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Abstract Certain classes of antibiotics, including tetracyclines and macrolides, are known to exert immune suppressive effects in other species but the immune modulatory effects of these antibiotics have not been previously studied in cattle. To address this question, we investigated the effects of oxytetracycline, gamithromycin, and tulathromycin on T cell and macrophage responses to activation, using in vitro assays. In addition, we assessed the impact of these antibiotics on T cell responses in vivo following treatment of healthy cattle with currently recommended doses of each of the three antibiotics. We found that all 3 antibiotics markedly suppressed T cell proliferation in vitro at relevant therapeutic drug concentrations and significantly suppressed macrophage activation responses to LPS. In cattle treated with a single dose of each antibiotic, we observed significant suppression of T cell proliferation and cytokine production beginning as early as 6 h after administration, with increasing immune suppression observed at 48 h. Taken together, these results indicate that commonly used antibiotics in cattle exert significant immune modulatory activity, in addition to their antimicrobial activity. These off-target effects should be considered when using antibiotics for prophylaxis or metaphylaxis in high-risk dairy or beef cattle (192 words).

Abstract The compatibility of W-boson mass measurements performed by the ATLAS, LHCb, CDF, and D0 experiments is studied using a coherent framework with theory uncertainty correlations. The measurements are combined using a number of recent sets of parton distribution functions (PDF), and are further combined with the average value of measurements from the Large Electron–Positron collider. The considered PDF sets generally have a low compatibility with a suite of global rapidity-sensitive Drell–Yan measurements. The most compatible set is CT18 due to its larger uncertainties. A combination of all $$m_W$$ m W measurements yields a value of $$m_W = 80{,}394.6 \pm 11.5$$ m W = 80 , 394.6 ± 11.5 MeV with the CT18 set, but has a probability of compatibility of 0.5% and is therefore disfavoured. Combinations are performed removing each measurement individually, and a 91% probability of compatibility is obtained when the CDF measurement is removed. The corresponding value of the W boson mass is $$80{,}369.2 \pm 13.3$$ 80 , 369.2 ± 13.3 MeV, which differs by $$3.6\sigma $$ 3.6 σ from the CDF value determined using the same PDF set.

Abstract For the population of a given US city, the risk of premature death associated with heat exposure increases as temperatures rise, but risks in hotter cities are generally lower than in cooler cities at equivalent temperatures due to factors such as acclimatization. Those living in especially hot neighborhoods within cities might therefore suffer much more than average if such adaptation is only at the city‐wide level, whereas they might not experience greatly increased risk if adjustment is at the neighborhood level. To compare these possibilities, we use high spatial resolution temperature data to evaluated heat‐related deaths assuming either adjustment at the city‐wide or at the neighborhood scale in 10 large US cities. On average, we find that if inhabitants are adjusted to their local conditions, a neighborhood that was 10°C hotter than a cooler one would experience only about 1.0–1.5 excess heat deaths per year per 100,000 persons. By contrast, if inhabitants are acclimatized to city‐wide temperatures, the hotter neighborhood would experience about 15 excess deaths per year per 100,000 persons. Using idealized analyses, we demonstrate that current city‐wide epidemiological data do not differentiate between these differing adjustments. Given the very large effects of assumptions about neighborhood‐level acclimatization found here, as well as the fact that current literature is conflicting on the spatial scale of acclimatization, more neighborhood‐level epidemiological data are urgently needed to determine the health impacts of variations in heat exposure within urban areas, better constrain projected changes, and inform mitigation efforts.

Abstract Soil‐to‐groundwater contaminant mass discharge (Md) is the authoritative metric defining source strength at sites impacted by per‐ and polyfluoroalkyl substances (PFAS) and is increasingly being reported. Accurate estimates of groundwater recharge at representative spatial scales, however, is critical to quantitatively estimating Md, which to date has received comparatively little attention relative to PFAS‐specific partitioning and retention processes within unsaturated zone source areas despite a plethora of available literature. The objective of this review is to summarize the concept of Md as it applies to PFAS‐impacted sites, present standardized terminology, and collate published literature on groundwater recharge for a practitioner‐level summary of practical methods. Critically, the primary aim is to reduce uncertainty in recharge (and, thus, Md) estimates commensurate to a given site management application (i.e., the data quality objective process). Therefore, we propose a tiered system of increasing cost, complexity, and certainty depending on specific project requirements and site conditions and recommend applicable recharge methods for each tier based on these factors. Ultimately, a framework is presented for the assessment of PFAS‐impacted source areas based on the concept of Md.

Abstract Background Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. Methods A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call ‘tea breaks’ (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for ‘tea breaks’, with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. Discussion If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. Trial registration ISRCTN17325135 . Registration date 27 November 2019

This is the almost 2-year-long course of a 16-year-old male without significant psychiatry history who abruptly developed symptoms of obsessive-compulsive disorder (OCD) and psychosis following a confirmed coronavirus disease 2019 (COVID-19) infection. His symptoms worsened following a confirmed reinfection with COVID-19. He responded poorly to treatment with selective serotonin reuptake inhibitors, antipsychotics, and benzodiazepines. This case highlights an emerging phenomenon of post-COVID-19 neuropsychiatric sequelae and presents a complicated diagnostic and treatment challenge. The differential for this patient was explored and outlined in detail, and the medical workup recommendations for new-onset mental status changes were reviewed as they pertain to the patient’s assessment and treatment course. While there are several case reports of adolescents with abrupt-onset OCD and psychosis symptoms following COVID-19 infections, none of these reports include worsening of symptoms following reinfection, and few reports follow patients beyond initial hospitalization and treatment.

Newly up-potted ‘Soft Touch’ Japanese hollies (Ilex crenata ‘Soft Touch’) were grown in Mobile, AL in 1.5 L containers to evaluate the effects of growth from black or white container colors and container spacing (jammed or spaced) in relation to root zone temperature. Two treatments, container color and container spacing, were evaluated and root ratings were reported. At termination, an interaction was observed in growth from 43 to 141 days after potting between container color and spacing. Both white container treatments and the black-jammed treatment experienced 36% and 21% more growth than black-spaced plants. Root ratings for white containers (jammed and spaced) were 42% greater than for black-spaced. Black-jammed root ratings were 25% greater than black-spaced. Black-spaced containers experienced the greatest number of time intervals over the critical temperature of 39 °C when compared to other treatments. Results suggest that ‘Soft Touch’ holly may be grown at final spacing when using white containers and have little impact from elevated root zone temperatures.

Bacteriophages are the most abundant organisms on Earth. As there are few effective treatment options against some pathogens, the interest in the bacteriophage control of multi-drug-resistant bacterial pathogens is escalating, especially for Klebsiella pneumoniae. This study aimed to develop a phage-based solution to the rising incidence of extensively drug-resistant clinical Klebsiella pneumoniae sequence type (ST16) infections starting from a set of phages recently characterized against this lineage. A phage-cocktail (Katrice-16) composed of eight lytic phages was characterized for potential use in humans. In vitro and in vivo broth inhibition and Galleria mellonella rescue assays were used to demonstrate the efficacy of this approach using a collection of 56 strains of K. pneumoniae ST16, with distinct genetic backgrounds that were collected from clinical infections from four disparate nations. Additionally, Katrice-16 anti-biofilm activity, synergism with meropenem, and activity in human body fluids were also assessed. Katrice-16 was highly active in vitro against our K. pneumoniae ST16 collection (AUC% median = 86.48%; Q1 = 83.8%; Q2 = 96.85%; Q3 = 98.85%). It additionally demonstrated excellent in vivo activity in G. mellonella rescue assays, even with larvae infected by isolates that exhibited moderate in vitro inhibition. We measured significant anti-biofilm activity over 12 h (p = .0113) and synergic activity with meropenem. In addition, we also demonstrate that Katrice-16 maintained high activity in human body fluids. Our results indicate that our cocktail will likely be an effective solution for human infections with this increasingly prevalent and often highly resistant bacterial clone.

Abstract Background We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829 , posted November 11th, 2016)

Abstract Background There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK. Case presentation We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. Conclusions These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.

Abstract Background Cardiovascular disease is one of the main causes of death in the United States, and hypertension is a primary risk factor. Therefore, the primary causes of hypertension need to be identified so they may be addressed for treatment. The purpose of this study was to compare blood pressure with hemodynamic values and identify factors that may explain blood pressure differences between a cohort of healthy normotensive younger and older women. Methods Participants were 49 young (age: 33.8 ± 5.9) and 103 old (age: 65.8 ± 4) who were non-hypertensive, had no previous history of heart disease or type 2 diabetes, body mass index less than 30 kg/m2, normal electrocardiography response at rest and during exercise, nonsmokers, and no use of medications known to affect cardiovascular or metabolic function. Body composition measured by dual-energy X-ray absorptiometry. Hemodynamic values measured by non-invasive pulse wave velocity through radial artery tonometry. Markers of inflammation measured through blood sample analysis. Results Significant differences exist between young and old groups in %fat (P

Abstract Currently available evidence supports that the predominant route of human-to-human transmission of the SARS-CoV-2 is through respiratory droplets and/or contact routes. The report by the World Health Organization (WHO) Joint Mission on Coronavirus Disease 2019 (COVID-19) in China supports person-to-person droplet and fomite transmission during close unprotected contact with the vast majority of the investigated infection clusters occurring within families, with a household secondary attack rate varying between 3 and 10%, a finding that is not consistent with airborne transmission. The reproduction number (R0) for the SARS-CoV-2 is estimated to be between 2.2–2.7, compatible with other respiratory viruses associated with a droplet/contact mode of transmission and very different than an airborne virus like measles with a R0 widely cited to be between 12 and 18. Based on the scientific evidence accumulated to date, our view is that SARS-CoV-2 is not spread by the airborne route to any significant extent and the use of particulate respirators offers no advantage over medical masks as a component of personal protective equipment for the routine care of patients with COVID-19 in the health care setting. Moreover, prolonged use of particulate respirators may result in unintended harms. In conjunction with appropriate hand hygiene, personal protective equipment (PPE) used by health care workers caring for patients with COVID-19 must be used with attention to detail and precision of execution to prevent lapses in adherence and active failures in the donning and doffing of the PPE.

Background: Infectious intestinal disease affects 25% of the UK population annually; 1 in 50 affected people consult health professionals about their illness. Aims: We tested if anticipated treatment-seeking decisions for suspected infectious intestinal disease could be related to emotional response, tolerance of symptoms, or beliefs about the consequential benefits and harms of seeking treatment (or not). Methods: Questionnaire survey of adults living in the UK with statistical analysis of responses. A vignette was presented about a hypothetical gastrointestinal illness. People stated their emotional reactions, expected actions in response and beliefs about possible benefits or harms from seeking treatment (or not getting treatment). Multinomial regression looked for predictors of anticipated behaviour. Results: People were inclined to consult a GP when they believed that seeking treatment would be beneficial and that its absence would be harmful. Seeking treatment was less anticipated if the condition was expected to improve quickly. Respondents were also more likely to consult if they strongly disliked fever or headache, and/or if the illness made them feel anxious or angry. Treatment-seeking (or lack of it) was not linked to harms from treatment-seeking, other specific symptoms and emotional responses. Conclusion: It was possible to link anticipated treatment-seeking behaviour to specific factors: expected prognosis, perceived benefits of seeking treatment, some emotions and some specific symptoms. Keywords: Consultation, Gastrointestinal disease, Self management, Multinomial regression, Treatment-seeking

Abstract Background Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations’ Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. Main body Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. Conclusion These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that – in any context – a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

Abstract Vulnerability has become a key concept in emergency response research and is being critically discussed across several disciplines. While the concept has been adopted into global health, its conceptualisation and especially its role in the conceptualisation of risk and therefore in risk assessments is still lacking. This paper uses the risk concept pioneered in hazard research that assumes that risk is a function of the interaction between hazard and vulnerability rather than the neo-liberal conceptualisation of vulnerability and vulnerable groups and communities. By seeking to modify the original pressure and release model, the paper unpacks the representation or lack of representation of vulnerability in risk assessments in global health emergency response and discusses what benefits can be gained from making the underlying assumptions about vulnerability, which are present whether vulnerability is sufficiently conceptualised and consciously included or not, explicit. The paper argues that discussions about risk in global health emergencies should be better grounded in a theoretical understanding of the concept of vulnerability and that this theoretical understanding needs to inform risk assessments which implicitly used the concept of vulnerability. By using the hazard research approach to vulnerability, it offers an alternative narrative with new perspectives on the value and limits of vulnerability as a concept and a tool.

Background: Humanitarian emergencies including disasters associated with natural hazards, conflict, complex emergencies and famines can pose significant risks to public health, especially when they lead to population displacement into inadequate conditions. To reduce the risk of communicable disease outbreaks in such situations it is necessary to know the key risk factors, their thresholds (quantitative risk factors only) and their relative importance in different types of emergencies. Methods: We conducted a three-stage structured expert elicitation. Experts from the fields of health protection and humanitarian assistance were invited to complete three successive online questionnaires. Experts were asked to choose the 20 most critical risk factors and in subsequent rounds to determine thresholds for urgent (yellow threshold level) and critical action (red threshold level). Additionally, experts were asked to assign weights for the risk factors in different emergency types. Results: We identified 20 key risk factors, which include factors related to water, sanitation and hygiene, access to health care, vaccination, nutrition, political will and others. Nine out of the 20 risk factors were quantifiable, for those risk factors yellow and red thresholds are given. 11 risk factors were qualitative. All risk factors scored highly when weighted in different emergency types and differences between risk factor weights in different types of emergencies were limited. Conclusion: Communicable disease risks in humanitarian emergencies are a nexus of complex and often interrelated individual issues. Knowing key risk factors and their thresholds and weight in different types of emergencies can help guide emergency response and risk reduction efforts.

Abstract Background With over 800 million cases globally, campylobacteriosis is a major cause of food borne disease. In temperate climates incidence is highly seasonal but the underlying mechanisms are poorly understood, making human disease control difficult. We hypothesised that observed disease patterns reflect complex interactions between weather, patterns of human risk behaviour, immune status and level of food contamination. Only by understanding these can we find effective interventions. Methods We analysed trends in human Campylobacter cases in NE England from 2004 to 2009, investigating the associations between different risk factors and disease using time-series models. We then developed an individual-based (IB) model of risk behaviour, human immunological responses to infection and environmental contamination driven by weather and land use. We parameterised the IB model for NE England and compared outputs to observed numbers of reported cases each month in the population in 2004–2009. Finally, we used it to investigate different community level disease reduction strategies. Results Risk behaviours like countryside visits (t = 3.665, P

Abstract Background Globally cryptosporidiosis is one of the commonest causes of mortality in children under 24 months old and may be associated with important longterm health effects. Whilst most strains of Cryptosporidium parvum are zoonotic, C. parvum IIc is almost certainly anthroponotic. The global distribution of this potentially important emerging infection is not clear. Methods We conducted a systematic review of papers identifying the subtype distribution of C. parvum infections globally. We searched PubMed and Scopus using the following key terms Cryptospor* AND parvum AND (genotyp* OR subtyp* OR gp60). Studies were eligible for inclusion if they had found C. parvum within their human study population and had subtyped some or all of these samples using standard gp60 subtyping. Pooled analyses of the proportion of strains being of the IIc subtype were determined using StatsDirect. Meta-regression analyses were run to determine any association between the relative prevalence of IIc and Gross Domestic Product, proportion of the population with access to improved drinking water and improved sanitation. Results From an initial 843 studies, 85 were included in further analysis. Cryptosporidium parvum IIc was found in 43 of these 85 studies. Across all studies the pooled estimate of relative prevalence of IIc was 19.0% (95% CI: 12.9–25.9%), but there was substantial heterogeneity. In a meta-regression analysis, the relative proportion of all C. parvum infections being IIc decreased as the percentage of the population with access to improved sanitation increased and was some 3.4 times higher in those studies focussing on HIV-positive indivduals. Conclusions The anthroponotic C. parvum IIc predominates primarily in lower-income countries with poor sanitation and in HIV-positive individuals. Given the apparent enhanced post-infectious virulence of the other main anthroponotic species of Cryptosporidium (C. hominis), it is important to learn about the impact of this subtype on human health.

We describe drug-resistance mutation dynamics of the gag gene among individuals under antiretroviral virologic failure who underwent analytical treatment interruption (ATI). These mutations occur in and around the cleavage sites that form the particles that become the mature HIV-1 virus. The study involved a 12-week interruption in antiretroviral therapy (ART) and sequencing of the gag gene in 38 individuals experiencing virologic failure and harboring triple-class resistant HIV strains. Regions of the gag gene surrounding the NC-p2 and p1-p6 cleavage sites were sequenced at baseline before ATI and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Fourteen of the sixteen patients sequenced presented at least one mutation in the gag gene at baseline, with an average of 4.93 mutations per patient. All the mutations had reverted to the wild type by the end of the study. Mutations in the gag gene complement mutations in the pol gene to restore HIV fitness. Those mutations around cleavage sites and within substrates contribute to protease inhibitor resistance and difficulty in re-establishing effective virologic suppression. ART interruption in the presence of antiretroviral resistant HIV strains was used here as a practical measure for more adapted HIV profiles in the absence of ART selective pressure.

Abstract Very little is known about how metabolic health status, insulin resistance or metabolic challenges modulate the endocannabinoid (eCB) or polyunsaturated fatty acid (PUFA)‐derived oxylipin (OxL) lipid classes. To address these questions, plasma eCB and OxL concentrations were determined at rest, 10 and 20 min during an acute exercise bout (30 min total, ~45% of preintervention V̇O2peak, ~63 W), and following 20 min recovery in overnight‐fasted sedentary, obese, insulin‐resistant women under controlled diet conditions. We hypothesized that increased fitness and insulin sensitivity following a ~14‐week training and weight loss intervention would lead to significant changes in lipid signatures using an identical acute exercise protocol to preintervention. In the first 10 min of exercise, concentrations of a suite of OxL diols and hydroxyeicosatetraenoic acid (HETE) metabolites dropped significantly. There was no increase in 12,13‐DiHOME, previously reported to increase with exercise and proposed to activate muscle fatty acid uptake and tissue metabolism. Following weight loss intervention, exercise‐associated reductions were more pronounced for several linoleate and alpha‐linolenate metabolites including DiHOMEs, DiHODEs, KODEs, and EpODEs, and fasting concentrations of 9,10‐DiHODE, 12,13‐DiHODE, and 9,10‐DiHOME were reduced. These findings suggest that improved metabolic health modifies soluble epoxide hydrolase, cytochrome P450 epoxygenase (CYP), and lipoxygenase (LOX) systems. Acute exercise led to reductions for most eCB metabolites, with no evidence for concentration increases even at recovery. It is proposed that during submaximal aerobic exercise, nonoxidative fates of long‐chain saturated, monounsaturated, and PUFAs are attenuated in tissues that are important contributors to the blood OxL and eCB pools.

Abstract. Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The approval was based on a single, multicenter, phase II trial in previously treated WM patients. We sought to evaluate whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at our institution and participated in two prospective studies (ON trial; n = 72) or a prospective database (OFF trial; n = 157) were included. The median times from WM diagnosis to ibrutinib initiation were 3.1 and 3.5 years for ON and OFF trial patients, respectively (p = 0.38). Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4-year PFS and OS rates for ON trial and OFF trial patients were 72% and 63%, respectively (log-rank p = 0.14) and 83% and 81%, respectively (log-rank p = 0.14). CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4-year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively (p = 0.11). Ibrutinib is effective in the routine clinical care of both treatment-naïve and previously treated WM patients. The findings of our study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials.

Abstract Art therapies are a broad suite of treatments including drawing, painting and music that can facilitate non-verbal communication through artistic expression. They have been used as adjunctive therapies for a range of mental health conditions. Significant numbers of returning military personnel experience post-traumatic stress disorder (PTSD), and discontinuation of care is a concern. Using drawing-based art therapy as an adjuvant to classical therapies may provide a benefit for such military patients.