Perioperative intravenous lidocaine in thoracoscopic surgery for improved postoperative pain control: a randomized, placebo-controlled, double-blind, superiority trial.

Background: Pain, including associated pain management, remains a burden on patients after thoracic surgery. Our objective was to investigate whether perioperative intravenous administration of lidocaine reduces postoperative morphine consumption and pain intensity after video-assisted thoracoscopic surgery (VATS). Methods: In this double-blind, placebo-controlled superiority trial, patients undergoing VATS with a planned duration of ≤90 minutes were randomized within an intention-to-treat setting. Patients received either intravenous lidocaine or placebo as a bolus of 1.5 mg/kg 30 minutes before incision, followed by a continuous infusion of 3.0 mg/kg/hour until 2 hours after skin closure. Pain and morphine consumption were evaluated when resting and when coughing 1, 2, 4, 8, 16, 24, and 48 hours after skin closure and in a follow-up 14, 90, and 180 days postoperatively. Results: Twenty-eight patients were included in the lidocaine group, 24 in the placebo group. Patients' characteristics and preoperative pain scores were similar in both groups. When coughing, patients of the lidocaine group had less pain within 24 hours after skin closure than the placebo group (4.60±1.64 vs. 5.52±1.65; P=0.02). Morphine consumption was not statistically significantly lower in lidocaine group (18.22±12.87 vs. 21.26±9.39 mg; P=0.26). There were no significant differences between groups in secondary outcomes. Conclusions: Our results suggest that perioperative intravenous lidocaine administration reduces pain scores after VATS. The beneficial clinical effects are limited. Nevertheless, intravenous lidocaine may be helpful as part of a multimodal analgesia protocol or with patients in whom the use of other analgesics is contraindicated. Trial Registration: ClinicalTrials.gov NCT03677817.

Analgesic benefit of metamizole and ibuprofen vs. either medication alone: a randomized clinical trial.

BACKGROUND: Postoperative pain relief remains a key problem after surgery. Multimodal pain therapy has proven beneficial in alleviating pain to a certain extent. However, when combining non-opioids, the focus has been on NSAIDs and paracetamol, but effects of combined use are only moderate. Metamizole could be a potent adjunct, due to its preclusion in several countries, data on its combined use are sparse, despite its common use in many countries. The aim of this study was to examine whether the combination of metamizole and ibuprofen is superior in relieving postoperative pain to either drug alone. METHODS: For this randomized, placebo-controlled, cross-over study, 35 patients undergoing bilateral lower third molar extraction were randomized. Each patient received three applications of 1000 mg metamizole + 400 mg ibuprofen for surgery on one side and either 1000 mg metamizole + placebo or 400 mg ibuprofen + placebo on the other side. Pain ratings, rescue-medication (tramadol), and sleep were assessed for 18 hours. RESULTS: The combined treatment of metamizole and ibuprofen showed lower mean pain scores over 12 hours than ibuprofen (2.4±1.3 vs 3.8±1.6; P=0.005). Further, combined treatment showed lower mean pain scores over 6 hours than ibuprofen (2.0±1.2 vs. 3.1±1.6; P=0.022) or metamizole alone (2.0±1.2 vs. 3.3±1.7; P=0.015). Consumption of rescue medication was lowest in the combination-group (25% vs. 46%-metamizole; 50%-ibuprofen). The trial was stopped prematurely as the COVID-pandemic halted elective surgeries. CONCLUSIONS: Combined use enables superior pain control compared to ibuprofen after molar extraction and tends to be superior to metamizole alone. The premature study-termination may overestimate this effect.

Sediment Soot Radiocarbon Indicates that Recent Pollution Controls Slowed Fossil Fuel Emissions in Southeastern China.

Fossil fuel (FF) combustion emissions account for a large, but uncertain, amount of the soot in the atmosphere, play an important role in climate change, and adversely affect human health. However, historical estimates of FF contributions to air pollution are limited by uncertainties in fuel usage and emission factors. Here, we constrained FF soot emissions from southeastern China over the past 110 years, based on a novel radiocarbon method applied to sedimentary soot. The reconstructed soot accumulations reflect the integrated effects of increased FF use caused by economic development and reductions in emissions due to pollution controls. A sharp increase in FF soot started in 1950 as southeastern China industrialized and developed economically, but decreased FF soot fluxes in recent years suggest that pollution controls reduced soot emissions. We compare FF soot history to changes in CO2 emissions, industrial and economic activities, and pollution controls and show that FF soot fluxes are more readily controlled than atmospheric CO2. Our independent FF soot record provides insights into the effects of economic development and controls on air pollution and the environmental impacts from the changes in soot emissions.

Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial.

Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain. Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption. Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy. Ethics and Dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).

Complement regulation in tenocytes under the influence of leukocytes in an indirect co-culture model.

INTRODUCTION: The present in vitro study was undertaken to learn about the effects of leukocytes on tenocytes in respect to complement regulation simulating an inflammatory scenario of the traumatized tissue. METHODS: Human hamstring tendon-derived tenocyte monolayers were co-cultured indirectly with human leukocytes (either Peripheral Blood Mononuclear Cells [PBMCs] or neutrophils) using a transwell system with/without (+ /wo) 10 ng/ml tumor necrosis factor α (TNFα) for 4 and 24 h. Tenocyte and leukocyte cell survival was assessed by live-dead assay. Tenocyte gene expression of TNFα, the anaphylatoxin receptor C5aR and the cytoprotective complement regulatory proteins (CRP) CD46, CD55 and CD59 was monitored using qPCR. TNFα was detected in the culture supernatants using ELISA. RESULTS: C5aR gene expression was significantly induced by TNFα after 4 h, but impaired in the presence of leukocytes + TNFα after 24 h. At 4 h, PBMCs activated by TNFα induced the CRP CD46 gene expression. However, CD55 was significantly suppressed after 24 h by neutrophils + /woTNFα. Leukocytes activated by TNFα decreased also significantly the gene expression of the more downstream acting CRP CD59 after 4 h. TNFα gene expression and ELISA analysis revealed an amplified TNFα expression/release in tenocyte co-cultures with PBMC + /woTNFα, probably contributing to complement regulation. CONCLUSION: TNFα might represent a crucial soluble mediator exerting diverse time-dependent effects on tenocyte complement regulation.

A 150-year record of black carbon (soot and char) and polycyclic aromatic compounds deposition in Lake Phayao, north Thailand.

An improved understanding of the historical variation in the emissions and sources (biomass burning, BB vs. fossil fuel, FF combustion) of soot and char, the two components of black carbon (BC), and polycyclic aromatic compounds (PACs) may help in assessing the environmental effects of the Atmospheric Brown Cloud (ABC) in SE Asia. We therefore determined historical variations of the fluxes of soot, char, and PACs (24 polycyclic aromatic hydrocarbons (PAHs), 12 oxygenated PAHs (OPAHs), and 4 azaarenes) in a dated sediment core (covering the past ∼150 years) of Phayao Lake in Thailand. The soot fluxes have been increasing in recent times, but at a far lower rate than previously estimated based on BC emission inventories. This may be associated with a decreasing BB contribution as indicated by the decreasing char fluxes from old to young sediments. The fluxes of high- and low-molecular-weight (HMW and LMW) PAHs, OPAHs, and azaarenes all sharply increased after ∼1980, while the ΣLMW-/ΣHMW-PAHs ratios decreased, further supporting the reduction in BB contribution at the expense of increasing FF combustion emissions. We also suggest that the separate record of char and soot, which has up to now not been done in aerosol studies, is useful to assess the environmental effects of ABC because of the different light-absorbing properties of these two BC components. Our results suggest that besides the establishment of improved FF combustion technology, BB must be further reduced in the SE Asian region in order to weaken the ABC haze.

Conformational and functional characterization of artificially conjugated non-canonical ubiquitin dimers.

Ubiquitylation is an eminent posttranslational modification referring to the covalent attachment of single ubiquitin molecules or polyubiquitin chains to a target protein dictating the fate of such labeled polypeptide chains. Here, we have biochemically produced artificially Lys11-, and Lys27-, and Lys63-linked ubiquitin dimers based on click-chemistry generating milligram quantities in high purity. We show that the artificial linkage used for the conjugation of two ubiquitin moieties represents a fully reliable surrogate of the natural isopeptide bond by acquiring highly resolved nuclear magnetic resonance (NMR) spectroscopic data including ligand binding studies. Extensive coarse grained and atomistic molecular dynamics (MD) simulations allow to extract structures representing the ensemble of domain-domain conformations used to verify the experimental data. Advantageously, this methodology does not require individual isotopic labeling of both ubiquitin moieties as NMR data have been acquired on the isotopically labeled proximal moiety and complementary MD simulations have been used to fully interpret the experimental data in terms of domain-domain conformation. This combined approach intertwining NMR spectroscopy with MD simulations makes it possible to describe the conformational space non-canonically Lys11-, and Lys27-linked ubiquitin dimers occupy in a solution averaged ensemble by taking atomically resolved information representing all residues in ubiquitin dimers into account.

Prophylactic intra-aortic balloon counterpulsation before surgical myocardial revascularization in patients with acute myocardial infarction.

INTRODUCTION: Prophylactic intra-aortic balloon counterpulsation (pIABC) is recommended for high-risk patients undergoing coronary artery bypass grafting (CABG) surgery. Criteria for high-risk patients benefiting from pIABC are unclear. This study aimed to specifically describe the effect of pIABC on outcomes of patients with acute myocardial infarction (AMI) undergoing CABG. METHODS: In 178 of 484 AMI patients (non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI] ≤5 days before surgery) without cardiogenic shock who underwent CABG between 2008 and 2013, pIABC was initiated preoperatively. After propensity score matching, the outcomes of 400 patients were analyzed (pIABC: 150; Control: 250). RESULTS: After propensity score matching, baseline and operative characteristics were balanced between the groups except for a higher rate of patients with a left ventricular ejection fraction (LVEF)≤30% in the pIABC group (26% vs. Control: 13%; p=0.032). Seven point two percent (7.2%) of the control patients received an IABP intraoperatively or postoperatively. Postoperative extracorporeal life support (ECLS) was only needed in the control group (1.2% vs. 0%; p=0.01). Postoperative plasma curves of troponin I, creatine kinase (CK) and creatine kinase isoform MB (CK-MB) levels were reduced in the pIABC group compared with the control group. In-hospital mortality was reduced in the pIABC group (3.3% vs. control: 6.4%; p=0.18). After multivariate adjustment for other preoperative risk factors, pIABC was significantly protective concerning in-hospital mortality (HR 0.56; 95%-CI 0.023-0.74; p=0.021). Mortality (pIABC vs. control) was more affected in patients with preoperative LVEF≤30% (2/36 (5.6%) vs. 6/31 (19%); heart rate (HR) 0.25; 95%-CI 0.046-1.3; p=0.13) compared with LVEF>30% (3/114 (2.6%) vs. 10/219 (4.6%); HR 0.56; 95%-CI 0.15-2.1; p=0.55). Long-term survival did not differ between the groups. CONCLUSIONS: pIABC in CABG for AMI is associated with reduced perioperative cardiac injury and in-hospital mortality. Long-term survival is not affected.

Total arterial revascularization in patients with acute myocardial infarction - feasibility and outcomes.

BACKGROUND: In acute situations such as acute myocardial infarction (AMI) with indication for coronary artery bypass grafting (CABG), total arterial revascularization (TAR) is often rejected in favour of saphenous vein (SV) grafting, which is assumed to allow for quicker vessel harvesting, a simpler anastomosis technique, and thus quicker revascularization and fewer bleeding complications. The aim of this study was to evaluate whether reluctance to apply TAR in AMI is still justified from a technical point of view in the current era and whether superiority of TAR results is also evident in emergency patients with AMI undergoing CABG. METHODS: In this retrospective analysis of 434 consecutive patients undergoing CABG for AMI with either TAR or with a combination of one internal mammary artery and SV grafts between 2008 and 2014, procedural data, short-term and mid-term outcome were compared. Propensity score matching of the groups was performed. RESULTS: After propensity score matching, 250 patients were included in the analysis (TAR group: n = 98; SV group n = 152). The procedural time (TAR group: 211 min vs. SV group: 200 min, p = 0.46) did not differ between the groups. Erythrocyte transfusion rates were higher in the SV group (76% vs. 57%; p < 0.001). Rates of re-exploration for bleeding did not differ. Thirty-day mortality rates were comparable (TAR group: 3.4% vs. SV group: 4.5%, p = 0.68). Kaplan-Meier analysis until 7 years postoperatively revealed a tendency for improved survival after TAR (75% vs. 62%; log-rank p = 0.12). CONCLUSION: TAR neither impairs rapid revascularization nor reduces its safety in patients with AMI. It may result in improved long-term outcome and should be preferred in the clinical setting of AMI.

Is delayed surgical revascularization in acute myocardial infarction useful or dangerous? New insights into an old problem.

OBJECTIVES: Haemodynamically stable patients admitted for coronary artery bypass grafting in acute myocardial infarction often undergo delayed surgery in order to avoid the risks of emergency surgery. However, initially stable patients undergoing delayed surgery may develop low cardiac output syndrome (LCOS) during the waiting period, which might be a major drawback of this strategy. We aim to define risk factors and clinical consequences of LCOS during the waiting period. METHODS: A total of 530 consecutive patients with acute myocardial infarction (33% non-ST-segment elevation myocardial infarction and 67% ST-segment-elevation myocardial infarction) underwent isolated coronary artery bypass grafting between 2008 and 2013. Outcomes after either immediate (<48 h after onset of symptoms) or delayed (>48 h after onset of symptoms) therapy were compared. Predictors of preoperative development of LCOS were identified using multivariate regression analysis. RESULTS: Of the 327 patients undergoing delayed therapy, 39 (12%) developed preoperative LCOS, resulting in increased mortality compared with patients who remained stable (21 vs 7.6%, P < 0.001). Immediate therapy resulted in similar mortality compared with delayed therapy (6.4 vs 7.6%; P = 0.68) and better 7-year survival (70 vs 55%; P < 0.001). Predictors of developing LCOS were reduced left ventricular function (odds ratio 4.4), renal impairment (odds ratio 3.0), acute pulmonary infection (odds ratio 3.4) and the extent of troponin elevation at admission (odds ratio 1.01 per increase by 1 µg/l). CONCLUSIONS: In patients with acute myocardial infarction undergoing delayed coronary artery bypass grafting, preoperative LCOS is a relevant and dangerous condition that can be avoided by operating immediately or by carefully selecting patients to be delayed according to the risk parameters identified preoperatively.

Influence of dendritic polyglycerol sulfates on knee osteoarthritis: an experimental study in the rat osteoarthritis model.

BACKGROUND: Anti-inflammatory nanoparticular compounds could represent a strategy to diminish osteoarthritis (OA) progression. The present study was undertaken to prove the uptake of nanoparticular dendritic polyglycerol sulfates (dPGS) by rat-derived articular chondrocytes and to answer the question of whether dPGS could modulate knee joint cartilage degradation in a rat OA model and whether complications could arise. METHODS: dPGS uptake and cytotoxicity was assessed in cultured primary rat-derived articular chondrocytes. Subsequently, OA was induced in the right knee joints of 12 male Wistar rats by medial collateral ligament and meniscus transection. Unoperated left knees remained as controls. Six weeks post surgery six rats were either treated daily (14 days) with 30 mg/kg dPGS (s.c.) or a similar volume of physiological saline. Animals were analyzed clinically for gait alterations. Explanted knee joints were studied histologically using OA scores according to Mankin (1971), Glasson et al., (2010) and the synovitis score according to Krenn et al., (2006). Liver, spleen and kidneys were analyzed for degenerative changes due to dPGS accumulation. RESULTS: dPGS was taken up after 2 hours by the chondrocytes. Whereas no significant clinical signs of OA could be detected, at the histological level, all operated rat knee joints revealed features of OA in the medial compartment. The values produced by both OA score systems were lower in rats treated with dPGS compared with saline-treated animals. Synovitis score did not significantly differ between the groups. The analyzed organs revealed no degenerative changes. CONCLUSIONS: dPGS presented overall cyto- and biocompatibility, no accumulation in metabolizing organs and chondroprotective properties in the osteoarthritic knee joint.

Cardiovascular risk factors and thoracic aortic wall thickness in a general population.

PURPOSE: To evaluate the association of cardiovascular risk factors with wall thickness of the ascending and descending thoracic aorta in the general population. MATERIALS AND METHODS: The study included 1,176 individuals (523 women) 21-83 years old from the Study of Health in Pomerania without history of stroke or myocardial infarction. Aortic wall thickness (AWT) was determined by cine magnetic resonance imaging. The associations of AWT with the cardiovascular risk factors male sex, age, smoking, body mass index (BMI), systolic and diastolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were assessed by multivariable linear regression models, and interaction effects were tested. RESULTS: Male sex (ß = .086, P < .001), age (ß = .006, P < .001), and BMI (ß = .013, P < .001) were positively associated with the AWT of the ascending aorta. Male sex (ß = .105, P < .001), age (ß = .006, P < .001), current smoker (ß = .044, P = .010), BMI (ß = .013, P < .001), and HDL-C (ß = .057, P = .008) revealed a positive association with AWT of the descending aorta. LDL-C (ß = -.024, P = .009; ß = -.018, P = .010) was inversely associated with the AWT of the ascending and descending aorta, respectively. Triglyceride levels (ß = .024, P = .027; ß = .018, P = .024) showed a positive association with the AWT of the ascending and descending aorta, respectively, in men, but not in women. CONCLUSIONS: Established cardiovascular risk factors, including male sex, older age, smoking, high BMI, and high triglyceride levels, were associated with increasing thoracic AWT of the ascending and descending aorta. High HDL-C and low LDL-C levels were correlated with AWT.

Selectivity in bone targeting with multivalent dendritic polyanion dye conjugates.

Targeting bone with anionic macromolecules is a potent approach for the development of novel diagnostics and therapeutics for bone related diseases. A highly efficient modular synthesis of dendritic polyglycerol (dPG) polyanion dye conjugates, namely, sulfates, sulfonates, carboxylates, phosphates, phosphonates, and bisphosphonates via click chemistry is presented. By investigating the microarchitecture of stained bone sections with confocal laser scanning microscopy, the bisphosphonate, phosphonate, and phosphate functionalized polymers are identified as strongly penetrating compounds, whereas sulfates, sulfonates, and carboxylates reveal a weaker binding to hydroxyapatite (HA) but a more pronounced affinity toward collagen. In a quantitative HA binding assay, the affinity of the dPG sulfonate, sulfate, and carboxylate toward collagen and the exceptional high HA affinity of the phosphorous containing polyelectrolytes are validated. This shows the potential of dendritic polyphosphates and phosphonates as alternatives to the commonly employed bisphosphonate modification. In cytotoxicity studies with murine fibroblasts, the conjugates have no significant effect on the cell viability at 10(-5) m. All polyanions are taken up into the cells within 24 h. The presented synthetic approach allows versatile extensions for preparing conjugates for selective bone imaging applications, tissue engineering, and drug delivery.

One pot, two phases: iron-catalyzed cyclopropanation with in†situ generated diazomethane.

Tamed! The safe handling of diazomethane can be accomplished by a two-phase reaction. After being generated in aqueous media, the highly reactive species transfers to the organic phase and directly converts alkenes into cyclopropanes (see scheme). An air-stable iron(III) porphyrin complex serves as the catalyst.