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BackgroundMask leak is common during newborn resuscitation, impacting delivered ventilation. Less is known about the effect of leak during assisted spontaneous breathing with continuous positive airway pressure (CPAP).AimCompare CPAP performance in the presence of leak of two T-piece resuscitation devices, with differing design-imposed resistances: high resistance Neopuff and low resistance rPAP.MethodsDevices were tested on a term dynamic lung model (compliance 1.0 mL/cmH2O, tidal volume (VT) 23 mL) at three incremental leak levels and set positive end expiratory pressure (PEEP) 5 cmH2O, 7 cmH2O and 9 cmH2O. Continuous leaks were generated by differing-length tubes open to atmosphere. Measured parameters were mean pressure, fluctuations around set pressure (∆P), VT and leak flow.Results2437 breaths were analysed (1216 rPAP, 1221 Neopuff). Leak reduced PEEP, with the largest reduction at the highest leak and 9 cmH2O set PEEP (Neopuff 2.6 cmH2O vs rPAP 7.0 cmH2O). Higher delivered PEEP was associated with higher leak flows (Neopuff 4.4 L/min vs rPAP 8.2 L/min, 9 cmH2O set PEEP). VT reduced with Neopuff compared with rPAP (Neopuff 18 mL vs rPAP 23.2 mL, no leak, 9 cmH2O set PEEP) and was affected by delivered PEEP.ConclusionThe delivered support differed between devices in the presence of leaks. rPAP maintained pressures closer to the set PEEP value at all leak levels, and higher leak flows were seen with the maintained distending pressure. Neopuff’s higher resistance led to reductions in VT that were more pronounced at low leak levels.

BackgroundContinuous positive airway pressure (CPAP) is a recommended first-line therapy for infants with respiratory distress at birth. Resuscitation devices incorporating CPAP delivery can have significantly different imposed resistances affecting airway pressure stability and work of breathing.AimTo compare CPAP performance of two resuscitation devices (Neopuff T-piece resuscitator and rPAP) in a neonatal lung model simulating spontaneous breathing effort at birth.MethodsThe parameters assessed were variation in delivered pressures (∆P), tidal volume (VT), inspiratory effort (model pressure respiratory muscle (PRM)) and work of breathing (WOB). Two data sequences were required with Neopuff and one with rPAP: (1) set PRM with changes in VT and (2) constant VT (preterm 6 mL, term 22 mL) with increased effort. Data were collected at CPAP settings of 5, 7 and 9 cmH2O using a 1 kg preterm (Compliance: 0.5 mL/cmH2O) and 3.5 kg term (1.0 mL/cmH2O) model.Results2298 breaths were analysed (760 rPAP, 795 Neopuff constant VT, 743 Neopuff constant PRM). With CPAP at 9 cmH2O and set VT the mean ∆P (cmH2O) rPAP vs Neopuff 1.1 vs 5.6 (preterm) and 1.9 vs 13.4 (term), WOB (mJ) 4.6 vs 6.1 (preterm) and 35.3 vs 44.5 (term), and with set PRM mean VT (ml) decreased to 6.2 vs 5.2 (preterm) and 22.3 vs 17.5 (term) p<0.001. Similar results were found at pressures of 5 and 7 cmH2O.ConclusionrPAP had smaller pressure swings than Neopuff at all CPAP levels and was thus more pressure stable. WOB was higher with Neopuff when VT was held constant. VT reduced with Neopuff when respiratory effort was constant.

The browning of fruit juices and nectars is a common issue in the beverage industry and is a particular problem in strawberry nectars, where it significantly reduces the shelf-life. Polyphenol oxidases (PPOs), which are multicopper enzymes responsible for the oxidation of a wide plethora of polyphenols in plants, have been widely assumed to be involved in the enzymatic browning of strawberry nectar. To investigate the possible involvement of PPOs, the substrate specificity of four recombinant PPOs and their gene expression pattern in 10 cultivars of Fragaria × ananassa at five ripening stages were determined. This allowed us to obtain adequate amounts of enzymes to study them independently and without interfering matrix effects. All four PPOs possess monophenolase activity, which was particularly high for PPO4. PPO3 did not show sufficient stability for the kinetic studies. The other three showed a high preference for the flavan 3-ol catechin with a 2-fold higher catalytic efficiency compared to dopamine for PPO1 and PPO2. At a neutral pH, they also showed activity with cyanidin but not with pelargonidin, which is the prevalent anthocyanidin type in strawberry. The enzymes showed a high affinity but only low turnover rates for the dihydrochalcone phloretin, resulting in an inhibitory effect that was strong enough to extend the shelf-life of the strawberry nectar by one week if phloretin was added in high concentrations (600 µM). PPO1 and PPO2 were prevalently expressed in all fruit stages. The gene expression of the four PPOs did not correlate with the color stability of the nectars of the 10 varieties and also showed a random expression pattern during fruit development. The limited activity in acidic conditions and the low substrate specificity for pelargonidin does not point to a crucial role for PPOs in the browning of strawberry nectar, but the high catalytic efficiency with catechin as a substrate could contribute to anthocyanin degradation via mechanisms such as copolymerization.

Among fruits, the apple is unique for producing large amounts of the dihydrochalcone phloridzin, which, together with phloretin, its aglycone, is valuable to the pharmaceutical and food industries for its antidiabetic, antioxidant, and anticarcinogenic properties, as well as its use as a sweetener. We analysed the phloridzin concentration, total phenolic content, and antioxidant activity in the peel, flesh, seeds, juice, and pomace of 13 international and local apple varieties. In the unprocessed fruit, the seeds had the highest phloridzin content, while the highest total phenolic contents were mostly found in the peel. In processed samples, phloridzin and the total phenolic compounds especially were higher mostly in juice than in pomace. Moreover, the total phenolic content was much higher than the phloridzin content. Juice showed the highest antioxidant activity, followed by the peel and flesh. Across all samples, antioxidant activity did not directly correlate with phloridzin concentrations, suggesting that the antioxidant activity ascribed to phloridzin may need re-evaluation. In the Ferric Reducing Antioxidant Power (FRAP) assay, phloridzin only showed antioxidant activity at high concentrations when compared to its aglycone, phloretin. Considering the large amounts of apple juice produced by the juice industry, residual pomace is a promising source of phloridzin. For technical use, processing this phloridzin to phloretin would be advantageous.

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class. A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or “slow” substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.

Background/Aim: For patients undergoing cancer surgery, the risk for cancer progression is enhanced during the perioperative period. To what extent the type of anesthetic can affect the metastatic process and finally the outcome of patients with cancer is under debate. For this reason, the aim of this study was to investigate the effects of the volatile anesthetics sevoflurane and desflurane on colon cancer cells in vitro. Materials and Methods: SW480 colon carcinoma cells were exposed for 3 or 6 h to sevoflurane (1 or 2.5 vol%) or desflurane (6 or 12 vol%). Cell cycle distribution was analyzed by flow cytometry after a 24-72 h recovery and apoptosis was detected by annexin V staining after a 0-48 h recovery. Viability was tested by measuring ATP content after 0 and 24 h recovery. Results: Treatment with sevoflurane or desflurane caused no or only slight changes in cell-cycle distribution and apoptosis rate. Desflurane at 12vol% significantly reduced cell viability by 17±25% and 11±22% after 3 and 6 h incubation and 24 h recovery, respectively, while 2.5 vol% sevoflurane slightly increased viability. Conclusion: At clinically relevant concentrations, sevoflurane and desflurane had only slight effects on SW480 colon cancer cells in vitro.

In the era of the coronavirus pandemic, one of the most demanding areas was the supply of healthcare systems in essential Personal Protection Equipment (PPE), including face-shields and hands-free door openers. This need, impossible to fill by traditional manufacturing methods, was met by implementing of such emerging technologies as additive manufacturing (AM/3D printing). In this article, Poly(lactic acid) (PLA) filaments for Fused filament fabrication (FFF) technology in the context of the antibacterial properties of finished products were analyzed. The methodology included 2D radiography and scanning electron microscopy (SEM) analysis to determine the presence of antimicrobial additives in the material and their impact on such hospital pathogens as Staphylococcus aureus, Pseudomonas aeruginosa, and Clostridium difficile. The results show that not all tested materials displayed the expected antimicrobial properties after processing in FFF technology. The results showed that in the case of specific species of bacteria, the FFF samples, produced using the declared antibacterial materials, may even stimulate the microbial growth. The novelty of the results relies on methodological approach exceeding scope of ISO 22196 standard and is based on tests with three different species of bacteria in two types of media simulating common body fluids that can be found on frequently touched, nosocomial surfaces. The data presented in this article is of pivotal meaning taking under consideration the increasing interest in application of such products in the clinical setting.

•One of the largest prospective studies on covid-19 vaccination in cancer patients.•Wide array of solid tumour entities.•High vaccination acceptance in this prioritised collective.•Most oncologic patients showed a measurable humoral response after vaccination.•Risk factors for non– and low humoral responders in uni/multivariate analysis. SARS-CoV-2 infection has been and, in some parts, still is a threat to oncologic patients, making it crucial to understand perception of vaccination and immunologic responses in this vulnerable patient segment. SARS-CoV-2 vaccines in relation to malignant disease characteristics and therapies have so far not been studied consecutively in larger oncologic patient populations. This study captures SARS-CoV-2 vaccination willingness and humoral immune response in a large consecutive oncologic patient collective at the beginning of 2021. 1142 patients were consecutively recruited over 5.5 months at a tertiary department for radiation oncology and were assessed for vaccination willingness via a standardized interview. In already vaccinated patients total SARS-CoV-2 S antibody titres against the spike protein (Anti-SARS-CoV-2 S) and were evaluated 35 days or later after the first dose of SARS-CoV-2 vaccine. Vaccination willingness was high with a rate of 90 %. The most frequent reasons for rejection were: undecided/potential vaccination after therapy, distrust in the vaccine and fear of interaction with comorbidities. Factors associated with lower vaccination willingness were: worse general condition, lower age and female sex. 80 % of the participants had been previously vaccinated, 8 % reported previous infection and 16 % received vaccination during antineoplastic therapy. In 97.5 % of the vaccinated patients Anti-SARS-CoV-2 S was detected. In a univariable analysis parameters associated with non-conversion were: lower performance status, spread to the local lymphatics (N + ), hematologic disease and diffuse metastases. All patients with oligometastatic disease achieved positive Anti-SARS-CoV-2 S titres. For patients with two vaccinations several risk factors were identified, that were associated with low antibody concentrations. SARS-CoV-2 vaccination willingness among oncologic patients was high in the first months after its availability, and most patients had already received one or two doses. Over 97 % of vaccinated patients had measurable anti-SARS-CoV-2 S titres. Our data supports early identification of low humoral responders after vaccination and could facilitate the design of future oncologic vaccine trials (clinicaltrials.gov Identifier: NCT04918888).

Hyperoxic BOLD-MRI targeting tumor hypoxia may provide imaging biomarkers that represent breast cancer molecular subtypes without the use of injected contrast agents. However, the diagnostic performance of hyperoxic BOLD-MRI using different levels of oxygen remains unclear. We hypothesized that molecular subtype characterization with hyperoxic BOLD-MRI is feasible independently of the amount of oxygen. Twenty-three nude mice that were inoculated into the flank with luminal A (n = 9), Her2+ (n = 5), and triple-negative (n = 9) human breast cancer cells were imaged using a 9.4 T Bruker BioSpin system. During BOLD-MRI, anesthesia was supplemented with four different levels of oxygen (normoxic: 21%; hyperoxic: 41%, 71%, 100%). The change in the spin–spin relaxation rate in relation to the normoxic state, ΔR2*, dependent on the amount of erythrocyte-bound oxygen, was calculated using in-house MATLAB code. ΔR2* was significantly different between luminal A and Her2+ as well as between luminal A and triple-negative breast cancer, reflective of the less aggressive luminal A breast cancer’s ability to better deliver oxygen-rich hemoglobin to its tissue. Differences in ΔR2* between subtypes were independent of the amount of oxygen, with robust distinction already achieved with 41% oxygen. In conclusion, hyperoxic BOLD-MRI may be used as a biomarker for luminal A breast cancer identification without the use of exogenous contrast agents.