Following a loss of balance, proper reactive responses are needed to avoid a fall. Efforts have focused on how physiological factors affect these responses, but few have addressed psychological states. One psychological factor of particular interest is fear of falling (FoF); while prevalent in older adults, the mechanisms by which it increases fall risk are not fully understood. The purpose of this study was to use a well-established, postural-threat manipulation (standing at a height) to evaluate how such threat affects reactive stepping behavior during a perturbation protocol designed to identify the perturbation magnitude at which stepping became necessary for balance recovery. Ten healthy, young adults completed a single-step threshold (SST) test using a waist-mounted spring scale device to provide progressively-ordered anterior and posterior perturbations while standing on level ground and on a 1-m-high platform. Stepping kinematics and dynamic stability (i.e., margin of stability, MoS) were assessed. For a given direction, standing at a height (increased postural threat) did not significantly alter SST, although a trend toward lower posterior SST at height was observed (p = 0.057). However, increased postural threat substantially altered the timing and execution of the recovery step performed at SST. Participants initiated steps 200-300 ms earlier and took shorter steps at raised height (p < 0.05), yet achieved greater MoS at foot contact. Under threat, MoS was reduced to a lesser extent before stepping, with participants often stepping before MoS < 0, indicating that steps were initiated at a larger safety margin relative to instability. Findings suggest that within the current paradigm, postural threat influences when recovery steps are initiated and how they are executed at SST, even when the perturbation magnitude required to evoke stepping remains largely unchanged. Future work should evaluate whether older adults with FoF adopt such strategies and whether this impacts fall risk.
High-fidelity physical simulation is a cornerstone of embodied intelligence, yet simulating high-dimensional nonlinear multi-body systems involves a fundamental trade-off between numerical stability and computational efficiency. Conventional explicit integrators suffer from energy drift in long-horizon tasks. Conversely, symplectic variational integrators (VIs) often have high computational costs due to implicit constraints. To bridge the gap, this paper reformulates the step-size adaptation as a dynamic closed-loop feedback control process instead of a rigid root-finding problem, proposing a Control-Theory-Inspired Adaptive Time-step Variational Integrator (C-ATSVI). A Lyapunov-based controller is designed to ensure asymptotic stability of the energy error, augmented by the Internal Model Principle (IMP) to eliminate steady-state residuals caused by numerical truncation. Simulations on a low-dimensional 2-DoF pendulum, a high-dimensional 7-DoF pendulum and a 7-DoF manipulator with external force are conducted. Numerical results demonstrate that C-ATSVI achieves energy fidelity comparable to adaptive schemes, while maintaining computational efficiency similar to explicit fixed-step methods. Therefore, the proposed method offers a robust solution for analyzing complex Hamiltonian dynamics.
Pulsed-field ablation (PFA) is an emerging technique for pulmonary vein isolation in atrial fibrillation. However, its implementation is commonly guided by fluoroscopy with or without 3D electroanatomic mapping, increasing either radiation exposure or procedural cost. We describe a practical, step-by-step workflow for performing completely fluoroless pulmonary vein isolation using a pentaspline PFA ablation catheter guided exclusively by intracardiac echocardiography (ICE). All procedural stages-including transseptal access, intracardiac navigation, catheter deployment, energy delivery, and acute assessment of electrical isolation-are performed under continuous ICE visualization. Although this workflow is designed for pulmonary vein isolation, selected examples of extra-pulmonary vein ablation guided by ICE are included to illustrate catheter manipulation and energy delivery. This ICE-only approach suggests that fluoroless PFA is achievable using continuous ICE guidance while avoiding radiation exposure. In centers where the combined use of ICE and 3D mapping systems may be limited, this workflow may also represent a practical alternative for the treatment of atrial fibrillation.
Postoperative retraction is a significant limitation of traditional penile lengthening procedures that rely solely on suspensory ligament release. This retraction can lead to dissatisfaction among patients seeking enhancement. To address this issue, a novel two-step lengthening technique has been developed, which combines suspensory ligament release with an autologous dermal-fat graft and reinforcement using spermatic cord-associated fat. To evaluate the efficacy and safety of this innovative two-step lengthening technique in reducing postoperative retraction and improving overall patient outcomes in penile augmentation surgery. Between September 2024 and March 2025, thirty-one adult male patients underwent suspensory ligament release via a reversed V-shaped suprapubic incision. The resulting retropubic space was filled using an autologous dermal-fat graft harvested from the lateral abdomen, customized to the assessed cavity volume. Transposed spermatic cord-associated fat pads were anchored to the base of the corpora cavernosa to reinforce the scaffold. Patients were followed up at 3, 6, and 12 months postoperatively. Penile length (flaccid and erect), complication rates, and patient satisfaction were assessed. All wounds achieved primary closure with no major complications. Mean flaccid penile length increased from 5.23 ± 0.58 cm preoperatively to 6.89 ± 0.47 cm postoperatively (p < 0.001), and mean erect length increased from 7.78 ± 0.63 to 9.73 ± 0.71 cm (p < 0.001). No significant length loss was observed during the 12-month follow-up. Patient satisfaction levels were notably high, with 93.3% reporting satisfied or very satisfied. This vascularized, multilayer autologous scaffold approach effectively stabilizes length gains following suspensory ligament release. It represents a promising and safe strategy to minimize postoperative retraction and enhance long-term outcomes in penile augmentation surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
We provide a step-by-step guide on conducting a quantitative systematic review (i.e., meta-analysis) using the open-source programming language R, as well as conducting a multilevel meta-analysis, in contexts where effect sizes are non-independent (e.g., multiple studies from the same lab). Quantitative systematic reviews offer researchers a method for synthesizing large bodies of literature, helping clarify inconsistent findings, identify research gaps, and refine theoretical models. However, existing tutorials often assume prior knowledge and/or experience, often overlooking foundational concepts. To address this gap, a comprehensive walkthrough of the systematic review process is presented, covering pre-registration, literature search and retrieval, screening, risk of bias assessment, and data extraction following the PRISMA framework. We then present detailed guidance on how to conduct both traditional and multilevel meta-analyses in R. Specifically, the tutorial explains how to estimate overall meta-analytic effect sizes when effect sizes are independent (traditional meta-analysis) and when effect sizes are nested within labs (multilevel meta-analysis). Procedures for assessing heterogeneity, testing for publication bias, and conducting moderation analyses are also covered. To accompany this tutorial, we supplement annotated R scripts and R notebooks to support transparency, reproducibility, and accessibility for researchers of all levels of experience.
Major laparoscopic hepatectomy along the major hepatic veins requires accurate orientation to the transection plane and safe management of the hepatic venous branches. We developed an extracorporeal ventral traction (EVT) method combined with a 3-step dorsal approach (3SDA) to standardize laparoscopic hemihepatectomy. In EVT, a traction suture secured on the caudal edge of the transection line is brought out through the epigastrium and pulled extracorporeally, elevating the liver parenchyma ventrally and allowing dorsal access under the caudal laparoscopic view. In 3SDA, the transection plane containing the major hepatic vein is divided into three areas: Area A, caudal to the hilum; Area B, dorsal to the hepatic vein; and Area C, ventral to the hepatic vein. These areas are approached sequentially to open the caudal view, maintain anatomical landmarks, and reduce venous injury. EVT and 3SDA provide a reproducible framework for laparoscopic hemihepatectomy.
Embryo implantation is a critical and tightly regulated process essential for successful human reproduction. Although the role of endometrial receptivity is well established, the molecular mechanisms governing this process are not thoroughly understood. Circadian rhythm regulators, particularly brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1), have emerged as key modulators in reproductive biology. In this study, we investigated the role of BMAL1 in regulating endometrial receptivity and embryo implantation. Ishikawa cells were transfected with BMAL1-specific or control siRNA, followed by RT-qPCR, western blotting, and immunofluorescence analyses. Functional assays, including migration assays, co-culture with JEG-3 spheroids, cell viability, and cytotoxicity, were also performed. Our results demonstrated that BMAL1-knockdown in Ishikawa cells downregulated adhesion-related genes, including ITGAV, ITGB3, and ITGB5. Although total ITGB5 protein levels remained stable, its localized expression intensity was significantly reduced; the protein expression of ITGAV and ITGB3 was decreased, and cell migration was impaired. Notably, while BMAL1-knockdown compromised cellular motility, it had no significant effect on cell viability or cytotoxicity. A co-culture model with JEG-3 spheroids further demonstrated significantly decreased embryo adhesion following BMAL1-knockdown. In conclusion, BMAL1 is a critical regulator of integrin-mediated adhesion and endometrial receptivity, underscoring its potential as a therapeutic target for recurrent implantation failure.
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Hydrogen storage methods represent one of the main bottlenecks to achieving a global hydrogen-based economy, particularly for light-duty vehicles. Several classes of materials have been investigated to address current demands. However, a fully satisfactory solution has yet to be achieved. In this context, nanostructures have emerged as promising candidates, offering new possibilities for attaining the performance required for efficient hydrogen storage. This review discusses the advantages and limitations of the main hydrogen storage materials, with special emphasis on nanostructured systems. It also addresses the main characterization techniques used for hydrogen storage materials, as well as future perspectives for the field.
This study developed two lipid-polymeric hybrid nanoparticle thermosensitive gels, hypothesizing enhanced physicochemical properties, antimicrobial efficacy, and dentinal penetration compared to free drugs. Ciprofloxacin-loaded lecithin-PLGA nanoparticles (CIP-LPNPs) and chitosan-lecithin nanoparticles (CS-LNPs) were synthesized via nanoprecipitation and characterized by DLS, SEM, FTIR and HPLC. Antimicrobial activity against Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa was assessed by disk diffusion, MIC and biofilm assays; dentinal penetration of FITC-labeled CS-LNPs was evaluated by confocal microscopy. CIP-LPNPs and CS-LNPs measured 140.6 and 130.9 nm with zeta potentials of -29.4 and +28.9 mV, respectively. CIP-LPNPs showed 55.7% encapsulation and biphasic release. Both nanoparticles enhanced biofilm eradication against all strains; CS-LNPs exhibited two-fold lower MICs and significantly deeper tubular penetration than free chitosan (p < 0.0001). Both CIP-LPNPs and CS-LNPs improved physicochemical and antibiofilm properties over their free drugs; however, as no biocompatibility assessment was performed, these formulations cannot be considered safe without such validation.
New diagnostic tools, such as high fluorescence cells (HFc) and tumor markers (TMs), have emerged in the quest to accurately diagnose malignant pleural effusion (MPE). This study evaluated the diagnostic performance of the HFc and TMs combination. Hospitalized patients with pleural effusion were recruited at Parc Taulí University Hospital in Sabadell (Spain). Pleural fluid (PF) and serum samples were collected and analyzed in the Clinical Laboratory, and PF samples were sent to the Pathology Department for cytological examination. PF cell counts were determined using an XN-10 analyzer (Sysmex, Kobe, Japan); TMs (CEA, CA 19.9, CA 15.3, CA 72.4, and CYFRA 21.1) were assessed using Cobas e801 (Roche Diagnostics, Mannheim, Germany). An MPE diagnosis was made based on positive cytology and/or positive pleural biopsy. A diagnostic algorithm was developed to detect MPE starting with an initial HFc screening, followed by TM determination with specific cutoffs depending on fluid type. The study included 300 pleural effusions from 209 patients. The algorithm had a sensitivity of 68% and a negative predictive value of 93%; its specificity and positive predictive value were both 100%. When combined with cytology, the sensitivity of the algorithm increased to 85%, and its negative predictive value to 96%. Our algorithm exhibited promising diagnostic performance and could serve as a non-invasive tool for MPE detection. HFc screening helps identify potential MPE cases, and TM assessment, with its high specificity, contributes to MPE confirmation. Furthermore, establishing different TM cutoffs based on fluid type increases sensitivity without reducing specificity by introducing false positives.
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Higher step width variability while walking is associated with poor physical function and falls. Sleep is an established modifiable risk factor for both gait and physical function impairments, but it remains to be examined whether sleep is also related to step width variability. This study aimed to evaluate the cross-sectional associations between objectively measured sleep quality, using cardiopulmonary coupling spectrograms, and step width variability during a preferred walking condition among middle-aged and older adults. This study included 72 adults (mean age 71, SD 8.3 y; n=37, 51% female; n=65, 90% non-Hispanic White) who had ≥2 nights of objectively measured sleep (cardiopulmonary coupling via SleepImage ring) and completed a 10-m walk at preferred speed while wearing inertial sensors (APDM Mobility Lab). Sleep measures included sleep duration, efficiency, fragmentation, stability, apnea-hypopnea index, percentage of time oxygen saturation level <90%, oxygen desaturation index, and respiratory disturbance index. Additional derived sleep variables were explored using least absolute shrinkage and selection operator models. Step width variability was defined by the asymmetry of lateral step variability and categorized as medial (≤-7.5 cm), minimal (within ±7.5 cm; reference), or lateral displacement (≥7.5 cm). Multinomial logistic regression models adjusted for age, sex, race, education, BMI, and usual gait speed evaluated cross-sectional associations between sleep and step width variability categories. We found that a 1% higher sleep fragmentation was associated with a 6% higher probability of step width variability ≥7.5 cm (95% CI 1.01-1.11), while a 1% higher sleep stability was associated with a 5% lower probability of variability ≥7.5 cm (95% CI 0.91-0.99), compared to minimal variability. From the least absolute shrinkage and selection operator models, we found that a 1% higher sleep quality index, a 1% higher rapid eye movement sleep, a 1-second shorter apnea duration, and a 1-beat per minute slower mean heart rate were also associated with a lower probability of lateral compared to minimal displacement. Poor sleep quality was associated with higher step width variability among middle-aged and older adults. This suggests that sleep may be a modifiable risk factor for maintaining postural stability while walking among middle-aged and older adults. Future studies are needed to examine whether intervening in these sleep measures also lowers the risk of falls.
ObjectiveShared decision-making (SDM) is a key component of patient-centred care and major driver of healthcare policy, clinical practice and research globally. Widespread implementation of SDM is hindered by uncertainty about how to best measure decision-making processes. A seminal methodological review of SDM instruments published in 2018 identified widespread deficiencies in instrument quality and provided recommendations for improvement. This systematic review and COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) quality appraisal aims to provide an update SDM instrument inventory, re-evaluated progress in the field and provided future direction for researchers, funders and policymakers. This systematic review and COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) quality appraisal aims to provide an update SDM instrument inventory, re-evaluated progress in the field and provided future direction for researchers, funders and policymakers. A systematic search of six databases (September 2017-December 2024) identified studies of instruments measuring the process of SDM. Instrument appraisal followed COSMIN guidelines in a three-step process: appraisal of the methodological quality of instruments and of the quality of the measurement properties of newly identified measures (steps i, ii). This informed the comprehensive best-evidence synthesis which included the data from the original review (step iii). A total of 127 studies were included describing the development and/or evaluation of 105 unique instruments to measure the process of SDM. Some 61 new instruments were identified since the last review, of which 35 (57%) were translations/revisions to existing ones. The best-evidence synthesis revealed positive results for internal consistency (72%), structural validity (75%) and intrarater reliability (50%), but also negative or unknown results for test-retest reliability (58%), content validity (54%) and intrarater reliability (50%), where evaluated. No single instrument consistently showed positive evidence across all relevant measurement properties. Evidence gaps for many properties remain. This updated inventory guides researchers, clinicians and policymakers to the most appropriate instrument for an intended context/population. There was a proliferation of new, primarily patient-reported measurement instruments, but no single instrument had sufficient evidence of measurement quality. Methods were aligned with the original review and applied the 2011 COSMIN checklist which was updated in 2024, although using a previous checklist version is unlikely to affect overall conclusions. We recommend an international consensus with key interest holders on preferred instrument(s) for further validation and future core measurement set for efficient evidence synthesis. Prospero: CRD42024485655.
The mechanism of the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), an adaptable, regioselective, and high-yielding click reaction, was investigated using the Unified Reaction Valley Approach (URVA) and Local Mode Analysis (LMA). The cycloaddition and ring contraction steps of catalysis via both mononuclear and dinuclear catalysts, in the form of Cu(I)-acetylides forming 1,4- and 1,5-products, were explored at the B3LYP/cc-pVTZ level of theory as well as at the CCDT(T) level. The dinuclear mechanism for 1,4-addition was found to have the lowest activation energy and was identified as the most effective catalytic pathway. With the first cycloaddition step presenting the highest energy barrier, single-point energy calculations showed that this barrier is lowest for the dinuclear catalyst, while LMA suggests that regioselectivity may arise from catalyst dissociation and stronger stabilization of the final product. URVA analysis indicated that the transition state of the first step occurs prior to any C-N bond formation, signifying that the energy barrier originates from initial electronic structural changes. These mechanistic insights provide a basis for the design of more efficient CuAAC catalysts.
In 2023, the European Academy of Allergy and Clinical Immunology (EAACI) proposed an immune response-based classification that integrates molecular, endotypic, and clinical characteristics to define predominant and co-occurring immune response groups in asthma. Applying this framework may clarify disease heterogeneity and support personalized treatment. To classify asthma patients according to the EAACI immune response system and describe predominant and overlapping groups together with related clinical features. A retrospective chart review was conducted between February and April 2025 in our tertiary asthma outpatient clinic. Patients meeting ≥1 clinical criterion for an immune response type were categorized into seven EAACI-defined groups. Demographic variables, Asthma Control Test (ACT) scores, treatment steps, and disease severity were analyzed. Among 401 patients (332 female, 69 male; mean age 53.4 ± 14 years), Type 1, 4b, 4a, 4c, 6, and 7 immune responses were present in 44.6%, 90%, 32.2%, 58.9%, 41.6%, and 15.5%, respectively, while all patients exhibited Type 5 features. The most frequent co-occurrence was among Types 4b, 4c, and 6. Step 5 treatment was more common in Type 4b (p = 0.002), whereas Step 3 predominated in Type 1 (p = 0.002). ACT scores did not differ significantly across immune response groups. Classification based on the EAACI immune response framework is feasible and clinically meaningful. The predominance of Type 4b, often coexisting with Types 4c and 6, underscores its clinical relevance. This phenotypic-endotypic linkage may inform future personalized therapy strategies in asthma.
Disruption of mitochondrial morphology occurs during various diseases, but the biological significance is not entirely clear. Here, we describe a detailed step-by-step protocol for a chemically inducible dimerization (CID) system-based synthetic protein device, termed inducible counter mitochondrial morphology (iCMM). This system allows artificial manipulation of mitochondrial morphology on a timescale of minutes in living mammalian cells. We also describe an AI-assisted image processing approach. For complete details on the use and execution of this protocol, please refer to Miyamoto et al.1 This protocol provides an updated version of the method described by Miyamoto et al.2.
Low-molecular-weight proteins (LWPs, <30 kDa) are crucial in the identification of tumor markers and disease diagnosis. However, current methods for analyzing LWPs typically involve complex workflows, high sample consumption, poor automation, and prolonged reaction times. In this study, immobilized enzyme microreactors (IMERs) were prepared by immobilizing trypsin encapsulated in zeolitic imidazolate frameworks (ZIF-L) within a capillary, which was then integrated with capillary electrophoresis (CE) to develop a novel strategy for the pretreatment and assay of LWPs. Compared to traditional LWP analysis protocols, which typically involved a three-step process of sequential separation, denaturation, and enzymatic digestion, the proposed strategy achieved the LWP analysis in a single step within just 4 min in a 10 μL sample, significantly reducing sample pretreatment procedures and analytical time while offering advantages such as high efficiency, rapid processing, automation, and low consumption. The prepared trypsin@ZIF-L@IMER exhibited superior activity, enhanced affinity, remarkable stability, and excellent reusability when compared with free enzyme. In addition, the trypsin@ZIF-L@IMER demonstrated high selectivity toward LWPs after the pretreatment of single, binary, quaternary, and septenary model proteins. Additionally, the development method demonstrated ultrahigh sensitivity (0.05 nM cytochrome c (CYC)) and excellent anti-interference capability (CYC/bovine serum albumin (BSA) = 1:1000), outperforming previously reported methods. Finally, the developed strategy based on trypsin@ZIF-L@IMER was used for LWP analysis in human serum. The results showed that trypsin@ZIF-L@IMER possessed higher selectivity and pretreatment capability toward LWPs in human serum when compared with other methods and free trypsin, and the identified LWPs played critical functions and roles in serum-related biological processes by Gene Ontology analysis. The developed method provides a novel strategy for efficient protein pretreatment analysis, which can be further extended to the pretreatment analysis of other proteins.
Two key enzymes, HMG CoA reductase (HMGCR) and squalene monooxygenase (SM), are subjected to distinct endoplasmic reticulum-associated degradation (ERAD) pathways to maintain cholesterol homeostasis. HMGCR catalyzes conversion of HMG CoA to mevalonate, the first rate-limiting step in cholesterol synthesis. Sterols accelerate ERAD of HMGCR by promoting its binding to Insig proteins, which recruit E3 ubiquitin ligases for ubiquitination and degradation. Downstream, SM catalyzes oxygenation of squalene, committing intermediates to sterol synthesis. Cholesterol stimulates ERAD of SM, but through an Insig-independent mechanism mediated by the E3 ligase MARCH6. Here, we report a mechanism of posttranslational regulation involving a stable complex between HMGCR and SM in sterol-deprived cells. The two enzymes physically interact within ER membranes in an Insig-independent manner, and this interaction protects both proteins from ERAD. Loss of either enzyme destabilizes the other, indicating a costabilization mechanism. These findings uncover a layer of coordination in cholesterol synthesis, suggesting HMGCR and SM function as an integrated complex to ensure synchronization of early and late steps of the pathway.
In the past decade, many successful networks are on novel architectures, which almost exclusively use the same type of neurons. Recently, more and more deep learning studies have been inspired by the idea of NeuroAI and the neuronal diversity observed in human brains, leading to the proposal of novel artificial neuron designs. Designing well-performing neurons represents a new dimension relative to designing well-performing neural architectures. Biologically, the brain does not rely on a single type of neuron that universally functions in all aspects. Instead, in our brain, neurons are often task-based. In this study, we address the following question: since the human brain is a task-based neuron user, can the artificial network design go from the task-based architecture design to the task-based neuron design? Since methodologically there are no one-size-fits-all neurons, given the same structure, task-based neurons can enhance the feature representation ability relative to the existing universal neurons due to the intrinsic inductive bias for the task. Specifically, we propose a two-step framework for prototyping task-based neurons. First, symbolic regression is used to identify optimal formulas that fit input data by utilizing base functions such as polynomials. We introduce VSR that stacks all variables in a vector and regularizes each input variable to perform the same computation, which can increase the regression speed, facilitate efficacy in high dimensions, and enable parallel computation. Second, we parameterize the acquired elementary formula to make parameters learnable, which serves as the aggregation function of the neuron. The activation functions such as ReLU and the sigmoidal functions remain the same because they have proven to be good. As the initial step, we evaluate the proposed framework using polynomials as base functions. Empirically, systematic experimental results on synthetic data, classic benchmarks, and real-world applications show that the proposed task-based neuron design is not only feasible but also delivers competitive performance over other state-of-the-art models. We have shared our code in https://github.com/NewT123-WM/Task_based_neurons.