Formylated Peptide Receptor-1-Mediated Gut Inflammation as a Therapeutic Target in Inflammatory Bowel Disease.

Background: Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation. Aim: We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD). Methods: We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD. Results: Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P < .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn's disease (CD) (both P < .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P < .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0-4.99; range 0-53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity. Conclusions: Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.

Analysis of AT7519 as a pro-resolution compound in an acetaminophen-induced mouse model of acute inflammation by UPLC-MS/MS.

BACKGROUND: Uncontrolled inflammation contributes to the progression of organ damage in acute conditions, such as acetaminophen-induced acute liver injury (APAP-ALI) and there are limited treatments for this condition. AT7519, a cyclic-dependent kinase inhibitor (CDKI), has been used successfully in several conditions, to resolve inflammation and return tissue homeostatic functions. AT7519 has not been assessed in APAP-ALI and its effect on APAP metabolism is unknown. Targeted chromatography and mass spectrometry can be used to assess multiple compounds simultaneously and this approach has not been applied yet to measure APAP and AT7519 in a mouse model. RESULTS: We show an optimised simple and sensitive LC-MS/MS method for determining concentrations of AT7519 and APAP in low volumes of mouse serum. Using positive ion mode electrospray ionisation, separation of AT7519 and APAP and their corresponding isotopically labelled internal standards [2H]8-AT16043M (d8-AT7519) and [2H]8-APAP (d4-APAP), was achieved on an Acquity UPLC BEH C18 column (100 × 2.1 mm; 1.7µm). A gradient mobile phase system of water and methanol was delivered at a flow rate of 0.5 mL/min with a run time of 9 min. Calibration curves were linear, intra-day and inter-day precision and accuracy were acceptable and the covariates of all standards and quality control replicates were less than 15%. The method was successfully applied to evaluate AT7519 and APAP levels 20 h post AT7519 (10 mg/mg) in C57Bl6J wild type mouse serum treated with either vehicle or APAP. Serum AT7519 was significantly higher in mice that had received APAP compared to control, but there was no correlation between APAP and AT7519 quantification. There was also no correlation of AT7519 and hepatic damage or proliferation markers. CONCLUSION: We optimised an LC-MS/MS method to quantify both AT7519 and APAP in mouse serum (50 µL), using labelled internal standards. Application of this method to a mouse model of APAP toxicity proved effective in accurately measuring APAP and AT7519 concentrations after i.p. dosing. AT7519 was significantly higher in mice with APAP toxicity, indicating hepatic metabolism of this CDKI, but there was no correlation with markers of hepatic damage or proliferation, demonstrating that this dose of AT7519 (10 mg/kg) does not contribute to hepatic damage or repair. This optimised method can be used for future investigations of AT7519 in APAP in mice.

Inhibition of Cyclin-Dependent Kinase 9 Downregulates Cytokine Production Without Detrimentally Affecting Human Monocyte-Derived Macrophage Viability.

Cyclin-dependent kinase (CDK) inhibitor drugs (CDKi), such as R-roscovitine and AT7519, induce neutrophil apoptosis in vitro and enhance the resolution of inflammation in a number of in vivo models. This class of compounds are potential novel therapeutic agents that could promote the resolution of acute and chronic inflammatory conditions where neutrophil activation contributes to tissue damage and aberrant tissue repair. In this study we investigated CDKi effects on macrophage pro-inflammatory mediator production and viability. Treatment of human monocyte-derived macrophages (MDMs) with the CDKi AT7519 and R-roscovitine at concentrations that induce neutrophil apoptosis had no significant effect on control or LPS-activated MDM apoptosis and viability, and did not detrimentally affect MDM efferocytosis of apoptotic cells. In addition, enhanced efferocytosis, induced by the glucocorticoid dexamethasone, was also unaffected after a short time treatment with R-roscovitine. Macrophage cytokine responses to inflammatory stimuli are also of importance during inflammation and resolution. As a key target of CDKi, CDK9, is involved in protein transcription via the RNA polymerase II complex, we investigated the effect of CDKi drugs on cytokine production. Our data show that treatment with AT7519 significantly downregulated expression and release of key MDM cytokines IL-6, TNF, IL-10 and IL-1ß, as well as markers of pro-inflammatory macrophage polarisation. R-Roscovitine was also able to downregulate inflammatory cytokine protein secretion from MDMs. Using siRNA transfection, we demonstrate that genetic knock-down of CDK9 replicates these findings, reducing expression and release of pro-inflammatory cytokines. Furthermore, overexpression of CDK9 in THP-1 cells can promote a pro-inflammatory phenotype in these cells, suggesting that CDK9 plays an important role in the inflammatory phenotype of macrophages. Overall, this study demonstrates that pharmacological and genetic targeting of CDK9 inhibits an inflammatory phenotype in human MDMs. As such these data indicate that CDK9 may be key to therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation.

Applicability of a national strategy for patient-oriented research to people who use(d) substances: a Canadian experience.

BACKGROUND: Europe and North America are in the grips of a devastating overdose crisis. People who use substances often feel unsafe to access healthcare due to fears of stigma, blame, judgement, poor treatment, or other repercussions. As a result, they often avoid, delay, or leave care, resulting in premature death and missed opportunities for care. Internationally, there have been concerted efforts to move towards patient-engaged research to enhance the quality of health care systems and services. In Canada, the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR) initiative promotes engagement of patients as active partners in health care research. As part of a community based patient oriented research project, we critically analyze the SPOR framework to provide insights into what constitutes safer research with people who use(d) substances. METHODS: We undertook a two-stage process that began with a review of community based research principles and the SPOR framework. At the second stage, we undertook a qualitative descriptive study employing focus groups to generate description of the adequacy and appropriateness of the SPOR framework for guiding research with people who use(d) substances on four key dimensions (patient engagement, guiding principles, core areas of engagement and benefits). The data were analyzed using qualitative content analysis to identify key issues and insights. RESULTS: While the SPOR framework includes a range of patient roles, principles and areas for engagement, there are issues and gaps related to essential elements of safe patient-oriented research for people who use substances. These include an individualized focus on patients as partners, lack of recognition of community benefits, power imbalances and distrust due to systemic stigma, engagement as one way capacity building and learning, and lack of accountability for taking action on research findings. CONCLUSIONS: Given the extent of stigma in health care and the ongoing illicit drug policy crisis, strategies for enhancing equitable Patient-Oriented Research (POR) include shifting language from patient partners to community researchers, recognizing power inequities and adding trust and equity as core POR principles including pay equity. Employing community based participatory research as a POR methodology allows the lead researchers to fully engage community throughout the research process, enhances community benefits and accountability for action.

Intestinal Protein Characterisation of SARS-CoV-2 Entry Molecules ACE2 and TMPRSS2 in Inflammatory Bowel Disease (IBD) and Fatal COVID-19 Infection.

The coronavirus SARS-CoV-2 contributes to morbidity and mortality mainly as a result of immune-pathology in the lungs. Recent data has shown multi-system involvement with widespread viral tropism. Here we present a detailed intestinal protein characterisation of SARS-Cov-2 entry molecules ACE2 and TMPRSS2 in patients with inflammatory bowel disease ([IBD]; ulcerative colitis [UC] and Crohn's disease [CD]) with age- and sex-matched non-IBD controls, and in those with fatal COVID-19 infection. In our dataset, ACE2 and TMPRSS2 displayed a membrane enterocyte staining in the ileum (due to presence of brush border/microvilli) in contrast to a cytoplasmic pattern in the colon. We also showed a high ACE2/low TMPRSS2 expression pattern in the ileum with a reverse trend in the colon. In UC, colonic ACE2 and TMPRSS2 are cytoplasmic in nature, with significantly higher ACE2 staining intensity compared to non-IBD controls. In inflamed and unaffected IBD mucosa, ileal and colonic enterocyte ACE2 and TMPRSS2 expressions are not modified in the histologic presence of inflammation. We observed immune cells within the lamina propria that expressed ACE2 and TMPRSS2, at higher frequencies in IBD when compared to non-IBD controls. These were identified as plasma cells with multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) expression. We further analysed the gut histology of six fatal COVID-19 cases, with no difference in colonic and ileal ACE2/TMRPSS2 staining (compared to non-IBD controls) and identified ACE2 + lamina propria plasma cells. Of interest, in this COVID-19 cohort, there was no histologic evidence gut inflammation despite known evidence of viral tropism within the enterocytes. Our data provides evidence for tissue expression of entry molecules ACE2 and TMPRSS2 including a close apposition to plasma cells - both pointing towards a role of the gut in the antecedent immune response to SARS-CoV-2 infection.

Improving species status assessments under the U.S. Endangered Species Act and implications for multispecies conservation challenges worldwide.

Despite its successes, the U.S. Endangered Species Act (ESA) has proven challenging to implement due to funding limitations, workload backlog, and other problems. As threats to species survival intensify and as more species come under threat, the need for the ESA and similar conservation laws and policies in other countries to function efficiently has grown. Attempts by the U.S. Fish and Wildlife Service (USFWS) to streamline ESA decisions include multispecies recovery plans and habitat conservation plans. We address species status assessment (SSA), a USFWS process to inform ESA decisions from listing to recovery, within the context of multispecies and ecosystem planning. Although existing SSAs have a single-species focus, ecosystem-based research can efficiently inform multiple SSAs within a region and provide a foundation for transition to multispecies SSAs in the future. We considered at-risk grassland species and ecosystems within the southeastern United States, where a disproportionate number of rare and endemic species are associated with grasslands. To initiate our ecosystem-based approach, we used a combined literature-based and structured World Café workshop format to identify science needs for SSAs. Discussions concentrated on 5 categories of threats to grassland species and ecosystems, consistent with recommendations to make shared threats a focus of planning under the ESA: (1) habitat loss, fragmentation, and disruption of functional connectivity; (2) climate change; (3) altered disturbance regimes; (4) invasive species; and (5) localized impacts. For each threat, workshop participants identified science and information needs, including database availability, research priorities, and modeling and mapping needs. Grouping species by habitat and shared threats can make the SSA process and other planning processes for conservation of at-risk species worldwide more efficient and useful. We found a combination of literature review and structured discussion effective for identifying the scientific information and analysis needed to support the development of multiple SSAs. Article impact statement: Species status assessments can be improved by an ecosystem-based approach that groups imperiled species by shared habitats and threats.

Mejoramiento de la Evaluación del Estado de una Especie bajo el Acta de Especies en Peligro de los Estados Unidos y Sus Consecuencias para los Retos de la Conservación Multiespecie a Nivel Mundial Resumen A pesar de su éxito, el Acta de Especies en Peligro de los E.U.A. (AEP) ha sido un reto de implementación por las limitaciones en su financiamiento, el retraso en la carga de trabajo y otros problemas. Conforme se intensifican las amenazas a la supervivencia de las especies y más especies resultan amenazadas, aumenta la necesidad de que la AEP y las políticas similares de otros países funcionen efectivamente. Los intentos por parte del Servicio Estadounidense de Pesca y Fauna (SEPF) para optimizar las decisiones de la AEP incluyen planes multiespecie de recuperación y planes de conservación de hábitat (PRH). Abordamos la evaluación del estado de las especies (EEE), un proceso del SEPF para orientar las decisiones del AEP desde el listado hasta la recuperación, dentro del contexto de la planeación multiespecie y de ecosistemas. Aunque las EEE existentes tienen un enfoque sobre una única especie, la investigación basada en el ecosistema puede orientar eficientemente a múltiples EEE dentro de una región y proporcionar una base para la transición a las EEE multiespecie en el futuro. Consideramos a las especies y los ecosistemas en riesgo de los pastizales del sureste de los Estados Unidos, en donde un número desproporcionado de especies raras y endémicas está asociado con los pastizales. Para iniciar nuestra estrategia basada en el ecosistema, usamos un formato de taller de World Café estructurado y basado en la literatura para identificar la necesidad de tener EEE. Las discusiones se centraron en cinco categorías de amenazas para las especies y ecosistemas de los pastizales, consistentes con las recomendaciones para volver a las amenazas compartidas un foco de la planeación bajo la AEP: (1) pérdida del hábitat, fragmentación y disrupción de la conectividad funcional; (2) cambio climático; (3) regímenes alterados de perturbación; (4) especies invasoras; y (5) impactos localizados. Para cada amenaza, los participantes del taller identificaron las necesidades científicas y de información, incluyendo la disponibilidad de bases de datos, prioridades de la investigación y necesidades de modelado y mapeado. La agrupación de las especies por hábitat y amenaza compartida puede hacer más eficientes y útiles el proceso de EEE y otros procesos de planeación de la conservación de especies en riesgo a nivel mundial. Encontramos una combinación de revisiones bibliográficas y discusiones estructuradas para identificar la información y el análisis necesarios para respaldar el desarrollo de múltiples EEE.

Acute Ulcerative Enterocolitis With Severe Protein Loss Due to Mucosal Invasion With Enterococcus spp. in a Dog With Exocrine Pancreatic Insufficiency: A Case Report.

We describe an unusual case of severe acute protein-losing enteropathy in a dog, which presented with a systemic inflammatory response syndrome. This dog's condition could not be categorized as any well-known canine intestinal condition. Instead, components of several enteropathies like acute hemorrhagic diarrhea syndrome (AHDS), chronic inflammatory enteropathy (CIE), and ulcerative and granulomatous colitis were present. Thorough investigations identified concurrent exocrine pancreatic insufficiency (EPI) and hypocobalaminemia. On histopathology, marked diffuse chronic-active ileitis and ulcerative colitis with fibroplasia and neovascularization were present. Intestinal biopsy cultures identified E.coli and multiresistant Enterococcus spp. The latter was identified as mucosally invasive using fluorescent in situ hybridization (FISH). Protracted clinical signs following the acute presentation required intensive care including enteral and parenteral feeding for a successful outcome, but eventually stabilized with antibiotics and immunosuppressive doses of glucocorticoids. This case highlights a potentially previously unrecognized condition, suspected to be a form of CIE manifesting acutely after bacterial mucosal invasion. In this case, this might have been facilitated by EPI-induced dysbiosis. The use of FISH and mucosal culture in this context provided important clinical information and should be considered more frequently in CIE and non-responsive AHDS.

Topographic, soil, and climate drivers of drought sensitivity in forests and shrublands of the Pacific Northwest, USA.

Climate change is anticipated to increase the frequency and intensity of droughts, with major impacts to ecosystems globally. Broad-scale assessments of vegetation responses to drought are needed to anticipate, manage, and potentially mitigate climate-change effects on ecosystems. We quantified the drought sensitivity of vegetation in the Pacific Northwest, USA, as the percent reduction in vegetation greenness under droughts relative to baseline moisture conditions. At a regional scale, shrub-steppe ecosystems-with drier climates and lower biomass-showed greater drought sensitivity than conifer forests. However, variability in drought sensitivity was considerable within biomes and within ecosystems and was mediated by landscape topography, climate, and soil characteristics. Drought sensitivity was generally greater in areas with higher elevation, drier climate, and greater soil bulk density. Ecosystems with high drought sensitivity included dry forests along ecotones to shrublands, Rocky Mountain subalpine forests, and cold upland sagebrush communities. In forests, valley bottoms and areas with low soil bulk density and high soil available water capacity showed reduced drought sensitivity, suggesting their potential as drought refugia. These regional-scale drought-sensitivity patterns discerned from remote sensing can complement plot-scale studies of plant physiological responses to drought to help inform climate-adaptation planning as drought conditions intensify.

A fluorogenic cyclic peptide for imaging and quantification of drug-induced apoptosis.

Programmed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tissues that restrict the use of annexins. In this manuscript, we report the rational design of a highly stable fluorogenic peptide (termed Apo-15) that selectively stains apoptotic cells in vitro and in vivo in a calcium-independent manner and under wash-free conditions. Furthermore, using a combination of chemical and biophysical methods, we identify phosphatidylserine as a molecular target of Apo-15. We demonstrate that Apo-15 can be used for the quantification and imaging of drug-induced apoptosis in preclinical mouse models, thus creating opportunities for assessing the in vivo efficacy of anti-inflammatory and anti-cancer therapeutics.

Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation.

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

Resolution of Inflammation and Gut Repair in IBD: Translational Steps Towards Complete Mucosal Healing.

Despite significant recent therapeutic advances, complete mucosal healing remains a difficult treatment target for many patients with inflammatory bowel diseases (IBD) to achieve. Our review focuses on the translational concept of promoting resolution of inflammation and repair as a necessary adjunctive step to reach this goal. We explore the roles of inflammatory cell apoptosis and efferocytosis to promote resolution, the new knowledge of gut monocyte-macrophage populations and their secreted prorepair mediators, and the processes of gut epithelial repair and regeneration to bridge this gap. We discuss the need and rationale for this vision and the tangible steps toward integrating proresolution therapies in IBD.

Alternatively activated macrophages promote resolution of necrosis following acute liver injury.

BACKGROUND & AIM: Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). METHODS: Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. RESULTS: BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. CONCLUSION: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. LAY SUMMARY: After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

Low vitamin D status is associated with anaemia in hospitalised cats.

BACKGROUND: The major physiological role of vitamin D has traditionally been considered to be the regulation of calcium homeostasis and maintenance of skeletal health. However, there is increasing evidence that vitamin D influences a wider range of physiological processes including erythropoiesis. Vitamin D (25-hydroxyvitamin D, 25(OH)D) deficiency concentrations have been associated with anaemia in human beings. In contrast, the relationship between vitamin D status and erythropoiesis has not been investigated in cats. METHODS: Clinical records of cats consecutively presenting between November 2013 and February 2015 were reviewed. For each cat, data including sex, age, breed, serum albumin and creatinine concentrations, and appetite scores were extracted. A multivariable linear regression model was constructed to examine the relationship between 25(OH)D concentrations and these variables. RESULTS: Cats with anaemia had significantly lower 25(OH)D concentrations (median 49.5 nmol/l, n=31) than cats with packed cell volume above the lower limit of the reference range (median 109.0 nmol/l, n=130) (P<0.001). A binary logistic regression found that red blood cell count and mean corpuscular volume were negatively correlated with serum 25(OH)D concentrations (P<0.001 and P=0.007, respectively). CONCLUSION: Vitamin D (25(OH)D) concentration is positively associated with red blood cell count and mean corpuscular volume in cats with a wide range of different illnesses.

Climate-change refugia: biodiversity in the slow lane.

Climate-change adaptation focuses on conducting and translating research to minimize the dire impacts of anthropogenic climate change, including threats to biodiversity and human welfare. One adaptation strategy is to focus conservation on climate-change refugia (that is, areas relatively buffered from contemporary climate change over time that enable persistence of valued physical, ecological, and sociocultural resources). In this Special Issue, recent methodological and conceptual advances in refugia science will be highlighted. Advances in this emerging subdiscipline are improving scientific understanding and conservation in the face of climate change by considering scale and ecosystem dynamics, and looking beyond climate exposure to sensitivity and adaptive capacity. We propose considering refugia in the context of a multifaceted, long-term, network-based approach, as temporal and spatial gradients of ecological persistence that can act as "slow lanes" rather than areas of stasis. After years of discussion confined primarily to the scientific literature, researchers and resource managers are now working together to put refugia conservation into practice.

Exercise treatment effect modifiers in persistent low back pain: an individual participant data meta-analysis of 3514 participants from 27 randomised controlled trials.

BACKGROUND: Low back pain is one of the leading causes of disability worldwide. Exercise therapy is widely recommended to treat persistent non-specific low back pain. While evidence suggests exercise is, on average, moderately effective, there remains uncertainty about which individuals might benefit the most from exercise. METHODS: In parallel with a Cochrane review update, we requested individual participant data (IPD) from high-quality randomised clinical trials of adults with our two primary outcomes of interest, pain and functional limitations, and calculated global recovery. We compiled a master data set including baseline participant characteristics, exercise and comparison characteristics, and outcomes at short-term, moderate-term and long-term follow-up. We conducted descriptive analyses and one-stage IPD meta-analysis using multilevel mixed-effects regression of the overall treatment effect and prespecified potential treatment effect modifiers. RESULTS: We received IPD for 27 trials (3514 participants). For studies included in this analysis, compared with no treatment/usual care, exercise therapy on average reduced pain (mean effect/100 (95% CI) -10.7 (-14.1 to -7.4)), a result compatible with a clinically important 20% smallest worthwhile effect. Exercise therapy reduced functional limitations with a clinically important 23% improvement (mean effect/100 (95% CI) -10.2 (-13.2 to -7.3)) at short-term follow-up. Not having heavy physical demands at work and medication use for low back pain were potential treatment effect modifiers-these were associated with superior exercise outcomes relative to non-exercise comparisons. Lower body mass index was also associated with better outcomes in exercise compared with no treatment/usual care. This study was limited by inconsistent availability and measurement of participant characteristics. CONCLUSIONS: This study provides potentially useful information to help treat patients and design future studies of exercise interventions that are better matched to specific subgroups. PROTOCOL PUBLICATION: https://doi.org/10.1186/2046-4053-1-64.

Pilot study evaluating the monitoring of canine diabetes mellitus in primary care practice.

OBJECTIVES: This study aimed to describe how canine diabetes mellitus (CDM) is monitored in primary care practice (PCP) and to report outcomes. DESIGN: Retrospective case review. SETTING: PCP. PARTICIPANTS: 40 dogs of 22 different pedigrees and five crossbreeds. Median age at diagnosis was nine years and six months (eight years six months to 10 years five months). Dogs were diagnosed with CDM between January 1, 2008 and December 30, 2012 and remained with the practice to the study end or until death. PRIMARY AND SECONDARY OUTCOME MEASURES: Stability achievement and death or euthanasia. Consultations for each dog were identified and recorded through records collected from the PCP (January 1, 2008 to December 30, 2012). RESULTS: A median of three consultations per dog occurred in the first month, subsequently falling to a median of one consultation every 19 days thereafter. After the first month postdiagnosis, weight and single blood glucose concentrations were most frequently recorded at 66.8 and 42 per cent of consultations respectively and a blood glucose curve was performed infrequently (17.4 per cent). Serum biochemistry was measured at 8 per cent of consultations and urine culture at only 0.8 per cent. Median survival time (MST) for all dogs was eight months (2-21 months). Eighteen dogs stabilised within three months of diagnosis and their MST was 20.5 months, (10.25-25.75 months), significantly longer than the 22 dogs not achieving stability within three months (MST 2.5 months, 0-5.5 months) (P<0.001). Those dogs not surviving beyond the first month had significantly fewer consultations than those still alive (P<0.005). CONCLUSIONS: This pilot study indicates dogs with CDM managed solely in PCP experience limited monitoring tests and have lower MST than reported in the literature. Recruitment of a larger cohort of CDM cases from a larger number of PCP will help determine whether these results accurately represent this demographic and verify if infrequent testing is associated with a poor outcome. Importantly, prospective evaluation of decision-making around monitoring CDM in PCP is required, to help determine the effectiveness and feasibility of more frequent monitoring strategies, such as those recommended by the American Animal Hospital Association, particularly to influence MST.

Inflammation Resolution and the Induction of Granulocyte Apoptosis by Cyclin-Dependent Kinase Inhibitor Drugs.

Inflammation is a necessary dynamic tissue response to injury or infection and it's resolution is essential to return tissue homeostasis and function. Defective or dysregulated inflammation resolution contributes significantly to the pathogenesis of many, often common and challenging to treat human conditions. The transition of inflammation to resolution is an active process, involving the clearance of inflammatory cells (granulocytes), a change of mediators and their receptors, and prevention of further inflammatory cell infiltration. This review focuses on the use of cyclin dependent kinase inhibitor drugs to pharmacologically target this inflammatory resolution switch, specifically through inducing granulocyte apoptosis and phagocytic clearance of apoptotic cells (efferocytosis). The key processes and pathways required for granulocyte apoptosis, recruitment of phagocytes and mechanisms of engulfment are discussed along with the cumulating evidence for cyclin dependent kinase inhibitor drugs as pro-resolution therapeutics.

Relationship between vitamin D status and leukocytes in hospitalised cats.

Objectives Vitamin D deficiency, as assessed by serum 25-hydroxyvitamin D (25[OH]D) concentrations, has been linked to markers of systemic inflammation in human and canine medicine. However, the relationship between vitamin D status and inflammation has not been previously investigated in cats. The aim of this study was to examine the relationship between serum 25(OH)D concentrations and leukocyte counts in hospitalised sick cats. Methods Serum 25(OH)D concentrations and haematology profiles were measured in 170 consecutive hospitalised sick cats. A binary logistical regression model examined the relationship between serum 25(OH)D concentration, age, sex, breed and neutrophil, monocyte, eosinophil and lymphocyte counts. Results Cats with neutrophilia had lower serum 25(OH)D concentrations than cats with neutrophil concentrations below the upper limit of the reference interval (RI). There were no differences in serum 25(OH)D concentrations in cats with monocyte, lymphocyte or eosinophil counts above their respective RI compared with cats with counts below the upper limit of the RI. Conclusions and relevance Hospitalised cats with a neutrophil count above the RI had lower vitamin D status. There is a need to establish whether lower vitamin D status is a cause or consequence of increased neutrophil counts.

IMAGING DIAGNOSIS-A CASE OF SPONTANEOUS HEPATIC PORTAL VEIN GAS IN AN 11-MONTH-OLD WEST HIGHLAND WHITE TERRIER.

An 11-month-old female entire West Highland White Terrier presented for chronic diarrhea with acute deterioration in demeanor and progression to systemic inflammatory response syndrome. Transcutaneous abdominal ultrasonography identified colonic ulceration and secondary mucosal gas. Suspected hepatic portal vein gas and hepatic parenchyma gas were also visualized. The patient was stabilized and managed for ulcerative colitis. Based on endoscopic biopsies, the dog was diagnosed with severe, chronic, pyogranulomatous colitis. On repeat ultrasonographic evaluation the portal vein and hepatic gas had resolved but the patient deteriorated and was ultimately euthanized due to sepsis.