Cardiovascular response to different types of acute stress stimulations

Introduction: Stress is an ubiquitous phenomenon in the modern world and one of the major risk factors for cardiovascular disease. Th e aim of our study was to evaluate the eff ect of various acute stress stimuli on autonomic nervous system (ANS) activity, assessed on the basis of heart rate (HRV) and blood pressure (BPV) variability analysis. Materials and Methods: The study included 15 healthy volunteers: 9 women, 6 men aged 20- 30 years (23.3 ± 1.8). ANS activity was assessed by HRV and BPV measurement using Task Force Monitor 3040 (CNSystems, Austria). ECG registration and Blood Pressure (BP) measurement was done 10 minutes at rest, 10 minutes aft er the stress stimulus (sound signal, acoustic startle, frequency 1100 Hz, duration 0.5 sec, at the intensity 95 dB) and 10 minutes aft er the cold pressor test. The cold pressor test (CPT) was done by placing the person’s hand by wrist in ice water (0-4°C) for 120 s. Results: Every kind of stress stimulation (acoustic startle; the CPT) caused changes of HRV indicator values. The time domain HRV analysis parameters (pNN50, RMSSD) decreased aft er acoustic stress and the CPT, but were signifi cantly lower aft er the CPT. In frequency domain HRV analysis, signifi cant diff erences were observed only after the CPT: (LF-RRI 921.23 ms2 vs. 700.09 ms2; p = 0.009 and HF-RRI 820.75 ms2 vs. 659.52 ms2; p = 0.002). Th e decrease of LF-RRI and HF-RRI value aft er the CPT was signifi cantly higher than aft er the acoustic startle (LF-RRI 34% vs. 0.4%, p = 0.022; HF-RRI 19.7% vs. 7% ms2, p = 0.011). The decreased value of the LF and HF components of HRV analysis are indicative of sympathetic activation. Nonlinear analysis of HRV indicated a signifi cant decrease in the Poincare plot SD1 (p = 0.039) and an increase of DFAα2 (p = 0.001) in response to the CPT stress stimulation. The systolic BPV parameter LF/HF-sBP increased significantly after the CPT (2.84 vs. 3.31; p = 0.019) and was higher than aft er the acoustic startle (3.31 vs. 3.06; p = 0.035). Signifi cantly higher values of diastolic BP (67.17 ± 8.10 vs. 69.65 ± 9.94 mmHg, p = 0.038) and median BP (83.39 ± 8.65 vs. 85.30 ± 10.20 mmHg, p = 0.039) were observed in the CPT group than in the acoustic startle group. Conclusions: The Cold Pressor Test has a greater stimulatory effect on the sympathetic autonomic system in comparison to the unexpected acoustic startle stress. Regardless of whether the stimulation originates from the central nervous system (acoustic startle) or the peripheral nervous system (CPT), the final response is demonstrated by an increase in the low frequency components of blood pressure variability and a decrease in the low and high frequency components of heart rate variability

Anti-cytokine targeted therapies for ANCA-associated vasculitis

BACKGROUND: Anti‐neutrophilic cytoplasmic antibodies (ANCA)‐associated vasculitis (AAV) are a group of rare auto‐inflammatory diseases that affects mainly small vessels. AAV includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Anti‐cytokine targeted therapy uses biological agents capable of specifically targeting and neutralising cytokine mediators of the inflammatory response. OBJECTIVES: To assess the benefits and harms of anti‐cytokine targeted therapy for adults with AAV. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), MEDLINE and Embase up to 16 August 2019. We also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials of targeted anti‐cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti‐cytokine therapy of different type or dose. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included four RCTs with a total of 440 participants (mean age 48 to 56 years). We analysed the studies in three groups: 1) mepolizumab (300 mg; three separate injections every four weeks for 52 weeks) versus placebo in participants with relapsing or refractory EGPA; 2) belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised) or etanercept (25 mg twice a week) with standard therapy (median 25 months) versus placebo with standard therapy (median 19 months) in participants with GPA/MPA; and 3) infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m(2) on days 1, 8, 15 and 22) in participants with refractory GPA for up to 12 months. None of the studies were assessed as low risk of bias in all domains: one study did not report randomisation or blinding methods clearly. Three studies were at high risk and one study was at unclear risk of bias for selective outcome reporting. One trial with 136 participants with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow‐up and observed one death in the mepolizumab group (1/68, 1.5%) and none in the placebo group (0/68, 0%) (Peto odds ratio (OR) 7.39, 95% confidence interval (CI) 0.15 to 372.38; low‐certainty evidence). Low‐certainty evidence suggests that more participants in the mepolizumab group had ≥ 24 weeks of accrued remission over 52 weeks compared to placebo (27.9% versus 2.9%; risk ratio (RR) 9.5, 95% CI 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1% mepolizumab versus 1.5% placebo; RR 13.0, 95% CI 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% Cl 4 to 13). Mepolizumab probably decreases risk of relapse (55.8% versus 82.4%; RR 0.68, 95% CI 0.53 to 0.86; NNTB 4, 95% CI 3 to 9; moderate‐certainty evidence). There was low‐certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9% versus 1.5%; RR 2.00, 95% CI 0.19 to 21.54). Disease flares were not measured. Based on two trials with different follow‐up periods (mean of 27 months for etanercept study; up to four years for belimumab study) including people with GPA (n = 263) and a small group of participants with MPA (n = 22) analysed together, we found low‐certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy does not increase or reduce mortality (3.4% versus 1.4%; Peto OR 2.45, 95% CI 0.55 to 10.97). Etanercept may have little or no effect on remission (92.3% versus 89.5%; RR 0.97, 95% CI 0.89 to 1.07), durable remission (70% versus 75.3%; RR 0.93, 95% CI 0.77 to 1.11; low‐certainty evidence) and disease flares (56% versus 57.1%; RR 0.98, 95% CI 0.76 to 1.27; moderate‐certainty evidence). Low‐certainty evidence suggests that belimumab does not increase or reduce major relapse (1.9% versus 0%; RR 2.94, 95% CI 0.12 to 70.67) or any AE (92.5% versus 82.7%; RR 1.12, 95% CI 0.97 to 1.29). Low‐certainty evidence suggests a similar frequency of serious or severe AEs (47.6% versus 47.6%; RR 1.00, 95% CI 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2%) compared to the placebo group (4.2%), RR 2.66, 95% CI 1.07 to 6.59). One trial involving 17 participants with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months. One participant died in each group (Peto OR 0.88, 95% CI, 0.05 to 15.51; 11% versus 12.5%). We have very low‐certainty evidence for remission (22% versus 50%, RR 0.44, 95% Cl 0.11 to 1.81) and durable remission (11% versus 50%, RR 0.22, 95% CI 0.03 to 1.60), any severe AE (22.3% versus 12.5%; RR 1.78, 95% CI 0.2 to 16.1) and withdrawals due to AEs (0% versus 0%; RR 2.70, 95% CI 0.13 to 58.24). Disease flare/relapse and the frequency of any AE were not reported. AUTHORS' CONCLUSIONS: We found four studies but concerns about risk of bias and small sample sizes preclude firm conclusions. We found moderate‐certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreases disease relapse and low‐certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission. There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably assess these outcomes. Mepolizumab may result in little to no difference in mortality. However, there were very few events. In participants with GPA (and a small subgroup of participants with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs. Etanercept may have little or no impact on durable remission and probably does not reduce disease flare

NMR-Based Metabolomics of Blood Serum in Predicting Response to Induction Chemotherapy in Head and Neck Cancer—A Preliminary Approach

The role of induction chemotherapy (iCHT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is still to be established due to high toxicity and variable response rates. The aim of this retrospective study is to use NMR-based serum metabolomics to predict the response rates to iCHT from the pretreatment samples. The studied group consisted of 46 LA-HNSCC patients treated with iCHT. The response to the treatment was evaluated by the clinical, fiberoptic, and radiological examinations made before and after iCHT. The proton nuclear magnetic resonance (1H NMR) serum spectra of the samples collected before iCHT were acquired with a 400 MHz spectrometer and were analyzed using multivariate and univariate statistical methods. A significant multivariate model was obtained only for the male patients. The treatment-responsive men with >75% primary tumor regression after iCHT showed pretreatment elevated levels of isoleucine, alanine, glycine, tyrosine, N-acetylcysteine, and the lipid compounds, as well as decreased levels of acetate, glutamate, formate, and ketone bodies compared to those who did not respond (regression of the primary tumor <75%). The results indicate that the nutritional status, capacity of the immune system, and the efficiency of metabolism related to protein synthesis may be prognostic factors for the response to induction chemotherapy in male HNSCC patients. However, larger studies are required that would validate the findings and could contribute to the development of more personalized treatment protocols for HNSCC patients