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Abstract Low anterior resection (LAR) and abdominoperineal resection (APR) are the two main surgical procedures after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. APR is associated with poorer prognosis; however existing data do not consider intensified CRT (5-Fluorouracil (5-FU)/Oxaliplatin + radiation) protocols. Clinicopathological data of patients treated with APR and LAR from the CAO/ARO/AIO-04 trial were analysed in terms of prognostic parameters and quality of life (QoL). Based on higher response rate after intensified CRT, subgroup analyses were performed. Data from n = 1173 patients were assessed. APR after preoperative CRT was associated with a significantly worse overall survival (p = 0.0056), disease-free survival (p more...

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards. more...

Context: Understanding Paralympic athletes' perspectives on the importance of sleep is the first step toward developing effective sleep hygiene (SH) strategies. We aim to describe and compare the knowledge about SH and sleep behaviors practiced by medalists and nonmedalists Paralympic athletes at the Tokyo 2020 Paralympic Games and between sexes (female vs male), identify whether the coaching staff encourages SH, and the perspective of these athletes on the importance of SH. Methods: 98 Paralympic athletes responded to the Sleep Beliefs Scale and the Athlete Sleep Behavior Questionnaire-BR. Results: Medalists (68%) and nonmedalists (78%) Paralympic athletes had low knowledge about SH (60% vs 55%; P =.20), with no difference between groups. The Athlete Sleep Behavior Questionnaire-BR score (48.7 [5.9]) for all Paralympic athletes (n = 98) indicated high practice of maladaptive sleep behaviors. Male athletes had significantly worse sleep behaviors than female athletes (49.1 [6.0] vs 39.5 [7.2]; P <.01) and less knowledge about behaviors that can affect sleep (64% vs 72%; P <.05), 26% of Paralympic athletes considered SH practices necessary, and the frequency of coaching staff encouraging SH was higher among medalists Paralympic athletes compared to nonmedalists athletes (29% vs 13%, P =.04). Conclusions: Most Paralympic athletes have inadequate sleep behaviors and knowledge about SH. There was no difference between knowledge about SH and sleep behaviors between medalists and nonmedalists Paralympic athletes, although medalists athletes were more encouraged to practice SH. Male Paralympic athletes had worse sleep behaviors and worse knowledge about SH than female athletes. [ABSTRACT FROM AUTHOR] more...

Abstract Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP‐activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF‐3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF‐3758309 shows activity in pre‐clinical PDAC models, including primary patient‐derived organoids. Genetic loss‐of‐function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF‐3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK‐targeting compounds and deciphered the framework for the development of AMPK inhibitor‐based combination therapies tailored for PDAC. more...

Introduction: Many patients have unaddressed social needs that significantly impact their health, yet navigating the landscape of available resources and eligibility requirements is complex for both patients and clinicians.  Methods: Using an iterative design-thinking approach, our multidisciplinary team built, tested, and deployed a digital decision tool called “Discharge Navigator” (edrive.ucsf.edu/dcnav) that helps emergency clinicians identify targeted social resources for patients upon discharge from the acute care setting. The tool uses each patient’s clinical and demographic information to tailor recommended community resources, providing the clinician with action items, pandemic restrictions, and patient handouts for relevant resources in five languages. We implemented two modules at our urban, academic, Level I trauma center.  Results: Over the 10-week period following product launch, between 4-81 on-shift emergency clinicians used our tool each week. Anonymously surveyed clinicians (n = 53) reported a significant increase in awareness of homelessness resources (33% pre to 70% post, P more...

Introduction: Reperfusion therapy is generally recommended in acute high-risk pulmonary embolism (HR-PE), but several population-based studies report that it is underused. Data on epidemiology, management and outcomes of HR-PE in Portugal are scarce. Objective: To determine the reperfusion rate in HR-PE patients, the reasons for non-reperfusion, and how it influences outcomes. Methods: In this retrospective cohort study of consecutive HR-PE patients admitted to a thromboembolic disease referral center between 2008 and 2018, independent predictors for non-reperfusion were assessed by multivariate logistic regression. PE-related mortality and long-term MACE (cardiovascular mortality, PE recurrence and chronic thromboembolic disease) were calculated according to the Kaplan–Meier method. Differences stratified by reperfusion were assessed using the log-rank test. Results: Of 1955 acute PE patients, 3.8% presented with hemodynamic instability. The overall reperfusion rate was 50%: 35 patients underwent systemic thrombolysis, one received first-line percutaneous embolectomy and one rescue endovascular treatment. Independent predictors of non-reperfusion were: age, with >75 years representing 12 times the risk of non-treatment (OR 11.9, 95% CI 2.7–52.3, p=0.001); absolute contraindication for thrombolysis (31.1%), with recent major surgery and central nervous system disease as the most common reasons (OR 16.7, 95% CI 3.2–87.0, p 75 anos associou-se a 12 vezes mais risco de NR (OR 11,9, 95%CI 2,7-52,3, p=0,001); contraindicações absolutas para trombólise (31,1%), sendo a cirurgia major recente e a doença do sistema nervoso central as causas mais comuns (OR 16,7, IC95% 3,2-87,0, p more...

Background/objectiveBurnout is common among resident physicians, which has the potential to translate into diagnostic and management errors. Our study investigates the relationship between sleepiness, depression, anxiety, burnout, and lack of professional fulfillment with clinical performance during a critically ill patient simulation. Methods/Approach: Emergency medicine residents were recruited to participate in a high-fidelity simulation case of a critically ill patient. A survey with validated wellbeing measures (National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH PROMIS), Linzer burnout measure, and professional fulfillment index) was administered prior to the simulation. Each encounter was video-recorded and analyzed by two blinded raters based on a binary critical-actions checklist. Time-to-intubation, management errors, and misdiagnosis rates were assessed.ResultsTwenty residents participated, with most subjects endorsing sleepiness (70%) and less than half reporting depression (40%) and anxiety (45%). Burnout was identified to be in 50% of participants by the Linzer measure and 85% by the professional fulfillment index. No significant difference was found between mean performance scores in sleepy, depressed, and anxious cohorts in comparison to groups without those symptoms. Similarly, burnout and professional fulfillment did not yield any significant difference, nor did comparisons with time to intubation, management errors, and frequency of misdiagnosis.ConclusionResident burnout, depression, anxiety, sleepiness, and lack of professional fulfillment did not appear to have a measurable impact on clinical performance in managing a critically ill patient. There is no evidence from this study that the lack of resident physician well-being adversely impacts patient care by increasing errors in management or misdiagnoses during this high-fidelity simulation. more...

BackgroundPostnatal maternal anxiety is common (estimates as high as 40% prevalence) and is associated with altered mother-infant interactions (e.g., reduced maternal emotional expression and engagement). Neural circuitry supporting infants' face and emotion processing develops in their first year. Thus, early exposure to maternal anxiety may impact infants' developing understanding of emotional displays. We examine whether maternal anxiety is associated with individual differences in typically developing infants' neural responses to emotional faces.MethodsOne hundred and forty two mother-infant dyads were assessed when infants were 5, 7, or 12 months old. Infants' electroencephalographic (EEG) data were recorded while passively viewing female happy, fearful, and angry faces. Three event-related potential (ERP) components, each linked to face and emotion processing, were evaluated: NC, N290, and P400. Infant ERP amplitude was related to concurrent maternal-report anxiety assessed with the Spielberger State-Trait Anxiety Inventory (Trait form).ResultsGreater maternal anxiety predicted more negative NC amplitude for happy and fearful faces in left and mid-central scalp regions, beyond covarying influences of maternal depression symptoms, infant negative emotionality, and infant age.ConclusionsPostnatal maternal anxiety is related to infants' neural processing of emotional expressions. Infants of mothers endorsing high trait anxiety may need additional attentional resources to process happy and fearful faces (expressions less likely experienced in mother-infant interactions). Future research should investigate mechanisms underlying this association, given possibilities include experiential, genetic, and prenatal factors. more...

The power relations manifest themselves on our social interactions and act upon the bodies of all individuals. The body, for that matter, constitutes a very important element on social construction of male and female identities — for women, it has the power of preventing personal development possibilities, defining their social roles in family and in society. In this scenario, starting from the assumptions of GilbertDurand ́s imaginary theory, the present work intends to explore, on the figurative context of the novel Meu corpo ainda quente (2020), of Sheyla Smanioto, the idea of feminine body colonization and the many violences that result from it. The bookin question, as an expression of historical and social conditions of the time when it was produced, represents, in its own way, women fight for the exercise of a full citizenship, historically built by claiming a voice that for a long time was denied for them. more...

ABSTRACTVector-borne infections may underlie some rheumatic diseases, particularly in people with joint effusions. This study aimed to compare serum and synovial fluid antibodies to B. burgdorferi and Bartonella spp. in patients with rheumatic diseases. This observational, cross-sectional study examined paired synovial fluid and serum specimens collected from 110 patients with joint effusion between October 2017 and January 2022. Testing for antibodies to B. burgdorferi (using CDC criteria) and Bartonella spp. via two indirect fluorescent antibody (IFA) assays was performed as part of routine patient care at the Institute for Specialized Medicine (San Diego, CA, USA). There were 30 participants (27%) with positive two-tier B. burgdorferi serology and 26 participants (24%) with IFA seroreactivity (≥1:256) to B. henselae and/or B. quintana. Both B. burgdorferi IgM and IgG were detected more frequently in synovial fluid than serum: 27% of patients were either IgM or IgG positive in synovial fluid, compared to 15.5% in serum (P = 0.048). Conversely, B. henselae and B. quintana antibodies were detected more frequently in serum than synovial fluid; overall only 2% of patients had positive IFA titers in synovial fluid, compared to 24% who had positive IFA titers in serum (P < 0.001). There were no significant associations between B. burgdorferi or Bartonella spp. seroreactivity with any of the clinical rheumatological diagnoses. This study provides preliminary support for the importance of synovial fluid antibody testing for documenting exposure to B. burgdorferi but not for documenting exposure to Bartonella spp.IMPORTANCEThis study focuses on diagnostic testing for two common vector-borne diseases in an affected patient population. In it, we provide data showing that antibodies to B. burgdorferi, but not Bartonella spp., are more commonly found in synovial fluid than serum of patients with joint effusion. Since Lyme arthritis is a common—and sometimes difficult to diagnose—rheumatic disease, improving diagnostic capabilities is of utmost importance. While our findings are certainly not definitive for changes to practice, they do suggest that synovial fluid could be a useful sample for the clinical diagnosis of Lyme disease, and future prospective studies evaluating this claim are warranted. more...

The increasing frequency and duration of marine heatwaves (MHWs) due to climate change pose severe threats to aquaculture, causing drastic physiological and growth impairments in farmed fish, undermining their resilience against additional environmental pressures. To ensure sustainable production that meets the global seafood demand and animal welfare standards, cost-effective and eco-friendly strategies are urgently needed. This study explored the efficacy of the red macroalga Asparagopsis taxiformis on juvenile white seabream Diplodus sargus reared under optimal conditions and upon exposure to a MHW. Fish were fed with four experimental diets (0%, 1.5%, 3% or 6% of dried powdered A. taxiformis) for a prophylactic period of 30 days (T30) and subsequently exposed to a Mediterranean category II MHW for 15 days (T53). Biometric data and samples were collected at T30, T53 and T61 (8 days post-MHW recovery), to assess performance indicators, biomarker responses and histopathological alterations. Results showed that A. taxiformis supplementation improved catalase and glutathione S-transferase activities and reduced lipid peroxidation promoted by the MHW, particularly in fish biofortified with 1.5% inclusion level. No histopathological alterations were observed after 30 days. Additionally, fish biofortified with 1.5% A. taxiformis exhibited increased citrate synthase activity and fish supplemented with 1.5% and 3% showed improved digestive enzyme activities (e.g., pepsin and trypsin activities). Overall, the present findings pointed to 1.5% inclusion as the optimal dosage for aquafeeds biofortification with A. taxiformis, and confirmed that this seaweed species is a promising cost-effective ingredient with functional properties and great potential for usage in a climate-smart context. more...

Siloxanes are a group of substances characterized by Si-O-Si functional group. Siloxanes can react with alcohols to form Si-O-C bond. Siloxanes have been widely used as crossing linking agents and graft copolymers as well as additives for plastics. Lignin contains both phenolic and aliphatic hydroxy groups which have the potential to instigate bonding with siloxane compounds. However, there has not been any attempt to apply siloxanes as crosslinking agents for biobased composite formation. This manuscript presents the first study of applying siloxanes compounds to lignin and Cellulose nanofibers (CNF) with respective PLA, PETG, and HDPE to prepare biocomposites. Both Tetramethyl Tetraphenyl Trisiloxane (TTT) and Tetraethoxysilane (TEOS) were used as cross-linking agents. We have successfully incorporated 20 wt% lignin and 10 wt% CNF into the biocomposite filaments. The tensile properties of ensuing biocomposite were investigated. The objective of this work is to demonstrate the potential of lignin and CNF as a sustainable co-polymer to improve the properties of PLA/PETG/HDPE-based materials for 3D printing. This paper will also discuss the challenges and opportunities associated with the use of lignin in 3D printing, including the effect of lignin and CNF content on the mechanical and thermal properties, the compatibility of lignin and CNF with PLA/PETG/HDPE, and the potential for further optimization of the cross-linking chemistry using TTT and TEOS. more...

ObjectiveHypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies.Research design & methodsRandomized, controlled trial of 5,047 participants with T2DM of 7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose ResultsWhile participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (pConclusionsIn metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin.Trial registrationClinicalTrials.gov Identifier: NCT01794143. more...

The increasing demand for healthy aquatic products has contributed to the rapid growth of aquaculture. Despite the many progresses, over the years, in aquaculture production, animal welfare and reduction of the stress induced by captivity remain a challenge in this sector, and overcoming it is fundamental to improve animal growth performance and resilience to environmental threats (e.g., disease outbreaks and/or climate change impacts). To address this challenge, aquafeeds biofortified with natural ingredients with functional properties, such as macroalgae, have emerged as a promising strategy to enhance fish immunity. The present study aimed at evaluating the potential of Laminaria digitata to improve juvenile gilthead seabream (Sparus aurata) physiological status and resilience, through the modulation of immunomodulatory and antioxidant responses. To explore this hypothesis, four independent treatments were carried out in which fish were fed with different experimental aquafeeds: control feed and biofortified feeds with 1.5%, 3% and 6% of whole L. digitata (incorporated as a dried and powdered ingredient). Fish (n=9) were collected from each treatment upon 30 and 60 days of biofortification in order to assess animal growth and condition indexes, haematological parameters, innate humoral parameters (antiprotease (AP) activity, peroxidase (POD) activity and immunoglobulin M (IgM)) and oxidative stress biomarkers (lipid peroxidation (LPO), catalase (CAT) activity, glutathione S-transferase (GST) activity, superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC)). Significant differences (α = 0.05) between treatments in biomarker responses were tested through a nested-design ANOVA, followed by Tukey HSD multiple comparisons. Pearson correlations between the different endpoints were also explored. Results indicate that a dietary inclusion of 1.5% L. digitata is the most effective biofortification dose, significantly improving antioxidant responses of S. aurata, by increasing levels of CAT, GST and T-AOC, along with the reduction in LPO levels. Additionally, the inclusion of 1.5% L. digitata enhances immunity by increasing the levels of IgM and POD, while maintaining the growth performance and condition indices of the fish. These findings underscore the potential utilization of L. digitata as a functional feed ingredient in aquaculture with relevant immune and antioxidant attributes. more...

The unprecedented COVID-19 pandemic has resulted in rapidly evolving best practices for transmission reduction, diagnosis, and treatment. A regular influx of new information has upended traditionally static hospital protocols, adding additional stress and potential for error to an already overextended system. To help equip frontline emergency clinicians with up-to-date protocols throughout the evolving COVID-19 crisis, our team set out to create a dynamic digital tool that centralized and standardized resources from a broad range of platforms across our hospital. Using a design thinking approach, we rapidly built, tested, and deployed a solution using simple, out-of-the-box web technology that enables clinicians to access the specific information they seek within moments. This platform has been rapidly adopted throughout the emergency department, with up to 70% of clinicians using the digital tool on any given shift and 78.6% of users reporting that they “agree” or “strongly agree” that the platform has affected their management of COVID-19 patients. The tool has also proven easily adaptable, with multiple protocols being updated nearly 20 times over two months without issue. This paper describes our development process, challenges, and results to enable other institutions to replicate this process to ensure consistent, high-quality care for patients as the COVID-19 pandemic continues its unpredictable course. more...

Background: Postoperative liver failure (PLF) is a severe complication after major liver resection (MLR). To increase the safety of patients, clinical bedside tests are of great importance. However, limitations of their applicability and validity impair their value. Methods: Preoperative measurements of the liver maximum capacity (LiMAx) were performed in n = 40 patients, who underwent MLR (≥3 segments). Matched postoperative LiMAx was measured in n = 21 patients. Liver function was compared between pretreated patients (n = 11 with portal vein embolisation (PVE) and n = 19 patients with preoperative chemotherapy) and therapy naïve patients. The LiMAx values were compared with liver-specific blood parameters and volumetric analysis. Results: In total, n = 40 patients were enrolled in this study. The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (>315 µg/kg/h), while only seven patients (17.5%) had medium values (140–315 µg/kg/h), and none of the patients had low values (p > 0.05). The preoperative LiMAx values were significantly higher than the matched postoperative values on postoperative day 1 (p < 0.0001). A comparison between the expected and measured postoperative LiMAx showed a difference (≥10%) in 7 out of 13 patients (53.8%). After an initial postoperative decrease in the LiMAx, the patients without complications (n = 12) showed a continuous increase until 14 days after surgery. In the patients with postoperative complications, a decrease in the LiMAx was associated with a prolonged recovery. Conclusions: For patients undergoing MLR within the 0.5% rule, which is the clinical gold standard, the LiMAx values do not offer any additional information. Additionally, the LiMAx may have reflected liver function, but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule. more...