Macrophage-derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection.

The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.

5-Years Analysis of Effectivity and Toxicity of Ultra-Hypofractionated Proton Radiotherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer-A Retrospective Analysis.

BACKGROUND: We retrospectively analyzed the 5-year biochemical disease-free survival (bDFS) and occurrence of late toxicity in prostate cancer patients treated with pencil beam scanning (PBS) proton radiotherapy. METHODOLOGY: In the period from January 2013 to June 2018, 853 patients with prostate cancer were treated with an ultra-hypofractionated schedule (36.25 GyE/five fractions). The mean PSA value was 6.7 (0.7-19.7) µg/L. There were 318 (37.3%), 314 (36.8%), and 221 (25.9%) patients at low (LR), favorable intermediate (F-IR), and unfavorable intermediate risk (U-IR), respectively. Neoadjuvant hormonal therapy was administered to 197 (23.1%) patients, and 7 (0.8%) patients had adjuvant hormonal therapy. The whole group of patients reached median follow-up time at 62.7 months, and their mean age was 64.8 (40.0-85.7) years. The bDFS rates and late toxicity profile were evaluated. RESULTS: Median treatment time was 10 (7-38) days. Estimated 5-year bDFS rates were 96.5%, 93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk groups, respectively. Cumulative late toxicity (CTCAE v4.0) of G2+ was as follows: gastrointestinal (GI)-G2: 9.1%; G3: 0.5%; genitourinary (GU)-G2: 4.3%, and no G3 toxicity was observed. PSA relapse was observed in 58 (6.8%) patients: 16 local, 22 lymph node, 4 bone recurrences, and 10 combined sites of relapse were detected. Throughout the follow-up period, 40 patients (4.7%) died, though none due to prostate cancer. CONCLUSION: Ultra-hypofractionated proton beam radiotherapy is an effective treatment for low- and favorable intermediate-risk prostate cancer, with long-term bDFS rates comparable to other techniques. It is promising for unfavorable intermediate-risk prostate cancer and has acceptable long-term GI and favorable GU toxicity.

The Impact of Subclinical Hypothyroidism on the Quality of Life During Pregnancy: Mapping 5-Level Version of EQ-5D and ThyPRO-39.

OBJECTIVES: To describe how subclinical hypothyroidism (SubHypo) influences the quality of life (QoL) during pregnancy. METHODS: In primary data collection (NCT04167423), thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibodies, generic quality of life (QoL; 5-level version of EQ-5D [EQ-5D-5L]), and disease-specific QoL (ThyPRO-39) were measured among pregnant women. SubHypo during each trimester was defined according to the 2014 European Thyroid Association guidelines (TSH > 2.5, 3.0, and 3.5 IU/L, respectively; with normal FT4). Path analysis described relationships and tested mediation. Linear ordinary least squares, beta, tobit, and two-part regressions were used to map ThyPRO-39 and EQ-5D-5L. Alternative SubHypo definition was tested in sensitivity analysis. RESULTS: A total of 253 women at 14 sites (31 ± 5 years old, 15 ± 6 weeks pregnant) completed the questionnaires. Sixty-one (26%) had SubHypo and differed from 174 (74%) euthyroid women in smoking history (61% vs 41%), primiparity (62% vs 43%) and TSH level (4.1 ± 1.4 vs 1.5 ± 0.7 mIU/L, P < .001). EQ-5D-5L utility in SubHypo (0.89 ± 0.12) was lower than that in euthyroid (0.92 ± 0.11; P = .028) even after adjustment (difference -0.04, P = .033), whereas ocular (P = .001, ThyPRO-39), cognitive symptoms (P = .043), anxiety (P < .0001), and the composite score were higher. The impact of SubHypo on utility was mediated by anxiety. Results were confirmed by sensitivity analysis. Final mapping equation (ordinary least squares) includes goiter symptoms, anxiety, upset stomach, composite score (ThyPRO-39), FT4 levels, and week of pregnancy (determination coefficient 0.36). CONCLUSION: This is the first QoL mapping of SubHypo during pregnancy and the first evidence that SubHypo is associated with a negative impact on QoL. The effect is mediated by anxiety. EQ-5D-5L utilities can be generated based on ThyPRO-39 scores collected in pregnant euthyroid and patients with SubHypo.

Patient-reported symptoms are a more reliable predictor of the societal burden compared to established physician-reported activity indices in inflammatory bowel disease: a cross-sectional study.

BACKGROUND: The societal burden of inflammatory bowel diseases (IBD) is not well documented, and further studies are needed to quantify the costs of the disease state. Thus, the aim was to estimate the societal burden and identify its predictors. METHODS: A cross-sectional questionnaire-based study complemented by objective data from patient medical records was performed for patients with Crohn's disease (CD) and ulcerative colitis (UC). RESULTS: We analyzed data from 161 patients (CD: 102, UC: 59). The overall work impairment reached 15.4%, 11.2% vs. 28.8% without/with self-reported symptoms (p = 0.006). Daily activity impairment was 19.3%, 14.1% vs. 35.6% (p < 0.001). The disability pension rate was 28%, 23% vs. 44% (p = 0.012). The total productivity loss due to absenteeism, presenteeism, and disability amounted to 7,673 €/patient/year, 6,018 vs. 12,354 €/patient/year (p = 0.000). Out-of-pocket costs amounted to 562 €/patient/year, 472 vs. 844 €/patient/year (p = 0.001). Self-reported symptoms were the strongest predictor of costs (p < 0.001). CONCLUSION: We found a high societal burden for IBD and a significant association between patient-reported disease symptoms and work disability, daily activity impairment, disability pensions, and out-of-pocket costs. Physician-reported disease activity is not a reliable predictor of costs except for out-of-pocket expenses.

Time in remission as an alternative outcome measure for rheumatoid arthritis: a 10-year prospective study of 2618 new users of anti-TNF.

OBJECTIVE: Achieving targeted disease activity (DA) is the primary therapeutic strategy in RA. Point measurements of DA are done at out-patient visits, however true DA between visits remains unobserved. This study sought to describe and validate a new outcome measure, i.e. time in remission (TIR). METHODS: Patients were enrolled in the Czech ATTRA-RA registry. TIR was calculated using linear interpolation of the DAS28-ESR determined at outpatient visits. Correlation coefficients were computed between TIR and DAS28-CRP, HAQ, Simple Disease Activity Index (SDAI), patient global assessment (PGA) and physician global assessment (PhGA). Using logistic regression, TIR was used as a predictor of remission (SDAI ≤3.3) and non-disability (HAQ <0.5). The predictive value of TIR was compared with point and sustained remission using the cross-validated area under receiver-operating curves. RESULTS: Since 2010, 2618 RA patients started anti-TNF therapy and were followed until 2020 or until treatment discontinuation. During the first 6 months of therapy, 56% of patients had no remission (TIR = 0), and 22% of patients reached sustained remission (TIR = 1), while 22% of patients had point remissions with 0 < TIR < 1. EULAR good responders and moderate/non-responders spent 64 ± 42% and 6 ± 18% of time in remission, respectively. The mean TIR grew during the follow-up and was correlated with DAS28-CRP, SDAI, HAQ, PGA, and PhGA (P < 0.0001). TIR at 3 and 6 months predicted remission (SDAI ≤3.3) and non-disability (HAQ <0.5) at 13 and 19 months better than point or sustained remission. CONCLUSIONS: TIR is an intuitive way of estimating unobserved DA between scheduled visits; its calculation only requires two consecutive DA values (https://www.medevio.cz/tir-calculator/). TIR is a valid predictor of RA outcomes.

Health-related quality of life in women with autoimmune thyroid disease during pregnancy and postpartum: systematic review including 321,850 pregnancies.

BACKGROUND: Utilities of the general population or expert estimates have been used for all published cost-effectiveness analyses of screening for thyroid disorders in pregnancy. METHODS: A systematic review CRD42019120897 of studies with patient-reported outcomes (PRO) and laboratory evidence of thyroid function/autoimmunity was conducted using PubMed, Cochrane Central, EconLit, SocIndex, DARE, NHS EEDS, Annual Reviews, and CINAHL. Quality was assessed using Joanna Briggs Institute appraisal tool. RESULTS: Of 664 abstracts screened, we analyzed 97 full texts. All studies describing the impact of thyroid disease on the generic QoL excluded pregnant and postpartum women. 21 reports of acceptable quality (321,850 pregnancies) determined depression and anxiety with validated tools and/or reported subjective symptoms. During pregnancy, contradictory conclusions were published on the impact of thyroid disease on PRO. Postpartum, antithyroid antibodies coincide with alexithymia and depression, postpartum thyroiditis negatively impacts mood. No conclusion could be drawn on the impact of thyroid hormonal levels. CONCLUSIONS: The generic QoL in autoimmune thyroid disease during pregnancy has never been described, which represents an obstacle for the construction of economic models. We found contradictory information on the impact of thyroid disease on depression, anxiety, and specific symptoms.

Smoking in women with chronic vaginal discomfort is not associated with decreased abundance of Lactobacillus spp. but promotes Mobiluncus and Gardnerella spp. overgrowth - secondary analysis of trial data including microbio-me analysis.

BACKGROUND: Smoking is considered a risk factor for bacterial vaginosis. It is currently unknown which parameters of the vaginal environment are affected and how smoking triggers the disease. AIM OF THE STUDY: The primary objective is to estimate the effect size of smoking on vaginal pH and the Nugent score in patients with chronic vulvovaginal discomfort prior to the development of episode of vaginosis. The secondary goal is to investigate the effect of smoking on individual microscopic parameters of the vaginal environment and on subjectively reported symptoms of vaginal discomfort. METHODS: Smoking reported by patients was tested as a predictor, using multivariate logistic and ordinal logistic regression analysis on a dataset from the first visit of a randomized trial NCT04171947, which enrolled patients with intermediate vaginal environment. We tested the primary hypothesis (odds ratio (OR) for vaginal pH > 4.5 and Nugent score > 3 in smokers) at the significance level á = 5%. For exploratory analyses of the effect of smoking on the parameters of the vaginal environment, á was corrected as per Bonferoni. RESULTS: In a cross-sectional sample of 250 women after adjusting for other risk factors, smoking had an impact on the Nugent score (OR = 3.3 (1.3-8.5), P = 0.011), while pH was not affected (OR = 1.2 (0.5-2.8), P = 0.698). Smoking was associated with the prevalence of clue cells (P < 0.000), Gardnerella spp. (P = 0.001) and Mobiluncus spp. (P = 0.001), while the prevalence of Lactobacillus remained unchanged (P = 0.049). CONCLUSION: Contrarily to common assumptions, vaginal Lactobacillus is not directly affected by smoking, which rather promotes the growth of bacteria of Gardnerella and Mobiluncus spp. Given that other parameters remained unaffected, it appears that smoking leads to vaginal dysbio-sis by creating specific favourable conditions for these two opportunistic  pathogens.

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research.

Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. Although the origin of these metabolic syndromes has not been fully comprehended yet, a growing body of evidence indicates their possible interconnection with the acute and chronic activation of an innate immune response. Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation to provide them with nutrients and thus support the immune function. That anticipates the involvement of macrophage-derived systemic factors mediating the inter-organ signaling between macrophages and central energy-storing organs. Although it is crucial to coordinate the macrophage cellular metabolism with systemic metabolic changes during the acute phase of bacterial infection, the action of macrophage-derived factors may become maladaptive if chronic or in case of infection by an intracellular pathogen. We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. The adoption of aerobic glycolysis by bactericidal macrophages as well as the induction of insulin resistance by macrophage-derived factors are conserved between insects and mammals. Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.

Ultrahypofractionated Proton Radiation Therapy in the Treatment of Low and Intermediate-Risk Prostate Cancer-5-Year Outcomes.

PURPOSE: To analyze the 5-year biochemical disease-free survival (bDFS) and late toxicity profile in patients with prostate cancer treated with pencil beam scanning (PBS) proton radiation therapy. METHODS AND MATERIALS: Between January 2013 and March 2016, 284 patients with prostate cancer were treated using intensity modulated proton therapy (IMPT), with an ultrahypofractionated schedule (36.25 GyE in 5 fractions). Five patients were immediately lost from follow-up and thus were excluded from analysis. Data for 279 patients were prospectively collected and analyzed with a median follow-up time of 56.5 (range, 3.4-87.5) months. The mean age at time of treatment was 64.5 (40.1-85.7) years, and the median prostate-specific antigen (PSA) value was 6.35 µg/L (0.67-17.3 µg/L). A total of 121 (43.4%) patients had low-risk, 125 patients (44.8%) had favorable, and 33 (11.8%) unfavorable intermediate-risk cancer. In addition, 49 (17.6%) patients underwent neoadjuvant hormonal therapy, and no patients had adjuvant hormonal therapy. bDFS and late toxicity profiles were evaluated. RESULTS: The median treatment time was 9 days (range, 7-18 days). The 5-year bDFS was 96.9%, 91.7%, and 83.5% for the low-, favorable, and unfavorable intermediate-risk group, respectively. Late toxicity (Common Terminology Criteria for Adverse Events v.4) was as follows: gastrointestinal: grade 1, 62 patients (22%), grade 2, 20 patients (7.2%), and grade 3, 1 patient (0.36%); genitourinary: grade 1, 80 patients (28.7%), grade 2, 14 patients (5%), and grade 3, 0 patients. PSA relapse was observed in 17 patients (6.1%), and lymph node or bone recurrence was detected in 11 patients. Four (1.4%) local recurrences were detected. Nine patients (3.2%) died of causes unrelated to prostate cancer. No deaths related to prostate cancer were reported. CONCLUSION: Ultrahypofractionated proton beam radiation therapy for prostate cancer is effective with long-term bDFS comparable with other fractionation schedules and with minimal serious long-term GI and GU toxicity.

Cost-Effectiveness Analysis of Parenteral Methotrexate for the Treatment of Crohn's Disease.

BACKGROUND: Despite worldwide use of parenteral methotrexate (pMTX), health economic evidence for its use in Crohn's disease (CD) is limited. The low price of this generic drug has removed any commercial incentive to further invest in research. However, there is an unmet need for treatment of mild-to-moderate CD, since biological/targeted therapies are usually reserved for patients with more severe disease due to the higher costs of these treatments. OBJECTIVE: To evaluate the cost-effectiveness of pMTX compared to the standard of care (SOC, i.e., high doses of oral corticosteroids (hdCS) followed by gradual tapering) for the treatment of mild-to-moderate CD in the Czech Republic. METHODS: We developed a 3-year Markov model with a 1-week cycle length comprising five health states. The model projected quality-adjusted life-years (QALYs) and costs from the healthcare payers' perspective. Efficacy data were obtained from a systematic literature review of clinical trials and extrapolated using survival analysis. RESULTS: Over a 3-year time-horizon, pMTX yields additional 0.111 QALYs (1.798 vs. 1.687) at an additional cost of €513 (€3087 vs. €2574), with an incremental deterministic (probabilistic) cost-effectiveness ratio of €4627 (€4742)/QALY, far below the willingness-to-pay (WTP) threshold (≈ €47,000/QALY). The probabilistic sensitivity analysis showed that the probability of pMTX being cost-effective was 100%. A one-way sensitivity and scenario analysis confirmed the robustness of the base-case result. CONCLUSION: Parenteral MTX proved to be cost-effective in patients with mild-to-moderate CD. This is the first published cost-effectiveness analysis of pMTX for this indication. It also shows an example of a lack of valuation of generic therapy despite its cost-effectiveness and a clear benefit to the healthcare system.

Outcomes According to MSKCC Risk Score with Focus on the Intermediate-Risk Group in Metastatic Renal Cell Carcinoma Patients Treated with First-Line Sunitinib: A Retrospective Analysis of 2390 Patients.

BACKGROUND: The Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model has been widely used for the prediction of the outcome of metastatic renal cell carcinoma (mRCC) patients treated with systemic therapies, however, data from large studies are limited. This study aimed at the evaluation of the impact of the MSKCC score on the outcomes in mRCC patients treated with first-line sunitinib, with a focus on the intermediate-risk group. METHODS: Clinical data from 2390 mRCC patients were analysed retrospectively. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analysed according to the MSKCC risk score. RESULTS: ORR, median PFS, and OS for patients with one risk factor were 26.7%, 10.1, and 28.2 months versus 18.7%, 6.2, and 16.2 months, respectively, for those with two risk factors (ORR: p = 0.001, PFS: p < 0.001, OS: p < 0.001). ORR, median PFS, and OS were 33.0%, 17.0, and 44.7 months versus 24.1%, 9.0, and 24.1 months versus 13.4%, 4.5, and 9.5 months in the favourable-, intermediate-, and poor-risk groups, respectively (ORR: p < 0.001, PFS: p < 0.001, OS: p < 0.001). CONCLUSIONS: The results of the present retrospective study demonstrate the suitability of the MSKCC model in mRCC patients treated with first-line sunitinib and suggest different outcomes between patients with one or two risk factors.

Short-term response in new users of anti-TNF predicts long-term productivity and non-disability: analysis of Czech ATTRA ankylosing spondylitis biologic registry.

Objectives: To assess the role of short-term response to first anti-TNF in long-term prediction of disability.Methods: In nationwide registry ATTRA, we identified ankylosing spondylitis patients starting anti-TNF between 01/2003 and 12/2016. Full disability and work impairment (WI; WPAI questionnaire) were predicted via the Cox- and lagged-parameter mixed-effect regression.Results: 2,274 biologicals-naïve patients newly indicated to anti-TNF were prospectively followed (6,333 patient-years; median follow-up 1.9 years). Reaching BASDAI < 4 (77.4%) and ASDAS-CRP < 2.1 (61.1%) after 3 months of anti-TNF both decreased the risk of future disability by ≈2.5-fold. ASDAS-CRP < 2.1 predicted non-disability better than BASDAI < 4 & CRP < 5 mg/L (p = 0.032). BASDAI < 4 & CRP < 5 mg/L was comparable to BASDAI < 4 (p = 0.941) and to BASDAI change by >50% or by >2 points (p = 0.902). ASDAS-CRP change >1.1 and >2.0 both failed to predict non-disability. Once on anti-TNF therapy, the strongest predictor of WI was Pain (SF36). Yearly increase in indirect costs remains below €3,000 in those reaching ASDAS-CRP < 2.1.Conclusions: Low disease activity measured by ASDAS-CRP ≤ 2.1 should be used to measure the outcome of new anti-TNF therapy. Continuous WI could be decreased through pain management.

Propensity Score Weighting Using Overlap Weights: A New Method Applied to Regorafenib Clinical Data and a Cost-Effectiveness Analysis.

BACKGROUND: In situations of markedly different population characteristics and weak population overlap, inverse propensity score (PS) weights suffer from extreme values. The new propensity score weighting method using overlap weights (PSOW) overcomes this limitation by estimating the overlap population at the point of highest mutual overlap, thus may be preferred to other balancing methods (trimming, target, or inverse weights) in some situations. OBJECTIVES: To evaluate the performance of PSOW with regorafenib effectiveness data from previously treated patients with metastatic colorectal cancer based on the Czech national registry data (regorafenib) and a global phase 3 randomized clinical trial (RCT) (placebo). The second goal was to assess the cost-effectiveness of regorafenib versus placebo. METHODS: Individual data on progression-free survival (PFS)/overall survival (OS) were balanced via PSOW for age, sex, Eastern Cooperative Oncology Group performance status, number of treatment lines, metastatic colorectal cancer location, KRAS mutation, and time from metastases estimated using logistic regression. The weighted Kaplan-Meier PFS/OS curves were used in a 3-state partitioned survival model. The R code is provided. RESULTS: In comparison with target or inverse PS weights, PSOW showed remarkable performance measured by effective sample size and PS weight distribution or extreme weights despite the weak overlap between the registry and RCT. In the registry or RCT cohort, regorafenib provided better survival compared with the RCT. The new PSOW hazard ratio for OS was 0.53 (RCT: 0.79), which is conservative compared with inverse or target weights with a hazard ratio of 0.44 and 0.27, respectively. CONCLUSION: This is the first use of PSOW for clinical data and cost-effectiveness analysis. It is promising in cases of weak or small population overlap and makes pharmacoeconomic modeling, in such cases, feasible.

Drosophila macrophages switch to aerobic glycolysis to mount effective antibacterial defense.

Macrophage-mediated phagocytosis and cytokine production represent the front lines of resistance to bacterial invaders. A key feature of this pro-inflammatory response in mammals is the complex remodeling of cellular metabolism towards aerobic glycolysis. Although the function of bactericidal macrophages is highly conserved, the metabolic remodeling of insect macrophages remains poorly understood. Here, we used adults of the fruit fly Drosophila melanogaster to investigate the metabolic changes that occur in macrophages during the acute and resolution phases of Streptococcus-induced sepsis. Our studies revealed that orthologs of Hypoxia inducible factor 1α (HIF1α) and Lactate dehydrogenase (LDH) are required for macrophage activation, their bactericidal function, and resistance to infection, thus documenting the conservation of this cellular response between insects and mammals. Further, we show that macrophages employing aerobic glycolysis induce changes in systemic metabolism that are necessary to meet the biosynthetic and energetic demands of their function and resistance to bacterial infection.

Yeast glucan particles enable intracellular protein delivery in Drosophila without compromising the immune system.

Glucan particles derived from yeast have been recently proposed as potential drug delivery carriers. Here, we demonstrate the potential of glucan particles for protein delivery in vivo, using the insect Drosophila melanogaster as a model organism. By employing genetic tools, we demonstrate the capacity of yeast glucan particles to spread efficiently through the Drosophila body, to enter macrophages and to deliver an active transcription factor protein successfully. Moreover, the glucan particles were nontoxic and induced only minimal immune response. The injection of glucan particles did not impair the ability of Drosophila to fight and survive infection by pathogenic bacteria. From this study, Drosophila emerges as an excellent model to test and develop drug delivery systems based on glucan particles, specifically aimed to regulate macrophages.

Molecular regulations of metabolism during immune response in insects.

Mounting an immune response is an energy-consuming process. Activating immune functions requires the synthesis of many new molecules and the undertaking of numerous cellular tasks and it must happen rapidly. Therefore, immune cells undergo a metabolic switch, which enables the rapid production of ATP and new biomolecules. Such metabolism is very nutrient-demanding, especially of glucose and glutamine, and thus the immune response is associated with a systemic metabolic switch, redirecting nutrient flow towards immunity and away from storage and consumption by non-immune processes. The immune system during its activation becomes privileged in terms of using organismal resources and the activated immune cells usurp nutrients by producing signals which reduce the metabolism of non-immune tissues. The insect fat body plays a dual role in which it is both a metabolic organ, storing energy and providing energy to the rest of the organism, but also an organ important for humoral immunity. Therefore, the internal switch from anabolism to the production of antimicrobial peptides occurs in the fat body during infection. The mechanisms regulating metabolism during the immune response ensure adequate energy for an effective response (resistance) but they must be properly regulated because energy is not unlimited and the energy needs of the immune system thus interfere with the needs of other physiological traits. If not properly regulated, the immune response may in the end decrease fitness via decreasing disease tolerance.

Mammaplasty and reduction mammaplasty - significant change in quality of life.

Breast shape, symmetry and size significantly influence womens psyche, if there is any deviation in generally recognized standard. Currently cosmetic breast defects belong to most common problems in the field of the aesthetic surgery. The target of the mammaplasty is the restoration of the shape, volume and position of the nippleareolar complex. One of the most important factors of the well-done surgery is the protection of the nippleareolar complex. The knowledge of the arterial blood supply and the venous drainage of the breast is the integral part of the successful surgery. In aesthetic breast surgeries its always necessary not to concentrate just at health aspect of mammaplasty, but mainly at the its psychological aspect, which has a significant role in whole process. Keywords: mammaplasty, breast reduction, aesthetic surgery, nippleareolar complex.

Highly Innovative Drug Program in the Czech Republic: Description and Pharmacoeconomic Results-Cost-Effectiveness and Budget Impact Analyses.

BACKGROUND: Highly innovative drugs (HIDs) can be granted 2 to 3 years of temporary reimbursement (TR) to provide timely patient access and to collect real-world evidence through registries in the Czech Republic. A TR applicant does not need to comply with cost-effectiveness (CE) requirements and the willingness-to-pay threshold. It is only when mandatory transition to permanent reimbursement (PR) status occurs does the drug need to comply with CE and willingness-to-pay requirements. OBJECTIVES: To describe and evaluate the HID program in the Czech Republic by analyzing the pharmacoeconomic results when a drug starts with TR status and transitions to PR status. METHODS: The study was a retrospective analysis of reimbursement decisions of HIDs. All drugs approved for TR (valid from January 2008 to January 2018) were identified. A description of the HIDs and their pharmacoeconomic results were analyzed. RESULTS: Fifty TR drugs were identified. Most (68%) were oncology drugs and 44% were orphan drugs. After the expiration of their TR status, 83% were successfully transitioned to PR status. Cost-utility analysis was used to support CE results in 42% of the TR drugs. The mean incremental cost-effectiveness ratio (cost/quality-adjusted life-year) of drugs that entered TR status was €97,868. When the time came for transition to PR status, the mean incremental cost-effectiveness ratio was €34,086 (lower by 65%). Net budget impact increased by 3% and decreased by 25% in the first and fifth years, respectively, after applying for PR. CONCLUSIONS: This analysis provides better insight into the HID program for costly innovative drugs over a 10-year follow-up. A successful transition to PR status was observed for most of the HIDs (83%).

Extracellular adenosine modulates host-pathogen interactions through regulation of systemic metabolism during immune response in Drosophila.

Phagocytosis by hemocytes, Drosophila macrophages, is essential for resistance to Streptococcus pneumoniae in adult flies. Activated macrophages require an increased supply of energy and we show here that a systemic metabolic switch, involving the release of glucose from glycogen, is required for effective resistance to S. pneumoniae. This metabolic switch is mediated by extracellular adenosine, as evidenced by the fact that blocking adenosine signaling in the adoR mutant suppresses the systemic metabolic switch and decreases resistance to infection, while enhancing adenosine effects by lowering adenosine deaminase ADGF-A increases resistance to S. pneumoniae. Further, that ADGF-A is later expressed by immune cells during infection to regulate these effects of adenosine on the systemic metabolism and immune response. Such regulation proved to be important during chronic infection caused by Listeria monocytogenes. Lowering ADGF-A specifically in immune cells prolonged the systemic metabolic effects, leading to lower glycogen stores, and increased the intracellular load of L. monocytogenes, possibly by feeding the bacteria. An adenosine-mediated systemic metabolic switch is thus essential for effective resistance but must be regulated by ADGF-A expression from immune cells to prevent the loss of energy reserves and possibly to avoid the exploitation of energy by the pathogen.

Mapping Quality of Life (EQ-5D) from DAPsA, Clinical DAPsA and HAQ in Psoriatic Arthritis.

BACKGROUND: Clinical trials and observational studies lacking measures of health-related quality of life (QoL) are often inapplicable when conducting cost-effectiveness analyses using quality-adjusted life-years (QALYs). The only solution is to map QoL ex post from additionally collected clinical outcomes and generic QoL instruments. Nonetheless, mapping studies are absent in psoriatic arthritis (PsA). METHODS: In this 2-year, prospective, multicentre, non-interventional study of PsA patients, EQ-5D and key clinical parameters such as Disease Activity in PsA (DAPsA), clinical DAPsA (cDAPsA; DAPsA without C-reactive protein [CRP]), and Health Assessment Questionnaire disability index (HAQ) were collected. We employed a linear mixed-effect regression model (ME) of the longitudinal dataset to explore the best predictors of QoL. RESULTS: A total of 228 patients were followed over 873 appointments/observations. DAPsA, cDAPsA and HAQ were stable and highly significant predictors of EQ-5D utilities in both cross-sectional and longitudinal analyses. The best prediction was provided using a linear ME with HAQ and cDAPsA or DAPsA. A HAQ increase of 1 point represented a decrease in EQ-5D by -0.204 or -0.203 (p < 0.0001); a one-point increase in cDAPsA or DAPsA dropped EQ-5D equally by -0.005 (p < 0.0001). The ME revealed steeper and more accurate association compared with cross-sectional regressions or non-linear models/transformations. CONCLUSIONS: This is the first mapping study conducted in PsA and we hope that our study will encourage further mapping studies in PsA. The results showed that in cases where CRP is absent, cDAPsA provides similar results to DAPsA in predicting QoL.