POPULATION PHARMACOKINETICS OF CEFPODOXIME IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS).

Cefpodoxime proxetil is commonly used to treat cetacean patients with suspected or confirmed bacterial infections; however, pharmacokinetic data are needed to guide proper dosing in these species. Cefpodoxime proxetil is a time-dependent, semisynthetic, third-generation cephalosporin, appropriate for once-daily dosing and U.S. Food and Drug Administration-approved for use in dogs with a broad spectrum of activity including gram-positive and gram-negative species. The objective of this study was to evaluate the population pharmacokinetics of cefpodoxime in bottlenose dolphins (Tursiops truncatus). A sparse-sampling design was used, with serum from dolphins receiving cefpodoxime proxetil at 10 mg/kg orally every 24 h to treat suspected or confirmed bacterial infections. Serum samples (n = 57) from 24 dolphins were analyzed at 12 time points from 0 to 96 h postdose. Serum samples were analyzed using liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment linear models with first order absorption were tested. Covariates including weight, age, and sex were considered for inclusion in the model, and between-subject variability was incorporated. A two-compartment model performed best, where following an oral dose of 10 mg/kg, serum concentration reached a mean maximum concentration of 23.0 µg/ml, mean time to maximum concentration of 5.0 h, and mean half-life of 11.4 h. With daily dosing, accumulation was approximately 18% and steady state was reached by the second dose. Serum protein binding was 82.8% as determined by equilibrium dialysis, similar to plasma protein binding reported in dogs. Based on the population pharmacokinetic model, once-daily oral dosing was systemically absorbed and quickly reached maximum concentrations. The half-life in dolphins appears to be longer than other species studied to date. Given the paucity of antimicrobial pharmacokinetic studies in dolphins, and limited once-daily oral antibiotic options for this species, these data are helpful for clinicians to make informed antimicrobial choices.

Epigenetic control of commensal induced Th2 Responses and Intestinal immunopathology.

Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2 , a DNA demethylase, reprograms naïve T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas , associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens. Sentence Summary: Regulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.

Charge separation in a copper(I) donor-chromophore-acceptor assembly for both photoanode and photocathode sensitization.

A copper(I) donor-chromophore-acceptor triad bearing 1,8-napthalenemonoimide as the electron acceptor and triphenylamine as the electron donor was synthesized. Photophysical and electrochemical characterization suggest stepwise photoinduced charge separation upon excitation of the copper(I)-based metal-to-ligand charge transfer (MLCT) transition. Analyses of femtosecond transient absorption data of the triad show that intersystem crossing from the 1MLCT to the 3MLCT state is followed by two electron-transfer steps with time constants of 20 ps and 722 ps yielding a presumed final charge-separated state with a radical cation on the donor and radical anion on the acceptor that has an 18 ns lifetime in acetonitrile. Finally, this triad was anchored onto n-type (ZnO) and p-type (NiO) semiconductor surfaces to construct a photoanode and photocathode respectively. Successful photocurrent generation from both electrodes upon white light illumination confirms the potential utilization of such systems in dye-sensitized photoelectrochemical cells.

Spatial cognitive ability is associated with longevity in food-caching chickadees.

Cognitive abilities are hypothesized to affect survival and life span in nonhuman animals. However, most tests of this hypothesis have relied on interspecific comparisons of indirect measures of cognitive ability, such as brain size. We present direct evidence that individual variation in cognitive abilities is associated with differences in life span in a wild food caching bird. We measured the spatial cognitive abilities and tracked the life span of 227 mountain chickadees (Poecile gambeli) in their natural environment and found that individuals with better spatial learning and memory abilities involved in food caching lived longer. These results confirm that enhanced cognitive abilities can be associated with longer life in wild animals and that selection on cognitive abilities can lead to increased life span.

Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial.

BACKGROUND: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. METHODS: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. INTERPRETATION: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. FUNDING: UK Research and Innovation and National Institute for Health and Care Research.

Respiratory syncytial virus infections in adults: a narrative review.

Respiratory syncytial virus (RSV), an RNA virus spread by droplet infection that affects all ages, is increasingly recognised as an important pathogen in adults, especially among older people living with comorbidities. Distinguishing RSV from other acute viral infections on clinical grounds alone, with sufficient precision to be clinically useful, is not possible. The reference standard diagnosis is by PCR: point-of-care tests perform less well with lower viral loads. Testing samples from a single respiratory tract site could result in underdetection. RSV is identified in 6-11% of outpatient respiratory tract infection (RTI) consultations in older adults (≥60 years, or ≥65 years, depending on the study) and accounts for 4-11% of adults (≥18 years) hospitalised with RTI, with 6-15% of those hospitalised admitted to intensive care, and 1-12% of all adults hospitalised with RSV respiratory tract infection dying. Community-based studies estimate the yearly incidence of RSV infection at around 3-7% in adults aged 60 years and older in high-income countries. Although RSV accounts for a similar disease burden as influenza in adults, those hospitalised with severe RSV disease are typically older (most ≥60 years) and have more comorbidities, more respiratory symptoms, and are frequently without fever. Long-term sequelae are common and include deterioration of underlying disease (typically heart failure and COPD). There are few evidence-based RSV-specific treatments currently available, with supportive care being the main modality. Two protein subunit vaccines for protection from severe RSV in adults aged 60 years and older were licensed in 2023, and a third-an mRNA-based vaccine-recently gained market approval in the USA. The phase 3 studies in these three vaccines showed good protection against severe disease. Data on real-world vaccine effectiveness in older adults, including subgroups at high risk for RSV-associated hospitalisation, are needed to establish the best use of these newly approved RSV vaccines. New diagnostics and therapeutics are being developed, which will also need rigorous evaluation within their target populations to ensure they are used only for those in whom there is evidence of improved outcomes. There is an urgent need to reconceptualise this illness from one that is serious in children, but far less important than influenza in older people, to thinking of RSV as also a major risk to health for older people that needs targeted prevention and treatment.

Frontloaded Home Health Physical Therapy Reduces Hospital Readmissions among Medicare Fee-for-Service Beneficiaries.

OBJECTIVE: The purpose of this paper is to determine a claims-based definition of frontloaded home health physical therapy (HHPT) and examine the effect of frontloaded HHPT visits on all-cause 30-day hospital readmissions. METHODS: This study used a retrospective analysis of Medicare fee-for-service claims from older adults (≥65 years) in the National Health and Aging Trends Study (NHATS; 2011-2017) with ≥1 HHPT visit within 30 days of a hospitalization (n = 1344 hospitalizations; weighted n = 7,727,384). An exploratory analysis of home health claim distribution was conducted to determine definitions of frontloaded HHPT. Generalized linear models were then used to examine the relationship between hospital readmission and each definition of frontloading. RESULTS: Four definitions of frontloaded HHPT were identified: ≥2 HHPT visits in the first week after discharge; ≥3 visits in the first week; ≥4 visits in the first 2 weeks; and ≥ 5 visits in the first 2 weeks. The adjusted risk of readmission was lower for older adults receiving frontloaded HHPT in the first week: (risk ratio [RR] for ≥2 vs <2 visits = 0.57; 95% CI = 0.41-0.79; RR for ≥3 vs <3 visits = 0.39; 95% CI = 0.22-0.72). The reduction in risk of readmission was even greater for older adults receiving ≥4 versus <4 HHPT visits (RR = 0.32; 95% CI = 0.21-0.48) and ≥ 5 versus <5 HHPT visits (RR = 0.27; 95% CI = 0.14-0.50) within the first 2 weeks. The effect of HHPT frontloading was greater for patients hospitalized with surgical versus medical diagnoses and for patients with diagnoses targeted by the Hospital Readmissions Reduction Program. CONCLUSION: Frontloaded HHPT reduces 30-day hospital readmissions among Medicare beneficiaries. Additional research is needed to determine the optimal number of visits and those most likely to benefit from frontloaded HHPT. IMPACT: Frontloaded HHPT can be an effective approach for reducing 30-day hospital readmissions among Medicare beneficiaries.

This study found that providing home health physical therapist visits early and often after hospital discharge decreases the risk that patients will be readmitted over the next 30 days.

Inflammation mediated by gut microbiome alterations promotes lung cancer development and an immunosuppressed tumor microenvironment.

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely associated with tobacco-associated lung adenocarcinoma (LUAD) in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice, exacerbates pro-tumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on LUAD development remains poorly understood. Here, we investigated the role of gut microbiome changes in LUAD development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of pro-inflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL-6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with LUAD with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in LUAD and present new potential targets for interception and therapy.

A prospective examination of sleep chronotype and future suicide intent among adults in the United Kingdom: A test of the integrated motivational volitional model of suicide.

OBJECTIVES/BACKGROUND: Prior research identified a connection between evening chronotype and suicidality, but the mechanism underlying that connection is not well understood. The Integrated Motivational Volitional (IMV) Model of Suicide may provide a theoretical explanation for this link. The current project includes a three-time point longitudinal survey to examine whether 1) suicide intent likelihood varies across time, 2) chronotype affects suicide intent likelihood prospectively, and 3) defeat and entrapment explain the association between chronotype and suicide intent likelihood. PATIENTS/METHODS: Participants (n = 187 UK adults) completed a baseline survey (demographics, chronotype (morning-eveningness; MEQ), defeat and entrapment, and perceived intent to make a future suicide attempt), and follow-up surveys (MEQ and suicide intent likelihood) 3 and 6 months later. RESULTS: Results indicated that suicidal intent at 6-month follow-up was lower than baseline or 3-month follow-up. It was also found that strong evening chronotype at baseline is associated with increased suicidal intent 6 months later, and that defeat mediates this relationship. CONCLUSION: Our theoretically informed findings shed light on the psychological mechanisms linking chronotype (i.e., eveningness) and future suicide intent by highlighting the role of defeat and entrapment. We propose that feelings of defeat might be derived from evening types' experiences of social jetlag (resulting from conflict between biologically driven sleep schedules and externally dictated social schedules), which consequently drives entrapment and greater future suicide intent. Within this context, defeat and entrapment may be good transdiagnostic and modifiable target variables for future intervention development.

Fecal microbiome transfer an investigative tool and treatment strategy in cancer.

The gut microbiome plays a critical role in the development, progression, and treatment of cancer. As interest in microbiome-immune-cancer interactions expands, the prevalence of fecal microbial transplant (FMT) models has increased proportionally. However, current literature does not provide adequate details or consistent approaches to allow for necessary rigor and experimental reproducibility. In this review, we evaluate key studies utilizing FMT to investigate the relationship between the gut microbiome and various types of cancer. Additionally, we will discuss the common pitfalls of these experiments and methods for improved standardization and validation as the field utilizes FMT with greater frequency. Last, this review focuses on the impacts of the gut and extra-intestinal microbes, pre-biotics, pro-biotics, and post-biotics in cancer risk and response to therapy across a variety of tumor types.

Identifying Improvements in Treating Extremity Musculoskeletal Injuries During Prolonged Care.

INTRODUCTION: In prolonged care scenarios, where medical evacuations are significantly delayed, the treatment and transport of casualties with extremity musculoskeletal injuries will drain combat units' human resources. Developing enhanced splinting techniques to restore casualty mobility and function can alleviate this drain. To guide this development, a panel of tactical combat and wilderness medicine experts was assembled to determine which extremity musculoskeletal injuries had the greatest impact on unit capabilities, and the materials available for splinting these injuries. INFORMATION GATHERING: Unstructured consultations with panel members yielded preliminary lists of injuries and materials. These lists were consolidated and redistributed to panel members for final evaluation where they ranked the injuries based on frequency and human resource cost and assessed the accessibility of materials. Responses for the final evaluation were statistically analyzed using Wilcoxon rank-sum tests and Placket Luce models. LESSONS LEARNED: Aggregated responses indicated that panel members thought that knee and ankle ligamentous injuries and radial head fractures were the most frequently occurring injuries, although closed distal femoral fractures, below knee amputations, and open tibia fractures would require the most demand for injury care. Assessing the combined impact of frequency and human resource cost indicated that knee and ankle ligamentous injuries and closed tibia fractures had the greatest impact on unit readiness. Responses also indicated that a variety of materials would be available for applying or improvising splints. CONCLUSION: Although the combined impact of knee and ankle ligamentous injuries were ranked the highest, limitations in relative rankings and the existence of effective low-cost treatments for these injuries suggest that greater gains in unit effectiveness would come from focusing on developing solutions for fractures with higher human resource cost, such as leg and arm fractures. This information can be used to develop enhanced splints that can preserve unit readiness in the field.

Somatic mutations in 3929 HPV positive cervical cells associated with infection outcome and HPV type.

Invasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S. using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis. Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis. Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers.

Efficacy of Gamified Digital Mental Health Interventions for Pediatric Mental Health Conditions: A Systematic Review and Meta-Analysis.

Importance: Anxiety, depression, and attention-deficit/hyperactivity disorder (ADHD) affect up to 20% of children and adolescents. Despite demonstrated efficacy, evidence-based treatments for these conditions are often inaccessible; innovative solutions are essential to meet the demand for pediatric mental health care. Objective: To examine the efficacy and moderators of gamified DMHIs for anxiety, depression, and ADHD in randomized clinical trials (RCTs) for children and adolescents. Data Sources: A systematic search of PubMed, PsycInfo, and Web of Science was conducted for RCTs published before March 20, 2024. Study Selection: RCTs that evaluated the efficacy of gamified DMHIs for treating pediatric ADHD, depression, or anxiety were included. Studies were excluded if they did not use a gamified DMHI, provide sufficient data for effect sizes, or were unavailable in English. Data Extraction and Synthesis: Efficacy data were extracted from rating scales for ADHD, depression, and anxiety. Extracted moderator variables included participant characteristics (eg, age and sex), intervention characteristics (eg, delivery modality and time limit), and trial design characteristics (eg, outcome measure and risk of bias). Main Outcomes and Measures: The primary outcome was change in ADHD, depression, or anxiety severity in the treatment group compared to the control group. Hedges g quantified treatment effects. Results: The search strategy identified 27 RCTs that included 2911 participants across ADHD, depression, and anxiety disorders. There were modest significant effects of gamified DMHIs on ADHD (g, 0.28; 95% CI, 0.09 to 0.48) and depression (g, 0.28; 95% CI, 0.08 to 0.47) but small, nonsignificant effects for anxiety disorders (g, 0.07; 95% CI, -0.02 to 0.17). Moderator analyses revealed that DMHIs for ADHD delivered on a computer and those RCTs that had a greater preponderance of male participants produced larger treatment effects. DMHIs for depressive disorders that used preset time limits for gamified DMHIs also exhibited larger treatment effects. Conclusions and Relevance: The findings suggest a benefit of gamified DMHIs for youth with ADHD or depressive disorder. Pediatricians and other health care professionals have new information about novel, accessible, and efficacious options for pediatric mental health care.

INTRA- AND INTER-HOST EVOLUTION OF HUMAN NOROVIRUS IN HEALTHY ADULTS.

Background: Human noroviruses are a leading cause of acute and sporadic gastroenteritis worldwide. The evolution of human noroviruses in immunocompromised persons has been evaluated in many studies. Much less is known about the evolutionary dynamics of human norovirus in healthy adults. Methods: We used sequential samples collected from a controlled human infection study with GI.1/Norwalk/US/68 virus to evaluate intra- and inter-host evolution of a human norovirus in healthy adults. Up to 12 samples from day 1 to day 56 post-challenge were sequenced using a norovirus-specific capture probe method. Results: Complete genomes were assembled, even in samples that were below the limit of detection of standard RT-qPCR assays, up to 28 days post-challenge. Analysis of 123 complete genomes showed changes in the GI.1 genome in all persons, but there were no conserved changes across all persons. Single nucleotide variants resulting in non-synonymous amino acid changes were observed in all proteins, with the capsid VP1 and nonstructural protein NS3 having the largest numbers of changes. Conclusions: These data highlight the potential of a new capture-based sequencing approach to assemble human norovirus genomes with high sensitivity and demonstrate limited conserved immune pressure-driven evolution of GI.1 virus in healthy adults.

Examining intra-host genetic variation of RSV by short read high-throughput sequencing.

Every viral infection entails an evolving population of viral genomes. High-throughput sequencing technologies can be used to characterize such populations, but to date there are few published examples of such work. In addition, mixed sequencing data are sometimes used to infer properties of infecting genomes without discriminating between genome-derived reads and reads from the much more abundant, in the case of a typical active viral infection, transcripts. Here we apply capture probe-based short read high-throughput sequencing to nasal wash samples taken from a previously described group of adult hematopoietic cell transplant (HCT) recipients naturally infected with respiratory syncytial virus (RSV). We separately analyzed reads from genomes and transcripts for the levels and distribution of genetic variation by calculating per position Shannon entropies. Our analysis reveals a low level of genetic variation within the RSV infections analyzed here, but with interesting differences between genomes and transcripts in 1) average per sample Shannon entropies; 2) the genomic distribution of variation 'hotspots'; and 3) the genomic distribution of hotspots encoding alternative amino acids. In all, our results suggest the importance of separately analyzing reads from genomes and transcripts when interpreting high-throughput sequencing data for insight into intra-host viral genome replication, expression, and evolution.

Tree diversity across the Minneapolis-St. Paul Metropolitan Area in relation to climate and social vulnerability.

Urban tree canopy cover is often unequally distributed across cities such that more socially vulnerable neighborhoods often have lower tree canopy cover than less socially vulnerable neighborhoods. However, how the diversity and composition of the urban canopy affect the nature of social-ecological benefits (and burdens), including the urban forest's vulnerability to climate change, remains underexamined. Here, we synthesize tree inventories developed by multiple organizations and present a species-specific, geolocated database of more than 600,000 urban trees across the 7-county Minneapolis-St. Paul (MSP) metropolitan area in the Upper Midwest of the United States. We find that tree diversity across the MSP is variable yet dominated by a few species (e.g., Fraxinus pennsylvanica, Acer platanoides, and Gleditsia triacanthos), contributing to the vulnerability of the MSP urban forest to future climate change and disturbances. In contrast to tree canopy cover, tree diversity was not well predicted by socioeconomic or demographic factors. However, our analysis identified areas where both climate and social vulnerability are high. Our results add to a growing body of literature emphasizing the importance of considering how complex and interacting social and ecological factors drive urban forest diversity and composition when pursuing management objectives.

Bimekizumab provided rapid improvements in patient-reported symptoms and health-related quality of life in patients with active psoriatic arthritis: pooled 16-week results from two phase 3 studies.

OBJECTIVES: To assess impact of bimekizumab treatment on patient-reported outcomes and health-related quality of life (HRQoL) in patients with active psoriatic arthritis (PsA), using 16-week data from two phase 3 studies. METHODS: BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug (bDMARD)-naïve) and BE COMPLETE (NCT03896581; tumour necrosis factor inhibitor inadequate response/intolerance (TNFi-IR)) are phase 3 studies of subcutaneous bimekizumab 160 mg Q4W; both were double-blind and placebo-controlled to 16 weeks. Patients were randomised 3:2:1 to bimekizumab, placebo or reference (subcutaneous adalimumab 40 mg Q2W) in BE OPTIMAL; 2:1 to bimekizumab or placebo in BE COMPLETE. Patient-reported outcomes for pain, fatigue, physical function and HRQoL are reported to week 16 using pooled and individual study data for bimekizumab and placebo patients. RESULTS: 1073/1112 (96.5%) patients completed week 16 (bimekizumab:| 677/698 [97.0%]; placebo: 396/414 [95.7%]). Bimekizumab-treated patients achieved rapid improvements vs placebo in pain, fatigue, physical function and HRQoL by week 4, after a single dose. Improvements continued to week 16 for all patient-reported outcomes, including Pain Visual Analogue Scale (VAS; mean (95% CI) change from baseline: bimekizumab: -|25.2 [-27.2, -23.1]; placebo:| -|5.7 [-8.2, -3.3]) and FACIT-Fatigue (bimekizumab: 4.5 [3.9, 5.1]; placebo: 1.1 [0.3, 2.0]); both nominal p<0.001. Greater proportions of bimekizumab-treated patients achieved minimal clinically important differences for patient-reported symptoms vs placebo, including FACIT-Fatigue (bimekizumab: 53.1%; placebo: 36.3%) and HAQ-DI (bimekizumab:| 53.0%; placebo: 28.7%); both nominal p<0.001. CONCLUSION: Bimekizumab treatment demonstrated rapid and greater improvements in patient-reported pain, fatigue, physical function and HRQoL to week 16 vs placebo in bDMARD-naïve and TNFi-IR patients. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03895203; NCT03896581.