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Abstract In this research, active packaging which was made of all-natural component hydrogels from nanocellulose composited with silver nanoparticles at various concentrations (AgH) was studied. The concentration of silver nanoparticles ranged from 0.0078 to 0.0624 phr. AgH was characterized in terms of basic properties, functional properties, and packaging applications. Biocompatibility testing with the Caco-2 cell line showed that higher concentrations of silver (higher than 0.0312 phr) provided a lower cell viability rate (lower than 70% cell viability). Here, 0.0156 phr of silver nanoparticle concentration was the maximum loading that is safe for the target cell (82% cell viability) and was thus selected for use as active packaging. The antimicrobial activity showed that AgH at all concentrations inhibited both Gram bacteria up to 99.99%. Total volatile basic nitrogen compound testing showed that chicken meat preserved by AgH had the lowest values, indicating that AgH can prolong the shelf life in freshness level 1 (15% TVB-N) for 6.2 days compared to 3.9 and 4.1 days of blank and neat cellulose hydrogel. In addition, all AgH were gradually degraded over time and eventually disappeared within 15–30 days in organic soil.

Abstract Background Chest wall deformities, though relatively uncommon in childhood and adolescence, significantly affect aesthetic perception and can impact cardiac and respiratory function. This study aims to compare individuals with pectus deformities to a healthy control group, shedding light on the condition’s etiology and prognosis. Method Conducted as a case-control study between 2020 and 2022, the research included a case group of 71 patients with pectus excavatum or pectus carinatum who were followed up at the Pediatric Cardiology outpatient clinic. The control group consisted of 80 children without chronic diseases. Researchers retrospectively reviewed patient files, recording demographic data, echocardiography findings, and serum levels of calcium, phosphate, vitamin D, and alkaline phosphatase. Results Patients with chest wall deformities exhibited significantly lower serum levels of vitamin D, calcium, and phosphorus compared to those without deformities. Males constituted 77% of the case group, with 15.5% exhibiting abnormal echocardiogram results, with mitral valve anomalies being most prevalent. Conclusion While pectus deformities may lead to cardiac or respiratory issues, patient concerns often center around aesthetics. Unlike typical studies focused on surgical techniques and postoperative patients, our study focused on all diagnosed patients. Findings emphasize the importance of monitoring calcium, phosphorus, and vitamin D levels in pectus patients to manage surgical risks and facilitate recovery.

Abstract Background Sarcopenia, characterized by the loss of skeletal muscle, is assessed using appendicular skeletal muscle mass indices (ASMI). Various international groups propose different ASMI thresholds for assessing sarcopenia. However, the optimal ASMI that correlates best with physical performance measures in older Turkish adults remains unexplored. This study aims to determine which ASMI is most closely associated with physical performance measures, particularly low handgrip strength (dynapenia), in Turkish older adults. Methods The study included 326 individuals aged 60 and above. Comprehensive geriatric assessments were conducted on all participants, along with anthropometric evaluations and body composition analyses. ASMI was calculated by adjusting height squared, weight, and body mass index (BMI). Physical performance was assessed through handgrip strength, gait speed, and the chair stand test. Results The mean age of the participants was 74 ± 5.77 years, with 59.8% being women and 37.5% having dynapenia. Height-squared adjusted ASMI was not significantly associated with gait speed or the chair stand test. Weight-adjusted ASMI correlated with handgrip strength and gait speed but not with the chair stand test. Both height and weight-adjusted ASMI did not differ significantly between participants with and without dynapenia (p > 0.05). BMI-adjusted ASMI significantly correlated with all physical performance parameters (p

Abstract Background The use of mobilizing agents for hematopoietic stem cell (HSC) transplantation is insufficient for an increasing number of patients. We previously reported lipid made endocannabinoid (eCB) ligands act on the human bone marrow (hBM) HSC migration in vitro, lacking long term stability to be therapeutic candidate. In this study, we hypothesized if a novel 2-AG-loaded polycaprolactone (PCL)-based nanoparticle delivery system that actively targets BM via phosphatidylserine (Ps) can be generated and validated. Methods PCL nanoparticles were prepared by using the emulsion evaporation method and characterized by Zetasizer and scanning electron microscopy (SEM). The encapsulation efficiency and release profile of 2-AG were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The presence of cannabinoid receptors (CBRs) in HSCs and monocytes was detected by flow cytometry. Cell morphology and viability were assessed using transmission electron microscopy (TEM), SEM, and the WST-1 viability assay. The migration efficacy of the 2-AG and 2-AG-loaded nanoparticle delivery system on HSCs and HPSCs (TF-1a and TF-1) and monocytes (THP-1) was evaluated using a transwell migration assay. Results The 140–225 nm PCL nanoparticles exhibited an increasing polydispersity index (PDI) after the addition of Ps and 2-AG, with a surface charge ranging from − 25 to -50 mV. The nanoparticles released up to 36% of 2-AG within the first 8 h. The 2-AG-Ps-PCL did not affect cellular viability compared to control on days 5 and 10. The HSCs and monocytes expressed CB1R and CB2R and revealed increased migration to media containing 1 µM 2-AG-Ps-PCL compared to control. The migration rate of the HSCs toward monocytes incubated with 1 µM 2-AG-Ps-PCL was higher than that of the monocytes of control. The 2-AG-Ps-PCL formulation provided a real time mobilization efficacy at 1 µM dose and 8 h time window via a specific CBR agonism. Conclusion The newly generated and validated 2-AG-loaded PCL nanoparticle delivery system can serve as a stable, long lasting, targeted mobilization agent for HSCs and as a candidate therapeutic to be included in HSC transplantation (HSCT) protocols following scale-up in vivo preclinical and subsequent clinical trials. Graphical Abstract

This article revisits the traditional definition and concept of seaworthiness against the backdrop of technological developments in maritime transport and maritime law. These developments in the maritime industry, coupled with the increasing volume of maritime commerce, have affected the traditional doctrine of seaworthiness and necessitate its redefinition. Of the many developments, this article focuses on maritime security generally and cyber-risk and hence cyber-worthiness in particular. The article argues that cyber risk management, as a part of maritime safety and security standards, should be reflected in the modern doctrine of seaworthiness. It is problematic to provide a generally acceptable uniform definition for seaworthiness in maritime law, because the concept is both relative and technical. Furthermore, and considering the components of a seaworthy ship, the need to assess new systems related to technology used in ships and safety in navigation, and to determine whether a ship can be deemed “cyber-secure” has become essential.

Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to outline its pharmaco-toxicological profile by employing two different in vitro human cell cultures (keratinocytes—HaCaT—and osteosarcoma SAOS-2 cells), employing different techniques (MTT assay, cell morphology assessment, LDH assay, Hoechst staining and RT-PCR). Additionally, the results obtained are compared with three commercially available phosphorus-containing compounds (P1, P2, P3). The results recorded for the newly developed compound (P4) revealed good biocompatibility (cell viability of 77%) when concentrations up to 5 mM were used on HaCaT cells for 24 h. Also, the HaCaT cultures showed no significant morphological alterations or gene modulation, thus achieving a biosafety profile even superior to some of the commercial products tested herein. Moreover, in terms of anti-osteosarcoma activity, 2-carboxyethylphenylphosphinic acid expressed promising activity on SAOS-2 monolayers, the cells showing viability of only 55%, as well as apoptosis features and important gene expression modulation, especially Bid downregulation. Therefore, the newly developed compound should be considered a promising candidate for further in vitro and in vivo research related to osteosarcoma therapy.

Abstract. Background. The impact of the coronavirus disease 2019 (COVID-19) pandemic on patient decision making remains uncertain. This study aimed to investigate the effect of the pandemic on treatment preferences of patients with proximal ureteral stones. Materials and methods. Retrospective data regarding treatment preferences of patients diagnosed with symptomatic proximal ureteral stones between July 2018 and November 2021 at a single center were analyzed. Data from 493 patients were analyzed according to 2 groups, including patients diagnosed during the COVID-19 pandemic and those diagnosed during an equivalent period of time before the pandemic. Results. Preference for conservative treatment increased during the COVID-19 pandemic (p = 0.009). In patients who had previously undergone shock wave lithotripsy (SWL), the preference for SWL decreased and the preference for conservative treatment increased during the COVID-19 pandemic (p = 0.042). Multiple logistic regression analysis revealed a significant correlation between a preference for conservative treatment during the pandemic and no prior spontaneous stone passage (p = 0.003; odds ratio [OR], 2.48; 95% confidence interval [CI], 1.45–4.23), no hydronephrosis (p = 0.035; OR, 3.57; 95% CI, 1.34–9.49), and a visual analog scale score of 4 or less (p = 0.018; OR, 1.97; 95% CI, 1.15–3.38). Conclusions. A significant increase in the preference for conservative treatment was observed among patients diagnosed during the pandemic, and patients with a history of SWL demonstrated a preference shift from SWL to conservative treatment.

Objective: Appropriate nutritional support has positive effects on both the growth and morbidity of patients who have undergone surgery due to congenital heart disease during their neonatal period. The aims of this study were to determine enteral feeding characteristics throughout the post-operative period, to define difficulties and obstacles in oral feeding, and to establish dietary guidelines based on the acquired data. Methods: From January 2012 to December 2014, 87 patients were retrospectively evaluated. All patients were diagnosed with transposition of the great arteries and were operated on during their neonatal periods. The median age of the cases was 9.37+-5.73 5.73 days (3-30 days). Pre-operative, intraoperative, and post-operative parameters were recorded. Results: During the intensive care unit stay, factors that delayed the transition to full enteral feeding or resulted in the discontinuation of feeding were identified. Enteral feeding was applicable to all patients within the first 24 h. Full enteral feeding was achieved at a median of 3.3 days. Gastric residual was observed in 63.2% of the patients; this was considered to be one of the major reasons for stopping feeding. In patients with gastric residual, transition to full enteral feeding was delayed, and the frequency of interruption and discontinuation of feeding increased. It was observed that patients with feeding discontinuations had longer periods of transition to full enteral feeding. Conclusion: It is believed that early post-operative enteral feeding contributes to shortening the hospitalization stay, to providing discharge without the requirement of feeding support, and to reducing post-discharge homecare feeding difficulties.

The sol–gel process is a green method used in the last few decades to synthesize new organic–inorganic phosphorus-containing hybrid materials. The sol–gel synthesis is a green method because it takes place in mild conditions, mostly by using water or alcohol as solvents, at room temperature. Therefore, the sol–gel method is, among others, a promising route for obtaining metal-phosphonate networks. In addition to phosphorus, the obtained hybrid materials could also contain titanium, zirconium, boron, and other elements, which influence their properties. The sol–gel process has two steps: first, the sol formation, and second, the transition to the gel phase. In other words, the sol–gel process converts the precursors into a colloidal solution (sol), followed by obtaining a network (gel). By using the sol–gel method, different organic moieties could be introduced into an inorganic matrix, resulting in organic–inorganic hybrid structures (sometimes they are also referred as organic–inorganic copolymers).

Objective This study aimed to evaluate the prevalence of sarcopenia and its clinical significance in Turkish women with SLE, exploring the association between muscle mass, muscle strength and SLE disease activity.Methods A cross-sectional study was conducted at Gazi University Hospital’s Department of Rheumatology from January to December 2020. It involved 82 patients with SLE, diagnosed according to the 2019 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria, and 69 healthy controls. Sarcopenia was assessed using hand grip dynamometry (hand grip strength (HGS)) and bioelectrical impedance analysis for muscle mass, with sarcopenia defined according to the 2018 European Working Group on Sarcopenia in Older People criteria and specific cut-offs for the Turkish population. The main outcomes measured were the presence of sarcopenia and probable sarcopenia, HGS values, skeletal muscle mass index and SLE Disease Activity Index 2000 (SLEDAI-2K).Results Among the patients with SLE, 51.2% met the criteria for probable sarcopenia and 12.9% were diagnosed with sarcopenia. The mean HGS was significantly lower in the SLE group (21.7±4.9 kg) compared with controls, indicating reduced muscle strength. The prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies was 82.9%. Multivariate regression analysis identified height and levels of anti-dsDNA antibodies as independent predictors for developing probable sarcopenia. No significant association was found between clinical parameters, including SLEDAI-2K scores, and sarcopenia status.Conclusions Sarcopenia is prevalent among Turkish women with SLE, with a significant proportion showing reduced muscle strength. The study found no direct association between sarcopenia and SLE disease activity or clinical parameters. These findings underscore the importance of including muscle strength assessments in the routine clinical evaluation of patients with SLE to potentially improve management and quality of life.

BackgroundBoth alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown. ObjectiveThe 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking. MethodsThe study design was a mechanistic experimental trial, in which all participants received an alcohol reduction intervention followed by repeated assessments of behavioral and clinical outcomes. Persons were eligible if they were 45 years of age or older, had weekly alcohol consumption of 21 or more drinks (men) or 14 or more drinks (women), and were not at high risk of alcohol withdrawal. After a baseline assessment, participants received an intervention consisting of contingency management (money for nondrinking days) for at least 30 days followed by a brief motivational interview. After this, participants could either resume drinking or not. Study questionnaires, neurocognitive assessments, neuroimaging, and blood, urine, and stool samples were collected at baseline, 30 days, 90 days, and 1 year after enrollment. ResultsWe enrolled 57 persons with heavy drinking who initiated the contingency management protocol (mean age 56 years, SD 4.6 years; 63%, n=36 male, 77%, n=44 Black, and 58%, n=33 people with HIV) of whom 50 completed 30-day follow-up and 43 the 90-day follow-up. The planned study procedures were interrupted and modified due to the COVID-19 pandemic of 2020-2021. ConclusionsThis was the first study seeking to assess changes in brain (neuroimaging) and cognition after alcohol intervention in nontreatment-seeking people with HIV together with people without HIV as controls. Study design strengths, limitations, and lessons for future study design considerations are discussed. Planned analyses are in progress, after which deidentified study data will be available for sharing. Trial RegistrationClinicalTrials.gov NCT03353701; https://clinicaltrials.gov/study/NCT03353701 International Registered Report Identifier (IRRID)DERR1-10.2196/53684

IntroductionSynced ads differ from other forms of targeted advertising on mobile devices because they target concurrent media usage rather than location or predicted interest in the brand. For example, a TV-viewer’s smartphone could listen to the ads playing on the TV set and show matching social media ads. These social media ads could be timed to appear simultaneously with the TV ad, or shortly before or after.MethodsThis research reports a meta-analysis (N = 980) of four lab studies that used representative samples of consumers and realistic manipulations of synced ads. These studies contrasted with most previous studies of synced ads, which have used student samples and unrealistic manipulations or imagined scenarios, which means little is known about whether or why synced ads are effective in real life. These four studies manipulated the effects of synced-ad timing (simultaneous vs. sequential before or after) and the size of the mobile ad, to see if these moderate the effects of synced ads.ResultsThe results showed that synced ads were more effective, measured by unaided brand recall, when they were shown after the TV commercial, rather than simultaneously. Ad size had no moderating effect, which suggests that normal ads can be used, rather than the full-screen or pop-up ads used in previous studies. A final study, in which ad timing was user-controlled, rather than advertiser-controlled, showed that precise timing is not important for synced-ad effectiveness.DiscussionThese results suggest the effects of synced ads are best explained by repetition rather than synergy between the two exposures. There were no significant effects on brand attitude, ad liking, or purchase intention. These results have implications for theoretical models of synced-ad effectiveness, and for advertisers planning to use synced ads.

When it comes to the process of ensuring the stability, quality, and reliability of a power system, one of the most crucial components is known as the load frequency controller (LFC). It does this by ensuring that there is a balance between the amount of power that is produced and the amount that is consumed. This paper proposes a novel evolutionary approach, referred to as the Honey Badger Algorithm (HBA), PI/PID controllers should be configured in the best possible way in order to address the LFC problem in the electrical power system. The research takes into account a power system that is integrated between two areas and uses renewable energy sources, such as a wind system and a solar system. The utilization of renewable energy sources has the potential to yield favorable outcomes in frequency control through the provision of prompt and adaptable responses to fluctuations in system frequency, helping to maintain grid stability. The proposed HBA method is utilized to refine the controller parameter values, using a fitness function anchored on the integral of absolute error (IAE) and the integral time multiplied by absolute error (ITAE). The performance of the proposed HBA-based controller has evaluated under 5% step load perturbation (SLP) in area-1. The HBA-based controllers demonstrate greater performance in terms of settling time, overshoot, and fitness value when compared to other well-known optimization algorithms such as Particle Swarm Optimization (PSO), Whale Optimization Algorithm (WOA), and Grey Wolf Optimization (GWO). According to the obtained results, the IAE-based PID controller has the best performance. The HBA-based PID controller is evaluated according to the following performance criteria; the objective function value is 0.4201, the settling time values and overshoot values for the area-1, area-2 and tie-line are 15.6, 33.7 and 27.9 s and −6.6, −0.7 and −0.0071 Hz, respectively. According to the findings, the HBA is both a dependable and effective tool for finding solutions to LFC research problems in multi-source power systems.

Cyclodextrins, a family of cyclic oligosaccharides, have received considerable interest in the field of pharmaceuticals due to their unique molecular structure and versatile properties. In the context of vaccines, cyclodextrins can effectively encapsulate antigens, ensuring their protection from degradation and improving their immunogenicity. Cyclodextrins offer stability advantages to vaccines by preventing the degradation of labile vaccine components during storage and transportation. Furthermore, cyclodextrins can serve as adjuvants, potentiating the immune response triggered by vaccines. Their unique structure and interaction with the immune system enhance the recognition of antigens by immune cells, leading to an improved activation of both innate and adaptive immune responses. This adjuvant effect contributes to the development of robust and long-lasting immune protection against targeted pathogens. Owing to the distinctive attributes inherent to nanoparticles, their integration into vaccine formulations has assumed an imperative role. Through the encapsulation of vaccine antigens/adjuvants within cyclodextrin nanoparticles, the potency and stability of vaccines can be notably enhanced. In particular, the capacity of amphiphilic cyclodextrins to form nanoparticles through self-assembly without surfactants or co-solvents is a captivating prospect for their application as carrier systems for antigens. In conclusion, cyclodextrins present a promising platform for enhancing the efficacy and stability of vaccines. Their ability to encapsulate antigens, stabilize labile vaccine components and act as adjuvants demonstrates their potential to revolutionize vaccine formulation and delivery. Further research and development in this field will facilitate the translation of cyclodextrin-based vaccine technologies into practical and impactful immunization strategies, ultimately benefiting global health and disease prevention.

The most common tachyarrhythmias in childhood are narrow QRS complex tachyarrhythmias. The majority of these are supraventricular tachycardia (SVT). If electrocardiography is inconsistent with typical SVT, another underlying arrhythmia should be considered. In this case, a patient with narrow complex tachycardia who was diagnosed with atrial flutter after adenosine was presented to increase awareness on the subject.

Abstract Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.

Background: Subjective measures of auditory development are equally important as objective measures to obtain a realistic image of the hearing status in infants and toddlers. Objectives: The objectives of the current study were to translate and validate the LittleEARS questionnaire into the Hindi language, to calculate its psychometric properties and establish a regression curve of the scores obtained as a function of age, to calculate the inter-test and test retest reliability of the same. The secondary objectives were to compare the scores obtained by the normal hearing children and those with hearing impairment and to plot a regression curve of total scores obtained by the hearing-impaired children as a function of the duration of auditory training attended since their first fit of the device. Materials and methods: The procedures involved conventional translation, reverse translation, and content validation before administering the questionnaire. The translated version was administered to parents of 59 children with normal hearing and 41 children with hearing impairment. Results: The finalized version had good reliability and efficient internal consistency with a Cronbach alpha value of 0.96. The mean scores obtained by the normal hearing children showed a progressive pattern as a function of age. Conclusion: The LittleEARS questionnaire has been successfully translated and validated into the Hindi language with excellent validity and reliability and can be used for screening and early identification of hearing impairment and in evaluating the outcome of audiological treatment approaches.

Analyzing exhaled breath for volatile organic compounds (VOCs) using thermal desorption–gas chromatography–mass spectrometry (TD-GC-MS) offers a non-invasive diagnostic approach for various diseases. Despite its promise, the method faces challenges like sampling heterogeneity and high costs. Following the European Respiratory Society’s advocacy for methodological standardization, we developed the SPIRITAS (Standardized Product for Inexpensive Respiratory InvesTigation: A breath Sampler), a low-cost, disposable breath sampler. This study evaluates the SPIRITAS’s effectiveness in detecting targeted VOCs. We tested the SPIRITAS using the Peppermint Experiment, a standardized protocol that allows for comparison between different breath sampling and analytical practices by assessing the ability to detect five peppermint-specific VOCs after ingestion of a 200-milligram peppermint oil capsule. We included ten subjects and performed six breath samples per participant, including a baseline measurement taken before ingestion. We used the Wilcoxon signed-rank test to evaluate whether baseline values were significantly lower than the peak values of the targeted VOCs. Additionally, we conducted an experiment utilizing humidified medical-grade air to identify any VOCs attributable to the SPIRITAS setup itself. Results showed successful detection of four out of five targeted “peppermint-associated” VOCs: alpha-pinene (p ≤ 0.01), beta-pinene (p ≤ 0.01), menthone (p = 0.01), and menthol (p = 0.02), indicating significant differences between the baseline and peak values in the volunteers’ breath. However, detection of eucalyptol was inconsistent. In addition, we identified 16 VOCs that were released by the SPIRITAS, one of which remains unidentified. Our findings underscore the SPIRITAS’s potential for clinical applications, paving the way for broader biomarker research. The combination of ease of use, low cost, reduced risk of contamination, and standardization makes SPIRITAS very suitable for large-scale international studies. Furthermore, we have demonstrated the SPIRITAS’s effectiveness in detecting specific VOCs and identified 16 compounds originating from the SPIRITAS, ensuring that these compounds would not be mis-qualified as potential biomarkers in future clinical studies.

Objectives To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes.Design Observational study.Setting Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals).Participants An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital.Outcome measures We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion.Results Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11–1.46; p