Individuals with lower extremity peripheral artery disease (LE PAD) represent a subset of patients with atherosclerotic cardiovascular disease that are among the highest risk for major adverse cardiovascular and limb events. Despite this, LE PAD is frequently under diagnosed, and an individual patient's risk for cardiovascular morbidity and limb loss is often underestimated and undertreated. To change the course of PAD disease progression, aggressive secondary prevention therapies are required. This is of particular importance among individuals undergoing surgical or endovascular lower extremity revascularization (LER), who represent the PAD subgroup with the highest risk of cardiovascular and limb adverse events. The cornerstone of secondary prevention is centered on symptom control, lifestyle and behavioural interventions that include exercise therapy, smoking cessation, healthy nutrition and weight management. Individuals with high-risk concomitant comorbidities, such as ongoing smoking, diabetes, and chronic kidney disease, represent an even higher risk population that warrant stringent monitoring and may benefit the most from pharmacological therapies. Guideline-recommended pharmacological therapies include antiplatelet and anticoagulant medications, lipid lowering therapies, diabetes medications, and cilostazol. Despite guideline recommendations, these medical therapies remain under-utilized in patients with PAD. Based on the elevated risk profile of individuals with LE PAD undergoing LER, increased efforts are required to initiate and escalate secondary prevention therapies. To achieve this, the development of effective, patient-centred and scalable implementation strategies remains a priority.
To evaluate the safety, etiological diagnostic value, and impact on clinical treatment decisions of transjugular liver biopsy (TJLB) and percutaneous liver biopsy (PLB) in patients with liver failure. This retrospective study included patients with liver failure who underwent liver biopsy between January 1, 2017, and November 30, 2025. Demographic characteristics, clinical data, post-procedural adverse events, and pathological diagnoses were collected and subjected to statistical analysis. A total of 53 patients with liver failure were included, comprising 40 patients with acute-on-chronic liver failure (ACLF) and 13 patients with acute or subacute liver failure. 13 patients received TJLB, all of whom had ACLF. Compared with the PLB, patients in the TJLB group had a higher international normalized ratio (INR) [1.61 (1.32, 1.98)], a lower platelet count (PLT) [89.00 (73.00, 129.00) × 10⁹/L], and were more frequently complicated by moderate to large ascites. Both PLB and TJLB were successfully performed, with a low overall complication rate and no serious adverse events. Even among patients with marked coagulation abnormalities or concomitant ascites, TJLB demonstrated acceptable safety. Histopathological examination following liver biopsy enables reclassification of both chronic liver disease etiologies and acute precipitating factors in patients with ACLF, as well as etiological diagnoses in patients with acute liver failure (ALF) or subacute liver failure (SALF). A substantial proportion of drug- or toxin-related acute liver injury was identified by histopathological examination (n = 32, 60%), leading to a decreased proportion of liver failure with unclear etiology. Based on the pathological diagnosis, treatment strategies were modified in 11% of patients, including the initiation or continuation of specific therapeutic regimens. In patients with liver failure, liver biopsy provides crucial information for determining the etiology and guiding clinical decision-making. With appropriate selection of the biopsy approach and patient population, TJLB can serve as a safe and feasible option, particularly for patients with coagulation disorders or severe ascites.
Maternal iron deficiency anemia (iron deficiency anemia) is a persistent global health challenge with increased risk of adverse perinatal outcomes. A recent multicenter clinical trial found reduced rates of low birthweight infants in mothers treated initially (early second trimester) with IV ferric carboxymaltose compared to oral iron. Secondary findings included improved hematologic indices 4 weeks post-treatment, as well as reduced rate of stillbirth with single dose IV iron infusion. We aimed to determine if the initial response to iron therapy was associated with risk of stillbirth and other adverse perinatal outcomes in pregnant singletons with moderate iron deficiency anemia STUDY DESIGN: This is a secondary analysis of a multi-center randomized controlled trial in India that compared single dose intravenous iron to oral iron for the initial management of moderate iron deficiency anemia (Hb 7.0-9.9g/dL) at 14-17 weeks gestation. The primary outcome for this secondary analysis is stillbirth. Secondary outcomes were early preterm birth <34 weeks, small for gestational age infants (<10%ile). The predictors of interest were maternal hemoglobin, ferritin, and transferrin saturation (TSAT), measured at 20-24 weeks gestation. Longitudinal hematologic and iron indices through pregnancy and association with outcomes were also assessed. Relative risk of each outcome based on post-treatment hemoglobin, ferritin, and TSAT was assessed with Poisson regression, adjusting for maternal age, BMI, parity, treatment modality, baseline Hb, and study site. Two-sided alpha=0.05 used for all analyses. Given that most nutrients exhibit U-shaped or threshold risk curves, we also fit models allowing for a quadratic function for the relationship between hematologic parameters at all times and risk of each event RESULTS: 4252 participants were included in this analysis, 1421, 1424, 1407 received intravenous ferric derisolmaltose, ferric carboxymaltose, and oral iron respectively. In evaluating the linear relationship, each unit of increasing Hb response at 20-24 weeks was significantly associated with reduced risk of stillbirth (RR 0.74 (0.56, 0.98). In evaluating the quadratic relationship, we found that there was a significantly progressively increased risk of stillbirth (p<0.0001) and early preterm birth< 34 weeks (p=0.01). Although there was a significant quadratic relationship identified with small for gestational age infant and Hb (p=0.008), the relative risk of SGA and lower Hb was not statistically significant. Inadequate improvement in hemoglobin at 20-24 weeks following iron therapy in pregnancies complicated by moderate iron deficiency anemia is associated with increased risk of stillbirth and early preterm birth. Our findings highlight the potential importance of early screening and treatment of maternal anemia,. Given the association between persistent anemia at 20-24 weeks and adverse outcome, prospective trials should focus on whether early pregnancy, or even preconception, improvement in hemoglobin is an effective intervention to prevent adverse perinatal outcomes such as stillbirth and early preterm birth.
Central nervous system (CNS) metastases from Wilms tumor (WT) are exceedingly rare. Intracerebral hemorrhage secondary to metastatic WT is even less common, and the management of such cases is further complicated when patients are receiving a direct oral anticoagulant (DOAC) like Rivaroxaban, for which pediatric reversal guidelines are lacking. We report on the case of a 5-year-old boy with relapsed stage IV Wilms tumor who presented with rapidly progressive neurological deterioration caused by brain metastases with extensive intraparenchymal and intraventricular hemorrhage while receiving Rivaroxaban due to prior thrombosis. An emergent craniotomy and tumor resection was safely performed after emergent reversal of anticoagulation with Rivaroxaban using Andexanet alfa, administered in this pediatric patient with off-label consent in the setting of a life-threatening intracranial hemorrhage requiring emergent neurosurgical intervention. No excessive intraoperative bleeding was noted. Treatment for relapsed WT according to the SIOP-UMBRELLA-Protocol was initiated. Three weeks after Andexanet alfa treatment, a thrombotic event in the left iliac veins occurred, requiring anticoagulation with unfractionated heparin. This case highlights the therapeutic challenges of managing intracranial hemorrhage in a pediatric patient requiring emergent neurosurgical debulking in the setting of Rivaroxaban anticoagulation. To our knowledge, this is the second case reporting on Rivaroxaban reversal through Andexanet alfa in children. Early multidisciplinary intervention, meticulous neurosurgical management and continuation of oncologic therapy can lead to favorable outcomes even in such complex presentations.
There are a range of clinical uncertainties for managing mild and unilateral deafness in infants, such as whether hearing interventions are effective or even required. This study aimed to explore parental experiences of decision making for their pre-school aged children with mild or unilateral deafness identified through newborn hearing screening. Grounded theory methodology was used to develop a theory of parental decision making. Semi-structured interviews were carried out with seventeen parents of children with mild and unilateral deafness age 5 months to 4 years old. Parents made decisions about use or non-use of hearing interventions. Negotiating uncertainty was the core category that explained the decision making process. Parental skills and values, trust in professionals, and external constraints enhanced or mitigated uncertainty. The process of negotiating uncertainty involved learning to notice any changes in their child's behaviours which could reinforce or cast doubt on medical advice. Parents engaged in trade-off actions, such as comparing their perceptions of their child's hearing with evidence provided by professionals. These actions led to specific decisions regarding ways of managing their child's deafness, whether they preferred to 'maximise hearing' or 'wait and see'. Parents of infants and young children with mild and unilateral deafness often experience significant uncertainty, particularly in the early stages following diagnosis. The parent-professional relationship is important in supporting families through uncertainty and decision making. Enhancing professionals' ability to communicate effectively about uncertainty could support early parental decision making about their child's deafness.
Demoralization is common among individuals with breast cancer, and both social support and resilience are recognized as protective factors. However, the way these two factors interact at the symptom level remains unclear. This study therefore sought to clarify how resilience modifies the association between social support and demoralization at both symptom and construct levels. In this cross-sectional analysis, a total of 412 patients with breast cancer from the Be Resilient to Breast Cancer (BRBC) program completed the Perceived Social Support Scale (PSSS), the Cancer-Specific Resilience Scale (RS-SC-10), and the Demoralization Scale-II (DS-II). Moderated network analysis, Johnson-Neyman techniques, and response surface analysis were used to examine the moderating role of resilience from both symptom-level (micro) and scale-level (macro) perspectives. The mean age of participants was 50.8 years, ranging from 28 to 85 years, and 43.2% of them were diagnosed with stage II cancer. Higher social support and resilience were each negatively associated with demoralization. Resilience significantly moderated the associations between social support and demoralization, including the edge between friends' actual assistance and feeling unsupported (β = -0.002, SE = 0.002, p = 0.024), and between others' emotional care and self-undervaluation (β = 0.013, SE = 0.004, p = 0.004). Demoralization was lowest when patients reported concurrently high social support and resilience, and remained relatively low even when patients reported low social support but high resilience (F = 29.18, P < 0.01). Resilience appears to be associated with an enhanced protective effect of social support on demoralization and, when high, may be associated with lower demoralization even in the context of low external social support. Interventions that concurrently enhance internal resilience and external social support may be promising strategies to reduce demoralization and improve psychological well-being in patients with breast cancer.
Despite modest improvement, the lifespan of a child on dialysis continues to be 40 years shorter compared to healthy children. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in these patients. Risk factors for CVD are present even in early stages of chronic kidney disease (CKD) and accelerate as the child's renal function deteriorates. As a result, the highest burden of CVD exists in patients on chronic dialysis. Although dialysis is life-sustaining, the dialysis procedure promotes cardiovascular damage. Both traditional and non-traditional CVD risk factors drive this acceleration. More concerning, the dialysis procedure itself is cardiotoxic. Because of coexisting poor cardiac reserve and altered sympathetic tone in this patient population, dialysis induces repetitive contractile, ischemic injury termed myocardial stunning. This ischemia-reperfusion injury is reversible at first. However, with repetitive episodes, this injury will trigger alterations in cardiac function that decrease contractile function in order to preserve viability. Ultimately, these adaptations lead to remodeling and fibrosis. There is no targeted therapy available to reverse cardiovascular damage in these patients. Intensive monitoring and management of modifiable risks such as hypertension and anemia in the early stages of CKD to optimize cardiovascular health is imperative. However, in late CKD, especially in those patients who are not candidates for preemptive renal transplantation, optimization of the dialysis procedure is critical to prevent acceleration of their CVD burden. Improved assessment of dry weight as well as data-driven fluid management programs may decrease some risk. More importantly, standard implementation of intensified dialysis prescriptions by increasing time or through the addition of convective clearance may mitigate progressive cardiovascular damage and enhance survival. In this review, the pathophysiology of dialysis-induced cardiovascular damage will be reviewed. The management strategies to limit the cardiovascular burden in our patients are also discussed.
Understanding the mechanisms of nickel (Ni) uptake by hyperaccumulator plants is essential for advancing sustainable phytomanagement. In this study, saponite materials containing either isotopically natural or 61Ni-enriched Ni were synthesised and applied in RHIZOtest experiments with Odontarrhena chalcidica. The amendments were mixed with two ultramafic soils differing in Ni content, alongside a serpentinite control. Ni bioavailability and uptake were evaluated via elemental and isotopic analysis of plant digests and diffusive gradients in thin films (DGT). Stable isotope spiking with 61Ni allowed tracing of amendment-derived Ni uptake into plant tissues, even though total Ni mass fractions in planted versus unplanted soils did not indicate significant mobilisation during the 14-day growth period. Isotope pattern deconvolution (IPD) revealed clear shifts in Ni isotopic composition in both plant and DGT samples. Tracer uptake was more pronounced in the low Ni soil, with amendment-derived Ni (xamendment) contributing 19.3 ± 5.0% of total Ni in shoots, compared to 7.7 ± 1.8% in the high-Ni soil. In standard solutions containing 50 ng g-1 total Ni, isotope pattern shifts were still detectable at enrichment levels as low as 0.01% xspike (≈ 5 pg g-1 61Ni). The findings demonstrate the sensitivity of stable isotope spiking combined with IPD in the detection of subtle uptake processes, even in short-term experiments. This approach enables the differentiation of various Ni sources in soil-plant systems that would not be achievable with quantification alone, and can thereby provide new insights into how soil mineralogy influences uptake dynamics in metal-hyperaccumulating species.
Cytomegalovirus (CMV) reactivation is a major cause of morbidity and mortality after haploidentical hematopoietic stem cell transplantation (Haplo-HSCT). While T cells are crucial for controlling CMV, the dynamic characteristics of the T-cell receptor (TCR) repertoire and their predictive value for refractory CMV reactivation remain poorly characterized. This study aimed to longitudinally monitor the TCR repertoire in Haplo-HSCT patients to identify features associated with CMV reactivation and to explore predictive biomarkers for refractory and recurrent CMV disease. We enrolled 164 Haplo-HSCT patients, of which a subset of 28 was prospectively monitored for TCR repertoire dynamics via multiplex PCR and high-throughput sequencing. Patients were stratified into control (no reactivation, n = 10), acute phase (first reactivation, n = 18), and resolution phase (after clearance, n = 18) groups. CMV-specific TCRs were identified by database matching. The incidence of CMV reactivation was 48.17% (79/164). CMV reactivation induced significant perturbations in TCR repertoire architecture, characterized by increased CDR3 clonality, reduced clonotype distribution evenness, and a decreased number of unique Clonotypes (all P < 0.05) compared to controls, indicating a state of oligoclonal expansion. This skewed architecture persisted even after viral clearance, suggesting delayed CMV-specific immune reconstitution. Consistent with this, patients with CMV reactivation had significantly lower CD4+ T cell counts compared to those without reactivation (P = 0.003). Longitudinal analysis revealed that impaired CD4+ T cell recovery preceded CMV reactivation. Patients with secondary reactivation (6/18) exhibited reduced diversity of V-J gene pairings (lower Shannon index, P < 0.05) and significant downregulation of specific TRBV28/TRBJ1-1 and TRBV6-1/TRBJ2-7 combinations. Crucially, lower abundance and total frequency of CMV-specific TCRs at initial reactivation predicted secondary reactivation (P < 0.05) and were correlated with a longer disease course. Four patients who failed letermovir prophylaxis lacked CMV-specific TCRs in their top clonotypes. The abundance of CMV-specific TCRs is a key predictor of refractory CMV reactivation post-Haplo-HSCT. Longitudinal TCR profiling offers a promising strategy for risk stratification, potentially guiding more personalized preemptive therapies. Not applicable.
Depression is a highly prevalent and disabling disorder affecting approximately 5% of the adult population worldwide. Despite its impact, the underlying pathophysiology remains insufficiently understood, and current treatments are only partially effective. Understanding electrophysiological correlates of depression offers promise for a better grasp of the underlying brain mechanisms and might even guide novel treatment approaches, including neuromodulation. EEG is particularly attractive for this purpose due to its wide availability, cost-effectiveness, and potential for direct neuromodulatory targeting. We conducted a PROSPERO-registered systematic review in accordance with PRISMA guidelines to assess resting-state EEG activity in adult patients with depression, diagnosed according to DSM-IV/V or ICD-10/11. Included studies reported cross-sectional or correlational data on well-established quantitative EEG measures such as power, cordance, peak frequency, and alpha asymmetry. Semiquantitative analyses using modified albatross plots and meta-analyses were performed. Study quality was assessed with a modified Newcastle-Ottawa Scale. Fifty-two studies met the inclusion criteria. Semiquantitative findings showed a trend for increased low-frequency (delta and theta) and high-frequency (beta and gamma) power, as well as left frontal alpha asymmetry, in depressed patients compared to healthy controls. However, meta-analysis only confirmed a significant increase in beta power. Results regarding disease severity correlations and data on peak alpha frequency and cordance were insufficient for interpretation. Risk of bias across studies was high. Our results support a potential role for increased beta oscillations in depression. These oscillations may reflect disrupted corticolimbic control and reward processing and partially overlap with mechanisms implicated in chronic pain and fatigue. Further investigation is warranted into their potential as a diagnostic tool or even a biomarker, as well as their potential use as a neuromodulatory treatment target.
PD-1/PD-L1 inhibitors combined with chemotherapy are the current standard first-line treatment for advanced lung adenocarcinoma (LUAD). However, chemotherapy typically becomes the main therapeutic approach for subsequent treatment once the development of resistance to this initial chemoimmunotherapy, and there are limited effective treatment options available. This case report describes a 41-year-old male patient with stage IVA LUAD (PD-L1 tumor proportion score: 5%, next-generation sequencing: no mutation) who achieved a partial response (PR) with first-line camrelizumab plus pemetrexed and carboplatin, but later experienced disease progression. Upon switching to second-line therapy with ivonescimab (an anti-PD-1/vascular endothelial growth factor-A bispecific antibody) combined with docetaxel, the patient achieved a significant clinical and radiographic response, again evaluated as PR, which was sustained over 12 treatment cycles. Up to now, the progression-free survival (PFS) is more than 12 months, which is significantly longer than the 9-month PFS achieved by the first-line treatment. The regimen was well-tolerated, with only grade 1 adverse events. This case highlights the potential of ivonescimab-based therapy as an effective and manageable second-line option for patients with advanced LUAD who have progressed on prior immune checkpoint inhibitor therapy, even with low PD-L1 expression.
Isolated locoregional recurrence of pancreatic adenocarcinoma occurs in 25-50% of cases after surgical resection and has limited treatment options. Data on ablative stereotactic body radiation therapy (SBRT) with daily online adaptation for this condition are limited. Our objective was to illustrate the efficacy and safety of adaptive radiation for isolated locoregional recurrences of pancreatic adenocarcinoma. This was a retrospective cohort study of 46 patients treated with adaptive 5-fraction SBRT for isolated locoregional recurrence of pancreatic adenocarcinoma after surgical resection between 2015-2024. Kaplan-Meier curves with log-rank analysis and Cox regression were conducted to assess oncologic outcomes including locoregional recurrence-free survival, distant metastasis-free survival, and overall survival. Variables of clinical significance including biologically effective dose, planning target volume, and receipt of salvage chemotherapy in conjunction with salvage radiation were assessed. Local failure was defined by RECIST criteria. Toxicities were assessed using CTCAE v5.0 criteria. Radiation dose median was 50 Gy in 5 fractions. Seven patients had prior radiation and 27 patients received chemotherapy as part of their salvage treatment. The median duration of chemotherapy was 3.9 months. 46 patients were treated with a median age of 65, the majority were White and male. Median time to local recurrence from initial diagnosis was 20 months. Online adaptation was performed for 91% of fractions. Median follow-up from recurrent diagnosis and end of salvage radiation was 14 and 10.4 months, respectively. One-year local control was 73%, and 1- and 2-year overall survival were 69% and 42%, respectively. Chemotherapy had a statistically significant effect on progression-free survival (HR 0.45, 95% CI 0.23-0.89, p = 0.02). No acute grade 3+ toxicities occurred but three late grade 3+ toxicities were documented. Adaptive SBRT permits high biologically effective dose in 5 fractions and results in local control concordant with conventionally fractionated salvage radiation for locoregionally recurrent PDAC after definitive surgery, even after prior radiation with a reasonable toxicity profile. Future work may combine adaptive radiation with coverage of extra-pancreatic neural tract anatomy and additional chemotherapy to improve outcomes.
Government-led repurposing programmes are reshaping the division of labour in pharmaceutical innovation. A new power drafted into the European Union pharmaceutical reform package will allow the European Medicines Agency (EMA) to add new therapeutic indications to marketed medicines without the marketing authorization holder's consent. Companies oppose this power, but in weighing up enacting the power, society has a poor understanding of its potential to help patients. This study offers the first empirical assessment of the promise of the power. It analyses 198 medicines from 12 years, comparing EMA-authorized labels with those authorized by the US Food and Drug Administration and a leading reference for off-label uses. Sixty-seven per cent of the medicines have at least one additional use supported by clinical evidence, yielding 320 potential new uses. Of these, 39 per cent are for new diseases and 61 per cent for new patient cohorts, a third of the latter concerning paediatric populations. Commentators generally omit discussing repurposing for new patient cohorts, even though it is a focus of the European Commission. The study's results suggest that the power could be used to authorize a meaningful number of evidence-based uses, especially those already authorized in the USA, while also revealing a policy synergy for neglected populations.
Group B Streptococcus (GBS) is a leading cause of early-onset neonatal sepsis (EOS). Intrapartum antibiotic prophylaxis (IAP) based on maternal GBS screening significantly reduces the incidence of neonatal GBS disease. We report a term neonate who developed early-onset GBS sepsis and meningitis despite a negative maternal GBS screening result obtained at 39 weeks of gestation. The infant presented with respiratory distress, poor feeding, and hypotonia shortly after birth. Blood culture confirmed GBS bacteremia, and cerebrospinal fluid (CSF) analysis supported concurrent meningitis. He was successfully treated with intravenous antibiotics, initially with penicillin and ceftazidime, then escalated to vancomycin for better central nervous system penetration following meningitis diagnosis, before de-escalation back to penicillin. Total antibiotic duration was 17 days. Cranial imaging revealed small hemorrhagic foci in the left centrum semiovale and periventricular area, which resolved on follow-up MRI. This case highlights the potential for false-negative maternal GBS screening and underscores the importance of clinical vigilance. Empirical antibiotic therapy for suspected neonatal sepsis should be considered based on clinical presentation, even when maternal screening is negative.
Coastal marshes, recognized as effective organic carbon (OC) sinks, have gained attention for their potential contribution to climate mitigation through protection and restoration. However, the climate mitigation potential of Nordic coastal marshes remains understudied, likely due to their heterogeneous and often non-tidal nature. To fill this gap, we examined soil OC storage and accumulation rates, and the effects of grazing, a common management practice, across eight Nordic coastal marsh areas spanning broad climate and environmental gradients. We also assessed soil methane emissions in selected areas. The Nordic marshes studied store a median of 7 kg OC m-2 (interquartile range, IQR: 6-8) in the top 15-35 cm of soil and accumulate 41 g OC m-2 yr.-1 (IQR: 32-47). Considering only the additional OC, attributed to the presence of the marsh habitat, these values drop to 4 kg OC m-2 (IQR: 2-6) and 21 g OC m-2 yr.-1 (IQR: 11-33). Globally, both rates are comparatively low. OC stocks and accumulation rates increased with marsh age, root: shoot ratio (stress adaptation), and δ15N (fast N cycling), but declined with soil δ13C (related to faster decomposition under warmer conditions and sandier soils). Danish marshes had the highest but also most vulnerable OC stocks due to faster turnover, labile compounds, and coarser soil grain sizes. Although grazing only weakly increased soil OC stocks and had no effect on OC accumulation rates, it significantly reduced methane fluxes compared to ungrazed marshes. In ungrazed areas, methane emissions weakened the carbon sink by 32% in Finland and 68% in Denmark. However, estimated greenhouse gas emissions from on-site cattle, even at low grazing intensity, largely outweighed the coastal marsh climate benefits. A comprehensive Nordic marsh management strategy is needed, extending beyond the focus on their limited, yet relevant, role in climate mitigation, and considering biodiversity, coastal protection and nutrient retention.
For total knee arthroplasty (TKA) performed in an ambulatory setting, reliable analgesia is essential for same-day discharge (SDD). Although adductor canal blocks (ACBs) are effective, access to anesthesiologist-performed ACBs (aACBs) may be limited by regional anesthesia availability in resource-constrained centers. Even when expertise exists, lack of perioperative workflow integration can reduce efficiency, prolong procedural time, and increase costs. The objective of this study was to evaluate whether surgeon-performed ACBs (sACBs) are non-inferior to aACBs regarding time to discharge, perioperative outcomes, and patient-reported outcome measures (PROMs). A prospective randomized controlled trial of 200 SDD TKA patients was conducted. Participants were randomized to receive preoperative aACB or intraoperative sACB. The primary outcome was time from spinal anesthetic reversal to discharge. The secondary outcomes included Numeric Pain Rating Scale (NPRS), 24-hour morphine milliequivalent (MME) use, SDD failure, 24-hour readmission, and PROMs at baseline and two weeks postoperatively. Power analysis used a representative SDD TKA sample detecting a 15% difference in the primary outcome (power 80%, α = 0.05). Time to discharge was not different in sACB compared to aACB: 209.5 minutes (range, 10 to 510) compared to 231.1 (range, 59 to 455), P = 0.06. Secondary outcomes showed no significant differences: NPRS at Baseline - 4.3 (aACB) versus 4.3 (sACB), P = 0.87, and NPRS at Discharge - 2.4 (aACB) versus 2.9 (sACB), P = 0.07. The 24-hour opioid consumption was 35.8 MME (aACB) versus 43.6 (sACB), P = 0.31. There were no 24-hour readmissions. There were 13 patients who failed SDD: 8 (aACB) versus 5(sACB), P = 0.42. The sACBs were non-inferior to aACBs for outpatient TKA. An sACB represents a safe alternative that may reduce reliance on limited anesthesia resources. With standardized perioperative integration, sACB may improve operating room efficiency and reduce costs.
In this research, a surface ligand engineering strategy is employed to fabricate UiO-66 confined Au nanoclusters (UiO-66@Au) with controllable multienzyme performances. Especially, ligand PSS and PVP can trigger optimized peroxidase (POD) and glucose oxidase (GOx) mimic activity respectively. Mechanistic studies revealed that electron transferring between Au and ligands can be an effective tactic to regulate the multienzyme activity. Theoretical calculations revealed that electron-withdrawing polystyrene sulfonate (PSS) can decrease the key energy barriers of ·OH desorption in POD process and electron-donating polyvinylpyrrolidone (PVP) decreased the key energy barriers of O2 to OOH∗ in GOx catalysis, which confirmed the enhanced POD and GOx activity correspondingly. For practical application, PSS-UiO-66@Au coupled lateral flow assay (LFA) can visually detect HER2-positive breast cancer exosomes as low as 428 exosomes/μL, about 16355-fold higher sensitivity than that of common LFA. PVP-UiO-66@Au with superior GOx-mimic activity can detect salivary glucose as low as 19 μM, meanwhile, due to the effective gluconic acid adsorption repulsion by PVP, PVP-UiO-66@Au displays superior stability even after 10 reuse cycles This work provides a simple route to regulate the multi-enzyme properties of UiO-66@Au and broadens the application in multiple target biosensing.
A generalization of the classical concordance correlation coefficient (CCC) is considered under a three-level design where multiple raters rate every subject over time, and each rater is rating every subject multiple times at each measuring time point. The ratings can be discrete or continuous. A methodology is developed for the interval estimation of the CCC based on a suitable linearization of the model along with an adaptation of the fiducial inference approach. The resulting confidence intervals have satisfactory coverage probabilities and shorter expected widths compared to the interval based on Fisher's Z-transformation, even under moderate sample sizes. Two real applications available in the literature are discussed. The first application is based on a clinical trial to determine if various treatments are more effective than a placebo for treating knee pain associated with osteoarthritis. The CCC was used to assess agreement among the manual measurements of the joint space widths on plain radiographs by two raters, and the computer-generated measurements of digitalized radiographs. The second example is on a corticospinal tractography and the CCC was once again applied in order to evaluate the agreement between a well-trained technologist and a neuroradiologist regarding the measurements of fiber number in both the right and left corticospinal tracts. Other relevant applications of our general approach are highlighted in many areas including artificial intelligence.
Photodynamic therapy (PDT) is promising but limited by its dependence on specialized photosources, clinic-based administration, and prolonged post-treatment light avoidance due to phototoxicity side effects. Here, we report mild-sunlight-activated PDT (SunPDT) microneedle patches incorporating polymeric photosensitizers with an intrinsic "on-off" reactive oxygen species (ROS)-generating mechanism, enabling bio-safe, deep-tissue, and self-administered PDT without fixed clinic visits and strictly prolonged light avoidance post-treatment. Rationally designed photosensitizers generate robust ROS under low-intensity mild sunlight (12 mW cm-2) excitation, and feature an intrinsic "on-off" ROS generation mechanism that confines ROS generation to lesions, even when photosensitizers diffuse into surrounding healthy tissues. Microneedle-enabled deep photosensitizer delivery and excitation by the near-infrared component of sunlight together allow self-administered treatment of deep-seated lesions without scheduled clinic visits. Importantly, the SunPDT patch's triple-safety design, low-intensity mild sunlight excitation, local delivery of photosensitizer by microneedles, and an intrinsic "on-off" ROS generation mechanism, eliminate post-treatment prolonged light avoidance, ensuring bio-safe PDT. Using female psoriatic mice as a proof-of-concept model, our "on-off" SunPDT microneedle patches achieve high therapeutic efficacy and patient-friendly, self-administered treatment, and outperform clinical Protoporphyrin IX patches, which demonstrate weaker effects and require prolonged light shielding. Therefore, this study establishes a promising design for a lifestyle-integrated PDT platform.
G-Quadruplexes (G4s) are non-canonical DNA structures formed in guanine-rich sequences and recognized as crucial regulators of gene expression. We identified potential G4-forming sequences within the 5'-flanking region of the human carboxylesterase 2 (CES2) gene, which encodes an enzyme that hydrolyses clinical drugs and endogenous lipids, including triacylglycerols. The aim of this study is to elucidate the impact of G4 formation on CES2 expression and metabolic function. qPCR stop assays and chromatin immunoprecipitation (ChIP) assays using an anti-G4 antibody demonstrated that two guanine-rich sequences in the 5'-flanking region of the CES2 form G4 structures. Treatment with the G4-stabilizing ligand pyridostatin (PDS) reduced CES2 expression and hydrolase activity in HepG2, Huh-1, and HepaSH cells. Luciferase and ChIP assays revealed that PDS suppressed CES2 transcription by inhibiting hepatocyte nuclear factor 4α (HNF4α) binding to the 5'-flanking region of the CES2. PDS also reduced HNF4α expression, through G4 formation within the HNF4α promoter. Notably, PDS decreased CES2 mRNA levels even under HNF4α-overexpressing conditions, indicating that CES2 repression involves both impaired HNF4α binding and reduced HNF4α expression. PDS treatment accumulated triacylglycerol in hepatic cells. Collectively, these findings indicate that G4 formation suppresses CES2 transcription and function, highlighting G4 structures as potential therapeutic avenues for modulating lipid homeostasis.