,787 PYs of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of AEs were 281 versus 272/100 PYs, and infections were 76.0 versus 72.2/100 PYs. Rates of serious AEs (5.6 vs. 7.8/100 PYs), AEs leading to discontinuation (4.9 vs. 6.6/100 PYs), serious infections (1.0 vs. 2.3/100 PYs), malignancy (0.59 vs. 0.25 patients/100 PYs), and major adverse cardiovascular events (MACE; 0.35 vs. 0.25/100 PYs) were low and comparable between guselkumab and placebo. Among guselkumab-treated patients, safety event rates through the end of the reporting period were numerically lower than or comparable with rates observed during the placebo-controlled period: AEs, 164/100 PYs; infections, 61.2/100 PYs; serious AEs, 5.4/100 PYs; AEs leading to discontinuation, 1.8/100 PYs; serious infections, 1.0/100 PYs; malignancy, 0.6/100 PYs; and MACE, 0.3/100 PYs. No AEs of Crohn's disease, ulcerative colitis, or active tuberculosis were reported among guselkumab-treated patients. In the psoriasis studies, no opportunistic infections were reported among guselkumab-treated patients. Three AEs of opportunistic infections were reported in guselkumab-treated patients with PsA (0.14/100 PYs; all after Week 52 in DISCOVER-2). AE rates were largely consistent across subgroups of guselkumab-treated patients defined by sex, age, BMI, and prior biologic use. CONCLUSIONS: In this analysis of 4399 guselkumab-treated patients with psoriatic disease followed for 10,787 PYs, guselkumab had a favorable AE profile. AE rates were similar between guselkumab- and placebo-treated patients and were consistent throughout long-term guselkumab treatment and across broad subgroups of patients with psoriatic disease. CLINICAL TRIALS REGISTRATIONS: Clinicaltrials.gov identifiers: NCT01483599, NCT02207231, NCT02207244, NCT02203032, NCT02905331, NCT03090100, NCT02325219, NCT02319759, NCT03162796, NCT03158285, and NCT03796858.

The activation of INF2 by Piezo1/Ca2+ is required for mesenchymal to amoeboid transition in confined environments.

To invade heterogenous tissues, transformed cells may undergo a mesenchymal to amoeboid transition (MAT). However, the molecular mechanisms regulating this transition are poorly defined. In invasive melanoma cells, we demonstrate that intracellular [Ca2+] increases with the degree of confinement in a Piezo1 dependent fashion. Moreover, Piezo1/Ca2+ is found to drive amoeboid and not mesenchymal migration in confined environments. Consistent with a model in which Piezo1 senses tension at the plasma membrane, the percentage of cells using amoeboid migration is further increased in undulating microchannels. Surprisingly, amoeboid migration was not promoted by myosin light chain kinase (MLCK), which is sensitive to intracellular [Ca2+]. Instead, we report that Piezo1/Ca2+ activates inverted formin-2 (INF2) to induce widespread actin cytoskeletal remodeling. Strikingly, the activation of INF2 is found to promote de-adhesion, which in turn facilitates MAT. Using micropatterned surfaces, we demonstrate that cells require INF2 to effectively migrate in environments with challenging mechanochemical properties.

Efficacy of Guselkumab on Axial-Related Symptoms Through up to 2 Years in Adults with Active Psoriatic Arthritis in the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Study.

INTRODUCTION: Guselkumab previously showed greater improvements versus placebo in axial symptoms in patients with psoriatic arthritis (PsA) (assessed by Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]), in post hoc analyses of the phase 3, placebo-controlled, randomized DISCOVER-1 and DISCOVER-2 studies. We now evaluate durability of response in axial-related outcomes through 2 years of DISCOVER-2. METHODS: DISCOVER-2 biologic-naive adults with active PsA (≥ 5 tender/ ≥ 5 swollen joints, C-reactive protein ≥ 0.6 mg/dl) were randomized to guselkumab 100 mg every 4 weeks (Q4W) or at week 0, week 4, then Q8W, or placebo → guselkumab Q4W at week 24. Among patients with imaging-confirmed sacroiliitis (investigator-identified), axial symptoms were assessed through 2 years utilizing BASDAI, BASDAI Question #2 (spinal pain), modified BASDAI (mBASDAI; excludes Question #3 [peripheral joint pain]), and ASDAS. Mean changes in scores and proportions of patients achieving ≥ 50% improvement in BASDAI (BASDAI 50) and ASDAS responses, including major improvement (decrease ≥ 2.0), were determined through week 100. Treatment failure rules (through week 24) and nonresponder imputation of missing data (post-week 24) were utilized. Mean BASDAI component scores were assessed through week 100 (observed data). Exploratory analyses evaluated efficacy by sex and HLA-B*27 status. RESULTS: Among 246 patients with PsA and imaging-confirmed sacroiliitis, guselkumab-treated patients had greater mean improvements in BASDAI, mBASDAI, spinal pain, and ASDAS scores, lower mean BASDAI component scores, and greater response rates in achieving BASDAI 50 and ASDAS major improvement vs. placebo at week 24. Differences from placebo were observed for guselkumab-treated patients in selected endpoints regardless of sex or HLA-B*27 status. At week 100, mean improvements were ~ 3 points for all BASDAI scores and 1.6-1.7 for ASDAS; 49-54% achieved BASDAI 50 and 39% achieved ASDAS major improvement at week 100. CONCLUSIONS: Guselkumab treatment provided durable and meaningful improvements in axial symptoms and disease activity in substantial proportions of patients with active PsA and imaging-confirmed sacroiliitis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03158285.

In the COVID-19 pandemic, who did we trust? An eight-country cross-sectional study.

Background: Trust is a key determinant of health, but has been undermined by the COVID-19 pandemic and the associated infodemic. Using data from eight countries, we aimed to epidemiologically describe levels of trust in health, governments, news media organisations, and experts, and measure the impact of political orientation and COVID-19 information sources on participant's levels of trust. Methods: We simultaneously conducted a stratified randomised online cross-sectional study across eight countries on adults aged ≥18 years between 6 and 18 November 2020. We employed crude and adjusted weighted regression analyses. Results: We included 9027 adults with a mean age of 47 years (range = 18-99), of whom 4667 (51.7%) were female. Trust in health experts ranked highest across all countries (mean (x̄) = 7.83; 95% confidence interval (CI) = 7.79-7.88), while trust in politicians ranked lowest (x̄ = 5.34; 95% CI = 5.28, 5.40). In adjusted analyses, political orientation and utilised information sources were significantly associated with trust. Individuals using higher levels of health information sources trusted health authorities more than those using lower levels (mean difference = 1.12; 95% CI = 1.02, 1.14). Similarly, individuals using higher levels of government information sources (mean difference = 1.55; 95% CI = 1.43, 1.64) and those using higher levels of new media information sources (mean difference = 1.17; 95% CI = 1.06, 1.28) had highest trust in governments/politicians and news media, respectively. However, there was little difference in trust in health, government, or news media between individuals using higher or lower levels of social media information sources. Conclusions: Trust is a key determinant of health, but has been politically fragile during this infodemic. High compliance with public health measures is key to combatting infectious diseases. In terms of people's trust, our findings suggest that politicians and governments worldwide should coordinate their response with health experts and authorities to maximise the success of public health measures.

Guselkumab Modulates Differentially Expressed Genes in Blood of Patients With Psoriatic Arthritis: Results from Two Phase 3, Randomized, Placebo-Controlled Trials.

OBJECTIVE: To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. METHODS: Whole blood transcriptome profiling via paired-end RNA sequencing was conducted using samples from DISCOVER-1 and DISCOVER-2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab-mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. RESULTS: At baseline, 355 upregulated and 314 downregulated genes (PsA-associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type-specific gene sets were identified among downregulated genes. Most PsA-associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA-associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. CONCLUSION: These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment.

Preference of Bacterial Rhamnosyltransferases for 6-Deoxysugars Reveals a Strategy To Deplete O-Antigens.

Bacteria synthesize hundreds of bacteria-specific or "rare" sugars that are absent in mammalian cells and enriched in 6-deoxy monosaccharides such as l-rhamnose (l-Rha). Across bacteria, l-Rha is incorporated into glycans by rhamnosyltransferases (RTs) that couple nucleotide sugar substrates (donors) to target biomolecules (acceptors). Since l-Rha is required for the biosynthesis of bacterial glycans involved in survival or host infection, RTs represent potential antibiotic or antivirulence targets. However, purified RTs and their unique bacterial sugar substrates have been difficult to obtain. Here, we use synthetic nucleotide rare sugar and glycolipid analogs to examine substrate recognition by three RTs that produce cell envelope components in diverse species, including a known pathogen. We find that bacterial RTs prefer pyrimidine nucleotide-linked 6-deoxysugars, not those containing a C6-hydroxyl, as donors. While glycolipid acceptors must contain a lipid, isoprenoid chain length, and stereochemistry can vary. Based on these observations, we demonstrate that a 6-deoxysugar transition state analog inhibits an RT in vitro and reduces levels of RT-dependent O-antigen polysaccharides in Gram-negative cells. As O-antigens are virulence factors, bacteria-specific sugar transferase inhibition represents a novel strategy to prevent bacterial infections.

Adolescent Long-Acting Reversible Contraceptive Use, Same-Day Insertions, and Pregnancies Following a Quality Initiative.

OBJECTIVE: To compare long-acting reversible contraceptive (LARC) use, pregnancy rate, and same-day LARC insertion among adolescents before and after a Kaiser Permanente Northern California quality initiative. METHODS: A 2016 Kaiser Permanente Northern California initiative aimed to increase adolescent LARC access. Interventions included patient education resources, electronic protocols, and insertion training for pediatric, family medicine, and gynecology providers. This study examined a retrospective cohort of adolescents aged 15-18 years who used contraception before (2014-2015, n = 30,094) and after (2017-2018, n = 28,710) implementation. Contraceptive types included LARC (intrauterine device or implant), injectable, and contraceptive pill, patch, or ring. We reviewed a random sample of LARC users (n = 726) to identify same-day insertions. Multivariable analysis examined the effects of year of provision, age, race, ethnicity, LARC type, and counseling clinic. RESULTS: Preintervention, 12.1% of adolescents used LARC, 13.6% used injectable, and 74.3% used pill, patch, or ring. Postintervention, the proportions were 23.0%, 11.6%, and 65.4%, respectively, with the odds of LARC provision of 2.57 (95% confidence interval (CI) 2.44-2.72). The pregnancy rate decreased from 2.2% to 1.4% (p < .0001). Higher rates of pregnancy were observed with injectable contraception and in Black and Hispanic adolescents. Same-day LARC insertion rate was 25.1% without significant variation post intervention (OR 1.44, 95% confidence interval 0.93-2.23). Contraceptive counseling in gynecology clinics increased the odds of same-day provision, while non-Hispanic Black race lowered odds. DISCUSSION: A multifaceted quality intervention was associated with a 90% increase in LARC use and a 36% decrease in teenage pregnancy rate. Future directions may include promoting same-day insertions, targeting interventions in pediatric clinics, and focusing on racial equity.

Optimization of overhead enclosure monitoring in juvenile male Dunkin Hartley guinea pigs (Cavia porcellus).

Overhead enclosure monitoring provides objective quantitative mobility measurements for animals undergoing open-field testing. Notably, protocols for testing optimization have been minimally established for the guinea pig. It is unknown whether (a) repeated exposure, (b) time-of-day, or (c) length of testing duration influence outcome parameters. We hypothesized that guinea pigs would display decreased activity following repeated exposure to the open field; heightened activity during the earliest testing period; and that 10 min would be adequate for data collection. The study was conducted in two separate phases to distinguish between enclosure habituation and time-of-day effects, respectively. Two cohorts of male Dunkin Hartley guinea pigs were allowed voluntary movement in an open-field enclosure for 14 min to quantify mobility outcomes, including total distance traveled, total time mobile, average speed while mobile, and total time spent in the shelter. For both phases, testing occurred at four different times of day, and overhead monitoring software was programmed to divide the total testing duration into 2-min bins. Habituation phase results showed time mobile and distance traveled were influenced significantly by repeat exposure, as animals were most active during the first testing event. Time-of-day phase animals spent significantly more time mobile during the earliest testing period. Interestingly, significant differences were observed across 2-min bins for the time-of-day phase but not during the habituation phase. Specifically, progressively decreased ambulatory activity was observed as testing duration increased. Thus, habituation and time-of-day should be accounted for when possible. Finally, a trial period greater than 10 min may not yield additional data.

Hypercoagulable Factors Attributing to Superior Mesenteric Vein Thrombosis and Acute Mesenteric Ischemia.

Acute mesenteric ischemia is rare and can be difficult to diagnose due to vague symptoms often endorsed by patients. It can be fatal if not discovered in time, as it can lead to bowel ischemia, sepsis, and ultimately death. Here, we present a case of a 23-year-old female with hepatic steatosis, obesity, and 5-year history of birth control use who developed acute mesenteric ischemia secondary to superior mesenteric venous (SMV) thrombosis, requiring small bowel resection of 238 cm out of 480 cm (49.5%) after delay in diagnosis. Hypercoagulable and genetic workup during admission later revealed heterozygous factor V Leiden (FVL) mutation. The patient was ultimately discharged to inpatient rehabilitation on anticoagulation.

Guselkumab, a Selective Interleukin-23 p19 Subunit Inhibitor, Resolves Dactylitis in Patients With Active Psoriatic Arthritis: Pooled Results Through Week 52 From Two Phase 3 Studies.

OBJECTIVE: Previous analyses of pooled DISCOVER-1 and DISCOVER-2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. METHODS: Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0-3/digit; total = 0-60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER-2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. RESULTS: Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab-randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new-onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab-randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER-2). CONCLUSION: Through 1 year, approximately 75% of guselkumab-randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long-term patient outcomes.

Low rates of radiographic progression associated with clinical efficacy following up to 2 years of treatment with guselkumab: results from a phase 3, randomised, double-blind, placebo-controlled study of biologic-naïve patients with active psoriatic arthritis.

OBJECTIVE: Evaluate relationship between radiographic progression and clinical outcomes in post hoc analyses of patients with psoriatic arthritis (PsA) receiving up to 2 years of guselkumab therapy in the phase 3, placebo-controlled, randomised trial, DISCOVER-2. METHODS: Biologic-naïve adults with active PsA (≥5 swollen joints /≥5 tender joints ; C reactive protein ≥0.6 mg/dL) were randomised to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then every 8 weeks (Q8W); or placebo→guselkumab 100 mg Q4W (week 24). Radiographs (hands/feet) at week 0, week 24, week 52 and week 100 were scored via PsA-modified van der Heijde-Sharp (vdH-S) methodology. In these post hoc analyses, mean changes in vdH-S scores were summarised according to achievement of American College of Rheumatology 20/50/70 response; low disease activity (LDA) defined by Disease Activity in Psoriatic Arthritis (DAPSA) ≤14 or Psoriatic ArthritiS Disease Activity Score (PASDAS) ≤3.2, or minimal/very low disease activity (MDA/VLDA); and normalised physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI) ≤0.5). Response rates for achieving MDA/VLDA and each component were determined among patients with and without radiographic progression (change in total vdH-S score >0.5). No formal hypothesis testing was performed. RESULTS: 664 of 739 treated patients in DISCOVER-2 continued study treatment at week 52 and were included in these analyses. Mean changes in vdH-S scores from weeks 0 to 100 among all patients in the Q4W and Q8W groups were 1.7 and 1.5, respectively. Among all guselkumab-randomised patients, those who achieved ACR20/50/70, DAPSA LDA, PASDAS LDA, MDA, VLDA and HAQ-DI ≤0.5 (normalised physical function) had smaller mean changes in vdH-S scores than did non-responders at week 52 (0.2-1.2 vs 1.7-4.1) and week 100 (0.3-1.2 vs 2.0-4.6). Relative to patients with radiographic progression, those without progression were more likely to achieve the MDA criteria related to swollen and tender joint counts, patient-reported pain and global assessment, and normalised physical function through week 100. CONCLUSION: In these post hoc analyses, the achievement of low levels of disease activity, including MDA, was associated with diminished rates of radiographic progression observed in patients receiving up to 2 years of guselkumab. Radiographic non-progressors were more likely to achieve patient-reported MDA criteria of minimal pain and normalised physical function compared with radiographic non-responders. TRIAL REGISTRATION NUMBER: NCT03158285.