Budesonide orodispersible tablets (BOT) are the first drug specifically developed for eosinophilic esophagitis (EoE), whereas budesonide viscous solution (BVS) is used off-label. We aimed to assess the histological, endoscopic, clinical, and safety outcomes before and after switching maintenance therapy from BVS to BOT. Observational cohort study of EoE patients who switched therapy from BVS to BOT at the same dose (1 mg) and dosing schedule (once daily (OD) or twice daily (BID)). We performed a retrospective analysis of a prospectively collected dataset. Routine procedures included endoscopy with biopsies to assess histological and endoscopic disease and whether candidiasis was present. Histological remission was defined as <15 eosinophils per high-power field (eos/HPF) and deep histological remission as <6 eos/HPF. Online questionnaires, including dysphagia symptom questionnaire (DSQ), eosinophilic esophagitis symptom activity index (EEsAI), numerical rating scale (NRS) for symptoms and adult eosinophilic esophagitis quality of life questionnaire (EoE-QoL-A), were filled out by patients to assess symptom severity and health-related quality of life (HRQoL). Data are presented as proportions or medians with interquartile ranges, using non-parametric paired tests for proportions or other variables. In total, 45 patients were included. The majority of patients switched to BOT 1 mg OD (n = 32, 25 males, age 35 (27.8-40.3) years and body mass index 24.3 (21.4-27.5) kg/m²). Endoscopy and questionnaires were repeated 170 (145.3-182) days after switch. The proportion of patients achieving histological (p = 0.04) and deep histological (p = 0.01) remission increased significantly. The total endoscopic reference score decreased significantly (p = 0.003). Symptoms remained low (DSQ: p = 1; EEsAI: p = 0.9; NRS: p = 0.1), while a significant improvement in HRQoL (EoE-QoL-A: p = 0.008) was observed. A numeric increase in candidiasis was noted (p = 0.3). Similar results were obtained for EoE patients switching maintenance therapy from BVS to BOT 1 mg BID. Maintenance therapy with BOT after BVS may be feasible and effective in the real-world management of EoE patients, with only a numeric increase in the endoscopic suspicion of candidiasis.
Quaternary ammonium compounds (QACs)-biocides used in households, agriculture, and industry-have been increasingly detected in aquatic environments. However, the occurrence of QACs attributed to manufacturing is not well documented. We therefore monitored 14 QACs (benzalkonium chloride-C8, C10, C12, C14, C16, C18; dialkyldimethylammonium chloride-C8, C10, C12; alkyltrimethylammonium chloride-C8, C10, C12; benzethonium chloride; and cetylpyridinium chloride), a disinfectant (chlorhexidine), and 17 human and veterinary drugs seasonally in 15 streams near industrial zones in Japan. The concentrations of four QACs exceeded the ranges reported in surface waters and treated effluent worldwide. Concentration ratios (ΣDrugs ÷ ΣQACs) at most sites were much lower than those reported in Japanese municipal sewage treatment plants and watersheds receiving wastewaters from unsewered households and swine farms, indicating QACs in the study area are mainly not attributable to domestic and livestock wastewaters, which largely contain pharmaceuticals. Given that most sites of ΣQACs >1000 ng/L, where ΣQACs were relatively stable throughout the year, largely receive textile wastewater (>1000 m3/day), main source of QACs here could be the textile industry. Though catchment-average concentrations of QACs reported in the above-mentioned watersheds were correlated with their mean raw sewage concentrations, those in the study area were linked with their emissions from the textile industry reported by a Japanese ministry, supporting the dominant impact of the textile industry here. Ecological risk quotients of several QACs were >1 at several sites. Our findings on pollution hotspots of QACs attributable to the textile industry could provide a new perspective on their management.
To evaluate the current literature to determine the impact of concomitant alignment or meniscal surgery on outcomes in patients undergoing cartilage restoration surgery. A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines utilizing a comprehensive search of MEDLINE, EMBASE, and The Cochrane Library databases. Studies were included if they reported clinical outcomes of cartilage restoration with concomitant osteotomy or meniscal allograft transplantation performed. Data extraction included functional outcomes, failure rates, and International Cartilage Repair Society/Magnetic Resonance Observation of Cartilage Repair Tissue scores. A total of 40 studies, comprising 1783 knees, were included. Patients undergoing cartilage restoration with concomitant osteotomy had a lower range of failure rates (0.0%-10.5%) compared with cartilage restoration alone (0%-41.7%). Similarly, cartilage repair with meniscal allograft transplantation had increased Lysholm and International Knee Documentation Committee scores from preoperative ranges of 41.9-70.6 and 32.9-45.5 to 63.6-88.0 and 55.3-76.0, respectively. The failure rates for cartilage restoration with concomitant meniscal allograft transplantation (range: 14.0-15.2) were comparable to cartilage restoration alone (range: 12.1-14.0). Additionally, the mean heterogeneity within the included studies ranged from 0% to 98%. Available evidence suggests that osteotomy and meniscal allograft transplantation can be performed concomitantly with cartilage restoration without adversely affecting overall outcomes. These procedures may be particularly relevant for patients with malalignment or meniscal deficiency, where mechanical factors contribute to disease progression. Level IV, systematic review of Level II, III, and IV studies.
Infantile tremor syndrome (ITS), a self-limiting disorder prevalent in the Indian subcontinent, is characterized by tremors, anemia, pigmentary skin changes, developmental delay or regression, and hypotonia. Although a nutritional etiology is suspected, particularly vitamin B12 deficiency, the roles of the bioactive marker holo-transcobalamin (holo-TC) and essential fatty acids (EFAs) remain unexplored. This comparative pilot study was conducted from December 1, 2023, to April 30, 2024, at Government Medical College, Datia, India. The study included 14 infants who were assigned to two groups. Group 1 (n = 7) comprised infants with ITS and tremors, and Group 2 (n = 7) included those with ITS without tremors to assess threshold-dependent biochemical markers across this clinical spectrum. Laboratory investigations included complete hemogram, serum vitamin B12, holo-TC, and EFA profiles. Data were summarized using medians and interquartile ranges. Between-group differences were expressed as effect sizes (median differences) with 95% confidence intervals. Severe developmental delays were more frequent in Group 1 (5/7) than in Group 2 (mild to moderate in 4/7). Both groups were anemic and had low serum vitamin B12 levels (median: 188 pg/mL in Group 1 vs. 198 pg/mL in Group 2). Holo-TC was undetectable (< 5 pmol/L) in Group 1 and in only one patient from Group 2 (median: 10.12 pmol/L in the remaining Group 2 patients). Macrocytosis was higher in Group 1 (median MCV: 98 fL vs. 75.5 fL), with a median difference of 22.5 fL (95% CI: 6.8 to 38.2). Clinical examination also revealed characteristic hair hypochromotrichia and progressive regression in both phenotypes. Both groups exhibited low omega (ω)-3 fatty acid levels, elevated saturated fatty acid levels, and high ω-6:ω-3 ratios (median: approximately 10:1), with small and imprecise between-group differences (confidence intervals crossing zero). Extremely low holo-TC levels were strongly associated with tremors in ITS, suggesting that holo-TC is a superior marker of bioactive vitamin B12 deficiency and a critical metabolic threshold for tremor manifestation. EFA imbalances were prevalent in both groups but not specific to tremor incidence, highlighting the need for larger studies. The overall pathophysiology points toward significant maternal nutritional depletion during pregnancy and lactation as the relevant origin of the syndrome.
Compression therapy with medical graduated compression garments is commonly used in the treatment of leg lymphedema. However, the relationship between the interface pressure applied by the garment and the resulting hydrostatic pressure within the soft tissues remains poorly understood. Women commonly use thigh-high garments, whereas men often use knee-high compression garments, but the effects of these different garment types remain unclear. The objective of this study was to evaluate pressure transmission within lymphedematous legs and to assess the effects of different garment types. Patient-specific finite element models were developed from magnetic resonance imaging data of eight female and three male lymphedematous legs. The models explicitly represented the skin, fascia cruris, subcutaneous tissue, and muscle. Interface and hydrostatic pressures were quantified for class 2 and class 3 compression garments, as well as for three garment superimposition configurations. For all legs wearing class 2 compression garments, and for female legs wearing class 3 compression garments, interface and hydrostatic pressures were below therapeutic ranges. Male legs wearing class 3 compression garments achieved hydrostatic pressure values within the therapeutic range due to higher garment stiffness. Superimposition of garments increased hydrostatic pressure in female legs and led to excessive compression in male legs. These findings highlight the influence of limb morphology and garment mechanical properties on compression therapy. Class 2 or class 3 garments alone may be insufficient for female patients, whereas superimposition should be applied cautiously in male patients. Patient-specific finite element analyses may support more individualized compression therapy prescriptions.
Alkaline phosphatase (ALP) plays an essential role in skeletal mineralization and bone metabolism. While elevated ALP levels are commonly investigated in clinical practice, persistently low ALP values are often overlooked despite their potential association with hypophosphatasia (HPP), a rare metabolic bone disorder caused by pathogenic variants in the ALPL gene. This study aimed to determine the prevalence and clinical characteristics of adults with persistently low ALP in a large tertiary care hospital. We conducted a retrospective review of adult patients who underwent serum ALP testing at King Abdulaziz Medical City, Riyadh, between January 2017 and December 2024. Patients with ≥ 2 ALP measurements < 40 IU/L separated by at least 30 days were identified. Secondary causes of low ALP were excluded through review of clinical history, laboratory data, and medication records. Demographic, clinical, biochemical, and imaging data were analyzed. Among 243,362 adults with 928,403 ALP measurements, 7,307 patients (3.0%) had at least one ALP value < 40 IU/L. A total of 179 patients had ≥ 2 ALP measurements < 40 IU/L. After excluding 154 patients with secondary causes or incomplete data, 25 patients were identified with unexplained persistently low ALP (0.01% of the total tested population). The mean age was 52.2 years (range 18-92), and 68% were female. The mean nadir ALP was 30.2 IU/L. Musculoskeletal (MSK) symptoms (92%) and fatigue (79%) were the most common clinical manifestations, followed by dental abnormalities (50%), anxiety (33%), and depression (29%). Fractures were reported in 46% of patients, most commonly affecting the vertebrae, hips, and metatarsals. In subgroup analysis, patients with MSK symptoms had significantly lower nadir ALP levels (p = 0.021). Familial clustering of persistently low ALP was observed in 25% of patients. Notably, none of the reviewed electronic medical records documented recognition of persistently low ALP or consideration of hypophosphatasia. Persistently low ALP is uncommon but clinically relevant. Many affected patients demonstrated clinical features compatible with possible adult hypophosphatasia, and familial clustering suggests a possible genetic contribution. Greater awareness of this biochemical finding may improve recognition of potential HPP, prevent inappropriate antiresorptive therapy, and facilitate earlier diagnostic evaluation, including biochemical and genetic testing.
Wavenumber-domain beamforming offers substantial computational advantage over conventional time-domain algorithms in ultrasound image formation. However, these methods are found to introduce distortions at large angles and greater depths, making it nontrivial to replace conventional processing pipelines with wavenumber-domain approaches. This paper presents a wavenumber-domain framework that produces images consistent with conventional delay-and-sum (DAS) beamforming, while retaining the computational efficiency of Fourier-domain processing. Building on recent work on DAS-consistent imaging for multistatic acquisition data, the key utility of this novel algorithm is its applicability in plane-wave, focused-transmit, and diverging-wave imaging. The approach compensates for the implicit spatial-frequency filtering of earlier wavenumber-domain formulations through a modified Fourier-domain weighting and an axial scaling to the reconstructed image. Using data from simulations, phantom experiments, and in-vivo liver imaging, we demonstrate that the proposed method preserves DAS-equivalent amplitude, speckle statistics, resolution, and contrast. Quantitative image comparison confirms a close agreement between DAS and the proposed method with Structural Similarity (SSIM) values exceeding 0.99, whereas SSIM between earlier wavenumber-domain beamformers and DAS is lower, ranging from 0.67 to 0.92 depending on the transmit scheme. The proposed method yields approximately one order-of-magnitude reduction in computational cost compared to conventional DAS, making it well-suited for real-time and resource-constrained ultrasound systems.
To investigate whether serum micro (miR)-145-5p for postoperative complications in patients with scarred uterus undergoing caesarean section, suggesting its potential as an adjunctive molecular biomarker for clinical preoperative risk assessment. A total of 198 women were divided into high-expression and low-expression groups based on the mean relative serum miR-145-5p level. Pelvic floor function, vaginal microecology, and abdominal adhesion status were assessed, and postoperative complications were monitored. Spearman's rank correlation was used to analyse the correlation between miR-145-5p expression and scar scores, while Receiver operating characteristic (ROC) curves were employed to evaluate its predictive efficacy for complications. Serum miR-145-5p was negatively correlated with abdominal scar Patient-Observation Scar Assessment Scale (POSAS) scores. The level of miR-145-5p was lower in the moderate-to-severe pelvic floor dysfunction (PFD) group, vaginal microecological disorder group, abdominal adhesion group, and postoperative complication group compared with the corresponding control groups. ROC curve analysis showed that miR-145-5p had good predictive value for these complications. miR-145-5p is closely correlated with abdominal scar, PFD, vaginal microecological disorders, abdominal adhesions, and other postoperative complications in patients with scarred uterus after caesarean section, which may serve as a potential molecular biomarker for preoperative risk assessment. Many women who have a previous caesarean birth have a scar on their uterus. These women often face higher risks of health problems after another caesarean delivery, including poor wound healing, weak pelvic floor muscles, imbalanced vaginal health, and internal tissue attachments. Among 198 patients, those with lower preoperative miR-145-5p levels showed poorer abdominal scar healing (higher POSAS scores) and higher rates of pelvic floor dysfunction, vaginal microecological disorders, abdominal adhesions, and other complications. ROC analysis demonstrated that miR-145-5p had good predictive value for these complications, with area under the curve (AUC) values ranging from 0.821 to 0.883. Specifically, lower miR-145-5p was associated with weaker pelvic floor muscle strength, abnormal vaginal inflammation markers, more severe abdominal adhesions, and other complications. Multivariate analysis confirmed high miR-145-5p as an independent protective factor. These findings suggest that preoperative serum miR-145-5p testing may serve as an adjunctive molecular biomarker to identify high-risk patients and guide early intervention strategies for improved postoperative outcomes.
Sensitive, specific, and stable detection of microRNAs (miRNAs) in complex biological environments remains a formidable challenge in molecular diagnostics. We introduce a novel bidirectional palindromic assembled multifunctional hairpin probe (A-MF-HP)-a molecular tool that integrates target recognition, cascade signal amplification, and fluorescence reporting into a single, compact system. Two palindromic arms drive autonomous, bidirectional self-assembly into a nuclease-resistant architecture, enabling robust operation in serum-rich environments. Upon recognition of miRNA-21, a structural switch in one hairpin triggers polymerase extension, nicking, and strand displacement all without auxiliary probes. This initiates a self-propagating disassembly cascade, unfolding additional hairpins and exponentially amplifying the signal. Under the optimized conditions, the platform demonstrates femtomolar-level sensitivity (about 1× 10-15 M) across a six-order dynamic range, with single-nucleotide mismatch discrimination and negligible cross-reactivity to unrelated miRNAs. Notably, A-MF-HP retains full functionality after 12 h in 10% human serum, and clinical application to blood samples from lung cancer patients revealed marked fluorescence elevation compared to healthy controls. By uniting biostability, multifunctionality, and autonomous amplification in a single programmable probe, this novel strategy addresses limitations commonly observed in multi-component isothermal amplification assays, such as poor nuclease tolerance and dependence on multiple separate probes, offering a powerful diagnostic tool for miRNA profiling in biomedical and clinical settings.
Genetic and environmental factors contribute to eating disorder risk, yet their interplay is poorly understood. We examined whether childhood maltreatment and polygenic scores for anorexia nervosa (PGS-AN) and binge-eating broad (PGS-BEB) are associated with eating disorders. We also examined the interactions between childhood maltreatment and PGSs in predicting eating disorders. This nested case-control study used data from up to 63,989 mothers in the MoBa (Norwegian Mother, Father and Child Cohort Study). Mothers reported on their own experiences of 4 childhood maltreatment types: long-term humiliation or degradation, threats to self or someone close, physical abuse, and sexual abuse. Diagnoses of AN, bulimia nervosa (BN), binge-eating disorder (BED), purging disorder (PD), and binge-eating spectrum disorders (BESP) were obtained using self-report data from 5 time points and population health registers. The prevalence of AN, BN, BED, PD, and BESP was 2.19%, 4.15%, 10.39%, 0.60%, and 12.96%, respectively. All childhood maltreatment types were strongly associated with elevated eating disorder likelihood (with odds ratios [ORs] ranging from 1.71 to 3.29) as were eating disorder PGSs (with ORs ranging from 1.05 to 1.31). There were no multiplicative interaction effects between childhood maltreatment and PGSs. Small additive interactions were observed between PGS-AN and PGS-BEB and degradation/humiliation for BN and BESP in exploratory analyses. Eating disorder PGSs and childhood maltreatment are associated with higher odds of eating disorders. Furthermore, we found tentative evidence of small additive interaction effects between polygenic liability and childhood maltreatment, suggesting that their combined influence further elevates the risk of some eating disorders. Genetic and environmental factors contribute to the development of eating disorders, but how these factors interact to predict eating disorder outcomes is not well understood. We examined associations between genetic risk for eating disorders, childhood maltreatment, and eating disorders in up to 63,989 mothers in the Norwegian Mother, Father and Child Cohort Study. Both genetic risk and childhood maltreatment exposure were associated with higher odds of several eating disorders. We also observed some small additive interaction effects, indicating that the combined impact of genetic risk and childhood maltreatment exposure may further increase the likelihood of some eating disorders.
Osteochondral allograft transplantation (OCA) has been established as a viable restorative chondral procedure, although few studies have examined its effectiveness in the setting of anterior cruciate ligament (ACL) reconstruction. To compare self-reported function and return-to-sport rates after ACL reconstruction with OCA to those of matched controls undergoing isolated ACL reconstruction. Cohort study; Level of evidence, 3. A retrospective matched cohort study was conducted utilizing a single-surgeon database of patients undergoing ACL reconstruction between 2016 and 2021. Included patients were 15 to 70 years of age, underwent ACL reconstruction with OCA, and desired to return to sport. Patients were age and sex matched to a cohort of patients who underwent isolated ACL reconstruction. Baseline characteristics were collected along with preinjury Marx score and surgical details. Outcomes at time of return to sport included self-reported function, time to return to sport, range of motion, and single-leg squat and hopping performance. Two-year outcomes included Single Assessment Numeric Evaluation (SANE) scores, return-to-sport rates, and reinjury rates. Between-group differences were analyzed utilizing chi-square analyses and 1-way analysis of variance with an a priori α value of .05. A total of 43 patients who underwent ACL reconstruction with OCA were identified and matched to 43 patients who underwent isolated ACL reconstruction. Patients in the ACL reconstruction with OCA group reported lower preinjury Marx scores (3.9 ± 5.7 vs 9.6 ± 5.9; P < .001). The ACL reconstruction with OCA group demonstrated a longer time to return to sport (9.1 ± 4.1 months vs 7.9 ± 3.4 months; P = .040); however, no differences existed between groups for all self-reported and objective outcomes at the time of return to sport. At 2 years, no differences existed regarding SANE scores (85.4 ± 12.1 vs 87.0 ± 13.5; P = .334), ACL graft reinjury rate (4.7% vs 2.3%; P = .481), and return to prior level of sport rates (69.8% vs 72.1%; P = .387). Patients undergoing ACL reconstruction with OCA demonstrate similar self-reported function and return-to-sport rates, along with a delayed time to return to sport, to those undergoing isolated ACL reconstruction. A majority (83.7%) of patients undergoing ACL reconstruction with OCA can return to level 1 to 3 sports with low graft failure rates.
Traumatic dental injuries (TDIs) are frequent in clinical practice and require rapid, guideline-based decisions, yet accessing accurate and reliable information may be challenging. Large language models (LLMs) such as ChatGPT, Gemini, DeepSeek, and Qwen are increasingly used as quick online information tools; however, evidence regarding their accuracy, consistency, and the influence of different user interfaces is limited. This study aimed to evaluate the performance of several LLMs in answering TDI-related questions through both web-based interfaces and mobile phone applications. Twenty questions were prepared according to the 2020 International Association of Dental Traumatology (IADT) guidelines, including 10 open-ended and 10 yes-no items. Four LLMs (ChatGPT-4o, DeepSeek-V3, Gemini 2.0 Flash, Qwen2.5-Max) were queried simultaneously via web and mobile interfaces over five consecutive days, generating 800 responses. Open-ended answers were assessed using the Global Quality Score (GQS) and modified DISCERN (mDISCERN), while yes-no responses were compared with a predetermined answer key. Statistical analyses were performed using IBM SPSS v23.0, with significance set at p < 0.05. Qwen2.5-Max demonstrated comparatively higher GQS and mDISCERN scores across both interfaces. Accuracy for yes-no questions ranged from 86% to 91% without significant differences among models. Interface comparisons showed that ChatGPT-4o generated comparatively higher-quality responses on the web, whereas Qwen2.5-Max performed better on mobile. Over the 5-day period, Qwen2.5-Max showed relatively higher temporal consistency, while DeepSeek-V3 exhibited notable day-to-day variation. LLMs may serve as useful supplementary tools for providing guideline-based information on TDIs, especially for straightforward, closed-ended clinical questions. However, their performance varies by model, interface, and question type. Qwen2.5-Max demonstrated comparatively higher performance across several evaluated measures. Despite these results, LLM-generated information should be interpreted cautiously and verified by dental professionals before being used in clinical decision-making.
The human body hosts an intricate array of microbial communities, outnumbering eukaryotic cells. Delving into the nuanced interplay between the microbiota and human cells is essential for comprehending health homeostasis and disease progression. Notably, the microbiota's influence commences even before birth, sculpting immune responses and delineating susceptibility to chronic diseases in later stages of life. Throughout the course of human life, variations in microbial composition have been observed to correlate with a wide range of pathologies, prompting the development of pioneering treatments aimed at reinstating a healthier microbial balance. Within this narrative review, we expound upon the fundamental role of the microbiota in the continuum of health and disease. Our endeavour is to contribute to a nuanced comprehension of diseases and the development of targeted interventions for their judicious management.
The global burden of obesity continues to rise, and metabolic and bariatric surgery is the most effective intervention for durable weight loss and improvement of obesity-related diseases. The International Federation for the Surgery and Other Therapies for Obesity (IFSO) Global Registry was established in 2013 to provide standardised, multinational surveillance of MBS. No longitudinal synthesis of the successive IFSO Global Registry reports has been undertaken. We performed a retrospective secondary analysis of all nine IFSO Global Registry reports published from 2014 to 2024; all source reports were accessed on October 18, 2025. Following RECORD principles, we prespecified core domains, harmonised definitions across editions, and documented transformations in a reproducible extraction log. Report-level patterns were described for registry participation, procedure volumes and mix, operative approach, patient demographics, perioperative outcomes, and methodological evolution. A FAIR-informed appraisal of report-level transparency was conducted using a pragmatic, registry-oriented rubric. Because the registry underwent a structural transition from individual-level or mixed reporting to aggregated national reporting between the sixth and seventh editions, analyses were structured into two non-equivalent reporting eras: Reports 1-6 and Reports 7-9. Cross-era comparisons were therefore interpreted as descriptive contrasts shaped by reporting architecture, rather than as continuous epidemiological trends. Reported metabolic and bariatric surgery activity ranged from 100,092 operations across 18 countries in the First Report to 598,736 operations across 36 countries in the Ninth Report, with the highest submitted volume in the Fifth Report. These values reflect changing contributor networks and reporting frameworks and should not be interpreted as directly comparable estimates of global procedural incidence. Within submitted primary-procedure data, Sleeve gastrectomy increased from 22.0% in the First Report to 60.4% in the Ninth Report, while Roux-en-Y gastric bypass decreased from 66.0% in the First Report to 29.7% in the Ninth Report; adjustable gastric banding became uncommon, and one-anastomosis gastric bypass accounted for 4-7% where reported. Median age and body mass index were broadly stable, and Female patients represented 71.3-79.5% of patients in reports with comparable sex reporting. Revisional procedures showed higher rates of unplanned reoperation, intensive care unit admission, readmission, and mortality than primary procedures. Report-level Findable, Accessible, Interoperable, and Reusable transparency scores improved modestly, mainly through gains in findability and accessibility, while interoperability and reusability remained limited. Across successive public reports, sleeve gastrectomy became the most frequently reported primary procedure within submitted registry data, with substantial regional heterogeneity and important limitations in cross-edition comparability. Further harmonisation of definitions, improved follow-up completeness, and privacy-preserving access to more granular data would enhance the registry's value for benchmarking, policy, and patient-level research. No specific funding was received for this study.
Personalized alignment strategies, including kinematic alignment (KA), restricted kinematic alignment (rKA), and functional alignment (FA), are emerging as alternatives to mechanical alignment in total knee arthroplasty (TKA). These approaches aim to restore patient-specific limb alignment and joint-line orientation, potentially improving functional outcomes. Although their use is well established in primary TKA, evidence supporting their application in revision total knee arthroplasty (rTKA) remains limited. The complexity of revision surgery, together (combined) with implant constraints and altered anatomy, has historically hindered the adoption of personalized alignment. This scoping review aims to evaluate the current evidence regarding the feasibility, accuracy, and clinical outcomes of personalized alignment strategies in rTKA and unicompartmental knee arthroplasty (UKA) toTKA conversion. A scoping review was conducted using PubMed, Scopus and Web of Science to identify English-language clinical studies published between January 2010 and December 2024. Eligible studies reported the use of KA, rKA, or FA in revision TKA or UKA conversion. Case reports, case series, cohort studies, and technical notes were included, whereas computational studies, cadaveric reports, and investigations limited to primary TKA were excluded. Two reviewers independently assessed study eligibility and extracted data regarding the alignment strategy, radiographic restoration, surgical workflow, range of motion (ROM), patient-reported outcome measures (PROMs), and complications. Ten clinical studies met the inclusion criteria. Across the included literature, personalized alignment demonstrated technical feasibility in revision settings and was associated with improved joint-line restoration, limb alignment closer to constitutional values, and good postoperative ROM. Patient-reported outcome measures (PROMs), when reported, showed a trend toward improvement. No major complications directly attributable to personalized alignment techniques were described. Robotic-assisted FA, described in four studies, suggested the precision of bone resections and soft-tissue balancing. However, the evidence base remains limited by small sample sizes, heterogeneous methodologies, and short-term follow-up. Personalized alignment strategies appear feasible and clinically beneficial in selected revision TKA cases. Early data suggest that KA, rKA, and FA may improve alignment accuracy and functional outcomes without increasing complications. Nevertheless, heterogeneity in study design and limited long-term evidence constrain broader adoption. Future research should prioritize standardized protocols, comparative trials, and long-term survivorship to define the role of personalized alignment in rTKA.
Age-related bone diseases are a heterogeneous group of metabolic disorders characterized by progressive degenerative changes. Although nanobiomaterials have emerged as a promising means of regulation at the cellular level, their therapeutic efficacy remains very limited due to the lack of treatment strategies that directly target mitochondrial pathology. In recent years, nanobiomaterial therapies centered on mitochondria have attracted widespread attention. This review aims to critically evaluate the latest advances in this emerging field and categorize them into four main strategies: enhancing mitochondrial autophagy, optimizing the mitochondrial microenvironment, repairing mitochondrial structure, and implementing mitochondrial transfer therapy. Based on existing research, we have preliminarily established a multi-level intervention framework ranging from the clearance of dysfunctional mitochondria to the regulation of the microenvironment, and from the repair of structural components to the transplantation of healthy mitochondria, which has demonstrated encouraging proof-of-concept results in vitro and in animal models. However, this field remains in the preclinical exploration phase: the vast majority of studies are based on rodent models, the efficiency of mitochondrial-targeted delivery is generally low, and long-term biosafety and the feasibility of large-scale production have not yet been systematically evaluated. This review discusses the latest advances in mitochondrial-based nanobiomaterial therapies for age-related bone diseases. Furthermore, this review explores potential drugs and targets for the development of more effective nanobiomaterials, focusing on the key challenges facing the transition from the laboratory to clinical applications in this field, and is expected to provide novel insights into the future development of mitochondria-based nanobiomaterial therapies.
Immune checkpoint inhibitors are widely used in solid tumors, but patient outcomes remain variable, and practical prognostic markers are still being clarified. This systematic review examined whether lymphopenia, defined by absolute lymphocyte count, assessed before treatment and/or during therapy, is associated with survival outcomes in adults with solid tumors treated with immune checkpoint inhibitors. A total of 21 studies were included, with sample sizes ranging from 22 to 18,186 patients. Several studies reported associations between lower absolute lymphocyte count and less favorable survival outcomes, although findings were heterogeneous and context-dependent. Overall, the available evidence suggests that absolute lymphocyte count-defined lymphopenia may have prognostic relevance in some settings, although substantial heterogeneity across studies limits firm conclusions and highlights the need for more standardized research.
Frail older patients are at high risk of both thromboembolism and bleeding, making anticoagulant therapy challenging. Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists because of comparable efficacy and lower bleeding risk. However, evidence supporting their use in frail older patients remains limited. Recent studies have demonstrated that a substantial proportion of frail older patients have DOAC plasma levels outside the expected on-therapy range, which may be associated with an increased risk of bleeding or thromboembolic events. The DOAC-FRAIL randomized controlled trial (RCT) aims to determine whether adjustment of DOAC therapy based on peak plasma concentrations improves the safety and efficacy of anticoagulant treatment compared with standard care in frail older patients. The DOAC-FRAIL study is an international, multicenter, randomized controlled trial including frail older patients aged ≥70 years with a Clinical Frailty Scale score >3 receiving DOAC therapy. Participants are randomized to either a Single Cycle Measurement and Adjustment Strategy based on peak DOAC plasma concentrations or standard care. Patients with a life expectancy of less than 3 months or previous DOAC dose adjustment based on plasma level measurements are excluded. The primary outcome is the composite of bleeding events, including clinically relevant non-major bleeding, and thromboembolic events during 2 years of follow-up. Secondary outcomes include feasibility, determinants of deviant peak DOAC plasma concentrations, quality of life, cost-effectiveness, and all-cause mortality. The DOAC-FRAIL trial is currently ongoing. Participant recruitment has been initiated, and study results are expected after completion of follow-up. The DOAC-FRAIL RCT will provide evidence on whether a plasma concentration-guided DOAC dosing strategy improves clinical outcomes compared with standard care in frail older patients. The findings may contribute to more personalized anticoagulant therapy in this vulnerable population. EU CT-2025-521362-10-00.
Multimodal communication, in which multiple signal modalities are combined to produce a single compound signal, is employed by many species and can mediate a wide range of fitness-relevant behaviours. While the form and function of multimodal signals have been extensively studied, we know little about how individual traits such as personality and experience influence receivers' responses to these signals. We investigated how aggressiveness and experience affect the behavioural responses to bimodal signals in the brilliant-thighed poison frog Allobates femoralis. In this species, male advertisement calls constitute a fixed bimodal signal, as the production of sound is coupled with the inflation of the vocal sac, which adds a visual cue. We presented territorial males with a synthetic advertisement call (acoustic cue) and a model frog with a pulsating vocal sac (visual cue), and manipulated signal ambiguity by varying the spatial distance between the two components. We predicted personality and experience would affect how males responded to the bimodal signal depending on its level of ambiguity, and expected younger and/or more aggressive males to respond faster and to attack the visual cue more frequently than older or less aggressive males, especially under high signal ambiguity. Contrary to our predictions, neither aggressiveness nor experience influenced response latency or attack likelihood. Instead, all males displayed a consistent population-level pattern: as the spatial separation between the visual and acoustic signal components increased, they were less likely to attack the model, and their initial and overall interactions shifted from the visual model to the sound source. These findings suggest that the fixed bimodal signals in A. femoralis selected for robust and uniform receiver responses to maintain reliable communication during high-stakes social interactions such as territorial defence. Aggressive receiver responses seem to be dual-staged, consisting of far-field phonotaxis to the acoustic signal component and visual and multimodal signals only becoming relevant during near-field aggression. Future studies should compare how ecological and social factors shape receivers' responses across species with varying degrees of coupling between the signal components in order to better understand the evolution of multimodal signalling and of the diversity of receiver strategies.
To evaluate the association between the weight-gain-for-gestational-age z-score and preterm birth (PTB) in a large Chinese twin pregnancy cohort. A hospital-based retrospective study included 2832 twin pregnancies between January 1, 2015, and December 31, 2019. The primary composite outcome was defined as PTB. The total gestational weight gain was converted into z-score, and logistic regression models were used to examine the associations between z-scores and PTB. We developed a weight-gain-for-gestational-age z-score to determine the gestational weight gain during twin pregnancies in Chinese women. Low (<P25) and high (≥P75) z-scores were associated with a higher risk for spontaneous PTB (SPTB) than scores between the 25th and 75th percentiles (adjusted odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.05-1.74; 1.28, 0.99-1.66; respectively). Similarly, low z-scores (1.40, 1.12-1.76) and high z-scores (1.97, 1.57-2.47) were also associated with an increased risk for iatrogenic PTB (IPTB). Normal weight subgroups exhibited comparable outcomes. In addition, z-scores between the 25th and 75th percentiles indicated an equivalent total gestational weight gain at 37 weeks of 15.8-20.9 kg for underweight, 14.6-20.3 kg for normal weight, and 11.8-18.6 kg for overweight or obese women, which are narrower than the 2009 IOM recommendation. Our findings indicate that inadequate gestational weight gain, as evaluated by the z-score, is associated with a significantly increased risk for SPTB, whereas inadequate and excessive gestational weight gain are associated with a significantly increased risk for IPTB, in a large Chinese twin pregnancy cohort. This study examined whether weight gain during pregnancy is linked to the risk of early birth in women carrying twins in China. Because women who deliver earlier have less time to gain weight, we used a special method that takes into account how far along the pregnancy was. This allowed us to fairly compare weight gain between women who delivered at different times. We studied over 2,800 women with twin pregnancies. We found that women who gained less weight than expected for their stage of pregnancy were more likely to have their babies born early. Women who gained more weight than expected also had some increased risk. The safest amount of weight gain appeared to be in the middle range. These findings suggest that keeping weight gain within a healthy range during twin pregnancy may help lower the chance of early birth. Women expecting twins should talk to their doctors about healthy eating and weight gain during pregnancy.