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Abstract European e-commerce sales are increasing every year. Nowadays, customers buy more frequently online in smaller quantities. Handling this large amount of customer orders puts the logistic activities of the supply chain under pressure. At the same time, customers have high expectations concerning the delivery of their online purchase. In order to meet these expectations at low cost, B2C e-commerce companies have to reconsider their logistic activities. Instead of optimizing every single process of the supply chain, related problems need to be tackled simultaneously. In the integrated order picking-vehicle routing problem(I-OP-VRP), picking lists and vehicle routes are determined simultaneously. One possibility to meet the high expectations of customers is to allow customers to choose the time window in which they want to be delivered. However, the more customers select a time window during the purchasing process, the higher the total costs for the B2C e-commerce company since the company has less flexibility to construct their delivery routes. To cover the cost increase, e-commerce companies often only provide this service at an additional cost. The objective of this paper is to estimate the additional cost of allowing customers to choose a preferred delivery time window using the integrated order picking-vehicle routing problem. An experimental design is set up to investigate this service cost under varying circumstances depending on customer characteristics, time window characteristics and operator size. Based on the results of the ANOVA it can be concluded that the investigated factors have a significant influence on the additional cost of allowing customers to select a delivery time window.

BACKGROUND: Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. OBJECTIVE: To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. DESIGN SETTING AND PARTICIPANTS: A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n = 182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n = 177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. RESULTS AND LIMITATIONS: There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. CONCLUSIONS: Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. PATIENT SUMMARY: In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

Introduction Knee osteoarthritis (OA) is a chronic condition affecting joint function. Regular physical activity can enhance functional capacity and reduce pain. However, there is a scarcity of studies relating to knee OA during the COVID-19 pandemic, particularly its impact on symptoms and quality of life.Methods This analytic cross-sectional study design will recruit participants aged 40 and above from Metro Manila with knee pain and COVID-19 history. The Filipino version of the Knee Injury and Osteoarthritis Outcome Score and International Physical Activity Questionnaire-Short Form will be used to assess the mediating variables.Analysis The study will employ descriptive and regression analyses for data analysis and follow the Strengthening the Reporting of Observational Studies in Epidemiology statement for reporting the data.Ethics and dissemination This study has received ethical approval from the Ethics Review Committee of the College of Rehabilitation Sciences. Study results will be disseminated through peer-reviewed journal publications and conference presentations to ensure accessibility to healthcare professionals and stakeholders, contributing to the advancement of knee OA management in post-COVID settings.

IntroductionCollagen is essential for maintaining lung structure and function and its remodeling has been associated with respiratory diseases including chronic obstructive pulmonary disease (COPD). However, the cellular mechanisms driving collagen remodeling and the functional implications of this process in the pathophysiology of pulmonary diseases remain poorly understood.MethodsTo address this question, we employed Lyve1wt/cre; Csf1rflox/flox mice with specific depletion of Lyve-1+ macrophages and assessed the content, types and organization of collagen in lung compartments at steady state and after chronic exposure to cigarette smoke (CS).ResultsUsing this mouse model, we found that the absence of this subpopulation of tissue resident macrophage led to the deposition of type I collagen fibers around the alveoli and bronchi at steady state. Further analysis by polarized light microscopy and Sircol collagen assay revealed that the collagen fibers accumulating in the lungs depleted of Lyve-1+ macrophages were thicker and crosslinked. A decrease in MMP-9 gene expression and proteolytic activity together with an increase in Col1a1, Timp-3 and Lox expression accompanied the collagen alterations. Next, we investigated the effect of the collagen remodeling on the pathophysiology of COPD and airway function in mice lacking Lyve-1+ macrophages exposed chronically to cigarette smoke (CS), a well-established animal model of COPD. We found that deposition of collagen prior CS exposure protected these mice against destruction of alveoli (emphysema), and bronchi thickening and prevented loss of airway function.DiscussionThus, we uncover that interstitial Lyve-1+ macrophages regulate the composition, amount, and architecture of collagen network in the lungs at steady state and that such collagen remodeling functionally impacts the development of COPD. This study further supports the potential of targeting collagen as promising approaches to treat respiratory diseases.

Background Over the past two decades, the use of Metaverse-enhanced simulations in medical education has witnessed significant advancement. These simulations offer immersive environments and technologies, such as augmented reality, virtual reality, and artificial intelligence that have the potential to revolutionize medical training by providing realistic, hands-on experiences in diagnosing and treating patients, practicing surgical procedures, and enhancing clinical decision-making skills. This scoping review aimed to examine the evolution of simulation technology and the emergence of metaverse applications in medical professionals’ training, guided by Friedman’s three dimensions in medical education: physical space, time, and content, along with an additional dimension of assessment.Methods In this scoping review, we examined the related literature in six major databases including PubMed, EMBASE, CINAHL, Scopus, Web of Science, and ERIC. A total of 173 publications were selected for the final review and analysis. We thematically analyzed these studies by combining Friedman’s three-dimensional framework with assessment.Results Our scoping review showed that Metaverse technologies, such as virtual reality simulation and online learning modules have enabled medical education to extend beyond physical classrooms and clinical sites by facilitating remote training. In terms of the Time dimension, simulation technologies have made partial but meaningful progress in supplementing traditional time-dependent curricula, helping to shorten learning curves, and improve knowledge retention. As for the Content dimension, high-quality simulation and metaverse content require alignment with learning objectives, interactivity, and deliberate practice that should be developmentally integrated from basic to advanced skills. With respect to the Assessment dimension, learning analytics and automated metrics from metaverse-enabled simulation systems have enhanced competency evaluation and formative feedback mechanisms. However, their integration into high-stakes testing is limited, and qualitative feedback and human observation remain crucial.Conclusion Our study provides an updated perspective on the achievements and limitations of using simulation to transform medical education, offering insights that can inform development priorities and research directions for human-centered, ethical metaverse applications that enhance healthcare professional training.

IntroductionThis study examines the effect of cochlear implant (CI) device usage metrics on post-operative outcomes in unilateral CI recipients. The primary objective is to investigate the relationship between CI usage frequency (average daily CI use) and duration (total years of CI use) on electrically evoked cortical auditory-evoked potential (eCAEP) response peak latency (ms) and amplitude (μV).MethodsAdult CI users (n = 41) who previously exhibited absent acoustically evoked CAEP responses participated in the study. The peak latency and amplitude of eCAEP P1-N1-P2 responses were recorded, when present for the apical, medial, and basal test electrode contacts. CI duration was defined as the number of years between the date of CI activation and date that eCAEP testing was performed. CI usage frequency was defined as the average number of hours per day of audio processor use, which was recorded using the CI programming software.ResultsOverall, 27 participants (65.85%) exhibited detectable eCAEP responses across one or more electrode contacts. Among these, 18 participants (43.9%) elicited eCAEP responses at all three electrode contacts, while 7 (17.07%) showed responses at two contacts, and 2 (4.88%) at one contact. For the remaining 14 participants (34.15%), eCAEP responses were either absent or undetectable. CI usage frequency (average daily CI use [hours/day]) was captured for 32 (78%) of the participants (median 10.35 h/day, range 0.2–16 h/day). Participants with present eCAEP responses for the basal electrode (n = 14) showed significantly higher CI usage frequency (11.8 h/day, p = 0.026) compared to those with non-detectable responses (6.25 h/day). An association was found between higher CI usage frequency and reduced N1 (p = 0.002), P2 (p = 0.0037) and P1-N1 inter-peak (p = 0.015) response latency (ms). While CI duration (total CI use [years]) did not differ significantly between groups based on the presence of eCAEP responses, an association was found between greater CI duration and increased eCAEP response amplitude (μV) for the P2 (p = 0.008) and N1-P2 peak-peak (p = 0.009) response components.DiscussionAdditionally, most (65.85%) participants who previously exhibited absent acoustic CAEP responses developed eCAEP responses after consistent CI use and increased CI experience. These findings may suggest a potential for cortical plasticity and adaptation with consistent CI use over time. Recognizing the impact of device usage metrics on neural responses post-implantation enhances our understanding of the importance of consistent daily CI use. Overall, these findings contribute to addressing the variability among CI users, improving post-operative outcomes and advancing the standard of personalized care in auditory rehabilitation.

Abstract Background and Aims The coronavirus disease 2019 (COVID‐19) pandemic has affected the management of inflammatory bowel disease (IBD) patients. Elective operations and surveillance endoscopies were postponed for IBD patients to preserve healthcare resources and to prevent the spread of COVID‐19. This study aimed to describe the trends and outcomes of IBD surgery during the pandemic. Methods This was a retrospective propensity score‐matched analysis using data extracted from TriNetX, a multi‐institutional research database. IBD patients admitted for surgery were identified between March 2019 to February 2020 (prepandemic) and March 2020 to February 2023 (pandemic). The monthly volume of IBD surgical procedures was compared during the pandemic to the prepandemic period. After matching, the risk of adverse outcomes following IBD surgery was compared between the 3 years of the pandemic compared to the prepandemic cohort. Results There was a reduction in both elective and emergency IBD operations during the pandemic. These trends were not significant. After matching, the risks of returning to theaters and hospital readmission were comparable across the 3 years of the pandemic. In the first and second years of the pandemic, elective patients were at a greater risk of mortality (risk ratio [RR], 2; 95% confidence interval [CI], 1.160–3.448 and RR, 1.778; 95% CI, 1.003–3.150, respectively) and the emergency cohort had a higher risk of critical care admission (RR, 1.759; 95% CI, 1.126–2.747 and RR, 1.742; 95% CI, 1.131–2.682, respectively). Conclusion Our study highlights the impact of the COVID‐19 pandemic on the management of IBD patients undergoing surgery. These results provide insights into the management of IBD surgery during times of crisis and can help guide decision‐making and resource allocation for IBD patients requiring surgical intervention.

Activated carbon is employed for the adsorption of organic micropollutants (OMPs) from water, typically present in concentrations ranging from ng L−1 to μg L−1. However, the efficacy of OMP removal is considerably deteriorated due to competitive adsorption from background dissolved organic matter (DOM), present at substantially higher concentrations in mg L−1. Interpreting the characteristics of competitive DOM is crucial in predicting OMP adsorption efficiencies across diverse natural waters. Molecular weight (MW), aromaticity, and polarity influence DOM competitiveness. Although the aromaticity-related metrics, such as UV254, of low MW DOM were proposed to correlate with DOM competitiveness, the method suffers from limitations in understanding the interplay of polarity and aromaticity in determining DOM competitiveness. Here, we elucidate the intricate influence of aromaticity and polarity in low MW DOM competition, spanning from a fraction level to a compound level, by employing direct sample injection liquid chromatography coupled with ultrahigh-resolution Fourier-transform ion cyclotron resonance mass spectrometry. Anion exchange resin pre-treatment eliminated 93% of UV254-active DOM, predominantly aromatic and polar DOM, and only minimally alleviated DOM competition. Molecular characterization revealed that nonpolar molecular formulas (constituting 26% PAC-adsorbable DOM) with medium aromaticity contributed more to the DOM competitiveness. Isomer-level analysis indicated that the competitiveness of highly aromatic LMW DOM compounds was strongly counterbalanced by increased polarity. Strong aromaticity-derived π-π interaction cannot facilitate the competitive adsorption of hydrophilic DOM compounds. Our results underscore the constraints of depending solely on aromaticity-based approaches as the exclusive interpretive measure for DOM competitiveness. In a broader context, this study demonstrates an effect-oriented DOM analysis, elucidating counterbalancing interactions of DOM molecular properties from fraction to compound level.

ABSTRACT BACKGROUND: Despite the preference for multimodal treatment for gastric cancer, abandonment of chemotherapy treatment as well as the need for upfront surgery in obstructed patients brings negative impacts on the treatment. The difficulty of accessing treatment in specialized centers in the Brazilian Unified National Health System (SUS) scenario is an aggravating factor. AIMS: To identify advantages, prognostic factors, complications, and neoadjuvant and adjuvant therapies survival in gastric cancer treatment in SUS setting. METHODS: The retrospective study included 81 patients with gastric adenocarcinoma who underwent treatment according to INT0116 trial (adjuvant chemoradiotherapy), CLASSIC trial (adjuvant chemotherapy), FLOT4-AIO trial (perioperative chemotherapy), and surgery with curative intention (R0 resection and D2 lymphadenectomy) in a single cancer center between 2015 and 2020. Individuals with other histological types, gastric stump, esophageal cancer, other treatment protocols, and stage Ia or IV were excluded. RESULTS: Patients were grouped into FLOT4-AIO (26 patients), CLASSIC (25 patients), and INT0116 (30 patients). The average age was 61 years old. More than 60% of patients had pathological stage III. The treatment completion rate was 56%. The pathological complete response rate of the FLOT4-AIO group was 7.7%. Among the prognostic factors that impacted overall survival and disease-free survival were alcoholism, early postoperative complications, and anatomopathological status pN2 and pN3. The 3-year overall survival rate was 64.9%, with the CLASSIC subgroup having the best survival (79.8%). CONCLUSIONS: The treatment strategy for gastric cancer varies according to the need for initial surgery. The CLASSIC subgroup had better overall survival and disease-free survival. The INT0116 regimen also protected against mortality, but not with statistical significance. Although FLOT4-AIO is the preferred treatment, the difficulty in carrying out neoadjuvant treatment in SUS scenario had a negative impact on the results due to the criticality of food intake and worse treatment tolerance.

IntroductionCochlear implant (CI) provision has been shown to be the only hearing rehabilitation option that can improve speech perception in noise and sound localization in SSD listeners. Individuals with SSD are known to exert increased listening effort when compared to normal hearing individuals, and this remains true even with CI use. Recently, reaction time (RT) has emerged as a promising metric for quantifying listening effort. As such, the current study compared performance (RT and Accuracy) of SSD participants (with and without the use of their CI) to normal hearing (NH) listeners. We assessed three listening conditions: (1) monaural listening in quiet, (2) free field listening in quiet, and (3) free field listening in background noise.MethodSSD CI data was retrospectively obtained from two past studies conducted by the group. For monaural listening and free field listening in quiet, the same 10 SSD CI participants and 10 NH controls was recruited. For free field listening in noise condition, 12 SSD CI participants and 12 NH controls were recruited. In all condition, participants were required to complete an auditory oddball task, discerning odd and even numbers. RT and target accuracy were the metrics recorded.ResultsIn monaural listening conditions, SSD CI users exhibited significantly delayed RTs compared to their NHE and to NH controls when stimuli was played directly through the CI. Surprisingly, the RT for the NHE of SSD CI users was also delayed when compared to the NH controls. Free field listening in quiet conditions showed increased RTs for SSD CI users, with and without CI, compared to NH controls, indicating the persistent impact of SSD on processing. In free field listening in noise, CI use significantly improved RTs for SSD individuals but did not reach NH levels. Despite the RT differences, task accuracy remained comparable between groups.DiscussionSSD CI users exhibited longer RTs in all test conditions, suggesting they expend more listening effort than normal hearing controls. This increased effort likely accounts for the delayed RTs, highlighting the additional processing challenges faced by SSD CI users.

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0–24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61–0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66–0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97–1.24), p > 0.05) and 2 (ratio 1.03 (0.94–1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

An 18-year-old woman presented to the emergency department. She had ingested 43 extended-release tablets of carbamazepine 400 mg. Although the patient had high carbamazepine plasma levels and classified as severe intoxication, her clinical symptoms were less severe than expected. With the combination of hemodialysis and continuous venovenous hemodialysis in addition to usual care, including multiple-dose activated charcoal, a fast decrease (within 3 days) in carbamazepine plasma levels to levels in the therapeutic range was achieved. Only one session of hemodialysis was performed because the clinical status of the patient stabilized. In retrospect, the patient did not suffer severe toxicological symptoms from carbamazepine. Therefore, continuous venovenous hemodialysis could have been discontinued earlier. On the other hand, the fast decrease in carbamazepine plasma levels during extracorporeal treatment may have prevented the development of severe or rebound toxicological symptoms. This case report adds evidence to the successful management of carbamazepine intoxication using hemodialysis followed by continuous venovenous hemodialysis.

Protein hydrolysates have gained interest as plant biostimulants due to their positive effects on plant performances. They are mainly composed of amino acids, but there is no evidence of the role of individual of amino acids as biostimulants. In this study we carried out in vitro experiments to monitor the development of Arabidopsis seedlings on amino acid containing media in order to analyze the biostimulant properties of the twenty individual proteinogenic amino acids. We demonstrated that proteinogenic amino acids are not good nitrogen sources as compared to nitrate for plant growth. Biostimulant analyses were based on leaf area measurements as a proxy of plant growth. We developed the Amino Acid Use Efficiency index to quantify the biostimulating effect of individual amino acids in the presence of nitrate. This index allowed us to classify amino acids into three groups, characterized by their inhibiting, neutral, and beneficial effects regarding leaf area. Glutamine and asparagine demonstrated the most significant effects in promoting leaf area in the presence of nitrate supply. The stimulating effect was confirmed by using the L and D enantiomeric forms. Both L-glutamine and L-asparagine stimulated leaf area at low concentrations, emphasizing their biostimulating properties. Our plant growth design and AAUE index pave the way for the identification of other bioactive molecules in protein hydrolysates and for the comparison of biostimulant performances.

Objectives The economic consequences of untreated surgical disease are potentially large. The aim of this study was to estimate the economic burden associated with unmet surgical needs in Liberia.Design A nationwide enumeration of surgical procedures and providers was conducted in Liberia in 2018. We estimated the number of disability-adjusted life years (DALYs) saved by operative activities and converted these into economic losses averted using gross national income per capita and value of a statistical life (VSL) approaches. The total, the met and the unmet needs for surgery were determined, and economic losses caused by unmet surgical needs were estimated. Finally, we valued the economic losses avoided by various surgical provider groups.Results A total of 55 890 DALYs were averted by surgical activities in 2018; these activities prevented an economic loss of between US$35 and US$141 million. About half of these values were generated by the non-specialist physician workforce. Furthermore, a non-specialist physician working a full-time position for 1 year prevented an economic loss of US$717 069 using the VSL approach, while a specialist resident and a certified specialist saved US$726 606 and US$698 877, respectively. The burden of unmet surgical need was associated with productivity losses of between US$388 million and US$1.6 billion; these losses equate to 11% and 46% of the annual gross domestic product for Liberia.Conclusion The economic burden of untreated surgical disease is large in Liberia. There is a need to strengthen the surgical system to reduce ongoing economic losses; a framework where specialist and non-specialist physicians collaborate may result in better economic return than a narrower focus on training specialists alone.