LIMPRINT: prevalence of chronic edema in health services in Copenhagen, Denmark

Background: The International Lymphedema Framework developed an international study, Lymphedema Impact and Prevalence International (LIMPRINT) to estimate the prevalence and impact of chronic edema in heterogeneous populations. Methods and results: A validation study using the LIMPRINT methodology was undertaken in Denmark. Participants with CO were identified from in-patient services and compared to those identified within a specialist lymphoedema service and 3 primary care settings. Of 452 inpatients available for screening CO was present in 177(39%) and absent in 275(61%). In addition, 723 participants were found from specialist and primary care services (LPCS). In-patients were significantly older and more likely to be underweight or normal weight. They were more likely to suffer from heart failure/IHD (44.6% vs 23.4%, p<0.001) and have neurological problems (18.1% vs 10.9% p=0.009). The inpatient group were nearly all suffering from secondary Lymphoedema and were less likely to have a cancer or venous diagnosis, but more likely to have immobility as the cause of CO (44.0% vs 17.7%, p<0.001). No in-patients had midline CO compared to 30 within LPCS. Fewer in the in-patient group had standard CO treatment (17.1% vs 73.5%, p<0.001) and subjective control of swelling was worse (19.9% vs 66.7%, p<0.001). Whilst the in-patient group experienced fewer acute infections, when they did so, they were more likely to be admitted to hospital for this (78.6% vs 51.0%, p=0.049). Conclusion: The prevalence of CO in inpatient facilities is high and those with CO have multiple comorbidities that vary according to setting. The feasibility study showed the methodology could be adapted for use in different health systems

App-delivered self-management intervention trial selfBACK for people with low back pain: protocol for implementation and process evaluation

Background: Implementation and process evaluation is vital for understanding how interventions function in different settings, including if and why interventions have different effects or do not work at all. Objective: This paper presents the protocol for an implementation and process evaluation embedded in a multicenter randomized controlled trial conducted in Denmark and Norway (the selfBACK project). selfBACK is a data-driven decision support system that provides participants with weekly self-management plans for low back pain. These plans are delivered through a smartphone app and tailored to individual participants by using case-based reasoning methodology. In the trial, we compare selfBACK in addition to usual care with usual care alone. Methods: The aim of this study is to conduct a convergent mixed-methods implementation and process evaluation of the selfBACK app by following the reach, effectiveness, adoption, implementation, and maintenance framework. We will evaluate the process of implementing selfBACK and investigate how participants use the intervention in daily life. The evaluation will also cover the reach of the intervention, health care provider willingness to adopt it, and participant satisfaction with the intervention. We will gather quantitative measures by questionnaires and measures of data analytics on app use and perform a qualitative exploration of the implementation using semistructured interviews theoretically informed by normalization process theory. Data collection will be conducted between March 2019 and October 2020. Results: The trial opened for recruitment in February 2019. This mixed-methods implementation and evaluation study is embedded in the randomized controlled trial and will be collecting data from March 2019 to October 2020; dissemination of trial results is planned thereafter. The results from the process evaluation are expected 2021-2022. Conclusions: This study will provide a detailed understanding of how self-management of low back pain can be improved and how a digital health intervention can be used as an add-on to usual care to support patients to self-manage their low back pain. We will provide knowledge that can be used to explore the possibilities of extending the generic components of the selfBACK system and key drivers that could be of use in other conditions and diseases where self-management is an essential prevention or treatment strategy. Trial Registration: ClinicalTrials.gov NCT03798288; https://www.clinicaltrials.gov/ct2/show/NCT03798288 International Registered Report Identifier (IRRID): DERR1-10.2196/20308

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

BACKGROUND: Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right-ventricular (RV) function are unknown. We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure. METHODS: Wistar rats were subjected to pulmonary trunk banding to induce compensated RV hypertrophy (n = 32) or manifest RV failure (n = 32). Rats without banding served as healthy controls (n = 30). The hearts were excised and perfused in a Langendorff system and subjected to iloprost, treprostinil, epoprostenol, or MRE-269 in increasing concentrations. The effect on RV function was evaluated using a balloon-tipped catheter inserted into the right ventricle. RESULTS: In control hearts, iloprost, treprostinil, and MRE-269 improved RV function. The effect was, however, absent in hearts with RV hypertrophy and failure. Treprostinil and MRE-269 even impaired RV function in hearts with manifest RV failure. CONCLUSIONS: Iloprost, treprostinil, and MRE-269 improved RV function in the healthy rat heart. RV hypertrophy abolished the positive inotropic effect, and in the failing right ventricle, MRE-269 and treprostinil impaired RV function. This may be related to changes in prostanoid receptor expression and reduced coronary flow reserve in the hypertrophic and failing right ventricle

White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment

Objective: Increasing adaptive thermogenesis by stimulating browning in white adipose tissue is a promising method of improving metabolic health. However, the molecular mechanisms underlying this transition remain elusive. Our study examined the molecular determinants driving the differentiation of precursor cells into thermogenic adipocytes. Methods: In this study, we conducted temporal high-resolution proteomic analysis of subcutaneous white adipose tissue (scWAT) after cold exposure in mice. This was followed by loss- and gain-of-function experiments using siRNA-mediated knockdown and CRISPRa-mediated induction of gene expression, respectively, to evaluate the function of the transcriptional regulator Y box-binding protein 1 (YBX1) during adipogenesis of brown pre-adipocytes and mesenchymal stem cells. Transcriptomic analysis of mesenchymal stem cells following induction of endogenous Ybx1 expression was conducted to elucidate transcriptomic events controlled by YBX1 during adipogenesis. Results: Our proteomics analysis uncovered 509 proteins differentially regulated by cold in a time-dependent manner. Overall, 44 transcriptional regulators were acutely upregulated following cold exposure, among which included the cold-shock domain containing protein YBX1, peaking after 24 h. Cold-induced upregulation of YBX1 also occurred in brown adipose tissue, but not in visceral white adipose tissue, suggesting a role of YBX1 in thermogenesis. This role was confirmed by Ybx1 knockdown in brown and brite preadipocytes, which significantly impaired their thermogenic potential. Conversely, inducing Ybx1 expression in mesenchymal stem cells during adipogenesis promoted browning concurrent with an increased expression of thermogenic markers and enhanced mitochondrial respiration. At a molecular level, our transcriptomic analysis showed that YBX1 regulates a subset of genes, including the histone H3K9 demethylase Jmjd1c, to promote thermogenic adipocyte differentiation. Conclusion: Our study mapped the dynamic proteomic changes of murine scWAT during browning and identified YBX1 as a novel factor coordinating the genomic mechanisms by which preadipocytes commit to brite/beige lineage

Structural imaging findings are related to clinical complications in chronic pancreatitis

Background/objectives: Structural pancreatic changes and complications related to chronic pancreatitis are well described, but little is known about their relationship. We aimed to explore the associations between pancreatic morphology and clinical complications in a large chronic pancreatitis cohort. Methods: The Scandinavian Baltic Pancreatic Club database collects registrations on patients with definite or probable chronic pancreatitis according to the M-ANNHEIM diagnostic criteria. In this cross-sectional study, we used multivariate logistic regression analyses to evaluate whether imaging-based structural pancreatic changes were associated with common clinical complications. We adjusted for sex, age, disease duration, current alcohol abuse and current smoking. Results: We included 742 patients with a mean age of 55 years. Among these, 68% were males, 69% had pancreatic exocrine insufficiency, 35% had diabetes, 12% were underweighted and 68% reported abdominal pain. Main pancreatic duct obstruction, severe (i.e. more than 14) calcifications, pancreatic atrophy and parenchymal changes throughout the entire pancreas (continuous organ involvement) were positively associated with pancreatic exocrine insufficiency. Continuous organ involvement and pseudocysts were positively and negatively associated with diabetes, respectively. Pancreatic atrophy and severe calcifications were positively associated with underweight, and severe calcifications were negatively associated with pain. Conclusions: This study shows independent associations between distinct structural changes on pancreatic imaging and clinical complications in chronic pancreatitis. Pancreatic atrophy, severe calcifications and continuous organ involvement may be of particular clinical relevance, and these findings should motivate monitoring of pancreatic function and nutritional status.publishedVersio

The host metabolite D-serine contributes to bacterial niche specificity through gene selection

Escherichia coli comprise a diverse array of both commensals and niche-specific pathotypes. The ability to cause disease results from both carriage of specific virulence factors and regulatory control of these via environmental stimuli. Moreover, host metabolites further refine the response of bacteria to their environment and can dramatically affect the outcome of the host–pathogen interaction. Here, we demonstrate that the host metabolite, D-serine, selectively affects gene expression in E. coli O157:H7. Transcriptomic profiling showed exposure to D-serine results in activation of the SOS response and suppresses expression of the Type 3 Secretion System (T3SS) used to attach to host cells. We also show that concurrent carriage of both the D-serine tolerance locus (dsdCXA) and the locus of enterocyte effacement pathogenicity island encoding a T3SS is extremely rare, a genotype that we attribute to an ‘evolutionary incompatibility’ between the two loci. This study demonstrates the importance of co-operation between both core and pathogenic genetic elements in defining niche specificity

Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis

Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis

An app-delivered self-management program for people with low back pain: protocol for the selfBACK randomized controlled trial.

Background: Low back pain (LBP) is prevalent across all social classes, in all age groups, and across industrialized and developing countries. From a global perspective, LBP is considered the leading cause of disability and negatively impacts everyday life and well-being. Self-management is a recommended first-line treatment, and mobile apps are a promising platform to support self-management of conditions like LBP. In the selfBACK project, we have developed a digital decision support system made available for the user via an app intended to support tailored self-management of nonspecific LBP. Objective: The trial aims to evaluate the effectiveness of using the selfBACK app to support self-management in addition to usual care (intervention group) versus usual care only (control group) in people with nonspecific LBP. Methods: This is a single-blinded, randomized controlled trial (RCT) with two parallel arms. The selfBACK app provides tailored self-management plans consisting of advice on physical activity, physical exercises, and educational content. Tailoring of plans is achieved by using case-based reasoning (CBR) methodology, which is a branch of artificial intelligence. The core of the CBR methodology is to use data about the current case (participant) along with knowledge about previous and similar cases to tailor the self-management plan to the current case. This enables a person-centered intervention based on what has and has not been successful in previous cases. Participants in the RCT are people with LBP who consulted a health care professional in primary care within the preceding 8 weeks. Participants are randomized to using the selfBACK app in addition to usual care versus usual care only. We aim to include a total of 350 participants (175 participants in each arm). Outcomes are collected at baseline, 6 weeks, and 3, 6, and 9 months. The primary end point is difference in pain-related disability between the intervention group and the control group assessed by the Roland-Morris Disability Questionnaire at 3 months. Results: The trial opened for recruitment in February 2019. Data collection is expected to be complete by fall 2020, and the results for the primary outcome are expected to be published in fall 2020. Conclusions: This RCT will provide insights regarding the benefits of supporting tailored self-management of LBP through an app available at times convenient for the user. If successful, the intervention has the potential to become a model for the provision of tailored self-management support to people with nonspecific LBP and inform future interventions for other painful musculoskeletal conditions

Ischemic Heart Disease in Chronic Hepatitis B: A Danish Nationwide Cohort Study

OBJECTIVE: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population. STUDY DESIGN AND SETTING: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model. RESULTS: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91–1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76–1.21). CONCLUSION: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population