optiPRM: A Targeted Immunopeptidomics LC-MS Workflow With Ultra-High Sensitivity for the Detection of Mutation-Derived Tumor Neoepitopes From Limited Input Material.

Personalized cancer immunotherapies such as therapeutic vaccines and adoptive transfer of T cell receptor-transgenic T cells rely on the presentation of tumor-specific peptides by human leukocyte antigen class I molecules to cytotoxic T cells. Such neoepitopes can for example arise from somatic mutations and their identification is crucial for the rational design of new therapeutic interventions. Liquid chromatography mass spectrometry (LC-MS)-based immunopeptidomics is the only method to directly prove actual peptide presentation and we have developed a parameter optimization workflow to tune targeted assays for maximum detection sensitivity on a per peptide basis, termed optiPRM. Optimization of collision energy using optiPRM allows for the improved detection of low abundant peptides that are very hard to detect using standard parameters. Applying this to immunopeptidomics, we detected a neoepitope in a patient-derived xenograft from as little as 2.5 × 106 cells input. Application of the workflow on small patient tumor samples allowed for the detection of five mutation-derived neoepitopes in three patients. One neoepitope was confirmed to be recognized by patient T cells. In conclusion, optiPRM, a targeted MS workflow reaching ultra-high sensitivity by per peptide parameter optimization, makes the identification of actionable neoepitopes possible from sample sizes usually available in the clinic.

Binary Coalescences as Sources of Ultrahigh-Energy Cosmic Rays.

Binary coalescences are known sources of gravitational waves (GWs) and they encompass combinations of black holes (BHs) and neutron stars (NSs). Here we show that when BHs are embedded in magnetic fields (B's) larger than approximately 10^{10} G, charged particles colliding around their event horizons can easily have center-of-mass energies in the range of ultrahigh energies (≳10^{18} eV) and become more likely to escape. Such B-embedding and high-energy particles can take place in BH-NS binaries, or even in BH-BH binaries with one of the BHs being charged (with charge-to-mass ratios as small as 10^{-5}, which do not change GW waveforms) and having a residual accretion disk. Ultrahigh center-of-mass energies for particle collisions arise for basically any rotation parameter of the BH when B≳10^{10} G, meaning that it should be a common aspect in binaries, especially in BH-NS ones given the natural presence of a B onto the BH and charged particles due to the magnetosphere of the NS. We estimate that the number of ultrahigh center-of-mass collisions ranges from a few up to millions before the merger of binary compact systems. Thus, binary coalescences may also be efficient sources of ultrahigh energy cosmic rays (UHECRs) and constraints to NS/BH parameters would be possible if UHECRs are detected along with GWs.

Certification of Basic Skills in Endovascular Aortic Repair Through a Modular Simulation Course With Real Time Performance Assessment.

OBJECTIVE: Endovascular aortic repair (EVAR) is being used increasingly for the treatment of infrarenal abdominal aortic aneurysms. Improvement in educational strategies is required to teach future vascular surgeons EVAR skills, but a comprehensive, pre-defined e-learning and simulation curriculum remains to be developed and tested. EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE), an assessment tool for simulation based education (SBE) in EVAR, has previously been designed to assess EVAR skills, and a pass limit defining mastery level has been set. However, EVARATE was developed for anonymous video ratings in a research setting, and its feasibility for real time ratings in a standardised SBE programme in EVAR is unproven. This study aimed to test the effect of a newly developed simulation based modular course in EVAR. In addition, the applicability of EVARATE for real time performance assessments was investigated. METHODS: The European Society of Vascular Surgery (ESVS) and Copenhagen Certification Programme in EVAR (ENHANCE-EVAR) was tested in a prospective cohort study. ENHANCE-EVAR is a modular SBE programme in EVAR consisting of e-learning and hands-on SBE. Participants were rated with the EVARATE tool by experienced EVAR surgeons. RESULTS: Twenty-four physicians completed the study. The mean improvement in EVARATE score during the course was +11.8 (95% confidence interval 9.8 - 13.7) points (p < .001). Twenty-two participants (92%) passed with a mean number of 2.8 ± 0.7 test attempts to reach the pass limit. Cronbach's alpha coefficient was 0.91, corresponding to excellent reliability of the EVARATE scale. Differences between instructors' EVARATE ratings were insignificant (p = .16), with a maximum variation between instructors of ± 1.3 points. CONCLUSION: ENHANCE-EVAR, a comprehensive certifying EVAR course, was proven to be effective. EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE) is a trustworthy tool for assessing performance within an authentic educational setting, enabling real time feedback.

HIV viral suppression and risk of viral rebound in patients on antiretroviral therapy: a two- year retrospective cohort study in Northern Tanzania.

BACKGROUND: The world is moving towards the third target of the Joint United Nations Programme on HIV/AIDS to ensure most people receiving antiretroviral therapy (ART) are virologically suppressed. Little is known about viral suppression at an undetectable level and the risk of viral rebound phenomenon in sub-Saharan Africa which covers 67% of the global HIV burden.This study aimed to investigate the proportion of viral suppression at an undetectable level and the risk of viral rebound among people living with HIV receiving ART in northern Tanzania. METHODOLOGY: A hospital based-retrospective study recruited people living with HIV who were on ART for at least two years at Kibong'oto Infectious Disease Hospital and Mawenzi Regional Referral Hospital in Kilimanjaro Region, Tanzania. Participants' two-year plasma HIV were captured at months 6, 12, and 24 of ART. Undetectable viral load was defined by plasma HIV of viral load (VL) less than 20copies/ml and viral rebound (VR) was considered to anyone having VL of more than 50 copies/ml after having history of undetectable level of the VL less than 20copies/ml. A multivariable log-binomial generalized linear model was used to determine factors for undetectable VL and viral VR. RESULTS: Among 416 PLHIV recruited, 226 (54.3%) were female. The mean (standard deviation) age was 43.7 (13.3) years. The overall proportion of undetectable VL was 68% (95% CI: 63.3-72.3) and 40.0% had viral rebound (95% CI: 34.7-45.6). Participants who had at least 3 clinic visits were 1.3 times more likely to have undetectable VL compared to those who had 1 to 2 clinic visits in a year (p = 0.029). Similarly, participants with many clinical visits ( > = 3 visits) per year were less likely to have VR compared to those with fewer visits ( = 2 visits) [adjusted relative risk (aRR) = 0.64; 95% CI: 0.44-0.93]. CONCLUSION: Participants who had fewer clinic visits per year(ART refills) were less likely to achieve viral suppression and more likely to experience viral rebound. Enhanced health education and close follow-up of PLHIV on antiretroviral therapy are crucial to reinforce adherence and maintain an undetectable viral load.

Miscarriage after SARS-CoV-2 vaccination: A population-based cohort study.

OBJECTIVE: To evaluate the risk of miscarriage following SARS-CoV-2 vaccination, while accounting for the competing risk of induced abortion. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Women aged 15-50 years with a confirmed pregnancy at ≤19 completed weeks' gestation. METHODS: Exposure to first SARS-CoV-2 vaccination, handled in a time-varying manner, was defined as (i) unvaccinated, (ii) remotely vaccinated >28 days before the estimated conception date or (iii) recently vaccinated ≤28 days before conception and up to 120 days after conception. MAIN OUTCOME MEASURES: The outcome was miscarriage, occurring between the estimated date of conception and up to 19 completed weeks of pregnancy. Fine-Grey hazard models, accounting for the competing risk of induced abortion, generated hazard ratios (aHR), adjusted for socio-demographic factors, comorbidities, and biweekly periods. RESULTS: Included were 246 259 pregnant women, of whom 34% received a first SARS-CoV-2 vaccination. Miscarriage occurred at a rate of 3.6 per 10 000 person-days among remotely vaccinated women and 3.2 per 10 000 person-days among those recently vaccinated, in contrast to a rate of 1.9 per 10 000 person-days among unvaccinated women, with corresponding aHR of 0.98 (95% confidence interval [CI] 0.91-1.07) and 1.00 (95% CI 0.93-1.08). CONCLUSIONS: SARS-CoV-2 vaccination was not associated with miscarriage while accounting for the competing risk of induced abortion. This study reiterates the importance of including pregnant women in new vaccine clinical trials and registries, and the rapid dissemination of vaccine safety data.

Impact of intra- and extramedullary alignment on blood loss in total knee arthroplasty: a retrospective study.

BACKGROUND: There is a scarcity of scientific data regarding the correlation between alignment techniques during total knee arthroplasty (TKA) and blood loss as well as transfusion rates. This study's hypothesis posited that intramedullary-aligned (IM) TKA exhibits higher blood loss and transfusion rates when contrasted with extramedullary-aligned (EM) TKA. METHODS: We conducted a retrospective examination of 883 patients who underwent total knee arthroplasty (TKA) in 2021 at a solitary orthopedic center in Germany. These patients were divided into two groups based on their tibial alignment technique: extramedullary alignment and intramedullary tibial alignment. RESULTS: In the intramedullary tibial alignment (IM) group, we observed a blood loss of 0.91 L, while in the extramedullary tibial alignment (EM) group, the blood loss was 0.89 L. These values did not demonstrate a significant difference (p = 0.69). Transfusion rates were 0.99% in the IM group and 0.21% in the EM group, and there was no significant distinction between them (Chi-squared test: p > 0.05). CONCLUSION: We observed no statistically significant variance in blood loss between the IM and EM groups. Likewise, there was no substantial disparity in transfusion rates between these groups. It can be concluded that the selection of a knee arthroplasty system incorporating either intramedullary tibial alignment or extramedullary alignment does not significantly impact blood loss.

Continuous Glucose Monitoring Reveals Perioperative Hypoglycemia in Most Patients With Diabetes Undergoing Major Surgery: A Prospective Cohort Study.

OBJECTIVE: To investigate the frequency and duration of hypo- and hyperglycemia, assessed by continuous glucose monitoring (CGM) during and after major surgery, in departments with implemented diabetes care protocols. SUMMARY BACKGROUND DATA: Inadequate glycemic control in the perioperative period is associated with serious adverse events, but monitoring currently relies on point blood glucose measurements, which may underreport glucose excursions. METHODS: Adult patients without (A) or with diabetes [non-insulin-treated type 2 (B), insulin-treated type 2 (C) or type 1 (D)] undergoing major surgery were monitored using CGM (Dexcom G6), with an electrochemical sensor in the interstitial fluid, during surgery and for up to 10 days postoperatively. Patients and health care staff were blinded to CGM values, and glucose management adhered to the standard diabetes care protocol. Thirty-day postoperative serious adverse events were recorded. The primary outcome was duration of hypoglycemia (glucose <70 mg/dL). Clinicaltrials.gov: NCT04473001. RESULTS: Seventy patients were included, with a median observation time of 4.0 days. CGM was recorded in median 96% of the observation time. The median daily duration of hypoglycemia was 2.5 minutes without significant difference between the 4 groups (A-D). Hypoglycemic events lasting ≥15 minutes occurred in 43% of all patients and 70% of patients with type 1 diabetes. Patients with type 1 diabetes spent a median of 40% of the monitoring time in the normoglycemic range 70 to 180 mg/dL and 27% in the hyperglycemic range >250 mg/dL. Duration of preceding hypo- and hyperglycemia tended to be longer in patients with serious adverse events, compared with patients without events, but these were exploratory analyses. CONCLUSIONS: Significant duration of both hypo- and hyperglycemia was detected in high proportions of patients, particularly in patients with diabetes, despite protocolized perioperative diabetes management.

Silicon, by promoting a homeostatic balance of C:N:P and nutrient use efficiency, attenuates K deficiency, favoring sustainable bean cultivation.

BACKGROUND: In many regions of the world, K is being depleted from soils due to agricultural intensification a lack of accessibility, and the high cost of K. Thus, there is an urgent need for a sustainable strategy for crops in this environment. Si is an option for mitigating stress due to nutritional deficiency. However, the underlying effects of Si in mitigating K deficiency C:N:P homeostasis still remains unknown for bean plants. This is a species of great worldwide importance. Thus, this study aims to evaluate whether i) K deficiency modifies the homeostatic balance of C, N and P, and, if so, ii) Si supply can reduce damage caused to nutritional stoichiometry, nutrient use efficiency, and production of dry mass in bean plants. RESULTS: K deficiency caused a reduction in the stoichiometric ratios C:N, C:P, and P:Si in shoots and C:N, C:P, C:Si, N:Si, and P:Si in roots, resulting in a decrease in K content and use efficiency and reducing biomass production. The application of Si in K-deficient plants modified the ratios C:N, C:Si, N:P, N:Si, and P:Si in shoots and C:N, C:P, C:Si, N:Si, N:P, and P:Si in roots, increasing the K content and efficiency, reducing the loss of biomass. In bean plants with K sufficiency, Si also changed the stoichiometric ratios C:N, C:P, C:Si, N:P, N:Si, and P:Si in shoots and C:N, C:Si, N:Si, and P:Si in roots, increasing K content only in roots and the use efficiency of C and P in shoots and C, N, and P in roots, increasing the biomass production only in roots. CONCLUSION: K deficiency causes damage to the C:N:P homeostatic balance, reducing the efficiency of nutrient use and biomass production. However, Si is a viable alternative to attenuate these nutritional damages, favoring bean growth. The future perspective is that the use of Si in agriculture in underdeveloped economies with restrictions on the use of K will constitute a sustainable strategy to increase food security.

New approaches to the effects of Si on sugarcane ratoon under irrigation in Quartzipsamments, Eutrophic Red Oxisol, and Dystrophic Red Oxisol.

BACKGROUND: C:N:P homeostasis in plants guarantees optimal levels of these nutrients in plant metabolism. H However, one of the causes to the effects of deficit irrigation is the loss of C:N:P homeostasis in leaves and stems that causes reduction in the growth of sugarcane. Being able to measure the impact of water deficit on C:N:P homeostasis in plants from the stoichiometric ratios of the concentrations of these nutrients in leaves and stems. This loss causes a decrease in nutritional efficiency, but can be mitigated with the use of silicon. Silicon favors the homeostasis of these nutrients and crop productivity. The magnitude of this benefit depends on the absorption of Si by the plant and Si availability in the soil, which varies with the type of soil used. Thus, this study aims to evaluate whether the application of Si via fertigation is efficient in increasing the absorption of Si and whether it is capable of modifying the homeostatic balance of C:N:P of the plant, causing an increase in nutritional efficiency and consequently in the production of biomass in leaves and stems of sugarcane ratoon cultivated with deficient and adequate irrigations in different tropical soils. RESULTS: Water deficit caused biological losses in concentrations and accumulation of C, N, and P, and reduced the nutrient use efficiency and biomass production of sugarcane plants cultivated in three tropical soils due to disturbances in the stoichiometric homeostasis of C:N:P. The application of Si increased the concentration and accumulation of Si, C, N, and P and their use efficiency and reduced the biological damage caused by water deficit due to the modification of homeostatic balance of C:N:P by ensuring sustainability of the production of sugarcane biomass in tropical soils. However, the intensity of attenuation of such deleterious effects stood out in plants cultivated in Eutrophic Red Oxisols. Si contributed biologically by improving the performance of sugarcane ratoon with an adequate irrigation due to the optimization of stoichiometric ratios of C:N:P; increased the accumulation and the use efficiency of C, N, and P, and promoted production gains in biomass of sugarcane in three tropical soils. CONCLUSION: Our study shows that fertigation with Si can mitigate the deleterious effects of deficient irrigation or potentiate the beneficial effects using an adequate irrigation system due to the induction of a new stoichiometric homeostasis of C:N:P, which in turn improves the nutritional efficiency of sugarcane cultivated in tropical soils.

Anticoagulants and reduced thrombus load in abdominal aortic aneurysms assessed with three-dimensional contrast-enhanced ultrasound examination.

OBJECTIVE: The relationship between intraluminal thrombus (ILT) and abdominal aortic aneurysm (AAA) growth and rupture risk remains ambiguous. Studies have shown a limited effect of antiplatelet therapy on ILT size, whereas the impact of anticoagulant therapy on ILT is unresolved. This study aims to evaluate an association between antithrombotic therapy and ILT size assessed with three-dimensional contrast-enhanced ultrasound (3D-CEUS) examination in a cohort of patients with AAA. METHODS: In a cross-sectional study, 309 patients with small AAAs were examined with 3D-CEUS. Patients were divided into three groups based on prescribed antithrombotic therapy: anticoagulant (n = 36), antiplatelet (n = 222), and no antithrombotic therapy (n = 51). Patient ILT size was calculated in volume and thickness and compared between the three groups. RESULTS: Patients on anticoagulants had a significantly lower estimated marginal mean ILT volume of 16 mL (standard error [SE], ±3.2) compared with 28 mL (SE, ±2.7) in the no antithrombotic group and 30 mL (SE, ±1.3) in the antiplatelet group when adjusting for AAA volume (P < .001) and comorbidities (P < .001). In addition, patients on anticoagulant therapy had significantly lower estimated marginal mean ILT thickness of 10 mm (SE, ±1.1) compared with 13 mm (SE, ±0.9) in the no antithrombotic group of and 13mm (SE, ±0.4) in the antiplatelet group when adjusting for AAA diameter (P = .03) and comorbidities (P = .035). CONCLUSIONS: A 3D-CEUS examination is applicable for ILT assessment and demonstrates that patients with AAA on anticoagulant therapy have lower ILT thickness and volume than patients with AAA on antiplatelet therapy and those without antithrombotic therapy. Causality between anticoagulants and ILT size, and extrapolation to AAA growth and rupture risk, is unknown and merits further investigations, to further nuance US-based AAA surveillance strategy.

Establishing stereochemical comparability in phosphorothioate oligonucleotides with nuclease P1 digestion coupled with LCMS analysis.

Stereochemical comparability is critical for ensuring manufacturing consistency in therapeutic phosphorothioate oligonucleotides. Currently, analytical methods for this assessment are limited. We hereby report on a novel protocol capable of detecting a stereochemistry change in a single phosphorothioate linkage by employing nuclease P1 digestion of the oligonucleotide with subsequent LCMS analysis of the resulting fragments. The method proves valuable for establishing stereochemical comparability and for ensuring manufacturing consistency of oligonucleotide therapeutics.

Blasticidin S inhibits mammalian translation and enhances production of protein encoded by nonsense mRNA.

Deciphering translation is of paramount importance for the understanding of many diseases, and antibiotics played a pivotal role in this endeavour. Blasticidin S (BlaS) targets translation by binding to the peptidyl transferase center of the large ribosomal subunit. Using biochemical, structural and cellular approaches, we show here that BlaS inhibits both translation elongation and termination in Mammalia. Bound to mammalian terminating ribosomes, BlaS distorts the 3'CCA tail of the P-site tRNA to a larger extent than previously reported for bacterial ribosomes, thus delaying both, peptide bond formation and peptidyl-tRNA hydrolysis. While BlaS does not inhibit stop codon recognition by the eukaryotic release factor 1 (eRF1), it interferes with eRF1's accommodation into the peptidyl transferase center and subsequent peptide release. In human cells, BlaS inhibits nonsense-mediated mRNA decay and, at subinhibitory concentrations, modulates translation dynamics at premature termination codons leading to enhanced protein production.

Indications and techniques for non-articulating spacers in massive bone loss following prosthetic knee joint infection: a scoping review.

INTRODUCTION: Prosthetic joint infection (PJI) is a destructive complication of knee replacement surgery (KR). In two-stage revision a spacer is required to maintain limb length and alignment and provide a stable limb on which to mobilise. Spacers may be articulating or static with the gold standard spacer yet to be defined. The aims of this scoping review were to summarise the types of static spacer used to treat PJI after KR, their indications for use and early complication rates. METHODS: We conducted a scoping review based on the Joanna Briggs Institute's "JBI Manual for Evidence Synthesis" Scoping review reported following Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. MEDLINE, EMBASE and CINAHL were searched from 2005 to 2022 for studies on the use of static spacers for PJI after KR. RESULTS: 41 studies (1230 patients/knees) were identified describing 42 static spacer constructs. Twenty-three (23/42 [54.2%]) incorporated cement augmented with metalwork, while nineteen (19/42, [45.9%]) were made of cement alone. Spacers were most frequently anchored in the diaphysis (22/42, [53.3%]), particularly in the setting of extensive bone loss (mean AORI Type = F3/T3; 11/15 studies 78.3% diaphyseal anchoring). 7.1% (79 of 1117 knees) of static spacers had a complication requiring further surgery prior to planned second stage with the most common complication being infection (86.1%). CONCLUSIONS: This study has summarised the large variety in static spacer constructs used for staged revision KR for PJI. Static spacers were associated with a high risk of complications and further work in this area is required to improve the quality of care in this vulnerable group.

Addition of silicon to boron foliar spray in cotton plants modulates the antioxidative system attenuating boron deficiency and toxicity.

BACKGROUND: Boron (B) nutritional disorders, either deficiency or toxicity, may lead to an increase in reactive oxygen species production, causing damage to cells. Oxidative damage in leaves can be attenuated by supplying silicon (Si). The aim of this study was to assess the effect of increasing foliar B accumulation on cotton plants to determine whether adding Si to the spray solution promotes gains to correct deficiency and toxicity of this micronutrient by decreasing oxidative stress via synthetizing proline and glycine-betaine, thereby raising dry matter production. RESULTS: B deficiency or toxicity increased H2O2 and MDA leaf concentration in cotton plants. H2O2 and MDA leaf concentration declined, with quadratic adjustment, as a function of increased leaf B accumulation. Proline and glycine-betaine leaf concentration increased under B-deficiency and B-toxicity. In addition, production of these nonenzymatic antioxidant compounds was greater in plants under toxicity, in relation to deficient plants. Adding Si to the B spray solution reduced H2O2 and MDA concentration in the plants under nutrient deficiency or toxicity. Si reduced H2O2, primarily in B-deficient plants. Si also increased proline and glycine-betaine concentration, mainly in plants under B toxicity. Dry matter production of B-deficient cotton plants increased up to an application of 1.2 g L- 1 of B. The critical B level in the spray solution for deficiency and toxicity was observed at a concentration of 0.5 and 1.9 g L- 1 of B, respectively, in the presence of Si, and 0.4 and 1.9 g L- 1 of B without it. In addition, the presence of Si in the B solution raised dry matter production in all B concentrations evaluated in this study. CONCLUSION: Our findings demonstrated that adding Si to a B solution is important in the foliar spraying of cotton plants because it increases proline and glycine-betaine production and reduces H2O2 and MDA concentration, in addition to mitigating the oxidative stress in cotton plants under B deficiency or toxicity.

Stress and Stress-Induced Glucocorticoids Facilitate Empathic Accuracy in Men but Have No Effects for Women.

Empathy, the ability to understand the feelings of other people, is critical for navigating our social world and maintaining social connections. Given that acute stress, and resulting increased glucocorticoids, triggers a shift in two large-scale brain networks, prioritizing salience over executive control, we predicted that acute psychosocial stress would facilitate empathic accuracy. We also investigated the moderating role of gender, given that men typically show a more robust glucocorticoid response to acute stress than women. As predicted, results from two independent experiments (N = 267 college-age participants; 2,256 observations) showed that acute psychosocial stress facilitated empathic accuracy for men, an effect related to their glucocorticoid response in the stress condition. Conversely, psychosocial stress had no effect on empathic accuracy for women, who also showed a smaller cortisol response to stress than men. Exploratory analyses further revealed that women taking oral contraceptives performed worse on the empathic-accuracy task than regularly cycling women. This research highlights the important, but complex, role of stress in cognitive empathy.

Hyperoxia and Antioxidants for Myocardial Injury in Noncardiac Surgery: A 2 × 2 Factorial, Blinded, Randomized Clinical Trial.

BACKGROUND: Hyperoxia and oxidative stress may be associated with increased risk of myocardial injury. The authors hypothesized that a perioperative inspiratory oxygen fraction of 0.80 versus 0.30 would increase the degree of myocardial injury within the first 3 days of surgery, and that an antioxidant intervention would reduce degree of myocardial injury versus placebo. METHODS: A 2 × 2 factorial, randomized, blinded, multicenter trial enrolled patients older than 45 yr who had cardiovascular risk factors undergoing major noncardiac surgery. Factorial randomization allocated patients to one of two oxygen interventions from intubation and at 2 h after surgery, as well as antioxidant intervention or matching placebo. Antioxidants were 3 g IV vitamin C and 100 mg/kg N-acetylcysteine. The primary outcome was the degree of myocardial injury assessed by the area under the curve for high-sensitive troponin within the first 3 postoperative days. RESULTS: The authors randomized 600 participants from April 2018 to January 2020 and analyzed 576 patients for the primary outcome. Baseline and intraoperative characteristics did not differ between groups. The primary outcome was 35 ng · day/l (19 to 58) in the 80% oxygen group; 35 ng · day/l (17 to 56) in the 30% oxygen group; 35 ng · day/l (19 to 54) in the antioxidants group; and 33 ng · day/l (18 to 57) in the placebo group. The median difference between oxygen groups was 1.5 ng · day/l (95% CI, -2.5 to 5.3; P = 0.202) and -0.5 ng · day/l (95% CI, -4.5 to 3.0; P = 0.228) between antioxidant groups. Mortality at 30 days occurred in 9 of 576 patients (1.6%; odds ratio, 2.01 [95% CI, 0.50 to 8.1]; P = 0.329 for the 80% vs. 30% oxygen groups; and odds ratio, 0.79 [95% CI, 0.214 to 2.99]; P = 0.732 for the antioxidants vs. placebo groups). CONCLUSIONS: Perioperative interventions with high inspiratory oxygen fraction and antioxidants did not change the degree of myocardial injury within the first 3 days of surgery. This implies safety with 80% oxygen and no cardiovascular benefits of vitamin C and N-acetylcysteine in major noncardiac surgery.

The use of implant-level connection in screw-retained fixed partial dentures: A 3-year randomised clinical trial.

OBJECTIVES: This randomised controlled trial compares the 3-year outcomes, that is, marginal bone-level (MBL) changes and clinical parameters, between an abutment-level (AL) and implant-level (IL) connection for implants with an internal conical connection (ICC) supporting a screw-retained fixed partial denture. MATERIAL AND METHODS: Fifty patients with 119 implants were randomly allocated to either the AL or IL group. Radiographic and clinical examinations were performed after one, two, and 3 years. A linear mixed model was used to evaluate the differences between groups. RESULTS: The MBL change was not significantly different between the groups at any point. The MBL was 0.12 ± 0.31 mm (AL) and 0.23 ± 0.26 mm (IL) after 1 year; 0.15 ± 0.34 mm (AL) and 0.17 ± 0.22 mm (IL) after 2 years; 0.18 ± 0.39 mm (AL) and 0.15 ± 0.21 mm (IL) after 3 years. The bleeding on probing was 43.44 ± 39.24% (AL) and 58.19 ± 41.20% (IL) after 1 year; 35.78 ± 39.22% (AL) and 50.43 ± 41.49% (IL) after 2 years; 51.27 ± 44.63% (AL) and 49.57 ± 37.31% (IL) after 3 years and was significantly different (p = .025) between 1 and 2 years. The probing depth showed a significant difference at each time point while the plaque was not significant between the groups. The overall technical, biological and prosthetic complication rates were 5.04%, 3.36%, and 16.00%, respectively. CONCLUSIONS: The MBL change was similar in the groups. The slight differences in the soft tissue complications between the groups are likely not of clinical relevance. An IL connection is considered to be a valid alternative to an AL set-up in ICC implants.

Acute toxicity and antitumor potential of 1,3,4-trisubstituted-1,2,3-triazole dhmtAc-loaded liposomes on a triple-negative breast cancer model.

For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.

Acute Psychosocial Stress Increases Cognitive-Effort Avoidance.

Adverse effects following acute stress are traditionally thought to reflect functional impairments of central executive-dependent cognitive-control processes. However, recent evidence demonstrates that cognitive-control application is perceived as effortful and aversive, indicating that stress-related decrements in cognitive performance could denote decreased motivation to expend effort instead. To investigate this hypothesis, we tested 40 young, healthy individuals (20 female, 20 male) under both stress and control conditions in a 2-day study that had a within-subjects design. Cognitive-effort avoidance was assessed using the demand-selection task, in which participants chose between performing low-demand and high-demand variants of a task-switching paradigm. We found that acute stress indeed increased participants' preference for less demanding behavior, whereas task-switching performance remained intact. Additional Bayesian and multiverse analyses confirmed the robustness of this effect. Our findings provide novel insights into how stressful experiences shape behavior by modulating our motivation to employ cognitive control.

Current status and further potential of lung donation after circulatory death.

Chronic organ shortage remains the most limiting factor in lung transplantation. To overcome this shortage, a minority of centers have started with efforts to reintroduce donation after circulatory death (DCD). This review aims to evaluate the experimental background, the current international clinical experience, and the further potential and challenges of the different DCD categories. Successful strategies have been implemented to reduce the problems of warm ischemic time, thrombosis after circulatory arrest, and difficulties in organ assessment, which come with DCD donation. From the currently reported results, controlled-DCD lungs are an effective and safe method with good mid-term and even long-term survival outcomes comparable to donation after brain death (DBD). Primary graft dysfunction and onset of chronic allograft dysfunction seem also comparable. Thus, controlled-DCD lungs should be ceased to be treated as marginal and instead be promoted as an equivalent alternative to DBD. A wide implementation of controlled-DCD-lung donation would significantly decrease the mortality on the waiting list. Therefore, further efforts in establishment of legislation and logistics are crucial. With regard to uncontrolled DCD, more data are needed analyzing long-term outcomes. To help with the detailed assessment and improvement of uncontrolled or otherwise questionable grafts after retrieval, ex-vivo lung perfusion is promising.