This protocol describes a step-by-step approach for the synthesis of a periodic mesoporous organosilica (PMO) with wall-embedded nitroxide monoradicals. It starts with the synthesis of an isoindoline-based nitroxide monoradical and its silylationa critical requirement for the condensation with the PMO's bisilylated building block. We also provide detailed instructions on how to synthesize the phenylene (Ph)-PMO's bisilylated precursor, 1,4-bis-(triethoxysilyl)-benzene (BTEB), and subsequent preparation of the Ph-PMO with in situ incorporation of the silylated nitroxide monoradical. The incorporation of the nitroxide into the Ph-PMO was monitored by electron paramagnetic resonance (EPR) spectroscopy, which clearly revealed the decrease in free radical concentration in solution as the condensation progressed. A comparison of the radical-containing Ph-PMO to a reference Ph-PMO, prepared from the same organic precursor in the absence of the radical, by powder X-ray diffraction (PXRD), N2 adsorption-desorption isotherms, thermal gravimetric analysis (TGA), and Fourier transform infrared with attenuated total reflectance (FTIR-ATR), showed that the radical did not induce structural changes to the PMO. All reactions and methodologies described in this protocol were performed at least in triplicate, demonstrating their reproducibility. Completion of the entire protocol takes 22 days (∼3 weeks).
Addiction consult services (ACSs) are a growing hospital-based care model that increases quality of care for patients with substance use disorders (SUDs). One implementation barrier has been concern about negative financial impacts for health systems. To examine whether starting an ACS changes hospital length-of-stay and 30-day readmissions for patients with opioid use disorder (OUD) served in a large academic health system. Quasi-experimental difference-in-differences study of opioid-related hospital admissions from January 2018 to December 2024, comparing one hospital that implemented an ACS to three hospitals in the same urban, academic system in Philadelphia, PA without ACSs. Adults (≥ 18 years) with opioid-related hospitalizations. A fully staffed, hospital-based, multidisciplinary ACS launched in July 2023. Primary outcomes were hospital length-of-stay and 30-day readmissions. Secondary outcomes were receipt of any medication for opioid use disorder (MOUD) during hospitalization, discharge on a therapeutic MOUD dose, emergency department visits within 6 months of discharge, and discharges before medically advised. In unadjusted analyses, ACS implementation was associated with a 5 percentage point increase in MOUD receipt (95% CI 0-10) and a 9 percentage point increase in discharge on therapeutic MOUD (95% CI 5-13), without significant changes in length-of-stay or 30-day readmissions. In adjusted analyses, therapeutic MOUD at discharge increased by 8 percentage points (95% CI 4-12), with no significant differences in length-of-stay or 30-day readmission. Results were robust to sensitivity analyses with alternative comparison groups and after accounting for the COVID-19 pandemic. Implementation of an ACS improved evidence-based care for hospitalized patients with OUD without prolonging length-of-stay or increasing readmissions.
Chlorophylls (Chls) harvest the solar energy that drives photosynthesis, which underpins most of the food chains on our planet. Starting from protoporphyrin IX, just seven biosynthetic reactions culminate in the synthesis of Chl a, the major light-absorbing pigment on Earth. Other such pigments, Chls b, c, d and f, widen the absorption range in the visible and red regions of the spectrum, and several bacteriochlorophylls (BChls), BChls a, b and g in particular, open new spectral windows allowing organisms to harvest near infra-red light. This perspective surveys the structural features of porphyrins, chlorins and bacteriochlorins that impart their characteristic absorption features, then presents a similar analysis of the biosynthetic intermediates leading to Chls a, b, c, d and f. The interlinked Chl and BChl biosynthetic pathways are summarised, then the rest of the perspective focusses on the enzymes that synthesise Chls a, b, c, d and f. AlphaFold 3 was used to model a complete set of structures for Chl biosynthesis enzymes, predicting intersubunit associations and the arrangements of cofactors and bound substrates, and providing insights into catalytic mechanisms. A new scheme for binding substrates and transferring products between pathway enzymes suggests how synthetic biology approaches can assemble hybrid Chl and BChl pathways to expand the spectral range for harvesting and using solar energy.
Despite the relative success of immuno-modulatory disease-modifying therapy in relapsing remitting multiple sclerosis, progressive worsening of disability remains a major problem, particularly for those with secondary progressive multiple sclerosis. Various underlying mechanisms are likely to contribute, augmented by comorbidities (such as vascular risk) and ageing. In the phase 2b MS-STAT trial, simvastatin (80 mg) (Sandoz Ltd, Camberley, UK) reduced the mean annualised whole brain atrophy rate by 43% compared to placebo in patients with secondary progressive multiple sclerosis (p = 0.003). We now report the phase 3, MS-STAT2 trial, with confirmed progression of disability as the primary outcome. A multicentre, phase 3, randomised, double-blind, placebo-controlled clinical trial was conducted at 31 UK neuroscience centres and district general hospitals. Secondary progressive multiple sclerosis participants aged 18-65 years were randomised 1 : 1 to oral simvastatin (80 mg), or matched placebo, based on a minimisation algorithm that incorporated the following factors: sex (male/female); age (< or ≥ 45 years); Expanded Disability Status Scale baseline score (≤ 5.5 or ≥ 6); whether participants were taking newly licensed (2017 onward) disease-modifying treatments for secondary progressive multiple sclerosis; and trial site. An independent and secure online randomisation service was used. All participants, site investigators and the trial co-ordinating team were blinded to treatment allocation. The Expanded Disability Status Scale was measured every 6 months and was compared to baseline scores, with remote data collection used when enforced by the COVID-19 pandemic. The primary outcome was time to Expanded Disability Status Scale-confirmed disability progression. Progression of disability was defined as an increase of at least one point on the Expanded Disability Status Scale if the baseline score was < 6, or an increase of 0.5 point if the baseline score was ≥ 6. The initial disability progression event was finalised as confirmed if the increase in Expanded Disability Status Scale score persisted at the next assessments ≥ 6 months later. Follow-up was for 36 months, or 54 months, for those without confirmed disability progression at 36 months who agreed to enter an optional blinded extension. An intention-to-treat analysis was carried out. The study was conducted between 10 May 2018 and 26 July 2024. There were 964 participants randomised, with 482 in the placebo group and 482 in the simvastatin group. 173 (35.9%) participants in the placebo group and 192 (39.8%) participants in the simvastatin group experienced Expanded Disability Status Scale-confirmed disability progression (adjusted hazard ratio = 1.13, 95% confidence interval 0.91 to 1.39, p = 0.263). No material differences in the secondary outcomes were observed. No major safety issues were seen. The MS-STAT2 trial did not demonstrate a treatment effect of simvastatin in slowing disability progression in participants with secondary progressive multiple sclerosis. Despite the favourable outcomes of the previous phase 2b trial, simvastatin use in secondary progressive multiple sclerosis should be confined to existing vascular indications. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/57/143. Multiple sclerosis is a lifelong condition that affects the brain and spinal cord. Many people with multiple sclerosis start with a type called relapsing-remitting multiple sclerosis, which can later become secondary progressive multiple sclerosis. Secondary progressive multiple sclerosis causes steady worsening of disability over time, and currently, there are very few treatment options for people without signs of active inflammation. Simvastatin is a cholesterol-lowering drug (a statin) that is widely used for heart disease. Earlier research (the Simvastatin in Secondary Progressive Multiple Sclerosis phase 2 trial) suggested that high-dose simvastatin might slow brain shrinkage and disability in people with secondary progressive multiple sclerosis. To test this further, researchers ran a large phase 3 clinical trial called Simvastatin in Secondary Progressive Multiple Sclerosis (phase 3 trial), involving 964 participants across the United Kingdom. Half were given simvastatin and half a placebo, and they were followed up while continuing to take these for 3 years. For participants whose disability was stable at 3 years, they could continue in the trial on the same medication for up to 4.5 years if they were happy to do so. The main aim was to see if simvastatin could slow down worsening disability, which was measured using a scale called Expanded Disability Status Scale. The Expanded Disability Status Scale data were mainly collected at face-to-face appointments, but some assessments were conducted by telephone when enforced by the COVID-19 pandemic. The results showed no significant difference between the simvastatin and placebo groups. Simvastatin did not delay disability progression. The trial also looked at other outcomes such as walking speed, hand function, memory and quality of life. Again, there were no meaningful differences. Importantly, simvastatin was generally safe, and side effects were rare. The trial also found that people with higher disability levels faced higher personal and financial costs, and many relied on unpaid care from family or friends. Overall, the Simvastatin in Secondary Progressive Multiple Sclerosis phase 3 trial provides clear evidence that simvastatin does not have a therapeutic effect in slowing disability progression in people with secondary progressive multiple sclerosis. It also offers valuable insights for future research into progressive multiple sclerosis and highlights the need for new treatments that target the disease’s underlying causes.
To investigate the association between low-flow time (LFT) and outcomes in out-of-hospital cardiac arrest (OHCA) patients treated with prehospital extracorporeal cardiopulmonary resuscitation (ECPR). This retrospective study included OHCA patients receiving prehospital ECPR (July 2023-August 2024). LFT, defined as the interval from conventional CPR start to ECPR flow initiation, was analyzed continuously (per 10 min increment). Due to limited events (13 favorable neurological outcomes), the primary logistic regression adjusted for two prespecified confounders (age, initial shockable rhythm). A sensitivity analysis was performed in patients with witnessed arrest and bystander CPR (no-flow time of approximately 0). All analyses are exploratory. Among 76 patients (mean age 58.80 ± 14.84 years, mean LFT 60.33 ± 13.89 min), survival to hospital discharge was 34.2% (26/76) and favorable neurological outcome 17.1% (13/76). Each 10 min LFT increase was associated with lower survival (aOR 0.557; 95% CI 0.368-0.844; P = 0.006) and favorable neurological outcome (aOR 0.461; 95% CI 0.255-0.834; P = 0.011). In the sensitivity subgroup (witnessed + bystander CPR, n = 44, 9 favorable outcomes), the univariable OR for favorable outcome was 0.395 (95% CI 0.176-0.886; P = 0.024), consistent with the primary estimate. Exploratory ROC analysis for favorable neurological outcome gave an AUC of 0.750 (95% CI 0.603-0.896), but the derived cutoff (55.5 min) is not proposed for clinical use. In this single-center study, longer LFT (per 10 min) was associated with worse outcomes, consistent in a no-flow-time-controlled subgroup. Given the exploratory design, external validation is required. No definitive LFT threshold can be recommended.
Asthma is characterized by variable airway obstruction, and proper inhaler choice and use are critical for effective treatment. This study aimed to identify factors influencing treatment response in newly diagnosed patients started on dry powder inhalers (DPIs) or metered-dose inhalers (MDIs). Between March and September 2025, 177 newly diagnosed asthma patients were screened. Eighty patients with at least high-school education, correct inhaler use, and good adherence were included (40 DPI, 40 MDI). Pulmonary function, respiratory muscle strength, Asthma Control Test (ACT), and handgrip strength (HGS) were assessed at baseline and after one month. After one month, improvements in forced expiratory volume in 1 second (FEV1) (% predicted), maximum inspiratory pressure (MIP) and MIP (%), and maximum expiratory pressure (MEP) (%) were significantly greater in the DPI group compared with the MDI group (p = 0.03, 0.04, 0.02 respectively). In multivariate regression, among MDI users, MIP (kPa) (B = -11.305, p = 0.001), MIP (%) (B = -0.902, p = 0.003), ACT (B = 1.277, p = 0.014), and HGS (B = 0.103, p = 0.039) were independent predictors of ΔFEV1 (%). Among DPI users, MIP (kPa) (B = 11.987, p = 0.015), MIP (%) (B = 1.041, p = 0.009), MEP (kPa) (B = -6.554, p = 0.014), MEP (%) (B = -0.816, p < 0.001), and HGS (B = 0.201, p = 0.005) were significant determinants of ΔFEV1. DPIs may be preferable for patients with higher inspiratory muscle strength, whereas MDIs may be better for those with lower MIP. HGS appears to be an important factor for both inhaler control and treatment efficacy.
Given the increasing prevalence of multidrug-resistant opportunistic pathogens and the high mortality rate associated with delayed diagnosis of disseminated infections, there is an urgent need for rapid diagnostic tools and closely monitored, individualized anti-infective strategies. This study aimed to explore the critical role of comprehensive pharmaceutical care in managing disseminated Nocardia infections complicated by complicated urinary tract infection (cUTI). Through detailed documentation of a 67-year-old male patient, this study focuses on optimizing antimicrobial regimens based on pathogenetic findings and adjusting treatments for severe adverse reactions. The patient was diagnosed with disseminated Nocardia brasiliensis infection complicated by Enterococcus faecalis urinary tract infection using metagenomic next-generation sequencing (mNGS). The treatment process underwent two critical adjustments. First, during the efficacy optimization phase, the initial empirical meropenem therapy was modified to a reinforced regimen centered on trimethoprim-sulfamethoxazole (TMP-SMX), combined with linezolid and short-term amikacin, effectively controlling the spread of infection. Subsequently, during the safety optimization phase, the patient developed severe thrombocytopenia during sequential oral therapy. Prompt identification and switching to amoxicillin/clavulanate potassium resolved the adverse reactions, enabling successful continuation of subsequent treatment. Follow-up revealed a favorable patient recovery. This case demonstrates that for such complex mixed infections, rapid pathogen diagnosis represented by mNGS serves as the starting point for precision treatment, whereas the intensive combination regimen centered on TMP-SMX forms the foundation for controlling disseminated Nocardia infection. More importantly, the core insight from this case is that successful treatment relies not only on appropriate initial medication, but more critically, on proactive, dynamic pharmaceutical monitoring throughout long-term therapy. This enables early intervention for severe adverse drug reactions and timely, flexible adjustments to treatment regimens, which are essential components for ensuring ultimate therapeutic success in patients with such complex infections.
In the pursuit of multifunctional therapeutic agents, a new series of thiocarbamoylpyrazoline derivatives were synthesized starting from chalcones, and all synthesized compounds (1-12) were structurally characterized using spectroscopic methods (NMR, FT-IR, and Q-TOF-LC-MS) and elemental analysis. The anticancer properties of the test compounds were evaluated in vitro against human bone cancer cell lines MG63 and SW1353 using MTT and LDH assays. LDH assay results demonstrated that the compounds exhibited no detectable cytotoxicity toward normal human chondrocyte (HC) cells. Compared to the reference drug 5-fluorouracil (5-FU), several compounds displayed notable antiproliferative activity. Tumor selectivity index (TSI) analysis identified compounds 1, 2, 4, and 10 as having high tumor selectivity, indicating a preferential cytotoxic effect toward cancer cells over normal cells. Among these, compounds 4 and 10 exhibited the most favorable anticancer profiles, combining potent antiproliferative activity with minimal toxicity to normal cells. Furthermore, to support the experimental anticancer findings, in silico molecular docking studies were performed using the crystal structures of caspase-3 (1GFW), human metalloproteinase-13 (3KEJ), human estrogen receptor (3ERT), and EGFR (1M17) against compounds 1, 2, 4, and 10, and their binding modes were analyzed.
Agentic AI systems have recently emerged as a critical and transformative approach in artificial intelligence, offering capabilities that extend far beyond traditional AI agents and contemporary generative AI models. This rapid evolution necessitates a clear conceptual and taxonomical understanding to differentiate this new paradigm. Our paper addresses this gap by providing a comprehensive review that establishes a precise definition and taxonomy for "agentic AI," with the aim of distinguishing it from previous AI paradigms. The concepts are gradually introduced, starting with a highlight of its diverse applications across the broader field of engineering. The paper then presents four detailed, state-of-the-art use-case applications within electrical power systems engineering, a domain where the impact of agentic AI systems is expected to be particularly significant. The high impact of agentic AI systems in the field of electrical power systems is primarily driven by global trends toward clean energy transition and higher levels of grid automations, all of which create an environment where agentic AI can be readily deployed and effectively leveraged. These case studies demonstrate current and innovative state-of-the-art, ranging from an advanced agentic framework for streamlining complex power system studies and benchmarking to a novel agentic AI system developed for survival analysis of dynamic pricing strategies in battery swapping stations. Finally, robust deployment of these autonomous agents brings a unique set of challenges that are discussed in this manuscript through detailed failure mode investigations. From these findings, we derive actionable recommendations for the design and implementation of safe, reliable, and accountable agentic AI systems, offering a critical resource for researchers and practitioners.
Little research has analysed the relation between childcare and positive psychological wellbeing, e.g., self-esteem and life satisfaction. Using data from the UK Millennium Cohort Study, this paper investigates the association of the age of starting and intensity of formal childcare with self-esteem trajectories between 11 and 17 years and life satisfaction at 11 and 14 years (N = 5,484). Proportional odds for having greater psychological wellbeing and odds ratios for having good compared to poor psychological wellbeing (lowest 25% scores) were estimated. After controlling for children's socio-economic position, childcare was not associated with self-esteem or life satisfaction. Changes in estimates after adjustment show that children from a lower socio-economic position attended less childcare and had lower odds of later psychological wellbeing.
Microbial rhodopsins exhibit diverse functions ranging from ion pumps and channels to light sensors, despite sharing a common seven-transmembrane (7TM) architecture. Understanding how this functional diversity evolved is a long-standing problem, and ancestral sequence reconstruction (ASR) offers a direct route to inferring and experimentally testing plausible ancestral rhodopsins. However, ASR of 7TM proteins is often limited by alignment ambiguity and insertion-deletion (indel) uncertainty, especially in extra-membrane (EM) loops and termini. As a result, many studies focus on trimmed transmembrane (TM) cores and treat EM regions by manual curation, leaving the evolutionary history of full-length architecture difficult to test experimentally. Here we reconstruct and resurrect full-length ancestral schizorhodopsins (Anc-SzR) and heliorhodopsins (Anc-HeR), two microbial rhodopsin families that share a retinal-binding 7TM core but differ in membrane topology and EM secondary-structure elements. Starting from untrimmed alignments, we combine structure-consistent multiple sequence alignments and profile-based evolutionary models with an explicit indel-aware refinement that merges amino-acid ancestral states with binary ancestral gap inference on a fixed topology. Indel-aware refinement prevents artificially overextended ancestors and yields compact full-length sequences. AlphaFold3 predictions for the indel-corrected ancestors support high-confidence 7TM folds and recover lineage-specific EM features, including characteristic β-strands and short helices. Both Anc-SzR and Anc-HeR can be expressed in Escherichia coli and recovered as stable, colored, retinal-binding holoproteins. In a whole-cell pH assay, Anc-SzR shows light-driven proton-transport activity, whereas Anc-HeR shows no detectable ion-pumping signal, consistent with extant heliorhodopsins. Together, these results show that full-length, indel-aware ASR can produce experimentally tractable ancestral microbial rhodopsins and enable direct tests of how EM architecture evolves alongside the 7TM core.
Health and mental health systems are increasingly employing community health workers and peer support specialists to expand service reach and effectiveness, yet role definitions and competency standards vary widely. Little is known about how to train or prepare these professionals to collaborate with health care teams, engage peers and community members, and address complex health and mental health needs. Tobacco use remains a leading cause of illness and death in the United States and disproportionately impacts people with low incomes and people with mental health conditions, including substance use disorders. Support for Tobacco Recovery Training (STaRT) was developed to provide brief but comprehensive training to support engagement in evidence-based tobacco treatment. This study describes STaRT's development and evaluates knowledge, reach, and satisfaction among graduates during its first 2 years. We developed STaRT using a community-engaged process with peer specialists, behavioral health professionals, and academic partners. The final program includes 8 self-paced online modules emphasizing recovery-oriented language, communication strategies, evidence-based treatment, and resource navigation. We collected demographics and a knowledge assessment at baseline, and a post-knowledge assessment and evaluation upon training completion. We used descriptive statistics to summarize demographics and evaluation items and a choropleth map of trainees demonstrates reach. We evaluated change in knowledge using a paired samples t-test. From November 2023 through October 2025, 256 trainees graduated from STaRT. Trainees were primarily women (83%) and worked across diverse settings, including public health, mental health, community health, and social service settings. Mean knowledge scores increased from 83% to 97% (P < .01). Trainees represented 46/105 counties, with reach ranging from 1 to 43 graduates/100 000 population. Program satisfaction was high (mean 4.6/5). STaRT is a feasible, scalable, and peer-informed training model that improves knowledge and expands the tobacco recovery workforce. Findings suggest strong potential for implementation and adaptation beyond Kansas.
Herpetic geometric glossitis (HGG) is a rare, atypical manifestation of herpes simplex virus type 1 (HSV-1) infection, most commonly reported in immunocompromised individuals. We report a case of a 43-year-old immunocompetent male presenting with edematous heme-crusted lips, fissured tongue, and severe oral pain, leading to significant oral intake limitation and subsequent inpatient admission. Dermatology was consulted for possible Stevens-Johnson syndrome, which was ruled out following evaluation.  Clinical findings were consistent with HGG, an uncommon presentation of HSV infection. The patient started empiric antiviral therapy, leading to symptom improvement, and HSV-1 polymerase chain reaction testing returned positive, confirming the diagnosis. This case highlights a rare presentation of HSV-1 in an immunocompetent host and emphasizes the importance of recognizing atypical morphologic variants to guide timely diagnosis and management.
accurate assessment of maximum oxygen uptake (VO2max) is fundamental to exercise physiology and cardiorespiratory fitness evaluation. While treadmills are the gold standard, there is a growing need for standardized vertical loading devices. This study aimed to evaluate the concurrent validity, construct validity, and reliability of the novel Tianyu climbing machine during progressive load exercise testing. Thirty-one male physical education students (mean age: 20.45 years) were recruited to perform maximal graded exercise tests on both a treadmill (using the Bruce protocol) and the Tianyu climbing machine (starting at 0.05 m/s with 0.01 m/s increments every minute). Physiological indicators, including VO2max, heart rate (HR), and respiratory exchange ratio (RER), were monitored. Concurrent validity was assessed using Bland-Altman plots and mean relative percentage error (MRPE), while construct validity was examined through canonical correlation analysis (CCA). Test-retest reliability of the machine's speed was evaluated via intraclass correlation coefficients (ICC).The climbing machine demonstrated high concurrent validity with the treadmill, with a mean relative percentage error (MRPE) of less than 10%.CCA revealed a significant linear relationship between physiological markers and climbing performance indicators (r = 0.779, P < 0.01). Furthermore, the device exhibited excellent speed accuracy (error < 1%) and high test-retest reliability (ICC = 0.74 - 0.85) across standardized speed ranges. The Tianyu climbing machine is a scientifically valid and reliable tool for assessing cardiorespiratory function. Its ability to provide precise, controllable vertical loads makes it an effective alternative to traditional modalities for standardized metabolic testing in athletic and clinical settings.
Workers in the textile dyeing industry are occupationally exposed to high concentrations of particulates and volatile organic compounds (VOCs). This work aimed to study the environment-gene interaction as a risk factor for rheumatoid arthritis in textile dyeing workers. This cross-sectional comparative study included 140 exposed male workers and 130 matched control workers. Air monitoring of chemical air pollutants in the workplace was conducted for 12 months. Estimation of anti-CCP, CRP, RF, ANA antibodies, and the CYP2E1 and GST genes polymorphisms was studied in both groups. High air concentrations of PM10, SO2, H2S, and VOCs were detected in the preparatory and dyeing sections compared to the printing section. Anti-CCP, CRP, RF, and ANA were statistically higher in exposed workers compared to the control group. Anti-CCP and RF in preparatory workers were significantly higher compared to printing workers. Multivariate analysis revealed interaction in CYP2E1, GST polymorphism and different environmental exposures on RF. The environment-gene interaction of the elevation of PM10 and VOCs concentrations in the dyeing section, with the CYP2E1 (C2/C2 mutant genotype) and the GST (M1 polymorphism), could be a risk factor for RF elevation in the workers from the dyeing section compared to the other two sections. The key recommendations include improving environmental control in the workplace, ensuring the proper use of personal protective equipment (PPE), conducting pre-employment screening for genetic susceptibility through genetic counseling for CYP2E1 and GST polymorphisms, and providing regular medical follow-up for workers carrying the CYP2E1 (C2/C2) genotype and the GST (M1) allele.
Lipoprotein glomerulopathy (LPG) is a rare hereditary glomerular disease characterized by lipoprotein thrombi within dilated glomerular capillaries for which effective treatments remain limited. This report concerns a 25-year-old Japanese woman with an 8-year history of persistent proteinuria and severe dyslipidemia who presented with heavy proteinuria (3.31 g/gCr) despite preserved renal function. Kidney biopsy revealed features typical of LPG on light and electron microscopy, and serum apoE levels were markedly elevated. The patient was started on pemafibrate, a selective peroxisome proliferator-activated receptor-alpha modulator known to exert stronger triglyceride-lowering effects and to have a more favorable hepatic and renal safety profile compared with conventional fibrates. Following treatment, the patient's triglyceride levels decreased substantially and her proteinuria progressively improved. Complete remission (0.05 g/gCr) was achieved within 7 months, and she remained stable thereafter. Although partial remission with fibrates has been previously reported in patients with LPG, there have been no reports of complete remission in those treated with pemafibrate. To our knowledge, this is the first documented case of complete remission of proteinuria induced by pemafibrate in a patient with LPG. Pemafibrate may be a promising targeted therapy for this rare glomerular disorder.
Contamination by heavy metals in mining area often leads to significant environmental hazards, with bioaccumulation of Cu in the food chain representing a critical pathway for human exposure. To investigate the characteristics of Cu content in major foodstuffs and assess the safety of dietary Cu exposure among residents living near mining areas in Nandan County, China.Dietary intake of Cu in mining-affected and reference area was investigated using the weighing method and chemical analysis. The Chronic Daily Intake (CDI) was calculated, and the potential non-carcinogenic health risks were evaluated. Results showed that Cu concentrations in various food categories were significantly higher in the mining-affected area compared to the reference area. Vegetables were identified as the primary source of dietary Cu exposure in both areas, contributing more than 46% to the total intake. The health risk assessment indicated that the Hazard Quotient (HQ) values for males and females in the mining-affected area were 1.02 and 1.13, respectively, both exceeding the safety threshold of 1. Residents in the mining-affected area of Nandan face potential health risks from dietary Cu exposure. These findings highlight the need for targeted attention and intervention measures to ensure public health safety.
To assess the feasibility of a nurse-supported, treat-to-target (T2T) self-monitoring approach for gout patients initiating urate-lowering therapy (ULT) using point-of-care testing (POCT) of serum urate (SU) levels. A 24-week prospective feasibility study was conducted at the Sint Maartenskliniek in the Netherlands among 32 patients starting ULT, or recently started ULT and not at target. Participants received a POCT device to self-measure SU levels at home and report results every 4 weeks via a digital platform. Nurses provided education and dosing advice based on SU levels and monitored patient follow-up. Feasibility was assessed using Bowen's framework. Patient data were obtained through questionnaires and chart review, and stakeholder perspectives were collected through semi-structured interviews. Patients found the intervention highly acceptable. Adherence to SU measurements was 93%, with minimal burden and few problems reported. The majority of the patients reached their SU target (75%). Patients had a median of 2 gout flares (interquartile range [IQR] 0-3). Stakeholders valued the intervention for the potential to increase patient engagement and care efficiency, though they emphasized the need for evidence on cost-effectiveness, clear protocols and appropriate patient selection. Nurse-supported self-monitoring for gout was acceptable, feasible and practical in this selected group of gout patients. The short-term SU target attainment was encouraging, warranting larger comparative randomized studies with longer follow-up to establish (cost-) effectiveness, and long-term disease control.
While alkylated and acylated aporphine derivatives are well-represented in the literature, O-arylated analogues remain scarce. We report here a practical and regioselective methodology for the synthesis of 9-O-arylboldine derivatives. Our approach utilizes a copper-catalyzed Chan-Lam coupling reaction, enabling the efficient preparation of 30 novel 9-O-arylboldine derivatives. This operationally simple procedure proceeds at room temperature under ambient air conditions, employing readily available phenylboronic acids as coupling partners. Extensive one- and two-dimensional NMR studies unequivocally confirmed the desired 9-O-regioselectivity. Further demonstrating the scope of this method, we synthesized five new 3-bromo-9-O-arylboldine derivatives starting from 3-bromoboldine. Additionally, some 9-O-phenylboldine derivatives served as versatile intermediates, undergoing transformations to access N,N-dimethylammonium derivatives and enabling the conversion of 4'-formylphenyl derivative 6w into four aminoaporphine derivatives via reductive amination. This study confirms the usefulness of the Chan-Lam cross-coupling reaction as a powerful and flexible synthetic tool for the derivatization of natural products, particularly with the goal of expanding the chemical diversity of aporphine alkaloids.
Rituximab (RTX) is an effective and safe treatment for rheumatoid arthritis (RA), but is associated with an increased risk of reactivation of hepatitis B virus (HBV) infection. Therefore, (inter)national guidelines recommend HBV screening prior to initiation of RTX treatment. However, the incidence of HBV in RA patients in nonendemic areas is expected to be very low, with known suboptimal screening adherence. This study aims to assess the added diagnostic value of routine serological HBV screening in RA patients initiating RTX. This retrospective single-centre cohort study included all patients with a clinical diagnosis of RA intending to initiate RTX between April 2012 and April 2024. Data on patient and disease characteristics, HBV screening results, and additional laboratory results were collected. Adherence to HBV screening, proportion of positive test results (hepatitis B surface antigen or core antibody positive), and incidence of HBV reactivation were assessed. Of 975 included patients, 270 (28 %) were serologically screened for HBV. Six of those (2.2 %) had a positive screening result, of whom 3 eventually did not receive RTX. All 6 had a known HBV history or risk factor. No active HBV infections were observed after initiating RTX (mean follow-up 6.97 years), regardless of screening. Routine serological HBV screening identified very few previously unrecognised infections, and-in spite of screening adherence being low-no HBV reactivations occurred. Routine serological HBV screening, therefore, seems redundant in a low-risk population and should be reserved for patients with known risk factors.