Biological AI tools for protein design and structure prediction are advancing rapidly, creating dual-use risks that existing safeguards cannot adequately address. Current model-level restrictions, including keyword filtering, output screening, and content-based access denials, are fundamentally ill-suited to biology, where reliable function prediction remains beyond reach and novel threats evade detection by design. Because the full spectrum of risks cannot be managed by any single actor, effective oversight requires shared responsibility between research institutions and model hosts. Hence, we propose a three-tier Know Your Customer (KYC) framework, inspired by anti-money laundering (AML) practices in the financial sector, that augments existing approaches, supplementing content inspection with complementary layers of user verification and monitoring. Tier I leverages research institutions as trust anchors to vouch for affiliated researchers and assume responsibility for vetting. Tier II applies output screening through sequence homology searches and functional annotation. Tier III monitors behavioral patterns to detect anomalies inconsistent with declared research purposes. This layered approach preserves access for legitimate researchers while raising the cost of misuse through institutional accountability and traceability. The framework can be implemented immediately using existing institutional infrastructure, requiring no new legislation or regulatory mandates.
Four-dimensional (4D) printing has emerged as a powerful strategy for creating reconfigurable soft actuators with applications in biomedical engineering and microrobotics. However, most existing methods, such as inkjet printing or photoalignment, are restricted to film-like or net-like architectures that only enable out-of-plane deformation and cannot be scaled to the microscale. Although two-photon polymerization provides submicron resolution and 3D microfabrication, its voxel-by-voxel laser scanning induces strong liquid crystal diffusion around each printed voxel, which cannot be effectively suppressed by external fields or laser-induced anchoring. Here, we harness this diffusion as a design principle for 4D microprinting of soft liquid crystal network microactuators, enabling hierarchical and volumetric alignment within complex 3D architectures. Diffusion-guided orientation emerges perpendicular to the printed surface profile, allowing programmed molecular alignment through controlled variation of the scanning direction. These microactuators incorporate volumetrically programmable 3D architectures and can be integrated into multi-jointed microarms and microgrippers, executing complex and coordinated actuations for advanced microrobotics.
There is apprehension regarding the agreement between capillary and venous hemoglobin (Hb) concentrations, which may have far-reaching consequences for global anemia prevalence estimates, heavily dependent on capillary Hb data. We investigated the discrepancies in Hb concentrations obtained from venous and capillary blood samples collected among school-age children in Zanzibar. Hb concentrations were measured in 810 children aged 10-19 years old. Both capillary and venous Hb measurements used a HemoCue 201+ analyzer (HemoCue, Angelholm, Sweden). Hb means, standard deviations, and anemia prevalence were analyzed using Stata. The means of the anemia categories were compared using paired t-tests. The agreement between capillary and venous Hb measurements was assessed using Pearson's correlation coefficients, a Passing-Bablok regression, and a Bland-Altman plot. The correlation between paired measurements of capillary and venous Hb concentration was high, r=0.72 (p<0.001). The prevalence of anemia using venous samples was 20.5 %, and using capillary samples was 44.7 %. Mean Hb concentrations were higher in venous than capillary samples (mean ± SD: 12.994 ± 1.54 vs. 12.085 ± 1.36 g/dL, p<0.001). The mean difference between the methods is -0.909 g/dL, and the limits of agreement are (-3.065 - 1.247). Passing-Bablok regression analysis showed no evidence of systematic error between capillary and venous hemoglobin measurements. Capillary and venous hemoglobin measurements differ significantly; capillary Hb cannot replace venous Hb for accurate anemia assessment.
l-Fuculose is a rare deoxyketohexose sugar and is a structural isomer of l-fucose, which exhibits skin-lightening, moisturizing, and anti-aging effects. Due to their structural similarity, l-fuculose is also expected to provide potential health benefits. However, l-fuculose exists only in trace amounts in nature, making extraction from natural sources virtually impossible; to date, it has been synthesized mainly by enzymatic conversion. This approach, however, suffers from major limitations: both the substrate (l-fucose) and the enzyme involved (l-fucose isomerase) are costly; the enzymatic reaction cannot achieve complete conversion due to the chemical equilibrium; and the methods for purification of l-fuculose from the reaction mixture containing both l-fucose and l-fuculose are inefficient and uneconomical. Microbial cell factories have been explored as an alternative route for l-fuculose biosynthesis, but their production titers remain extremely low, limiting their industrial applicability. In this study, a microbial cell factory was engineered in Escherichia coli by redirecting the pathway of l-fucose metabolism toward l-fuculose production. Overexpression of fucA enabled the aldol condensation of lactaldehyde and dihydroxyacetone phosphate to produce l-fuculose-1-phosphate, which was subsequently dephosphorylated to l-fuculose by a sugar phosphatase. To prevent diversion of substrates and products into competing pathways, the fucI, fucK, tpiA, fucO, and aldA genes were deleted. The final engineered strain produced 50.25 ± 4.30 mg/L of l-fuculose, a 32.4-fold increase compared to that achieved previously by microbial biosynthesis. This study establishes a foundation for the industrial production of l-fuculose, which has potential application as a valuable ingredient in cosmetics, functional foods, and pharmaceuticals.
The delivery of healthcare services within hospital facilities and the management of those services by a team of health professionals fundamentally changed the intrinsic characteristics of professional responsibility in the medical field. It is crucial to carefully evaluate the connection between the alleged cause and the alleged effect when proving the potential existence of medical professional liability profiles. It is imperative to emphasize that a sanitary expert cannot be held accountable for the outcomes of difficulties that are not directly linked to technical misconduct. To illustrate the critical role that forensic toxicology plays in determining the veracity of the evidence to support or refute a claim of professional responsibility in psychiatric context, the case of a claimed pentobarbital administration for euthanasic purposes is provided.
Ablation is an effective treatment for cardiac arrhythmias, and its primary goal is to remove excitability from cells to break pathological reentrant circuits or focal activities and thereby prevent recurrent arrhythmias. Ablation prevents excitation by destroying cells in targeted regions. However, if ablation does not eliminate sufficient cells, waves of action potentials (APs) may continue to propagate, and ablation may fail to suppress arrhythmias. In this study, we develop a theoretical approach that predicts the minimum number of ablated cells to break reentrant circuits and suppress the initiation and propagation of focal activities. Ablation creates a mixture of excitable and non-excitable cells. As the fraction of excitable cells increases, the probability of AP wave propagation increases, since an AP can only propagate when an excitable cell excites another excitable cell. When this fraction exceeds the "percolation threshold", as defined in percolation theory, AP waves always propagate successfully, regardless of the size of the ablated area. Therefore, for reentrant arrhythmias, the fraction of excitable cells in the ablation area must be below the percolation threshold to block AP waves. For focal arrhythmias, delayed afterdepolarizations (DADs) can trigger premature ventricular contractions (PVCs) when DADs overcome the source-sink mismatch. Ablation of excitable cells also reduces the functional electrical sink, making it easier to initiate triggered activities. However, if the fraction of excitable cells in the ablation area is below the percolation threshold, triggered activities also cannot propagate. On the other hand, when the fraction of excitable cells is high, even though AP waves can propagate more easily, the initiation of PVCs becomes more difficult due to the source-sink mismatch. The propensity for PVCs reaches its maximum at the percolation threshold. These scenarios can also apply to other pathological conditions, such as myocardial ischemia and infarction, where excitable myocytes are interspersed with non-excitable tissue.
Growing concern has emerged regarding the mental health of young adults, particularly within university settings where academic and psychosocial pressures are prominent. Exercise motivation (EM), conceptualized within self-determination theory (SDT), especially intrinsic and identified regulation, has been associated with psychological well-being. However, the structural associations among exercise motivation (EM), leisure satisfaction (LS), psychological resilience (PR), and self-efficacy (SE) in young adults remain insufficiently clarified. This cross-sectional study examined these associations in a sample of 437 university students aged 18-23 years in China. Data were collected through validated self-report instruments and analyzed using partial least squares structural equation modeling (PLS-SEM). The results indicated that exercise motivation was positively associated with leisure satisfaction (β = 0.794, p < 0.001), leisure satisfaction was positively associated with psychological resilience (β = 0.342, p < 0.001), and PR was positively associated with self-efficacy (β = 0.228, p < 0.001). Sequential mediation analysis showed that leisure satisfaction and PR jointly accounted for a significant indirect association between EM and SE (β = 0.062, p = 0.001). Model fit indices (SRMR = 0.055; NFI = 0.847) indicated an acceptable level of fit within the prediction-oriented PLS-SEM approach. These findings indicate that exercise motivation is statistically associated with psychological resources among young adults. Although causal inferences cannot be drawn due to the cross-sectional design, the study contributes to understanding motivational processes within the SDT framework and provides directions for future longitudinal research.
Meniscal preservation is a cornerstone of modern knee surgery given the meniscus's essential role in load transmission, joint stability, and cartilage protection. As indications for meniscal repair have expanded, understanding the factors associated with repair failure has become increasingly important. The purpose of this review is to synthesize contemporary evidence regarding risk factors for failure of meniscal repair, clarify how failure is defined and evaluated, and outline current strategies for management of failed repairs to guide clinical decision-making. Recent literature supports meniscal repair as a joint-preserving procedure with superior long-term outcomes compared with meniscectomy, though failure and reoperation remain clinically relevant concerns. Failure risk is influenced by a combination of patient-related factors, including smoking status, limb alignment, and medical comorbidities; tear characteristics such as vascular zone, tear pattern, chronicity, and meniscal laterality; and surgical variables including isolated repair versus concomitant ligament reconstruction, repair technique, and postoperative rehabilitation. Advances in repair devices, imaging, and biologic augmentation have improved healing potential, and growing evidence supports revision meniscal repair in select patients with favorable tissue quality and tear morphology. Meniscal repair failure is multifactorial and cannot be attributed to surgical technique alone. Successful outcomes depend on appropriate patient selection, careful assessment of tear biomechanics, selection of an optimal repair strategy, and individualized rehabilitation. Revision meniscal repair remains a viable option for preserving meniscal function in appropriately selected patients. Future research should prioritize standardized definitions of failure, comparative studies of repair techniques, and biologic strategies to further improve healing and long-term joint preservation.
Low back pain is a very common condition with significant healthcare and economic consequences. The acute form (<3 months duration) often progresses to the well-researched chronic state. Acute low back pain is less well understood but managing it more effectively may help address the growing burden of the chronic condition. This systematic review aimed to assess the evidence for the efficacy of exercise and opioid therapies to manage pain and function in acute low back pain using validated patient-reported outcome measures. Literature searches were performed of the databases, Web of Science, Pubmed, and Scopus, and a significant risk of bias analysis was performed on the results. After screening 1110 papers, 22 randomised controlled trials were included for review. Eighteen studies assessing various exercise interventions showed some evidence that they can improve pain and functioning outcomes up to 6 weeks from pain onset. Four opioid trials found limited evidence to support their use in managing acute low back pain. Risk of bias was found to be high for most of the exercise-based studies. Two opioid studies had a low risk of bias and two had some concerns. Trials for exercise interventions lacked the robustness to make reliable conclusions, although they indicated possible benefits of their use for improving pain and functional outcomes up to 6 weeks. Opioid interventions cannot be recommended for managing acute low back pain. More high-powered randomised controlled trials with lower risk of bias are required to make more meaningful conclusions.
To investigate the impact of empowerment-based health education combined with refined pain management in patients undergoing laparoscopic partial hepatectomy. Clinical data from 165 patients who underwent laparoscopic partial hepatectomy at The First Affiliated Hospital of Soochow University between March 2023 and March 2025 were retrospectively collected and analyzed. Based on documented nursing interventions, patients were assigned to an observation group (85 cases) or a control group (80 cases). The control group received routine nursing care, while the observation group received empowerment-based health education combined with refined pain management. Postoperative clinical indicators, postoperative pain intensity, quality of life, and the incidence of complications were compared between the two groups. The time to first ambulation, time to first flatus, and time to first defecation were significantly shorter in the observation group than in the control group (all p < 0.001). Postoperative pain scores at 12 h, 24 h, and 48 h were significantly lower in the observation group compared with the control group (Wald χ2 = 275.16, p < 0.001). At three months after the intervention, scores across all quality-of-life dimensions, including physical, psychological, social function, and material well-being, were significantly higher in the observation group than in the control group (p < 0.001). Additionally, the incidence of postoperative complications was significantly lower in the observation group (p < 0.05). Empowerment-based health education combined with refined pain management may facilitate early postoperative functional recovery and improve short-term quality of life in patients undergoing laparoscopic partial hepatectomy, while potentially reducing postoperative complications. These outcomes may be related to enhanced patient participation, optimized pain management, and improved adherence to rehabilitation protocols. This integrated nursing model may have potential value for clinical application. However, given the single-center retrospective design and the combined nature of the intervention, causal relationships cannot be established, and further validation through prospective, multicenter randomized controlled trials is warranted.
Metamizole is an analgesic drug with moderate cytochrome P450 (CYP) inductive properties. The antifungal triazoles are metabolized by several CYP enzymes, but the interaction with metamizole remains poorly described. We investigated the influence of metamizole on the exposure of voriconazole, isavuconazole, and posaconazole. Patients from UZ Leuven (Belgium) and Ljubljana University Medical Centre (Slovenia) receiving voriconazole, isavuconazole, or posaconazole concomitantly with metamizole were included in the study. Routine therapeutic drug monitoring (TDM) measurements collected between January 2019 and December 2024 were retrieved retrospectively. TDM concentrations outside of concomitant therapy were collected as controls. The influence of metamizole and other clinically relevant covariates was analysed using generalized estimating equations (GEE). A total of 126 distinct treatments with a triazole from 115 patients, accounting for 392 measurements, were included in the study. GEE analysis revealed a significant negative association between the 7-day cumulative metamizole dose and lower voriconazole and posaconazole concentrations. Additionally, C-reactive protein had a positive association with voriconazole concentrations. Only ICU admission and patient characteristics, that is, sex and weight, had a significant influence on isavuconazole concentrations. Concomitant therapy with metamizole led to lower voriconazole and posaconazole concentrations, presumably through induction of CYP enzymes and possibly UDP-glucuronyltransferase. We recommend avoiding concomitant use of metamizole with the antifungal triazoles to prevent underexposure and treatment failure or frequent TDM if the combination cannot be avoided. Further studies are needed to confirm our findings and investigate the influence of metamizole on other triazoles.
Post-traumatic confusional state (PTCS) is a disabling sequel of pediatric traumatic brain injury (TBI), with little guidance on pharmacologic management when aggression and poor impulse control dominate and adherence is poor. We describe a 9-year-old boy with severe TBI who evolved from coma to a prolonged PTCS characterized by agitation, externalizing behaviors, and dysexecutive symptoms. Multiple oral agents-risperidone, methylphenidate, olanzapine, and aripiprazole-were trialed over several years with minimal benefit and poor adherence. Following an acute agitation episode in 2022, long-acting injectable (LAI) paliperidone palmitate was initiated (100 mg then 150 mg monthly) with adjunct nightly risperidone 2 mg. Over two years, aggression markedly decreased and functional status improved from Rancho Los Amigos Level IV ("confused-agitated") to Level VIII ("purposeful-appropriate"). Cognitive testing at age 19 showed average intellectual ability but persistent executive dysfunction. Adverse effects were limited to weight gain and asymptomatic hyperprolactinemia; no extrapyramidal or cardiac events occurred. While spontaneous recovery and developmental maturation cannot be excluded, this case suggests LAI paliperidone can be a practical option to stabilize severe PTCS-related behavioral dysregulation when oral adherence fails. Larger, controlled studies are needed to clarify efficacy, safety, and long-term neurocognitive impact of LAI antipsychotics in pediatric TBI.
Immune checkpoint inhibitors (ICIs) are widely used in the treatment of hepatocellular carcinoma (HCC). Microwave ablation (MWA), a form of thermal ablation, may elicit systemic immune responses and could potentially augment the clinical activity of ICIs, particularly in advanced disease. The present study retrospectively assessed 52 eligible patients with limited progression or oligometastatic disease treated between January 2022 and January 2024 with either ICIs alone or ICIs plus MWA. A total of 21 patients received the combination regimen (predominantly programmed cell death protein 1 inhibitors), and 31 received ICI monotherapy. The recorded baseline characteristics did not suggest notable between-group imbalances; however, key tumor burden descriptors were incompletely captured, and residual confounding cannot be excluded. The objective response rate (ORR) and disease control rate (DCR) were 9.7 and 51.6% with ICIs alone, respectively, vs. 28.6 and 81.0% with ICIs plus MWA. The DCR was higher in the combination group (P=0.031), whereas the between-group difference in ORR was not statistically significant (P=0.133) compared with the monotherapy group. Median overall survival (OS) was 11.0 months with monotherapy and 16.8 months with combination therapy (log-rank P=0.008). In the multivariable Cox analysis, the combination therapy was associated with improved OS (adjusted HR=0.176; 95% CI, 0.048-0.642; Wald P=0.008); however, given the small sample size and limited number of OS events, this adjusted HR may be imprecise and sensitive to model specification and should be interpreted as exploratory. The median progression-free survival (PFS) was 4.0 vs. 9.0 months (log-rank P<0.001), consistent with the multivariable model (adjusted HR=0.270; 95% CI, 0.122-0.595; Wald P=0.001). There was not a clear unexpected safety pattern observed, but safety comparisons were descriptive only and underpowered. In the present retrospective cohort of selected patients with advanced HCC and limited progression/oligometastatic disease, ICIs plus MWA was associated with longer PFS and OS compared with ICIs alone. The interpretation is limited by the small sample size, potential residual confounding and model instability. The direction of benefit was consistent across Kaplan-Meier and Cox analyses, although the adjusted OS effect estimate may be imprecise. The present study was registered on ClinicalTrials.gov on 03 September 2024 (trial no. NCT06581497).
Children are a unique population with important differences in physical, physiological, and emotional differences from adults. Hence, research outcomes of studies conducted in adults cannot be extrapolated to pediatric population. However, there is scarcity of data on the safety and efficacy of new interventions in children, due to concerns about risks of research in children. It is vital to conduct scientifically robust and ethically sound observational noninterventional studies and interventional therapy clinical trials in children to provide supporting evidence for medical practices in the pediatric population, to advance understanding of diseases, and to provide quality health care. This is a brief review of scientific and ethical considerations in planning and conduct of clinical research in children.
During short-term frozen storage, crispy pork strips undergo moisture migration, crispness loss, and sensory deterioration. Traditional batters composed mainly of native starch, water, and whole egg cannot effectively retard these changes. This study evaluated the effects of four modified starches-oxidized starch, hydroxypropyl starch, acetate starch, and hydroxypropyl distarch phosphate-added at 0-10% (based on starchy raw material mass) to a traditional batter. Using a deep-fried crust model (DFCM), physicochemical and microstructural changes were assessed before and after 7 days of frozen storage. All modified starches significantly reduced quality deterioration. Comprehensive evaluation showed that 6-8% hydroxypropyl starch or hydroxypropyl distarch phosphate gave the best overall performance by balancing batter pickup with formation of a dense water-oil barrier, limiting ice crystal-induced structural damage, and preserving eating quality. These findings provide targeted guidance for optimizing batter formulations for frozen batter-coated meat products.
Proven protocols remain isolated inside institutions because EHR systems cannot understand each other's data semantically. Current data models each advance semantic interoperability, but none fully solves the problem of cross-institutional protocol portability. The authors suggest that large language models can translate data across systems using existing data model frameworks as "clinical constitutions" to achieve interoperability without universal standards.
In this narrative review, we summarize the current state of knowledge on novel isoquinolinium chlorofumarate diesters and pinnatoxins as potential neuromuscular blocking agents for modern anesthesia. Isoquinolinium derivatives gantacurium, CW002, CW011, and CW1759-50 are discussed due to promising initial findings, with animal and human studies presented to assess which agent may have the greatest potential for future clinical use. The approval process for gantacurium has reached Phase III clinical trials, but further trials are no longer ongoing. CW002 has undergone animal and human testing, and early results suggest fewer cardiovascular and pulmonary adverse effects; however, CW002 produces a longer neuromuscular block and is more difficult to antagonize than gantacurium. CW011 and CW1759-50 have been tested only in animal models. We also describe agents used to reverse neuromuscular block. L-cysteine is an amino acid that reverses the described fumarate-based neuromuscular blocking agents by reacting with the carbon-carbon double bond to form a stable thioether adduct that cannot bind to acetylcholine receptors. This adduct then slowly hydrolyses into inactive fragments, enabling rapid and complete reversal. Calabadion binds aminosteroid and benzylisoquinoline neuromuscular blockers by forming "host-guest" complexes, rapidly binding free relaxant molecules in plasma and acting faster than sugammadex, making it a potentially promising reversal agent. This article aims to review the role of nondepolarizing neuromuscular blocking agents in anesthesia.
An objective and anatomical "empty nose" refers to severe turbinate destruction and can be observed in dogs and cats following nasal diseases or surgical interventions, as evidenced on computed tomography and rhinoscopy. In contrast, true empty nose syndrome (ENS) in humans involves sensations of impaired airflow, discomfort and paradoxical nasal obstruction, despite enlarged or empty nasal cavities, which cannot be assessed in animals. Accurate grading of turbinate destruction requires a multimodal diagnostic approach. While human ENS studies may provide conceptual insights, direct extrapolation to veterinary patients remains limited.
Dental caries is a multifactorial infectious disease influenced by diet and dental biofilm activity, characterized by acid production from bacterial fermentation of dietary carbohydrates, with Streptococcus mutans playing a central role in its development. It remains one of the most prevalent noncommunicable diseases worldwide. In recent years, honey has emerged as a natural agent of interest in oral healthcare due to its antibacterial, antibiofilm, anti-inflammatory, and wound-healing properties. In vitro studies indicate that honey exerts a multifactorial antimicrobial effect mediated by hydrogen peroxide, polyphenols, bioactive peptides, and a complex mixture of over 200 compounds, effectively inhibiting bacterial growth and biofilm formation. Its activity has been demonstrated against key oral pathogens, including S. mutans and Lactobacillus species, although potency varies depending on honey type, concentration, and formulation. Clinical evidence suggests that honey may reduce plaque accumulation and improve gingival health, but its effectiveness generally remains inferior to conventional agents such as chlorhexidine. Novel honey-based formulations, including toothpastes and mouth rinses, show promising antibiofilm activity; however, clinical validation remains limited. In addition, the effects of honey on enamel integrity remain unclear, with in vitro studies reporting heterogeneous findings, ranging from potential protective or neutral outcomes to possible demineralizing effects depending on experimental conditions. Overall, honey may serve as a complementary adjunct in oral hygiene and caries prevention but cannot replace established preventive measures. Well-designed, long-term clinical trials with standardized formulations are needed to confirm its efficacy and establish practical guidelines for its use in dental care.
Bispecific T-cell engagers (TCEs) have transformed the treatment landscape for patients with relapsed/refractory multiple myeloma. However, the benefits of these therapies cannot be fully realized in real-world practice if patients are unable to access them. Poorer survival outcomes among certain patients with multiple myeloma are partly attributed to disparities in access to care driven by multiple barriers, including geographic constraints, socioeconomic, patient-level, and health system-level limitations. These inequities further restrict access to novel treatments, including bispecific T-cell engager therapies. This article provides an overview of the current barriers to accessing bispecific therapies and discusses potential, evidence-based strategies to improve equitable access.