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).
Drawing on the extensive correspondence between Pei-sung Tang and B. F. Skinner, this article traces their friendship and the main trajectory of Skinner's unfinished lecture visit to China. Building on these materials, it briefly examines the potential significance of the visit for Skinner himself and for the development of psychology in China. Finally, the article highlights the importance of harnessing public interest in psychology to advance the discipline. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, especially in patients with distant metastases. However, recent advances in multidisciplinary treatment strategies, including surgical resection, have led to successful outcomes even in patients with metastatic PDAC. Nevertheless, few cases have been reported with 2 or more resections of metachronous distant metastases. Herein, we report a case of PDAC in which a metachronous hepatic metastasis was successfully resected following prolonged chemotherapy after curative pancreatectomy and in which a metachronous pulmonary metastasis was subsequently resected following additional chemotherapy. A 69-year-old man was diagnosed with PDAC and received neoadjuvant chemotherapy in October 2019. In March 2020, a subtotal stomach-preserving pancreaticoduodenectomy was performed. The patient received 1 year of adjuvant chemotherapy following surgery. In September 2021, 18 months after surgery, CT showed a 10-mm nodule in segment (S) 6 of the liver, which was diagnosed as a hepatic recurrence of PDAC. After 19 months of chemotherapy, the metastatic liver lesion remained solitary and showed no change in size, suggesting that the tumor was well-controlled. In June 2023, a partial hepatectomy of S6 was performed. Chemotherapy with S-1 was continued after hepatic resection; however, a metastatic pulmonary lesion in the right lower lobe was identified on CT 15 months after the liver surgery. Right lower lobe partial resection was performed using video-assisted thoracoscopic surgery in January 2025. The patient remains alive and recurrence-free 1 year after the last surgery, 6 years and 1 month after the initial surgery, and 6 years and 6 months after the start of treatment. This report describes a case of long-term survival achieved with a multidisciplinary approach, including 2 surgical resections, for recurrent disease following a diagnosis of PDAC.
The present study presents a new approach to boost citric acid production by combining genetic improvement and enzyme inhibition in the fungus Aspergillus niger. A mutant strain, named NA-CYS3, was developed by chemically treating the wild-type strain to make it resistant to L-cysteine HCl, a chemical that normally limits growth. This mutant showed better tolerance and higher productivity. Optimal fermentation conditions including medium volume (50 mL), acidity (pH: 4.5), inoculum size (10%), incubation time (144 h), and temperature (30 °C) were optimized to maximize citric acid yield. Under these conditions, NA-CYS3 produced 26.35 g/L, a 2.7-fold increase in substrate use and higher yield compared to the wild-type strain. To further increase production, the activity of aconitase, an enzyme involved in the citric acid cycle, was partially blocked by adding two inhibitors, potassium ferrocyanide (K₄Fe(CN)₆; 0.004%) and methanol (1 mL), shortly after fermentation started. This "aconitase co-inhibition strategy" slowed down certain metabolic steps, leading NA-CYS3 to produce nearly 49 g/L of citric acid, significantly more than the wild-type's 35.65 g/L. Kinetic parameters (Yp/s, Qp, qp) further confirmed its superior production capacity. These findings demonstrate that combining strain mutation with targeted enzyme inhibition can greatly enhance citric acid biosynthesis. The NA-CYS3 strain shows promise for efficient and large-scale industrial production of citric acid. The online version contains supplementary material available at 10.1007/s13205-026-04929-2.
The hormone replacement therapy (HRT) is widely used for endometrial preparation in frozen-thawed embryo transfer (FET), but non-physiological estrogen levels may increase pregnancy complications. This study examined whether reducing the estrogen dose maintains clinical pregnancy rates. This retrospective cohort study included patients undergoing HRT-FET with single blastocyst transfer (Jan 2022 - Jun 2025). Patients were divided into a high-dose group (Group A, starting dose 6 mg/day, n = 1955) and a low-dose group (Group B, starting dose 2 mg/day, maximum increment 2 mg/day, n = 202). The primary outcome was clinical pregnancy rate. Due to the bias in clinical decision, the high estradiol dose protocol is typically prioritized, resulting in a significant difference in sample sizes between the two groups. Univariate analysis, multivariate logistic regression, and propensity score matching were used to control for confounders. Before adjustment, the clinical pregnancy rate was significantly higher in the low-dose group (79.21%) than in the high-dose group (69.57%). However, baseline differences existed in female age and ovarian reserve parameters between groups. After multivariate adjustment, the increase in clinical pregnancy rates in the low-dose group was not significant (aOR = 1.422, 95% CI: 0.983-2.055, P = 0.061). Analysis after propensity score matching also showed no significant differences in clinical pregnancy (76.3% vs. 78.6%, P = 0.599) or early miscarriage rates (10.2% vs. 13.9%, P = 0.251). The finding that reducing the starting dose of exogenous estrogen in HRT-FET cycles did not appear to compromise clinical pregnancy outcomes following single blastocyst transfer suggests that an individualized lower-dose estrogen strategy may be feasible, particularly for younger women or those with normal ovarian reserve. However, these results are preliminary, and prospective clinical trials are needed to confirm whether such an approach can maintain efficacy while potentially reducing risks associated with high estrogen exposure.
Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is critical for diagnosing solid lesions. The wet-suction technique, which pre-fills the needle lumen with saline, has been proposed to improve specimen quality compared with conventional dry suction. This study aimed to evaluate the efficacy of wet suction versus dry suction in EUS-TA. This study aimed to evaluate the efficacy of wet suction versus dry suction in EUS-TA. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following PRISMA 2020 guidelines. Electronic searches of PubMed, Embase, Cochrane CENTRAL, and additional databases were performed through January 2025. Primary outcomes were blood contamination, cellularity, and integrity scores; secondary outcomes were diagnostic accuracy and specimen adequacy. Effect sizes were calculated using Hedges' g or risk ratios (RRs) with 95% confidence intervals (CIs). Seven RCTs (784 patients; 1566 specimens) were included. Wet suction significantly reduced blood contamination (Hedges' g = 0.289, 95% CI: 0.178-0.401, p < 0.0001) and improved cellularity (Hedges' g = 0.420, 95% CI: 0.241-0.599, p < 0.0001) with low heterogeneity. Integrity score showed no significant difference (p = 0.054). Overall diagnostic accuracy was similar between techniques (RR = 1.025, p = 0.548), but subgroup analysis revealed higher accuracy for wet suction in EUS-fine needle aspiration (FNA; RR = 1.162, p = 0.001). Specimen adequacy did not differ significantly (p = 0.074). Wet suction improves sample quality by reducing blood contamination and increasing cellularity, with potential diagnostic benefit in FNA procedures. Effects on integrity and adequacy remain inconclusive. Larger, standardized trials are warranted to confirm these findings. Better samples, better results: using water to improve ultrasound-guided biopsies Improving biopsy quality: the “wet suction” advantage The challenge: When doctors need to diagnose a suspicious growth inside the body (such as in the pancreas), they use Endoscopic Ultrasound-Guided Tissue Acquisition (EUS-TA). A thin needle is guided by ultrasound to collect tissue samples. However, these samples often contain too much blood or too few diagnostic cells, making it difficult for pathologists to provide a clear answer. The “wet suction” technique: Traditionally, the biopsy needle is filled with air (Dry Suction). The Wet Suction technique is a simple modification: the needle is pre-filled with sterile saline (salt water) before the procedure. This saline replaces the air to create a more stable vacuum, helping to pull in more tissue while reducing blood interference. Our study and findings: We analyzed data from 7 clinical trials involving 784 patients and 1,566 tissue samples. Our goal was to confirm if the “wet” method is truly superior to the standard “dry” method. Cleaner Samples: Wet suction significantly reduced blood contamination, making samples easier to read under a microscope. Higher Cell Yield: Samples collected with wet suction contained a higher concentration of the actual target cells (better cellularity). Greater Accuracy: For specific needle types (FNA), wet suction significantly improved the accuracy of the final diagnosis. Better for Large Lesions: Larger growths showed a particularly strong benefit from the reduction in blood contamination. Why this matters: For patients, a better-quality sample means a higher chance of an accurate diagnosis on the first try. This simple, low-cost adjustment reduces the need for repeat procedures and helps patients start the correct treatment sooner, providing more certainty and less anxiety during the diagnostic process.
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.
Plasmonic nanoparticles have generated great attention due to their potential applications in photocatalysis. The dissociation of hydrogen on Au nanoparticles has served as a useful model for this process, but despite many previous studies, there are important details of the dynamics which remain uncertain, such how single-photon absorption triggers dissociation. This paper addresses these issues through the study of gold clusters interacting with H2, explicitly examining the effects of cluster size, shape, and excitation energy on the dissociation dynamics. By using time-dependent density functional theory (TDDFT) interfaced with trajectory surface hopping, we have examined the Au + H2 system for states with excitation energies similar to the plasmon energy in gold. Three distinct outcomes are observed: H-H bond dissociation, H2 desorption, and nonreactive relaxation. Trajectories starting in excited states of the cluster relax through extensive nonadiabatic surface hopping to lower excited states that couple to antibonding states where repulsion drives dissociation. In addition, hopping converts metal excitation to increased kinetic energy in H-H stretching that helps overcome dissociation barriers on reactive adiabats. This provides a detailed picture of the evolution of hot carriers into antibonding states of physisorbed molecules after extensive surface hopping that dissociate in ∼100 fs. Desorption and nonreactive relaxation compete with this picture. Our findings provide insights to photoinduced processes involving plasmonic nanoparticles showing how nonadiabatic dynamics plays a crucial role in accessing repulsive states while also releasing kinetic energy that drives dissociation.
Determining an optimal treatment strategy after tyrosine kinase inhibitor (TKI) failure remains challenging in oncogene-driven non-small cell lung cancer (NSCLC). We aimed to evaluate and compare the efficacy and safety of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) versus pemetrexed plus carboplatin or cisplatin (PC) in patients with progressive NSCLC harboring EGFR, ALK, or ROS1 alterations after TKI failure. Multicenter retrospective study. We analyzed 114 patients with NSCLC treated with either ABCP (n = 48) or PC (n = 66) post-TKI failure between November 2016 and July 2023. Treatment response, progression-free survival (PFS), overall survival (OS), and safety profiles were assessed. Among 106 evaluable participants, the ABCP arm demonstrated a higher response rate (50.0%) than the PC arm (35.0%). During the median follow-up of 29.9 months, PFS was significantly prolonged in the ABCP arm compared with that in the PC arm (7.3 vs 3.0 months, respectively; hazard ratio (HR) 0.643; p = 0.026), whereas OS showed no significant difference (p = 0.165). Subgroup analysis revealed notable improvements in PFS (7.2 vs 2.1 months, HR 0.235; p < 0.001) and OS (11.0 vs 4.1 months, HR 0.418; p = 0.001) in patients with three or more metastatic sites. ABCP significantly improved PFS compared with PC in patients with NSCLC that progressed despite prior TKI therapy. An OS benefit was observed in patients with three or more metastatic sites. Combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) improves progression-free survival compared to pemetrexed and carboplatin (PC) in patients with non-small cell lung cancer after targeted therapy fails. Why was this study done? Many patients with non-small cell lung cancer (NSCLC) have specific genetic alterations (mutations like EGFR, ALK, or ROS1). The standard first line treatment for this population is targeted therapy. However, many patients discontinue these drugs because cancer eventually gains resistance to the target therapy. There are unmet needs for patients whose target therapies are exhausted since there are no guideline for subsequent treatment. What did the researchers do? This study compared the effectiveness of two different chemotherapy combinations for patients whose cancer grew after taking targeted pills. The researchers retrospectively analyzed data from 114 patients treated between 2016 and 2023. The patients received either: ABCP: A four-drug combination of atezolizumab (immunotherapy), bevacizumab (anti-VEGF therapy), paclitaxel, and carboplatin (cytotoxic chemotherapy) PC: A two-drug cytotoxic chemotherapy regimen (pemetrexed plus carboplatin). What were the results? The study found that the four-drug combination (ABCP) was more effective at controlling the cancer: Delayed Growth: On average, patients on ABCP went 7.3 months before their cancer started growing again, compared to only 3.0 months for those on PC. Tumor Shrinkage: Tumors shrank in 50% of patients taking ABCP, compared to 35% of patients taking PC. Survival: While the overall survival time was similar for both groups, patients with more widespread cancer (spread to 3 or more sites) lived significantly longer if they received the ABCP treatment. What do these findings mean? For patients with NSCLC whose targeted therapy has been exhausted, using the ABCP combination appears to keep the cancer under control significantly longer than PC. It may be a particularly good option for patients whose cancer has spread to multiple parts of the body.
Gastric cancer (GC) is a highly malignant tumor with significant morbidity and mortality rates globally. Recent studies have shown that RUNX2, a member of the RUNX family known for its role in osteoblast differentiation and bone morphogenesis, is associated with the pathogenesis and progression of GC, while the underlying mechanisms of the pathogenesis and progression of GC are largely unknown. In this study, we investigated the role of RUNX2 in GC progression by analyzing its effects on gene expression and alternative splicing (AS) in HGC-27 cells. We silenced RUNX2 by small interfering RNA (siRUNX2), and then analyzed the globally regulated transcriptome profile by sequencing method (RNA-seq) to identify the differentially expressed genes (DEGs) and alternative splicing (AS) genes. The downstream targets of RUNX2 were identified by performing CUT&Tag and sequencing experiment in HGC-27 cells. Using RNA-seq, we identified 314 DEGs and 1120 regulated AS events (RASEs) in HGC-27 cells upon RUNX2 knockdown. The DEGs were enriched in pathways related to cell cycle regulation and apoptosis, while the RASEs were predominantly involved in cell cycle processes. These findings suggest that RUNX2 not only modulates gene expression but also extensively influences AS, which is crucial for cellular processes such as proliferation and survival. Notably, we found that RUNX2 regulates the expression of the splicing factor SF3B6 by binding to its promoter region. Our results showed that SF3B6 expression was significantly decreased in siRUNX2 samples, and its downregulation was associated with altered AS profiles of genes involved in the cell cycle. Our findings demonstrate that RUNX2 modulates the transcriptome and AS profile in GC cells, with a particular focus on its regulation of SF3B6. This study highlights the multifaceted role of RUNX2 in GC progression and suggests that targeting the RUNX2-SF3B6 axis could be a promising therapeutic strategy for GC.
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.
Opioid use disorder (OUD) and overdoses represent critical challenges linked to the widespread availability of opioid medications. To address these risks, the French National Authority for Health convened a multidisciplinary working group to develop comprehensive guidelines on the prevention and management of OUD and overdoses. These recommendations expand on the second part of the guidelines, which specifically addressed the prevention and management of OUD and overdoses. Grounded in the highest level of international evidence and developed through a rigorous formal consensus process, the guidelines emphasize appropriate opioid prescribing as the cornerstone of prevention. They provide practical recommendations for identifying patients at risk, detecting problematic use early, and initiating opioid agonist treatment when indicated. The role of naloxone as an essential tool to prevent fatal overdoses is highlighted, along with strategies for coordinated and multidisciplinary care across diverse healthcare settings. By integrating prevention, treatment, and harm reduction measures, these guidelines seek to balance legitimate access to opioid analgesics with robust safeguards against opioid use disorder and overdose. Although developed within the French healthcare system, their strong evidence base and underlying clinical principles make them applicable to international practice. Together with the first part on pain management, they constitute one of the most comprehensive and up-to-date sets of recommendations on the safe and effective use of opioid medications. Opioid medicines are important for treating pain, but they also carry risks of opioid use disorder and overdose, which can sometimes be fatal. These risks have increased as opioids have become more widely available. Clear national guidance is needed to help patients and healthcare professionals use these medicines safely. This second part of the French national practice guidelines focuses on the prevention and management of opioid use disorder and overdoses. The recommendations were developed with input from doctors, pharmacists, addiction specialists, patients, and public agencies, and are based on international scientific evidence. The guidelines stress the importance of safe prescribing from the start of treatment and educating patients about benefits and risks. They highlight how to recognize early warning signs of problematic use and recommend substitution treatments, such as buprenorphine or methadone, which reduce cravings and lower the risk of overdose. Another key recommendation is to make naloxone, the emergency medicine that reverses an opioid overdose, widely available to patients, relatives, and first responders. These guidelines also call for coordinated, multidisciplinary care that addresses medical, psychological, and social needs. Together with Part 1 of the guidelines, which focuses on clinical use of opioids for pain, they provide a comprehensive and consistent framework to ensure safe access to opioids while reducing harm.
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.
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.
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.
Allogeneic cell-based immunotherapies generated from pluripotent stem cells show considerable promise for the treatment of oncological, autoimmune, and viral diseases, however discovery platforms for induced pluripotent stem cell (iPSC)-derived cell therapies do not translate well to scalable manufacturing platforms. We applied a high-throughput combinatorial screening platform (CombiCult®) to identify novel, manufacturing-ready, feeder-free protocols for the generation of mature, functional NK cells from human iPSCs. We validated seven CombiCult®-derived differentiation protocols for the production of highly cytotoxic, phenotypically mature iPSC-derived NK (iNK) cells, which are comparable to donor-derived NK cells. Translation to a Stirred Tank Bioreactor (STR) system resulted in a 10x increase in productivity, from ∼20 to ∼190 iNK cells per starting iPSC. iNK cells demonstrate mature transcriptomic signatures, retained after translation to bioreactor-based production. The three-dimensional, bead-based screening approach enables seamless translation to bioreactor-based production of iNK cells exhibiting high cytotoxic activity against a range of cancer cell types.
Harm reduction vending machines (HRVMs) can expand low-barrier access to overdose prevention, sexual health, safer-use, and basic self-care supplies; however, practical guidance for implementing HRVMs in health system and supportive housing settings is limited. This practice report describes a clinical pharmacist practitioner (CPP)-led deployment of 15 HRVMs across a Veterans Affairs (VA) system and Veterans supportive housing in California. Beginning in December 2021, the CPP conducted site engagement, market research, and funding applications; convened cross-departmental stakeholders (logistics, engineering, biomedical, environmental management, information security/technology); and completed contracting. Contracts were awarded to VendNovation, LLC, for HRVMs which were placed in 7 community-based outpatient clinics, 6 supportive-housing sites, and 2 hospital locations. The CPP designed the HRVM wrap and interior layout; curated product assortments (eg, fentanyl/xylazine test strips, syringes, safer-sex supplies, wound-care, and hygiene items; naloxone added after launch) based on prior quality improvement interventions and Veteran feedback surveys; and established barcode-based user access and software-enabled inventory management. Implementation challenges included staff concerns (eg, stigma, not in my backyard attitudes), connectivity barriers (eg, Wi-Fi requirements), and added costs for deliveries to non-VA locations. HRVMs within VA clinics were accessible during business hours; supportive-housing HRVMs operate 24/7. Planning and installation required nearly 2 years, underscoring the need for dedicated staffing (CPP plus logistics technician), braided funding for start-up and recurring costs, and standardized purchasing and installation pathways. HRVMs seem feasible and acceptable in VA clinical and housing settings and may increase anonymous, low-barrier access to harm-reduction supplies. Implications for scale-up include development of centralized or prevetted procurement pathways, clearer implementation guidance, and operational supports to reduce site-level contracting burden.
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.
In patients with psoriatic arthritis (PsA) initiating treatment with secukinumab, we investigated the impact of smoking and body mass index (BMI) on secukinumab retention rate at 12 months and the achievement of low Disease Activity Index for PsA in 28 joints (DAPSA28 ≤14) at 6 months. Patients with PsA initiating secukinumab with available data on smoking and BMI were included. Patients were categorised according to smoking status (never/former/current) and BMI (normal/overweight/obese) at treatment start. Kaplan-Meier curves and adjusted Cox and logistic regression analyses were performed to compare secukinumab retention and response rates, respectively. Additional regression analyses were performed with BMI as a continuous variable. We included 1202 patients. Retention rates in never/former/current smokers were 79%/73%/72% and in normal/overweight/obese 72%/77%/77%, respectively. Adjusted hazard ratios for treatment withdrawal were numerically higher in former (1.32; 95 % CI 1.00-1.75) and current smokers (1.27; 0.93-1.74), while remaining roughly similar across BMI (overweight: 0.90; 0.67-1.21, obese: 0.89; 0.66-1.21, per BMI unit: 1.00; 0.97-1.02). Response rates in never/former/current smokers were 56%/61%/49% and in normal/overweight/obese 57%/59%/52%, respectively. Adjusted odds ratio for achieving low DAPSA28 was numerically lower for current smokers (0.74; 0.47-1.15) but higher for former smokers (1.30; 0.87-1.94), whereas it was numerically lower in patients with obesity (0.74; 0.49-1.11) and lower with each increase in BMI unit (0.97; 0.94-1.00). In real-world patients with PsA, secukinumab retention tended to be lower in current and former smokers. No clear association between BMI and secukinumab effectiveness was observed.
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.