Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling

The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases

Acceptability of a physiotherapeutic pain school treatment in trauma-affected populations in the Middle Eastern & Northern African region

Introduction: The aim of this study was to evaluate the acceptability of a physiotherapeutic pain treatment (Pain School), focusing on patient education, physical exercises and self-reliance, and a capacity building program developed for MENA based physiotherapists working with pain and trauma-affected populations.Method: The perceived benefits and challenges of the physiotherapy Pain School treatment were evaluated through qualitative interviews with seven physiotherapists participating in the Pain School training program. The acceptability and feasibility of the treatment manual and training program of the physiotherapists was evaluated. The preliminary results of the Pain School treatment were also analyzed with a paired-sample t-test pre- and post-treatment in 38 patients suffering from persistent pain and trauma-related stress in the MENA region. Results: The qualitative analysis showed good feasibility and high acceptance among the participating physiotherapists of this physiotherapeutic treatment and training program. The pre- to post-treatment evaluation of Pain School, also gave an indication of positive treatment effects. Monitoring and evaluation of treatment was found useful, but indications of mental health status were evaluated to be missing. Due to other limitations, such as author biases (authors carrying out training, interviews and analyzing qualitative results) and no control group, the results from this study do not provide a final conclusion on the training program nor treatment effects. Nevertheless, this study is an important first step to offer evidence-based standardized treatment for pain and trauma-affected populations in the MENA region

Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs

BACKGROUND: Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidism has been shown to correlate with decreased von Willebrand factor antigen and potentially increased bleeding tendency. Whether increased gastro intestinal bleeding risk is exacerbated due to changes in the hemostatic balance is unknown. The aim of this study was to investigate the hemostatic balance in sled dogs before and after exercise and in addition evaluate any correlation to thyroid status. Twenty sled dogs have been assessed in untrained and trained condition and immediately after exercise. The first sample was collected in the autumn following a resting period, and subsequently the dogs were exposed to increased intensity of training. After four months the peak of physical condition was reached and a 68 km long sled pulling exercise was performed. Samples were collected before and immediately after the exercise. Evaluated parameters were: plasma thromboelastographic (TEG) R, SP, α and MA, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, von Willebrand factor (vWf), D-dimer, platelet number, thyroid hormones, hematocrit and C-reactive protein (CRP). RESULTS: Exercise induced an overall hypercoagulable state characterized by significant decreases of TEG R and SP and an increase of α, increased concentrations of plasma vWf and decreased aPTT. In addition, a proinflammatory status was seen by a significant increase of serum CRP concentrations. Thyroid status was confirmed to be hypothyroid as training and exercise induced significant decrease of thyroxin (T4), free thyroxin (fT4) and thyroxin stimulating hormone (TSH) concentrations. Fibrinogen decreased significantly and PT increased. The training-induced changes showed correlation between T4, fT4 and aPTT and correlation between TSH and fibrinogen. Exercise-induced changes showed correlation between T4 and PT. CONCLUSIONS: Exercise was associated with a hypercoagulable state and an increase of vWf concentration in this group of sled dogs. Decreased thyroid hormone concentrations after training and exercise were confirmed, but were associated with increased and not decreased vWf in this group of sled dogs

Cost Effectiveness of Patient Self‑Managed Warfarin Compared with Direct Oral Anticoagulants in Atrial Fibrillation: An Economic Evaluation in a Danish Healthcare Sector Setting

BACKGROUND: Patient self-managed anticoagulant treatment with warfarin (PSM) has been proposed as an alternative to direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF); however, direct evidence on the cost effectiveness of PSM compared with DOACs is lacking. We aimed to evaluate the cost effectiveness of PSM versus DOACs for NVAF patients in the Danish healthcare setting using a model-based cost-utility analysis. METHODS: A cost-utility analysis was performed using a decision-analytic model including two treatment alternatives: continuous PSM and DOACs. The analysis was performed from an extended Danish healthcare sector perspective, including patient-paid costs of medication related to the anticoagulant treatment, with a lifetime horizon. Inputs for the model comprised of probabilities of events, costs in Danish estimates, when possible, and effect in utilities. The probabilities of events are primarily based on real-life data from a direct comparison of PSM and DOACs. The results are presented as the incremental cost-effectiveness ratio (ICER) with an assumed cost-effectiveness threshold of £20,000/quality-adjusted life-year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to investigate the robustness of the results. RESULTS: The base-analysis showed that PSM was dominant, with a decreased cost of £8495 and an increased QALY accumulation of 0.23 per patient (ICER = −£36,935/QALY). All deterministic sensitivity analyses indicated that PSM was dominant or at least cost effective. The probabilistic sensitivity analysis showed that 95% of the iterations were cost effective. CONCLUSIONS: The present study found that PSM is dominant (i.e., both more effective and cost saving) compared with DOACs, adding to the scarce evidence of the comparative cost effectiveness of PSM and DOACs in NVAF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s41669-022-00337-3

Micronutrient intake in relation to all-cause mortality in a prospective Danish cohort

Background: Few studies have considered source-specific micronutrient intake in relation to mortality under the consideration that dietary and supplemental intake could exhibit different effects. Objective: To evaluate the association between intake of vitamin C, E, folate, beta-carotene from diet and supplements, and overall mortality. Furthermore, to examine effect modification by smoking, alcohol intake, and BMI and to investigate if the effect of supplement use differs with dietary micronutrient intake. Methods and Material: In a prospective cohort study of 55,453 middle-aged Danes, information regarding diet, supplement use, and lifestyle was collected through questionnaires. During follow-up, 6,767 deaths were identified and incidence rate ratios (IRRs) of mortality related to micronutrient intake were calculated using Cox proportional hazards models. Results: The present study found no effect of dietary vitamin C, E, folate, or beta-carotene in relation to mortality. In contrast, supplemental folic acid was associated with a significantly increased mortality, whereas no other micronutrient supplement was associated with mortality. Effect modification by smoking and alcohol intake, but not BMI, was suggested in relation to some dietary micronutrients. The effect of supplements did not differ in groups defined by dietary micronutrient intake. Conclusion: This study suggests no effect of dietary micronutrients in relation to overall mortality. Supplemental folic acid was found to be associated with increased mortality, but further studies are required. No other supplemental micronutrient was associated with mortality

Sun Exposure Guidelines and Serum Vitamin D Status in Denmark: The StatusD Study

Little is known on how vitamin D status is affected by adherence to UVB-limiting sun exposure guidelines. Our aim was to investigate the relationship between adherence to the Danish sun exposure guidelines and vitamin D status. In total, 3194 Danes (2625 adults, 569 children) were recruited among the general population, and more than 92% had blood samples taken both autumn and spring. Using linear regression, we associated serum vitamin D concentrations to questionnaire responses on: seeking shade, wearing a sunhat, wearing protective clothing or using sunscreen. The odds ratio (OR) of either low (<25 or 50 nmol/L) or adequate/high (≥50 nmol/L) vitamin D status was examined using logistic regression. For adults, those who always sought shade or wore protective clothing compared to those who did not had lower levels of vitamin D (autumn concentrations for shade: 7.2 nmol/L lower (−11.0–−3.6 nmol/L); for protective clothing: 9.9 nmol/L lower (−13.6–−6.2 nmol/L). Adherence to all four guidelines was also associated with lower vitamin D concentrations (autumn: 9.7 nmol/L lower (−14.3–−5.1 nmol/L). Use of sunscreen was associated with adequate vitamin D status, as those who always sought shade compared to those who did not had an OR (95% CI) of 1.68 (1.25–2.35) of having ≥50 nmol/L during both spring and autumn. No associations were found with wearing a sunhat, and there were no clear associations for children. In conclusion, adherence to the sun exposure guidelines on shade and protective clothing was associated with lower vitamin D status among Danish adults, but not children

Systematic Evaluation of the Metabolic to Mitogenic Potency Ratio for B10-Substituted Insulin Analogues

Background: Insulin analogues comprising acidic amino acid substitutions at position B10 have previously been shown to display increased mitogenic potencies compared to human insulin and the underlying molecular mechanisms have been subject to much scrutiny and debate. However, B10 is still an attractive position for amino acid substitutions given its important role in hexamer formation. The aim of this study was to investigate the relationships between the receptor binding properties as well as the metabolic and mitogenic potencies of a series of insulin analogues with different amino acid substitutions at position B10 and to identify a B10-substituted insulin analogue without an increased mitogenic to metabolic potency ratio. Methodology/Principal Findings: A panel of ten singly-substituted B10 insulin analogues with different amino acid side chain characteristics were prepared and insulin receptor (both isoforms) and IGF-I receptor binding affinities using purified receptors, insulin receptor dissociation rates using BHK cells over-expressing the human insulin receptor, metabolic potencies by lipogenesis in isolated rat adipocytes, and mitogenic potencies using two different cell types predominantly expressing either the insulin or the IGF-I receptor were systematically investigated. Only analogues B10D and B10E with significantly increased insulin and IGF-I receptor affinities as well as decreased insulin receptor dissociation rates displayed enhanced mitogenic potencies in both cell types employed. For the remaining analogues with less pronounced changes i