QTc prolongation across CDK4/6 inhibitors: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16,196 patients, of whom 8,576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR 2.35; 95% CI 1.67-3.29; p < .001; I2=44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a risk ratio of 3.12 (RR 3.12; 95% CI 2.09-4.65; p < .001; I2 = 12%) while the palbociclib subgroup had a risk ratio of 1.51 (RR 1.51; 95% CI 1.05-2.15; p = .025, I2=0%). CONCLUSION: Palbociclib was associated with QTc prolongation, however, the RR for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

Immunotherapy Plus Chemotherapy Versus Chemotherapy Alone as First-Line Treatment for Advanced Urothelial Cancer: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Platinum-based chemotherapy (CTX) has historically been the primary treatment for advanced urothelial cancer (aUC), with limited alternative options. The therapeutic landscape experienced a paradigm shift following the results of the EV-302 and Checkmate-901 trials, which led to the approval of Enfortumab vedotin plus pembrolizumab (EV-P) as the preferred first-line treatment, and nivolumab plus CTX for those unable to receive the preferred regimen. Currently, further investigations are underway to explore PD-1 and PD-L1 inhibitors in the initial treatment of aUC. PATIENTS AND METHODS: We conducted a systematic search across PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) comparing immune checkpoint inhibitors (ICI)-CTX combinations versus CTX alone as first-line treatment for advanced UC. Employing a random-effects model, we pooled hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Our analysis encompassed 3 RCTs, involving 2162 participants, with 51.16% randomized to combination therapy with platinum-based CTX. Compared to CTX alone, immune-chemotherapy significantly improved overall survival (HR 0.84; 95% CI 0.75-0.93; P < .01), progression-free survival (HR 0.78; 95% CI 0.70-0.86; P < .01), and objective response rate (RR 1.20; 95% CI 1.06-1.36; P < .01), while elevating the risk of immune-related adverse events (P-value = .02). CONCLUSION: In this meta-analysis of RCTs, ICI plus CTX demonstrated a significant association with improved survival at the expense of an increased risk of immune-related adverse events. Therefore, our findings suggest that this combination should be considered as an initial treatment for aUC in platinum-eligible patients who cannot receive EV-P.

pKa Calculations of GPCRs: Understanding Protonation States in Receptor Activation.

The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation-conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp2.50 residue in five different class A GPCRs (active and inactive conformations) using a linear response approximation (LRA) pKa calculation protocol. We observed consistent differences (1.3 pK units) for the macroscopic pKa values between the inactive and active states of the A2AR and B2AR receptors, indicating the protonation of Asp2.50 during GPCR activation. This process seems to be specific and not conserved, as no differences were observed in the pKa values of the remaining receptors (CB1R, NT1R, and GHSR).

Baseline surveillance in Li Fraumeni syndrome using whole-body MRI: a systematic review and updated meta-analysis.

OBJECTIVES: Li-Fraumeni syndrome (LFS) is a cancer syndrome associated with early-onset neoplasias. The use of whole-body magnetic resonance imaging (WBMRI) is recommended for regular cancer screening, however, evidence supporting the benefits in asymptomatic LFS patients is limited. This study aims to assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline and follow-up. MATERIALS AND METHODS: We systematically searched PubMed, Cochrane, and Embase databases for studies evaluating WBMRI as an early detection method for tumor screening in patients with LFS. We pooled the prevalence of the included variables along with their corresponding 95% confidence intervals (CIs). Statistical analyses were performed using R software, version 4.3.1. RESULTS: From 1687 results, 11 comprising 703 patients (359 females (51%); with a median age of 32 years (IQR 1-74)) were included. An estimated detection rate of 31% (95% CI: 0.28, 0.34) for any suspicious lesions was found in asymptomatic TP53 carriers who underwent baseline WBMRI. A total of 277 lesions requiring clinical follow-up were identified in 215 patients. Cancer was confirmed in 46 lesions across 39 individuals. The estimated cancer diagnosis rate among suspicious lesions was 18% (95% CI: 0.13, 0.25). WBMRI detected 41 of the 46 cancers at an early-disease stage, with an overall detection rate of 6% (95% CI: 0.05, 0.08). The incidence rate was 2% per patient round of WBMRI (95% CI: 0.01, 0.04), including baseline and follow-up. CONCLUSION: This meta-analysis provides evidence that surveillance with WBMRI is effective in detecting cancers in asymptomatic patients with LFS. CLINICAL RELEVANCE STATEMENT: Our study demonstrates that whole-body MRI is an effective tool for early cancer detection in asymptomatic Li-Fraumeni Syndrome patients, highlighting its importance in surveillance protocols to improve diagnosis and treatment outcomes. KEY POINTS: Current evidence for whole-body MRI screening of asymptomatic Li-Fraumeni Syndrome (LFS) patients remains scarce. Whole-body MRI identified 41 out of 46 cancers at an early stage, achieving an overall detection rate of 6%. Whole-body MRI surveillance is a valuable method for detecting cancers in asymptomatic LFS patients.

Effects of environmental variability on phytoplankton structure, diversity and biomass at the Brazil-Malvinas Confluence (BMC).

The Brazil-Malvinas Confluence (BMC) is a significant biological frontier where distinct currents meet, fostering optimal conditions for phytoplankton development. In this study we tested the hypothesis that eddys promote an increase in phytoplankton biomass at the Brazil-Malvinas Confluence (BMC), altering species diversity. Phytoplankton were collected with Niskin bottles and nutrient concentrations assessed at two depths (Surface and Deep Chlorophyll Maximum Layer - DCML) in areas outside and under the influence of Cold-Core (CCE) and Warm-Core (WCE) Eddies. Environmental variables were determined in situ using a CTD profiler. Four regions were separated based on environmental variables and phytoplankton species, namely, the Brazil Current (BC), Malvinas Current (MC), CCE, and WCE. Species diversity was higher in the eddies. The conditions of the WCE were different from those of the CCE, with low temperature and salinity and high cell density values in the latter. The phylum Bacillariophyta was predominant in terms of species richness in all regions and was responsible for the higher cell density in the MC, while dinoflagellates were dominant in the BC and eddies. Therefore, eddy activity alters the structure, diversity and biomass of the phytoplankton community in the BMC.

Laparoscopic Versus Open Pancreatoduodenectomy for Periampullary Tumors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Laparoscopic pancreatoduodenectomy (LPD) has emerged as an alternative to open technique in treating periampullary tumors. However, the safety and efficacy of LPD compared to open pancreatoduodenectomy (OPD) remain unclear. Thus, we conducted an updated meta-analysis to evaluate the efficacy and safety of LPD versus OPD in patients with periampullary tumors, with a particular focus on the pancreatic ductal adenocarcinoma patient subgroup. METHODS: According to PRISMA guidelines, we searched PubMed, Embase, and Cochrane Library in December 2023 for randomized controlled trials (RCTs) that directly compare LPD versus OPD in patients with periampullary tumors. Endpoints and sensitive analysis were conducted for short-term endpoints. All statistical analysis was performed using R software version 4.3.1 with a random-effects model. RESULTS: Five RCTs yielding 1018 patients with periampullary tumors were included, of whom 511 (50.2%) were randomized to the LPD group. Total follow-up time was 90 days. LPD was associated with a longer operation time (MD 66.75; 95% CI 26.59 to 106.92; p = 0.001; I2 = 87%; Fig. 1A), lower intraoperative blood loss (MD - 124.05; 95% CI - 178.56 to - 69.53; p < 0.001; I2 = 86%; Fig. 1B), and shorter length of stay (MD - 1.37; 95% IC - 2.31 to - 0.43; p = 0.004; I2 = 14%; Fig. 1C) as compared with OPD. In terms of 90-day mortality rates and number of lymph nodes yield, no significant differences were found between both groups. CONCLUSION: Our meta-analysis of RCTs suggests that LPD is an effective and safe alternative for patients with periampullary tumors, with lower intraoperative blood loss and shorter length of stay.

Optimizing radiotherapy strategies for skull base chordoma: a comprehensive meta-analysis and systematic review of treatment modalities and outcomes.

OBJECTIVE: In the treatment of skull base chordoma (SBC) surgery is considered the mainstay approach, and gross-total resection has an established relationship with progression-free survival (PFS) and overall survival (OS). However, the tumor's location often interferes with attempts at complete resection. In this case, surgery for maximal resection followed by high-dose radiotherapy has been demonstrated to be the standard treatment. In this context, various modalities are available, yet no consensus exists on the most effective. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of different radiotherapy modalities for SBC. METHODS: Following PRISMA guidelines, the authors systematically searched for the treatment of SBC with radiation modalities in the PubMed, Cochrane, Web of Science, and EMBASE databases. Outcomes assessed for each modality were as follows: OS, PFS, local control (LC), and complications. The random-effects model was adopted. A single-proportion analysis with 95% CI was used to measure the effects in single-arm analysis. For the comparative analysis, the OR with 95% CI was used to compare outcome treatment effects. Heterogeneity was assessed using I2 statistics, and statistical significance was defined as p < 0.05. RESULTS: A total of 32 studies comprising 3663 patients, with 2322 patients who were treated with radiotherapeutic modalities, were included. Regarding 5-year OS findings in each modality study, the findings were as follows: in photon fractionated radiotherapy, an estimated rate of 77% (69%-84%, 568 patients); in conventional fractionated radiotherapy, 76% (65%-87%, 517 cases); in proton-based + carbon ion-based radiotherapy, 85% (82%-88%, 622 cases); and in a comparative analysis of proton-based and carbon ion-based therapy, there was an OR of 1.2 (95% CI 0.59-2.43, 306 cases). Regarding the 5-year PFS estimate, the rates were as follows: 35% (26%-45%, 95 cases) for photon fractionated therapy; 35% (25%-45%, 85 cases) for stereotactic radiotherapy; 77% (50%-100%, 180 cases) for proton-based and carbon ion-based radiotherapy; and 74% (45%-100%, 102 cases) for proton-based radiotherapy. Regarding LC in periods of 3 and 5 years after proton- and carbon ion-based therapy, the overall estimated rates were 84% (78%-90%, 326 cases) and 75% (65%-85%, 448 cases), respectively. For proton-based radiotherapy and carbon ion-based therapy, the 5-year LC rates were 76% (67%-86%, 259 cases) and 75% (59%-91%, 189 cases), respectively. CONCLUSIONS: The analysis highlights the finding that particle-based modalities like proton beam radiotherapy and carbon ion radiotherapy are the most effective radiation therapies available for the treatment of SBC. Furthermore, it reinforces the idea that surgery followed by radiotherapy constitutes the standard treatment.

PypKa server: online pKa predictions and biomolecular structure preparation with precomputed data from PDB and AlphaFold DB.

When preparing biomolecular structures for molecular dynamics simulations, pKa calculations are required to provide at least a representative protonation state at a given pH value. Neglecting this step and adopting the reference protonation states of the amino acid residues in water, often leads to wrong electrostatics and nonphysical simulations. Fortunately, several methods have been developed to prepare structures considering the protonation preference of residues in their specific environments (pKa values), and some are even available for online usage. In this work, we present the PypKa server, which allows users to run physics-based, as well as ML-accelerated methods suitable for larger systems, to obtain pKa values, isoelectric points, titration curves, and structures with representative pH-dependent protonation states compatible with commonly used force fields (AMBER, CHARMM, GROMOS). The user may upload a custom structure or submit an identifier code from PBD or UniProtKB. The results for over 200k structures taken from the Protein Data Bank and the AlphaFold DB have been precomputed, and their data can be retrieved without extra calculations. All this information can also be obtained from an application programming interface (API) facilitating its usage and integration into existing pipelines as well as other web services. The web server is available at pypka.org.

Laparoscopic Versus Open Gastrectomy for Advanced Gastric Cancer: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Laparoscopy-assisted gastrectomy (LAG) is a well-established surgical technique in treating patients with early gastric cancer. However, the efficacy and safety of LAG versus open gastrectomy (OG) in patients with advanced gastric cancer (AGC) remains unclear. METHODS: We systematically searched PubMed, Embase, and Cochrane Library in June 2023 for RCTs comparing LAG versus OG in patients with AGC. We pooled risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for binary and continuous endpoints, respectively. We performed all statistical analyses using R software version 4.3.1 and a random-effects model. RESULTS: Nine RCTs comprising 3827 patients were included. There were no differences in terms of intraoperative complications (RR 1.14; 95% CI 0.72 to 1.82), number of retrieved lymph nodes (MD -0.54 lymph nodes; 95% CI -1.18 to 0.09), or mortality (RR 0.91; 95% CI 0.30 to 2.83). LAG was associated with a longer operative time (MD 49.28 minutes; 95% CI 30.88 to 67.69), lower intraoperative blood loss (MD -51.24 milliliters; 95% CI -81.41 to -21.06), shorter length of stay (MD -0.83 days; 95% CI -1.60 to -0.06), and higher incidence of pancreatic fistula (RR 2.44; 95% CI 1.08 to 5.50). Postoperatively, LAG was also superior to OG in reducing bleeding rates (RR 0.44; 95% CI 0.22 to 0.86) and time to first flatus (MD -0.27 days; 95% CI -0.47 to -0.07), with comparable results in anastomotic leakage, wound healing issues, major complications, time to ambulation, or time to first liquid intake. In the long-term analyses at 3 and 5 years, there were no significant differences between LAG and OG in terms of overall survival (RR 0.99; 95% CI 0.96 to 1.03) or relapse-free survival (RR 0.99; 95% CI 0.94 to 1.04). CONCLUSION: This meta-analysis of RCTs suggests that LAG may be an effective and safe alternative to OG for treating AGC; albeit, it may be associated with an increased risk for pancreatic fistula.

Efficacy and Safety of Intraoperative Radiotherapy for High-Grade Gliomas: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: High-grade gliomas (HGGs) are aggressive tumors of the central nervous system that cause significant morbidity and mortality. Despite advances in surgery and radiation therapy (RT), HGG still has a high incidence of recurrence and treatment failure. Intraoperative radiotherapy (IORT) has emerged as a promising therapeutic approach to achieve local tumor control while sparing normal brain tissue from radiation-induced damage. METHODS: A systematic review and meta-analysis were conducted following PRISMA guidelines to evaluate the use of IORT for HGG. Eligible studies were included based on specific criteria, and data were independently extracted. Outcomes of interest included complications, IORT failure, survival rates at 12 and 24 months, and mortality. RESULTS: Sixteen studies comprising 436 patients were included. The overall complication rate after IORT was 17%, with significant heterogeneity observed. The IORT failure rate was 77%, while the survival rates at 12 and 24 months were 74% and 24%, respectively. The mortality rate was 62%. CONCLUSION: This meta-analysis suggests that IORT may be a promising adjuvant treatment for selected patients with HGG. Despite the high rate of complications and treatment failures, the survival outcomes were comparable or even superior to conventional methods. However, the limitations of the study, such as the lack of a control group and small sample sizes, warrant further investigation through prospective randomized controlled trials to better understand the specific patient populations that may benefit most from IORT. However, the limitations of the study, such as the lack of a control group and small sample sizes, warrant further investigation. Notably, the ongoing RP3 trial (NCT02685605) is currently underway, with the aim of providing a more comprehensive understanding of IORT. Moreover, future research should focus on managing complications associated with IORT to improve its safety and efficacy in treating HGG.

Polyvascular Disease Influences Long-Term Cardiovascular Morbidity in Carotid Endarterectomy.

INTRODUCTION/OBJECTIVE: Carotid stenosis (CS) is an important cause of ischemic stroke. Secondary prevention lies in performing a carotid endarterectomy (CEA) procedure, the recommended treatment in most cases. When 2 or more vascular regions are simultaneously affected by atherosclerosis, mainly the carotid arteries, coronary arteries, or limb arteries, a multivessel disease polyvascular disease (PVD) is present. This study aims to assess the potential role of PVD as a long-term predictor of major adverse cardiovascular events (MACE) and all-cause mortality in patients submitted to CEA. METHODS: From January 2012 to December 2021, patients submitted to CEA for carotid stenosis in a tertiary care and referral center were eligible from a prospective database. A posthoc survival analysis was performed using the Kaplan-Meier survival curve method. The primary outcome was the incidence of long-term MACE and all-cause mortality. Secondary outcomes included acute myocardial infarction (AMI), major adverse limb events (MALE), stroke, and acute heart failure (AHF). RESULTS: A total of 207 patients were enrolled, with a median follow-up of 63 months. The mean age was 70.4 ± 8.9, and 163 (78.7%) were male. There were 65 (31.4%) patients that had 2 arterial vascular territories affected, and 29 (14.0%) patients had PVD in 3 arterial beds. On multivariable analysis, both MACE and all-cause mortality had as independent risk factors age (aHR 1.039, P = 0.003; aHR 1.041, P = 0.019), chronic kidney disease (aHR 2.524, P = 0.003; aHR 3.377, P < 0.001) and PVD2 (aHR 3.381, P < 0.001; aHR 2.665, P = 0.013). PVD1 was only associated with MACE as a statistically significant risk factor (aHR 2.531, 1.439-4.450, P < 0.001). CONCLUSIONS: PVD in patients with cerebrovascular disease (CVD) was revealed to carry a 2-fold increased risk for all-cause mortality and MACE during long-term follow-up. PVD may be a simple yet valuable tool in predicting all-cause mortality, MACE, AMI, and MALE after CEA.

Phosphorylation Dynamics in a flg22-Induced, G Protein-Dependent Network Reveals the AtRGS1 Phosphatase.

The microbe-associated molecular pattern flg22 is recognized in a flagellin-sensitive 2-dependent manner in root tip cells. Here, we show a rapid and massive change in protein abundance and phosphorylation state of the Arabidopsis root cell proteome in WT and a mutant deficient in heterotrimeric G-protein-coupled signaling. flg22-induced changes fall on proteins comprising a subset of this proteome, the heterotrimeric G protein interactome, and on highly-populated hubs of the immunity network. Approximately 95% of the phosphorylation changes in the heterotrimeric G-protein interactome depend, at least partially, on a functional G protein complex. One member of this interactome is ATBα, a substrate-recognition subunit of a protein phosphatase 2A complex and an interactor to Arabidopsis thaliana Regulator of G Signaling 1 protein (AtRGS1), a flg22-phosphorylated, 7-transmembrane spanning modulator of the nucleotide-binding state of the core G-protein complex. A null mutation of ATBα strongly increases basal endocytosis of AtRGS1. AtRGS1 steady-state protein level is lower in the atbα mutant in a proteasome-dependent manner. We propose that phosphorylation-dependent endocytosis of AtRGS1 is part of the mechanism to degrade AtRGS1, thus sustaining activation of the heterotrimeric G protein complex required for the regulation of system dynamics in innate immunity. The PP2A(ATBα) complex is a critical regulator of this signaling pathway.

Safety and Serum Estradiol Levels in Hormonal Treatments for Vulvovaginal Atrophy in Breast Cancer Survivors: A Systematic Review and Meta-Analysis.

Vulvo-vaginal atrophy (VVA) or genitourinary syndrome of menopause (GSM) is a common condition among breast cancer (BC) patients, especially those undergoing antiestrogen therapy. Despite being an option in refractory cases, the safety of hormonal treatment remains uncertain in this population. The aim of this study was to review the safety and serum estrogen levels of hormonal therapy in patients with BC history presenting with VVA symptoms. Pubmed, Embase, and Cochrane were searched for studies comparing different hormonal treatment options for VVA in breast cancer survivors. Statistical analysis was performed using a random effects model and heterogeneity using Cochran's Q-statistic and the I2 index. We included 17 studies, of which 5 were randomized controlled trials (RCTs). Treatment modalities included in this study were topical vaginal estradiol and estriol preparations, vaginally applied testosterone, DHEA, and ospemifene. We found that, among patients treated with the estriol and estradiol preparations, there was an average increase of 7.67 pg/mL (SMD 7.67 pg/mL; 95% CI -1.00, 16.35; p < .001). Analysis of the testosterone group found temporary peaks of serum estradiol levels, but 1 study showed persistent elevation above normal postmenopausal levels. One study with prasterone revealed no elevation of serum estradiol concentration. One study with ospemifene demonstrated no increase in the risk of BC recurrence. In conclusion, among treatments available for BC survivors, low-dose vaginal estrogen showed the smallest changes in serum estradiol levels and had the most evidence, but safety remains unclear, especially for patients on aromatase inhibitors. Alternative treatments such as ospemifene need more data supporting safety and efficacy. These results suggest that concerns related to cancer recurrence should keep aiming for the lowest possible concentration.

Transmission-Blocking Vaccines for Canine Visceral Leishmaniasis: New Progress and Yet New Challenges.

Dogs with visceral leishmaniasis play a key role in the transmission cycle of Leishmania infantum to humans in the urban environment. There is a consensus regarding the importance of developing a vaccine to control this disease. Despite many efforts to develop a protective vaccine against CVL, the ones currently available, Leish-tec® and LetiFend®, have limited effectiveness. This is due, in part, to the complexity of the immune response of the naturally infected dogs against the parasite and the complexity of the parasite transmission cycle. Thus, strategies, such as the development of a transmission-blocking vaccines (TBVs) already being applied to other vector-borne diseases like malaria and dengue, would be an attractive alternative to control leishmaniasis. TBVs induce the production of antibodies in the vertebrate host, which can inhibit parasite development in the vector and/or interfere with aspects of vector biology, leading to an interruption of parasite transmission. To date, there are few TBV studies for CVL and other leishmaniasis forms. However, the few studies that exist show promising results, thus justifying the further development of this approach.

Fluid-structure interactions of bristled wings: the trade-off between weight and drag.

The smallest flying insects often have bristled wings resembling feathers or combs. We combined experiments and three-dimensional numerical simulations to investigate the trade-off between wing weight and drag generation. In experiments of bristled strips, a reduced physical model of the bristled wing, we found that the elasto-viscous number indicates when reconfiguration occurs in the bristles. Analysis of existing biological data suggested that bristled wings of miniature insects lie below the reconfiguration threshold, thus avoiding drag reduction. Numerical simulations of bristled strips showed that there exist optimal numbers of bristles that maximize the weighted drag when the additional volume due to the bristles is taken into account. We found a scaling relationship between the rescaled optimal numbers and the dimensionless bristle length. This result agrees qualitatively with and provides an upper bound for the bristled wing morphological data analysed in this study.

The strength of surgical knots involves a critical interplay between friction and elastoplasticity.

Knots are the weakest link in surgical sutures, serving as mechanical ligatures between filaments. Exceeding their safe operational limits can cause fatal complications. The empirical nature of present guidelines calls for a predictive understanding of the mechanisms underlying knot strength. We identify the primary ingredients dictating the mechanics of surgical sliding knots, highlighting the previously overlooked but critical effect of plasticity and its interplay with friction. The characterization of surgeon-tied knots reveals the relevant ranges of tightness and geometric features. Using model experiments coupled with finite element simulations, we uncover a robust master curve for the target knot strength versus the tying pre-tension, number of throws, and frictional properties. These findings could find applications in the training of surgeons and robotic-assisted surgical devices.

State-of-the-Art Molecular Plant Sciences in Brazil.

Brazil has a crucial role in global food security and biodiversity, boasting one of the largest agricultural areas and two globally vital biomes, the Amazon and the Atlantic Forest [...].

Regulation of the swimming kinematics of lampreys Petromyzon marinus across changes in viscosity.

The bodies of most swimming fishes are very flexible and deform as result of both external fluid dynamic forces and internal musculoskeletal forces. If fluid forces change, the body motion will also change unless the fish senses the change and alters its muscle activity to compensate. Lampreys and other fishes have mechanosensory cells in their spinal cords that allow them to sense how their body is bending. We hypothesized that lampreys (Petromyzon marinus) actively regulate body curvature to maintain a fairly constant swimming waveform even as swimming speed and fluid dynamic forces change. To test this hypothesis, we measured the steady swimming kinematics of lampreys swimming in normal water, and water in which the viscosity was increased by 10 or 20 times by adding methylcellulose. Increasing the viscosity over this range increases the drag coefficient, potentially increasing fluid forces up to 40%. Previous computational results suggested that if lampreys did not compensate for these forces, the swimming speed would drop by about 52%, the amplitude would drop by 39%, and posterior body curvature would increase by about 31%, while tail beat frequency would remain the same. Five juvenile sea lampreys were filmed swimming through still water, and midlines were digitized using standard techniques. Although swimming speed dropped by 44% from 1× to 10× viscosity, amplitude only decreased by 4%, and curvature increased by 7%, a much smaller change than the amount we estimated if there was no compensation. To examine the waveform overall, we performed a complex orthogonal decomposition and found that the first mode of the swimming waveform (the primary swimming pattern) did not change substantially, even at 20× viscosity. Thus, it appears that lampreys are compensating, at least partially, for the changes in viscosity, which in turn suggests that sensory feedback is involved in regulating the body waveform.

R2CHA2DS2-VA Predictsthe Cardiovascular Risk after Carotid Endarterectomy.

BACKGROUND: R2CHA2DS2-VA score has been used to predict short and long-term outcomes in many cardiovascular diseases. This study aims to validate the R2CHA2DS2-VA score as a long-term major adverse cardiovascular events (MACE) predictor after carotid endarterectomy (CEA). Secondary outcomes were also assessed regarding the incidence of all-cause mortality, acute myocardial infarction (AMI), major adverse limb events (MALE), and acute heart failure (AHF). METHODS: From January 2012 to December 2021, patients (n = 205) from a Portuguese tertiary care and referral center that underwent CEA with regional anesthesia (RA) for carotid stenosis (CS) were selected from a previously collected prospective database, and a posthoc analysis was performed. Demographics and comorbidities were registered. Clinical adverse events were assessed 30 days after the procedure and in the subsequent long-term surveillance period. Statistical analysis was performed by the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Of the patients enrolled, 78.5% were males with a mean age of 70.44 ± 8.9 years. Higher scores of R2CHA2DS2-VA were associated with long-term MACE (adjusted hazard ratio (aHR) 1.390; 95% confidence interval (CI) 1.173-1.647); and mortality (aHR 1.295; 95% CI 1.08-1.545). CONCLUSIONS: This study demonstrated the potential of the R2CHA2DS2-VA score to predict long-term outcomes, such as AMI, AHF, MACE, and all-cause mortality, in a population of patients submitted to carotid endarterectomy.

Snap buckling of bistable beams under combined mechanical and magnetic loading.

We investigate the mechanics of bistable, hard-magnetic, elastic beams, combining experiments, finite-element modelling (FEM) and a reduced-order theory. The beam is made of a hard magneto-rheological elastomer, comprising two segments with antiparallel magnetization along the centreline, and is set into a bistable curved configuration by imposing an end-to-end shortening. Reversible snapping is possible between these two stable states. First, we experimentally characterize the critical field strength for the onset of snapping, at different levels of end-to-end shortening. Second, we perform three-dimensional FEM simulations using the Riks method to analyse high-order deformation modes during snapping. Third, we develop a reduced-order centreline-based beam theory to rationalize the observed magneto-elastic response. The theory and simulations are validated against experiments, with an excellent quantitative agreement. Finally, we consider the case of combined magnetic loading and poking force, examining how the applied field affects the bistability and quantifying the maximum load-bearing capacity. Our work provides a set of predictive tools for the rational design of one-dimensional, bistable, magneto-elastic structural elements. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.