Search Results (7,703)

Background: Effective topical anesthesia is essential to patient comfort and adherence during minimally invasive esthetic procedures. We retrospectively reviewed pain scores recorded after microneedling in a single private clinic where two topical anesthetic formulations—lidocaine 7%/tetracaine 7% (Pliaglis) and lidocaine 2.5%/prilocaine 2.5% (Anesderm)—were used as part of standard clinical practice on different anatomical sites and under different application protocols. Methods: Records were reviewed from 26 healthy female patients (mean age 42 ± 4 years; range 34–48) who underwent microneedling on the face and neck during 2024 in a single private clinic. According to the established clinic protocol, which was not modified for research purposes, Pliaglis was applied to the face without additional occlusion (self-occlusive peel-off film, in accordance with the manufacturer’s recommendation) and Anesderm was applied to the neck under plastic-film occlusion (also in accordance with the manufacturer’s recommendation), both for 45 min prior to microneedling at a fixed depth of 1.25 mm. Treatment allocation was determined by clinic workflow; patients and the operator were not blinded, and the order of the two products within each session was not randomized. Post-procedural pain was recorded using a Visual Analog Scale (VAS, 0–10), with one decimal precision, separately for each anatomical site. Within-patient differences were analyzed using a paired-sample t-test, with a Wilcoxon signed-rank test as a non-parametric sensitivity analysis. Results: Pain scores were lower at the facial site (Pliaglis, no occlusion) than at the cervical site (Anesderm, occlusion): mean VAS 3.00 ± 0.63 vs. 5.38 ± 0.75; mean within-patient difference 2.38 points, 95% CI 1.97–2.80; paired t(25) = 11.87, p < 0.0001; Cohen’s d = 2.33. The Wilcoxon signed-rank test produced a concordant result (p < 0.0001). A within-patient pain reduction of at least 30% on the facial site relative to the cervical site was observed in 81% of patients (21/26). Both products were well tolerated, with only mild transient erythema reported. Conclusions: In this retrospective, non-randomized, non-blinded single-center analysis, lower pain scores were observed at the facial site (treated with lidocaine-tetracaine 7%/7% without additional occlusion, per manufacturer instructions) than at the cervical site (treated with lidocaine-prilocaine 2.5%/2.5% under occlusion, per manufacturer instructions) within the same patients. Because formulation, active-drug concentration, anatomical site, and the manufacturer-mandated occlusion technique co-varied between the two conditions, the observed difference cannot be attributed to formulation alone. These findings should be regarded as hypothesis-generating and require confirmation in prospective, randomized, split-region or split-face studies that disentangle formulation effects from site- and protocol-related factors. Full article

Background/Objectives: Dogs are important carriers and transmitters of staphylococci from surface microbiota. Carriage screening allows for the identification of animals colonised with pathogens such as methicillin-resistant S. pseudintermedius (MRSP) and methicillin-resistant S. aureus (MRSA), which are spread between animals and from dogs to humans. This cross-sectional study determined the diversity of staphylococci from the surface microbiota of clinically healthy dogs in Bulgaria and their susceptibility to antimicrobial agents. Methods: The study was performed with 30 healthy dogs reared in the region of Stara Zagora, Bulgaria in 2024 and 2025. Swabs were obtained from eight body sites from each dog and incubated on blood and mannitol salt agar. Random isolates were identified by MALDI-TOF MS and tested for resistance to oxacillin/cefoxitin and to 14 classes of antimicrobial drugs (AMD). Results: Ninety out of 100 tested isolates were confirmed as Staphylococcus spp. from 15 different species. The total share of coagulase-positive (CoPS) staphylococci significantly exceeded that of coagulase-negative (CoNS) ones. Fifteen phenotypically methicillin-resistant staphylococci were identified—eight CoNS and seven CoPS—and confirmed by MIC test. The highest resistance was against penicillin (64.4%), ampicillin and minocycline (52.2%), whereas the highest sensitivity was to rifampin, amikacin, cefquinome and amoxicillin + clavulanic acid. Conclusions: Data about the carriage of MRSP, MRSA and multidrug-resistant coagulase-negative staphylococci in healthy dogs are important in view of the increased risk of colonisation/infection for people in contact with these dogs in households and veterinary facilities (clinics, hospitals). This supports the “One Health” approach integrating animal, human and environmental health. Full article

Background and Objectives: Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous malignancy with variable clinical behavior and prognosis. Human papillomavirus (HPV)-associated tumors represent a distinct subgroup; however, data from Eastern European populations remain limited. This study aimed to evaluate the association between HPV DNA status and nodal involvement in a Bulgarian HNSCC cohort and to explore whether HPV genotype distribution is related to nodal involvement and therapeutic strategy. Materials and Methods: A prospective multicenter observational study with a cross-sectional analytical endpoint was conducted. Fifty patients with histologically confirmed HNSCC were included. Clinical and pathological data were collected, and HPV detection and genotyping were performed using molecular-based methods. Associations between HPV-related variables, nodal status (N0 vs. N+), and treatment strategy were evaluated using univariate tests. HPV status reflects DNA detection only and does not confirm transcriptionally active infection. Results: HPV DNA positivity was identified in 15/50 patients (30.0%). A higher proportion of nodal involvement was observed among HPV-positive patients compared with HPV-negative patients (46.7% vs. 17.1%, p = 0.040; crude OR = 4.23); however, this finding may be influenced by anatomical site distribution. In unadjusted analysis, HPV DNA positivity showed a relationship with nodal involvement (crude OR = 4.23; p = 0.040), although this should be interpreted cautiously. Multivariable analysis was not performed due to the limited number of outcome events. Differences in treatment allocation were observed between HPV-positive and HPV-negative patients; however, this finding may be confounded by anatomical site distribution and likely reflects differences in tumor localization rather than HPV-specific effects. Genotype analysis revealed heterogeneity, including multiple HPV types. Conclusions: HPV DNA positivity was observed in relation to nodal involvement in unadjusted analysis; however, this finding may be confounded by anatomical site and should be considered exploratory. Full article

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with cancer. The management of special situations—including recurrent venous thromboembolism (VTE), thrombosis at unusual sites, and central venous catheter-associated thrombosis (CVC-AT)—remains particularly challenging because of the limited availability of high-quality evidence. This narrative review synthesizes recommendations from major international and Spanish clinical practice guidelines and expert consensus documents, including those from SEOM, ESMO, ASCO, NCCN, ITAC and SEMI, to provide a structured framework for the management of these complex scenarios. Our analysis identified substantial heterogeneity across guidelines, particularly regarding anticoagulant selection, dosing strategies, and treatment duration. Although some convergence exists in the management of CVC-AT, important discrepancies and evidence gaps persist in areas such as splanchnic vein thrombosis, hepatic impairment, central nervous system involvement, and recurrent VTE despite treatment. In many cases, recommendations are based primarily on expert opinion rather than robust trial data, and several clinical scenarios are addressed by only a limited number of guidelines. These findings underscore the need for more standardized management strategies and prospective clinical studies to better inform decision-making in daily practice. Overall, this review highlights the growing importance of individualized anticoagulant management aimed at balancing thrombotic and bleeding risks in high-risk oncology patients, thereby helping to bridge the gap between expert consensus and evidence-based precision anticoagulation. Full article

Chitosan-based interpenetrating networks (IPNs) have become highly attractive as advanced super-adsorbent materials due to their ability to combine a high density of functional adsorption sites with enhanced structural stability under physiological conditions. While chitosan offers intrinsic advantages such as biocompatibility, biodegradability, and chemical functionality, its adsorption efficiency, mechanical strength, and long-term stability may offer limited performance in complex biomedical environments. The formation of interpenetrating networks provides an effective strategy to overcome these limitations by interlacing chitosan with other polymer networks, resulting in a synergistic enhancement of physicochemical and adsorption properties. The formation of chitosan-based IPNs offers tunable control of network structure, porosity, swelling behaviour, and adsorption kinetics, which in turn results in enhanced retention and controlled interaction of drugs, biomolecules, toxins, and other therapeutic agents. Variations in polymer composition, crosslinking density, and network interactions further facilitate the controlled tailoring of adsorption properties for targeted biomedical applications. This review presents a comprehensive and critical assessment of recent progress in the fabrication, functionalization, and structure–property relationships of chitosan-based IPNs, with a main emphasis on their super-adsorbent behaviour. Furthermore, this review highlights key biomedical applications of IPNs, including controlled drug delivery, wound healing systems, tissue engineering scaffolds, detoxification platforms, and biosensing devices. Current issues in scalability, stability, and clinical translation are discussed, as well as future perspectives that highlight the potential of chitosan-based IPNs as high-performance, sustainable super-adsorbent materials for advanced biomedical technologies. Full article

Background/Objectives: Prosthetic joint infection following total knee arthroplasty remains a significant public health challenge. Automated surveillance systems are increasingly used for national monitoring of surgical site infections after arthroplasty. This study assessed the performance of the French ISO-ORTHO automated surveillance indicator after primary total knee arthroplasty by comparing automated surveillance data with exhaustive clinical follow-up. It also reported the incidence of surgical site infections during the initial years of activity of a tertiary care university hospital. Methods: A retrospective cohort analysis of primary total knee arthroplasties performed between January 2016 and December 2018 was conducted using exhaustive clinical chart review and the French ISO-ORTHO automated surveillance system. Prosthetic joint infections were diagnosed according to the 2018 International Consensus Meeting criteria. The local ISO-ORTHO results were compared with the national ISO-ORTHO rates. Results: Clinical chart review identified 1138 primary total knee arthroplasties and five prosthetic joint infections. Prosthetic joint infection incidence was 0.44% with a mean follow-up of 40.5 months. ISO-ORTHO was not yet implemented in 2016. Between 2017 and 2018, ISO-ORTHO identified 519 procedures and one prosthetic joint infection, compared with 807 procedures and three infections identified by clinical review. Conclusions: The French ISO-ORTHO surveillance indicator aided local and national monitoring of surgical site infections after total knee arthroplasty, but discrepancies with clinical chart review highlighted important limitations of automated monitoring and the importance of prolonged clinical follow-up. Future surveillance strategies could integrate these complementary approaches to improve prosthetic joint infection detection. Full article

Fibroblast Growth Factor 2 (FGF2) is a highly effective regulator of cell proliferation, differentiation, migration, and adhesion, suggesting a significant therapeutic potential as a tissue regeneration promoter both in acute and chronic tissue damage settings. Despite an extensive list of pathologies that lend themselves as viable targets for FGF2-based therapy (ranging from periodontics to burns to diabetic ulcers to coronary artery disease), the success record in the clinic remains modest, with no FDA approvals obtained so far. The inferior stability of this protein is frequently cited as the most significant factor behind its disappointing performance as a biotherapeutic. Multiple strategies have been designed and tested in an effort to ameliorate this problem, but the success remains elusive. We investigate the aggregation propensity of a recombinantly produced FGF2 using native mass spectrometry (MS) to identify conditions favoring formation of small soluble oligomers, which are considered precursors to larger aggregates. Tandem MS of proteolytic fragments produced by digestion of the oligomeric species allows the formation of external disulfide bonds to be identified as the process leading to oligomerization. Specifically, Cys-31 (one of the two unpaired cysteine residues in intact FGF2) appears to be a particularly active promoter of oligomerization by forming external disulfide bonds. As a high-pI protein, FGF2 readily associates with heparin, and molecular modeling identifies a positive charge basin proximal to Cys-31 as a potential heparin binding site, which can readily accommodate a synthetic heparin mimetic fondaparinux. Adding an equimolar amount of the latter to the FGF2 solution not only leads to formation of a stable protein/polyanion complex (as revealed by native MS), but also inhibits formation of FGF2 oligomers (presumably via a combination of steric hindrance and electrostatic repulsion). These findings advance our understanding of FGF2 stability, which will be invaluable for optimizing its formulation, storage, and administration. Full article

Background: Tirbanibulin 1% ointment has demonstrated short-term efficacy and excellent tolerability in the treatment of actinic keratosis (AK) on the face and scalp. However, data on long-term efficacy are still lacking. Materials and Methods: This prospective, single-center, 12-month extension study included patients with facial and scalp AKs previously treated with tirbanibulin 1% ointment once daily for 5 consecutive days. Long-term analysis was restricted to lesions that had achieved complete clinical and dermoscopic clearance at the 2-month follow-up. At 12 months, the treated areas were reassessed clinically and dermoscopically. High-resolution images obtained at baseline, 2 months, and 12 months were compared lesion by lesion to distinguish sustained clearance, recurrence at the same anatomical site, and the development of new AKs within the treated field. Results: Thirty-seven patients were reassessed at 12 months. Of the 228 AKs treated at baseline, 116 lesions had achieved complete clearance at 2 months and were therefore eligible for long-term evaluation. At 1 year, 70/116 lesions (60.3%) remained free of recurrence, whereas 46/116 (39.7%) relapsed. Sustained clearance was observed in 35/51 grade 1 lesions (68.6%), 32/57 grade 2 lesions (56.1%), and 3/8 grade 3 lesions (37.5%). In addition, 35 new AKs developed within the previously treated field. No delayed local or systemic adverse events and no progression to invasive cSCC were observed during follow-up. Patient-reported satisfaction was high, and 94% of patients stated they would be willing to repeat the treatment. Conclusions: Tirbanibulin was associated with sustained lesion clearance at one year, particularly in lower-grade AKs. While recurrence remains relatively common—especially in thicker lesions—the treatment was well tolerated and associated with no delayed adverse effects. Its short application regimen and excellent safety profile support tirbanibulin’s role in the long-term management of field cancerization. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disease with both clinical and genetic heterogeneity. Several loss-of-function variants in the chromodomain helicase DNA-binding protein 8 (CHD8) gene have been identified in individuals with ASD and/or developmental delay/intellectual disability. These are associated with specific clinical manifestations, including overgrowth, macrocephaly, sleep disturbance, and gastrointestinal problems. Methods: We performed clinical exome sequencing in a female patient with ASD and macrocephaly. RNA analysis from peripheral blood was carried out to investigate the functional effect of the identified variants. Results: We identified a novel maternally inherited CHD8 variant (c.5390+2T>C). Transcript analysis demonstrated that this variant disrupts the canonical splice donor in intron 30, causing splicing anomalies in the CHD7-binding domain of the CHD8 protein, resulting in a truncated inactive protein. Conclusions: In conclusion, this study identified a novel splice-site variant in the CHD8 gene with experimentally confirmed pathogenic effects on RNA splicing, expanding the mutational spectrum of CHD8-related neurodevelopmental disorders. The considerable intrafamilial phenotypic variability associated with CHD8 haploinsufficiency supports the presence of reduced penetrance and highlights the influence of modifying factors on the clinical expression of CHD8-related disorders. Full article

Cannabidiol (CBD), a major non-psychoactive phytocannabinoid, has attracted considerable attention owing to its broad therapeutic potential. Its anti-inflammatory, antimicrobial, and antitumor properties make it a promising candidate for the treatment of mucosa-associated diseases. However, the clinical translation of CBD is significantly hindered by its unfavorable physicochemical properties, particularly high lipophilicity and poor aqueous solubility, which result in low bioavailability. To overcome these limitations, the rational selection of administration routes in combination with advanced drug delivery systems tailored to disease pathophysiology is essential. Such strategies are critical for improving the stability of CBD, enhancing mucosal permeation, and enabling controlled and targeted release at diseased sites. Nevertheless, a systematic review focusing on these aspects is still lacking. This review first summarizes the relationship between CBD and the mucosal endocannabinoid system, together with its pharmacological effects. It then discusses the therapeutic potential of CBD in mucosal disorders of the digestive and respiratory systems. In addition, current administration routes and advanced delivery systems for CBD are reviewed to provide insights for future research and clinical translation. Finally, the remaining challenges associated with the clinical application of CBD and future development directions are discussed. Full article

Background: Pneumococcal conjugate vaccines (PCVs) have substantially reduced pneumococcal disease in children; however, serotype distribution varies geographically, and residual disease due to non-PCV13 serotypes persists. Biological E’s PNEUBEVAX 14^® (BE-PCV14), a WHO-prequalified 14-valent PCV, expands coverage by including serotypes 22F and 33F. As PCVs are co-administered with routine Expanded Programme on Immunization (EPI) vaccines, post-licensure data on safety, co-administration, and lot-to-lot consistency are essential. This multicenter phase IV study evaluated BE-PCV14 in healthy PCV-naïve infants aged 6–8 weeks across 31 sites in India. Methods: A total of 2600 infants were enrolled and vaccinated at 6, 10, and 14 weeks of age; 2300 received BE-PCV14 and 300 received PCV13. All participants received concomitant DTwP-HepB-IPV-Hib and oral rotavirus vaccines per routine schedule. Safety was assessed through solicited and unsolicited adverse events (AEs) and serious adverse events (SAEs). Immunogenicity subsets evaluated responses to co-administered vaccines and serotype-specific responses across three BE-PCV14 lots. Results: Among 2600 vaccinated infants, at least one AE occurred in 26.35% (95% CI: 24.59, 28.19) of BE-PCV14 and 24.67% (95% CI: 20.13, 29.84) of PCV13 recipients; most were mild. Injection-site pain and pyrexia were the most common events. Immune responses to co-administered vaccines were comparable between groups and met the non-inferiority criteria: lower bound of the two-sided 95% CI > −10 percentage points for seroprotection/seroconversion rate differences using the Farrington–Manning method. Lot-to-lot consistency was demonstrated, with all GMC ratios within the predefined equivalence margin (0.5–2.0). Conclusions: BE-PCV14 was well tolerated. Immune responses to co-administered routine EPI vaccines met predefined non-inferiority criteria, supporting the interpretation that BE-PCV14 did not result in clinically meaningful immune interference. Consistent immune responses across manufacturing lots further support its use in infant immunization programs. Full article

The global emergence of the avian influenza virus (AIV) H5N1 clade 2.3.4.4B since 2016 has caused substantial losses in wild bird and poultry populations, along with heightened risks of transmission to humans and other mammals. Vaccination of poultry has been a key strategy to curb the virus’s spread and mitigate its socioeconomic impact. This report describes an outbreak of high pathogenicity avian influenza virus (HPAIV) H5N1 clade 2.3.4.4B in a flock of 15,000 brown layer chickens (170 days old), all of which had received a four-dose vaccination regimen with H5N1/H5N8 commercial vaccines at 17, 50, 100, and 125 days of age. Despite this vaccination history, H5N1 infection was confirmed approximately seven weeks post-vaccination. H5N1 infection was confirmed by RT-qPCR, virus isolation, and full genome sequencing covering all eight gene segments, followed by phylogenetic and molecular analyses. Clinical signs included reduced feed intake, decreased egg production, and a cumulative mortality rate of 35% over 52 days. Hemagglutination inhibition (HI) testing with various H5 antigens revealed inconsistent antibody titers (geometric mean: 4.0 to 9.1 log2). Genetic analysis of the full-length HA and NA gene sequences further revealed strong similarity to contemporaneous H5N1 clade 2.3.4.4B strains circulating in Egypt, with multiple mutations in the HA head domain, particularly near immunogenic epitopes and receptor binding sites. These findings highlight the limitations of current vaccination strategies under conditions of antigenic mismatch and complex immunization schedules, emphasizing the need for improved vaccine matching and continuous molecular surveillance. To improve outbreak management in poultry, enhanced vaccination protocols, stringent biosecurity measures, and rigorous monitoring practices are critical. Full article

Muscle oxygen nation impairment, defined as a mismatch between oxygen delivery, distribution, and oxidative utilization in active skeletal muscle, contributes to exercise intolerance and functional decline. Near-infrared spectroscopy (NIRS) has emerged as the leading non-invasive tool for monitoring local muscle oxygenation, but its clinical translation and optimal exercise-based management remain incompletely defined. This scoping review aimed to (1) synthesize the pathophysiology of muscle oxygenation impairment across the oxygen transport cascade, (2) evaluate NIRS-based diagnostic protocols, and (3) review exercise-based interventions targeting muscle oxygenation. The review followed PRISMA-ScR guidelines and was prospectively registered in OSF (DOI: 10.17605/OSF.IO/QW8R3) and PROSPERO (CRD420261365040). PubMed, Web of Science, Scopus, Cochrane CENTRAL, EMBASE, PEDro, and ClinicalTrials.gov were searched through to April 2026. Methodological quality was appraised using the PEDro scale, the Downs and Black checklist, and the Newcastle–Ottawa Scale. A total of 61 studies (2003–2025) were included, with fair-to-good methodological quality (PEDro 3–8, mean 5.3; Downs and Black 15–24, mean 18.6; Newcastle–Ottawa 5–8, mean 6.5). Regarding pathophysiology, muscle oxygenation impairment is a cascade-level phenomenon with four mechanistically distinct phenotypes corresponding to the dominant site of impairment, each with characteristic NIRS signatures. Regarding diagnostic assessment, NIRS has shown value in selected contexts including a validated threshold for peripheral artery disease, but most studies report group-level correlations without deriving receiver operating characteristic curves at validated thresholds, which together with device and calibration heterogeneity limits clinical translation. Regarding exercise-based interventions, adaptations align with the underlying cascade lesion, sprint and high-intensity interval training enhance oxidative capacity, while walking-based and vascular-targeted programs preferentially improve microvascular function. These findings support a unifying framework in which the site of cascade impairment guides diagnostic protocol selection and exercise prescription. The proposed cascade lesion phenotyping schema is hypothesis-generating and requires prospective validation. Full article

Background/Objectives: Artificial intelligence (AI) tools are increasingly integrated into acute stroke imaging workflows, but real-world performance for ischemia detection on non-contrast CT (NCCT) remains incompletely validated by investigators independent of the developer. This study externally validated the BrainScan AI system in an unselected, consecutively enrolled emergency cohort. Methods: Consecutive adult patients undergoing NCCT under the routine acute stroke protocol at a single tertiary centre between January and December 2025 were prospectively enrolled. The reference standard was the post-consensus radiological diagnosis, supplemented where available by follow-up imaging and clinical course. Primary outcomes were diagnostic accuracy for ischemia and intracranial haemorrhage detection, assessed by sensitivity, specificity, predictive values, likelihood ratios, and area under the ROC curve (AUC; DeLong). Pre-specified secondary analyses included regional sensitivity, confidence-score behaviour, artefact robustness, threshold sensitivity, a cluster-robust bootstrap for within-patient correlation, and a quantitative bias analysis under non-differential reference-standard misclassification. Sample size adequacy was assessed using a precision-based framework. Results: A total of 1419 NCCT examinations from 1260 patients were analysed. Ischemia sensitivity was 59.2% (95% CI 52.1–66.1) and specificity was 99.8% (99.4–100), with an AUC of 0.930 (0.906–0.954). The Youden-optimal threshold (0.055) recovered sensitivity to 86.1% with negligible specificity loss, reflecting a markedly bimodal score distribution. Regional sensitivity was lower in infratentorial structures. Bias-corrected estimates were stable across all reference-standard parameters consistent with the data. Haemorrhage detection performed substantially better (sensitivity 96.7%; AUC 0.983). Conclusions: The system shows excellent specificity and strong discrimination but moderate sensitivity for ischemia, supporting its role as a rule-in adjunct rather than a stand-alone tool, pending multicentre validation and site-specific threshold recalibration. Full article

Background: Multisite digital psychiatry trials increasingly rely on complex onboarding and implementation processes at local research sites. While outcome-focused evaluations are common, less attention has been paid to the site-level labor required to operationalize such studies in real-world settings, particularly at smaller or resource-constrained sites. This study addresses this gap by examining hidden implementation labor from a single-site reflexive perspective. Methods: This study adopts a reflexive qualitative case study approach to examine onboarding and implementation processes at a single research site participating in a multisite digital psychiatry trial (ClinicalTrials.gov: NCT04953208). The analysis draws on longitudinal experiential data, supported by site-specific documentation, onboarding timelines, troubleshooting records, device-management materials, data quality assurance activities, and internal communications generated during site coordination and implementation activities. Results: Five interrelated themes were identified: hidden labor and role overload; resource scarcity at small research sites; fragmented remote communication and technical coordination; multi-role professional contexts and competing demands; and the impact of external systemic disruptions. Findings show how administrative, technical, logistical, and coordination tasks were absorbed into individual roles, often exceeding initial role expectations. Despite limited resources, the site achieved high performance through intensified individual effort, masking the true implementation burden. This pattern is conceptualized as a high-performance paradox, in which apparent site efficiency may conceal substantial hidden labor and role compression. Conclusions: This site-level reflexive account highlights the central role of hidden labor in sustaining implementation in multisite digital psychiatry trials. Recognizing and explicitly resourcing implementation work, particularly at small research sites, may improve feasibility, sustainability, and equity across study settings. The study contributes a practice-based methodological perspective on how implementation burden can be identified through reflexive analysis of site-level trial processes. Full article