Effective, safe, and infant-friendly interventions are needed to prevent transitional neonatal hypoglycemia, neonatal unit admissions, and neurological sequelae. To determine if prophylactic buccal dextrose gel at 1 hour of age in at-risk late preterm and term infants improves neurocognitive function at 6 to 7 years of age, without adverse effects on general health and well-being. This study focused on school-age follow-up of children in the Hypoglycaemia Prevention With Oral Dextrose (hPOD) multicenter, double-blind, 2-arm, parallel, placebo-controlled trial. Participants were recruited at birth across 9 hospitals in New Zealand. Follow-up was conducted primarily at the children's schools. Children in the hPOD Trial were born at 35 weeks' or more gestation and weighed 2.2 kg or more with 1 or more risk factors for transitional neonatal hypoglycemia: preterm, maternal diabetes, small or large for gestational age, or birth weight less than 2.5 kg or more than 4.5 kg. The assessments for this study (data collection) were performed from April 2021 to July 2025. The primary database extraction was on July 24, 2025. Data analysis was completed in October 2025. A 0.2-g/kg dose of buccal or placebo (hydroxymethylcellulose, 2%) at 1 hour of age. The primary outcome for this follow-up study was neurocognitive impairment at 6 to 7 years of age, defined as a standard score more than 1 SD below the normative mean on 1 or more of 7 items from the National Institutes of Health Toolbox. Eleven main exploratory outcomes included components of the primary outcome, low numeracy, visual perception, emotional-behavioral difficulty (Strengths and Difficulties Questionnaire), low physical or psychosocial functioning (Child Health Questionnaire), and overweight/obesity. There were 532 of 652 (252 female and 280 male [82%]) eligible children assessed in the dextrose gel group and 535 of 642 (271 female and 264 male [83%]) in the placebo group. The proportion with neurocognitive impairment was similar between groups (dextrose gel, 59%, vs placebo, 57%; adjusted risk difference [aRD], 3%; 95% CI, -3% to 9%; P = .36). Of exploratory outcomes, children who received dextrose gel, compared with placebo, were more likely to have emotional-behavioral difficulty (24% vs 18%; aRD, 7%; 95% CI, 1%-12%) and low psychosocial function (17% vs 12%; aRD, 6%; 95% CI, 1%-10%). Other outcomes were similar between groups. In this follow-up study, a single dose of dextrose gel to prevent hypoglycemia, compared with placebo, had little to no effect on the risk of neurocognitive impairment at early school age, but could have adverse effects on psychological well-being. The current evidence does not support the routine use of dextrose gel for the prevention of neonatal transitional hypoglycemia. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001263684.
Mental health professionals frequently work with individuals who have addiction concerns; however, limited training is occurring in their educational programs. The purpose of this study was to evaluate counselors, psychologists, and social workers and investigate aspects of their addiction training and perceived addiction-related competency. The majority of the 1596 mental health professionals who participated in the study identified as White, non-Hispanic/Latino, heterosexual, women with a master's degree in social work. Over one-third had an addiction credential (35.81%) and worked in the addiction field (35.48%); 60.82% were counselors, 45.44% worked in an outpatient setting, and 24.51% worked in private practice. Half of the workforce felt unprepared in the area of addiction upon graduation, and over two-thirds wished they had taken more addiction coursework. Over nine out of 10 mental health professionals reported that addiction training is necessary in degree preparation programs, and almost three-fourths recommended that students complete one or more addiction-specific courses. The highest perceived competence among the participants was in the areas of motivational interviewing and diagnosis, and the lowest was in diversity aspects and drug policy. Despite being the largest group of mental health professionals within the USA, the social workers in the study reported the lowest overall perceived confidence. Results support the need for more addiction training in mental health professional preparation programs.
Androgenic alopecia (AGA) is the most common type of hair loss that occurs due to androgens, specially, dihydrotestosterone (DHT), and the 5-alpha reductase is the key enzyme to control AGA, as it is responsible for the conversion of testosterone to DHT, the more potent form of testosterone involved in the pathogenesis of AGA. Blockers of this enzyme suppress the conversion of androgens to DHT. Dutasteride is one of the 5-alpha reductase inhibitors and is frequently used as an anti-hair loss treatment. Gamma-oryzanol (GO) is an anti-oxidant and anti-5-alpha reductase, which has been introduced as an anti-hair loss treatment by some studies. The nanostructured lipid carriers (NLCs) were developed for targeting the dutasteride and GO in hair follicles. The NLCs were prepared from herbal oils pumpkin seed oil (PSO) and saw palmetto (SP), which also have a 5-alpha reductase inhibitory effect, contributing to the therapeutic effect. NLCs in follicular targeting enable to accumulation of the drugs in the target area (hair follicle cells), reduce the absorption of dutasteride in other organs and tissues, and reduce the side effects. NLCs were prepared by adopting a hot homogenization method and were characterized by particle size analyzer, scanning electron microscope, and X-ray diffraction. An in-vivo study was conducted using C57BL/6 mice to assess NLCs ability in drug delivery and accumulation in hair follicles. NLCs had great potentials for reducing the dutasteride daily dose. Moreover, the accumulation of NLCs was confirmed by histopathological images even after two weeks of the discontinued treatment. NLCs may have facilitated the follicular delivery of the anti-hair loss drugs. Since the NLCs have potential for accumulation in the hair follicles, the interval of formulation usage may have been increased to more than once a week which was of great interest to the practitioners aiming at developing more efficient formulations for androgenetic alopecia.
Mounting evidence suggests that ferroptosis is closely involved in the development of severe acute pancreatitis (SAP). This study aimed to investigate the association between abnormal lipid metabolism and ferroptosis and elucidate the role of the Keap1/Nrf2/SLC7A11/GPX4 pathway in pancreatic acinar cell injury during SAP. Rats were divided into four experimental groups: sham, hyperlipidemia (HL), SAP, and HL-SAP. Sprague-Dawley rats were adopted to establish HL-SAP model through administering high-fat emulsions via gastric infusion for 14 consecutive days and sodium taurocholic injection. Measure serum amylase, blood lipid, and inflammatory cytokine levels, perform histological analysis, determine the expression levels of proteins in the Keap1/Nrf2/SLC7A11/GPX4 signaling pathway, and evaluate ferroptosis-related changes and oxidative stress. High-fat emulsion feeding successfully induced hyperlipidemia with elevated blood lipids, while injection of 3.5% sodium taurocholate triggered SAP accompanied by increased serum amylase. The combined intervention effectively established the HL-SAP model. Compared with the SAP rats, the HL-SAP rats exhibited more severe pancreatic damage (72 h mortality: 80 vs. 50%, respectively, plus elevated amylase, inflammation, histopathology scores). Higher amylase levels, intensified inflammation, and increased histopathological scores were also observed in HL-SAP rats. Moreover, HL-SAP rats showed markedly enhanced oxidative stress and ferroptosis-related phenotypes, including increased MDA, ROS and Fe2⁺ levels, as well as decreased GSH and SOD levels. In both SAP and HL-SAP groups, abnormal lipid metabolism was associated with downregulated Nrf2, SLC7A11, and GPX4 expression and upregulated Keap1 expression, and these alterations were more prominent in the HL-SAP group. Abnormal lipid metabolism aggravates oxidative stress, inflammation, and pancreatic acinar cell injury in SAP, and promotes ferroptosis. These effects may be attributed to reduced activity of the Keap1/Nrf2/SLC7A11/GPX4 pathway.
Trypanosomatids, including the genera Trypanosoma and Leishmania, are protozoan parasites of significant medical and veterinary relevance. These organisms cause African trypanosomiasis, Chagas disease, and leishmaniasis, which are classified as neglected tropical diseases (NTDs). NTDs continue to present major public health challenges, particularly in sub-Saharan Africa, Latin America, and parts of Asia, resulting in substantial morbidity, mortality, and socioeconomic impacts. Chemotherapeutic interventions remain constrained by toxicity, high cost, limited accessibility, and the increasing prevalence of drug resistance. Significantly, there is a tight relationship between pathogenesis and drug resistance because processes that facilitate intracellular persistence, immunological evasion, and metabolic adaptation can also decrease drug sensitivity and increase treatment failure. This interaction makes it easier for more pathogenic and resilient strains to arise, which makes disease treatment and control more difficult. The absence of effective vaccines underscores the urgent need for novel therapeutic strategies. Advances in molecular parasitology have elucidated unique organellar structures, immune evasion mechanisms, and metabolic pathways in trypanosomatids, providing new therapeutic targets. Additionally, artificial intelligence and computational methodologies are facilitating drug discovery, predicting resistance, and improving diagnostics. In this review, we provide a narrative overview of current knowledge of trypanosomatid biology, prevalence, drug resistance mechanisms, and emerging control strategies. By integrating classical parasitology with computational approaches, new opportunities are identified to address resistance, enhance therapy, and mitigate the global health burden of trypanosomatid infections.
Organic semiconductor bulk-heterojunction nanoparticles have emerged as promising photocatalysts, due to their strong visible absorption in the Vis-NIR region, excellent optical/electronic adjustability, and spatially abundant interfaces for charge carrier separation. However, organic semiconductors generally suffer from inferior crystallinity and high lattice's susceptibility to molecular vibrations, which leads to the localization of separated charge carriers and severe recombination in nanoparticles, limiting the further improvement of photocatalytic H2 evolution rate. Herein, a methoxy-functionalized electron acceptor, ITIC-OMe, is developed and presents enhanced crystallinity, more compact molecular packing and weaker electron-phonon coupling, compared to the parent ITIC. This enables ZnTPP-3O:ITIC-OMe bulk-heterojunction nanoparticles to afford more ordered molecular stacking, reduced charge transfer resistance, and inhibited charge back transfer for triplet state formation, thereby suppressing charge carrier recombination and facilitating charge transport to the nanoparticle surface for proton reduction. Consequently, the photocatalyst based on ZnTPP-3O:ITIC-OMe bulk-heterojunction nanoparticles achieves an impressive hydrogen evolution rate up to 1017.7 mmol g-1 h-1 under AM 1.5G illumination, which is the record for organic photocatalysts so far. It highlights that suppressing charge carrier recombination via finely molecular design is a powerful route to enhance the photocatalytic H2 evolution performance.
Post-hepatectomy liver failure (PHLF) remains a major cause of morbidity after liver resection for hepatocellular carcinoma (HCC). Routine blood-count-based inflammatory indices may complement established liver reserve assessments. This study evaluated whether preoperative systemic pan-immune-inflammation value (S-PIV) predicts PHLF after conventional laparoscopic hepatectomy for HCC. We conducted a single-center retrospective cohort study of consecutive patients who completed conventional laparoscopic hepatectomy for liver tumors between January 2017 and December 2025. Eligible patients had pathologically confirmed HCC and complete preoperative laboratory data within 7 days before surgery. Planned open hepatectomy, conversion to open surgery, and robotic-assisted hepatectomy were outside the predefined cohort scope. S-PIV was calculated as neutrophil count × monocyte count × platelet count / lymphocyte count. The primary outcome was ISGLS-defined PHLF, analyzed as any-grade PHLF versus no PHLF. Discrimination was assessed using ROC analysis, dose-response using restricted cubic splines, and clinical utility using decision curve analysis. Among 582 screened patients, 356 were included; 68 (19.1%) developed PHLF. Preoperative S-PIV showed good discrimination for PHLF (AUC 0.873). The Youden index identified an optimal cut-off of 455.4, with sensitivity 0.726 and specificity 0.908. S-PIV showed higher AUCs than NLR (0.831) and PLR (0.848). Higher S-PIV was associated with PHLF in univariable analysis (per 100 units: OR 1.12, 95% CI 1.06-1.45; P<0.001) and remained independently associated after sequential adjustment for demographics/comorbidities, liver functional reserve, and tumor/operative factors (Model 3 per 100 units: OR 1.06, 95% CI 1.03-1.13; P<0.001). Restricted cubic splines showed a graded risk increase without evidence of nonlinearity, and decision curve analysis suggested net benefit across threshold probabilities of approximately 10%-70%. Preoperative S-PIV, derived from routine blood counts, may serve as a practical adjunct for PHLF risk stratification after conventional laparoscopic hepatectomy for HCC. External multicenter validation and calibration are urgently required before routine implementation. Liver surgery can help many patients with liver cancer, but some patients may have poor liver function after part of the liver is removed. This problem can slow recovery and may become serious. Doctors therefore need simple ways to identify patients who may need closer care before and after surgery. In this study, we reviewed people with this type of liver cancer who had laparoscopic liver surgery at our hospital. We tested whether information from a routine blood test before surgery could help estimate the chance of liver failure after surgery. This blood test reflects the balance between inflammation and immune status in the body. We found that patients with a higher inflammation-related blood score before surgery were more likely to develop liver failure after surgery. This score may help doctors discuss surgical risk with patients, plan perioperative care, and identify patients who may need closer monitoring after surgery. These findings are promising, but they come from one hospital. More studies from multiple hospitals are needed before this blood score can be used routinely in clinical practice. What do the terms mean? The terms used in this article are explained in plain language as follows. Hepatocellular carcinoma refers to the most common type of primary liver cancer. Laparoscopic liver surgery refers to liver surgery performed through small cuts in the abdomen using a camera and surgical instruments. Liver failure after surgery refers to a condition in which the remaining liver does not work well enough after part of the liver has been removed. A blood inflammation score is calculated from routine blood cell counts and reflects inflammation and immune status. Liver reserve refers to the ability of the liver to keep working after surgery. Closer monitoring means more careful observation and follow-up before and after surgery. Multicenter validation means testing the findings in patients from other hospitals to confirm whether the results are reliable.
Abiraterone (ABI) and enzalutamide (ENZA) are standard treatments for metastatic castration-resistant prostate cancer (mCRPC). However, their safety and efficacy have not been directly compared in prospective clinical trials. To directly compare their safety and efficacy in prospective clinical trials. A systematic search was performed in PubMed, Embase, and Cochrane Library databases (CRD42024608496) on 24 June 2025. Eligibility criteria included studies on patients with mCRPC treated with ABI or ENZA reporting outcomes such as overall survival (OS), prostate-specific antigen (PSA) response (PSA50/90), progression-free survival (rPFS/bPFS), and rates of grade ≥ 3 adverse events, dose reduction, treatment discontinuation, and major cardiovascular events (MACE). Both first- and second-line mCRPC treatment settings were considered. The inverse variance method was used to calculate pooled hazard ratios (HRs), using the natural logarithm of the HR and its standard error (SE) from the available data. A total of 47 real-world observation studies and data from 71,984 patients were included, with no randomized controlled trials available for direct comparison. ENZA proved more effective in terms of PSA50 (odds ratio (OR): 1.82; 95% confidence interval (CI): 1.38-2.4) and OS (HR: 0.79; 95% CI 0.71-0.87) in the overall cohort as well as in the first-line (PSA50: OR: 1.69; 95% CI 1.23-2.31, OS: HR: 0.85, 95% CI 0.79-0.92) and second-line setting (PSA50 OR: 1.78; 95% CI 1.23-2.58, OS: HR: 0.69; 95% CI 0.60-0.80). However, grade ≥ 3 AEs and treatment discontinuation rates were significantly more frequent with ENZA (OR: 2.17; 95% CI 0.85-5.54 and OR: 1.81; 95% CI 1.45-2.25, respectively), while MACE rates were lower (OR: 0.53; 95% CI 0.33-0.84). ENZA showed greater efficacy, whereas serious AEs were less frequent with ABI. However, this difference may decrease or even disappear upon switching these therapies. Therefore, individual decision-making is encouraged, balancing efficacy and safety. ENZA should be prioritized if OS is the main goal, whereas ABI may be preferred when minimizing AEs is important. ENZA is also associated with a lower risk of MACE.
Idiopathicshort stature (ISS) has been used for more than five decades to label children whose height is below -2 SDS without an identified underlying cause. Although originally conceived as a pragmatic diagnosis of exclusion, ISS has gradually been reified as a disease entity and is now embedded in clinical guidelines, regulatory frameworks and indications for recombinant human growth hormone therapy. In parallel, advances in genomic technologies have uncovered a growing spectrum of monogenic and chromosomal variants among children previously classified as ISS, and highlighted the continuous, polygenic architecture of height in the remainder. These developments render the idiopathic construct increasingly misleading and unstable, as every new etiological discovery shrinks - and conceptually undermines - the ISS category. In this article, we review the historical evolution and current use of ISS, summarize the impact of modern genetic testing on the classification of short stature, and argue that most children currently labeled as having ISS are better described as having "Healthy Short Stature". We define Healthy Short Stature as short stature in otherwise healthy children without systemic, syndromic or endocrine disease, in whom short stature represents the lower extreme of normal growth variation. We discuss how adopting Healthy Short Stature can reduce stigma, remain compatible with ongoing genetic investigation, and provide a more robust framework for aligning clinical practice, research and health policy with contemporary knowledge of human growth biology.
Rapid expansion of the therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has increased the complexity of treatment selection and sequencing. However, large, contemporary studies describing treatment patterns and attrition rates in clinical treatment of mCRPC are lacking. To investigate treatment patterns and attrition rates in patients with mCRPC from 2021 to 2025. This retrospective multicenter cohort study used the US-based, electronic health record-derived, deidentified Flatiron Health Research Database to identify patients with mCRPC who initiated first-line therapy between January 1, 2021, and June 30, 2025, at approximately 280 centers, primarily community oncology practices. Year of first-line treatment initiation and types of treatment for mCRPC. First- through fifth-line treatment and attrition rates were summarized using frequencies and percentages into respective categories: androgen receptor pathway inhibitors (ARPIs), taxanes, poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPIs), platinum-based therapies, lutetium Lu 177-prostate-specific membrane antigen 617 (Lu-177)-based therapies, radium Ra 223, sipuleucel-T, immunotherapy, and other. Of 27 979 patients in the dataset, 5096 with mCRPC initiating first-line therapy were included in the analysis. The median age was 75 (IQR, 68-82) years. Overall, 2731 patients (53.6%) received second-line treatment and 1334 (26.2%) received third-line treatment. ARPI was the most common first-line (4041 of 5096 [79.3%]) and second-line (1123 of 2731 [41.1%]) treatment, with decreasing use in subsequent lines. Taxane use increased from 637 of 5096 patients (12.5%) in first-line treatment to 953 of 2731 (34.9%) in second-line treatment and became the most common third-line treatment (485 of 1334 [36.4%]). Overall, 2192 patients (43.0%) received taxane-based therapies. Use of Lu-177 increased progressively from 113 of 5096 patients (2.2%) in first-line treatment to 71 of 226 patients (31.4%) by fifth-line initiation. PARPI use was limited and peaked at 99 of 1334 patients (7.4%) in third-line treatment. In this cohort study of patients with mCRPC, only slightly more than half of patients received second-line treatment, and attrition rose significantly across subsequent treatment lines. ARPIs and taxanes remained the most common first-line treatments, with increased use of Lu-177 and PARPIs in later treatment lines. These findings highlight the evolving complexity of mCRPC management and significant attrition with later lines, underscoring the need for optimized sequencing strategies, more efficacious frontline therapies, and interventions to improve access.
Understanding intrapulmonary pharmacokinetics (PK) following inhalation remains a significant challenge in drug development and repurposing. Current lung sampling methods include bronchoalveolar lavage (BAL), biopsies, and the more recent bronchosorption technique, which enhances regional specificity while reducing potential quantification errors. This study aimed to develop a pulmonary population physiologically based pharmacokinetic (PBPK) model for inhaled salbutamol by integrating data from all three sampling techniques to improve PK predictions and to compare different sampling strategies to optimize future study designs. A population-based minimal PBPK model was developed using data from a previously published study (NCT03524066) investigating salbutamol's pulmonary and plasma PK in 13 healthy volunteers after inhalation. Simulations assessed the impact of permeability on pulmonary PK profiles and BAL-derived epithelial lining fluid (ELF)-to-plasma ratios using salbutamol as a reference compound. Stochastic simulation-estimation (SSE) methods were employed to assess the feasibility of different sampling strategies for estimating key parameters of the PBPK model. First, we evaluated using one or two sampling techniques within a single bronchoscopy session. Second, we compared uniform and staggered bronchosorption-based sampling strategies for drugs from different permeability categories. The minimal PBPK model described pulmonary PK of salbutamol across the lung and estimated the unbound tissue-plasma partition coefficient for the lung ( K p , u , lung ) and the effective permeability ( P eff ) of salbutamol as 11.0 and 0.543 m/h, respectively. Inter-individual variabilities (IIV) were found on plasma clearance and lung deposition fraction. No significant IIV was detected on K p , u , lung or P eff . Simulations indicated that low-permeability drugs exhibited higher concentrations in the ELF, while high-permeability drugs accumulated more in lung tissues, after inhalation. Results from SSE showed that bronchosorption plus biopsy were the most informative two-technique combination and bronchosorption alone was the best single-technique option. Additionally, the optimal sampling strategy for both uniform and staggered sampling depended on drug permeability, with early time points favoured for high-permeability drugs and later or broader windows needed for low-permeability drugs. A pulmonary population PBPK model for inhaled salbutamol was developed by integrating detailed intrapulmonary data from bronchoalveolar lavage, biopsy, and bronchosorption. The study revealed that parameter estimates of K p , u , lung and P eff were sensitive to the sampling technique. Staggered sampling strategies mitigated the risk of biased estimates, though the ideal sampling windows varied by drug's permeability. These findings support model-informed, permeability-driven study design in inhaled drug development.
Light rare earth oxides (LREEs), such as cerium, lanthanum, neodymium, and praseodymium oxides, have unique redox and catalytic properties that may contribute to various therapeutic effects. Researchers in this study looked at LREEs' in vitro antioxidant, anti-diabetic, anti-Alzheimer's, anti-arthritic, and cytotoxic effects. The antioxidant potential was evaluated using Diphenyl-2-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), nitric oxide (NO), hydroxyl (OH), and hydrogen peroxide (H2O2) radical scavenging assays, showing a moderate inhibitory effect compared to ascorbic acid. Enzyme inhibition assays indicated weak AChE inhibition, suggesting limited anti-Alzheimer's disease potential. Moderate anti-arthritic effects were observed through inhibition of protein denaturation and proteinase activity. In anti-diabetic assays, LREEs dose-dependently inhibited α-amylase and α-glucosidase, although less potent than acarbose. Cytotoxicity testing on HepG2 cancer cells showed an IC50 of 281.80 µg/mL, significantly higher than doxorubicin (34.07 µg/mL), indicating weak anticancer potential. Elevated Caspase-3 levels and diminished Bcl-2 levels indicate the initiation of apoptosis. These results indicate that LREEs oxide exhibits adequate biological activity, warranting further exploration of its mechanisms and potential biomedical applications. The investigated material was evaluated as a mixed light rare earth oxide system to obtain an integrated biological response profile rather than to determine the contribution of individual oxide components. Therefore, the present findings represent system-level biological behaviour and serve as a foundation for more detailed component-specific investigations. The investigated material was evaluated as a mixed light rare earth oxide system to obtain an integrated biological response profile rather than to determine the contribution of individual oxide components. Therefore, the present findings represent system-level biological behaviour and serve as a foundation for more detailed component-specific investigations.
Etoposide-based protocols remain the first-line therapy for pediatric hemophagocytic lymphohistiocytosis (HLH), yet 20-30% of patients exhibit primary resistance. Early identification of non-responders is critical to enable timely salvage therapy. We aimed to develop and validate a predictive model for etoposide-based protocols resistance using readily available clinical and laboratory parameters. A retrospective cohort of 79 pediatric HLH patients (median age 3.5 years; 53% male) treated with etoposide-based protocols (HLH-94/2004) at Hunan Children's Hospital (2020-2024) was analyzed. Patients were stratified into refractory (n=20) and responsive (n=59) groups based on 8-week treatment outcomes. Chemosensitive patients were defined as those achieving complete response (CR) or entering maintenance by week 8; chemorefractory patients were defined as those who died during induction, required salvage therapy due to progression, or failed to achieve CR within 8 weeks. CR required normalization of all quantifiable disease markers (sCD25, ferritin, triglycerides, ALT, hemoglobin, neutrophils, platelets). Pre-chemotherapy and early post-chemotherapy (Day 3) variables were compared using t-tests, Mann-Whitney U-tests, and χ2 analyses. Multivariable logistic regression and ROC analyses identified predictors of resistance, with internal validation via 1000-bootstrapping. Pre-chemotherapy IL-10 >131.2 μmol/L (OR=5.1; 95% CI 1.9-13.7; P=0.001) and pre-chemotherapy platelet count <55.5×109/L (OR=4.2; 95% CI 1.6-11.3; P=0.004) independently predicted refractoriness. A combined model incorporating these parameters achieved an AUC of 0.822 (sensitivity 81.3%, specificity 75.0%). Post-chemotherapy Day 3 platelet count (OR=1.02 per 109/L increase; P=0.01) and lymphocyte count (OR=2.5 per 109/L increase; P=0.03) further refined prediction (AUC 0.880). Calibration curves and decision curve analysis confirmed clinical utility. Pre-chemotherapy IL-10 and platelet count reliably identify pediatric HLH patients at high risk of etoposide-based protocols resistance. Integration of Day 3 post-chemotherapy parameters enables ultra-early and more precise risk stratification, facilitating prompt transition to salvage therapies.
Copper is a naturally occurring element found in the Earth's crust, soil, water, and air. However, human activities such as smelting, refining, and producing copper-containing products pose a likelihood of occupational inhalation exposure. While copper is an essential element vital to human health, it is also a redox-active metal; thus, exposure beyond tolerable ranges could elicit a toxicological response. Previous occupational exposure limits (OELs) for copper and its compounds have been proposed, but most are based on limited datasets. More recent data available on the health effects of copper inhalation in exposed workforces, the characterization of copper forms in smelters during inhalation exposure, and inhalation effects in rodents have prompted a reevaluation of copper's inhalation toxicity in the context of deriving an up-to-date and more robust OEL. This review examines the toxicological impact of copper inhalation, from its toxicological mode of action to respiratory effects in animal models and humans, in the context of adversity, and identifies relevant points of departure (PoDs) for establishing an OEL. Coupled with data on the rapid clearance of copper from the lung, this information was used in a dosimetric model to quantitatively translate the PoD from the in vivo test model to a human equivalent concentration (HEC) for copper. To address areas of uncertainty and variability, the scientific rationale for chemical-specific versus default assessment factors is discussed.
Luminescent d10 carbene-metal-amide (CMA) complexes are a promising class of thermally activated delayed fluorescence (TADF) organic light-emitting diode (OLED) emitters. However, the principles for modifying ligands to maximize OLED efficiency and operational stability remain unclear. Here, we reveal the key role of metal (n+1)p-nd orbital hybridization and excited-state metal-ligand π-interactions in affecting the excited-state stability and electro-/photoluminescence efficiency of CMA emitters. Using density functional theory (DFT), high-level coupled cluster singles and doubles (CCSD) method, and combined DFT and multireference configuration interaction (DFT/MRCI) calculations, we found that in the excited state, metal atoms and carbazole nitrogen atoms form π-interactions, which is weakened by the weakening of metal (n+1)p-nd orbital hybridization. The weakened metal-nitrogen (M─N) π-interaction is conducive to more flexible rotation of the excited-state dihedral angle, thereby increasing the radiative decay rate (kTADF). This rationalizes the general trend of kTADF for CMA emitters: Ag > Au > Cu. However, the weakening of the excited-state M─N π-interaction reduces the strength of the M─N bond and facilitates bond dissociation in the excited state, thereby impairing the stability of the emitter. Our calculations show that introducing electron-withdrawing or π-extended substituents on carbazole ligands reduces excited-state M─N π-interactions, thereby improving kTADF, but may impair emitter stability and device operational lifetime.
Stress disorders are associated with immunosuppression, potentially reducing the ability to clear human papillomavirus (HPV) infections, leading to an increased risk of HPV-related cancers. We investigated the association between stress disorders and HPV-related cancers in Denmark. Using population-based medical registries, we identified patients with an incident hospital-diagnosed stress disorder between 1 January 1995 and 31 December 2021 (acute stress reaction, posttraumatic stress disorder, adjustment disorder, and other/unspecified reactions to severe stress), matched them by age and sex to individuals without any stress disorder diagnoses in the general population (1:5 ratio), and identified subsequent HPV-related cancer diagnoses (cervical, anal, vulvar, vaginal, penile, base of tongue, tonsillar, oropharyngeal) through 2022. Follow-up began after a 1-year lag period and was censored at first HPV-related cancer, other cancer diagnosis, emigration, death, or end of study. Covariates were measured prior to stress disorder diagnosis or matching date. We used Cox proportional hazards regression to estimate the sex-stratified adjusted hazard ratio (aHR) and 95% confidence interval (CI) of any HPV-related cancer and specific HPV-related cancers, adjusting for potential confounders. During a median follow-up of approximately 10 years, there were 755 cases of HPV-related cancer in the stress disorder cohort (n=242,828) and 2,820 cases in the comparison cohort. Women with diagnosed stress disorders were more likely to develop any HPV-related cancer (aHR=1.3, 95% CI: 1.1-1.4), while men with stress disorders had an elevated rate of anal cancer specifically (aHR=1.7, 95% CI: 1.0-2.9) than their counterparts without stress disorders. The association between stress disorders and HPV-related cancer increased with younger age at stress disorder diagnosis and with longer follow-up time. Our results suggest an association between stress disorders and slightly elevated rates of HPV-related cancer, which strengthens with longer follow-up, underscoring the need to understand biological and behavioral pathways linking stress disorders to increased risk of HPV-related cancer.
Clinicians rely on reference intervals (RIs) to interpret laboratory test results. In pediatric populations, estimating RIs typically requires partitioning data by age, sex, and other relevant factors, which can lead to limited sample size and imprecise estimates; these limitations are addressed by using curve estimation, modeling hemoglobin level as a continuous function of age. To establish hemoglobin reference curves (RCs) for children and to complement recently published World Health Organization (WHO) thresholds by estimating hemoglobin optimal curves (OCs) that may inform more appropriate reporting standards. This cross-sectional study included healthy Canadian children aged 2 weeks through 10 years attending scheduled primary care visits from June 3, 2008, to February 26, 2020, in Toronto, Ontario, Canada. Data were analyzed from October 16, 2024, to February 1, 2026. Blood samples were collected and analyzed for hemoglobin, ferritin, and C-reactive protein levels. Parents completed a questionnaire to collect variables used as optimality criteria. Sex-specific RCs and OCs were estimated using nonparametric quantile regression with restricted cubic splines. RCs were based on the full sample, whereas OCs excluded children with indicators of suboptimal iron status. A web-based platform was developed to visualize these curves and calculate sex-specific reference and optimal limits by age. Findings were examined in relation to WHO hemoglobin thresholds. Blood samples from 4597 children (2451 males [53%]; median age, 38 months [IQR, 18-63 months]) were used to estimate hemoglobin RCs, and samples from a subgroup of 3426 children (1798 males [52%]; median age, 45 months [IQR, 24-68 months]) were used to estimate OCs. For females, lower OC hemoglobin limits were slightly below the lower RC limits up until age 2 years and became higher after age 6 years (eg, at 6 months, the OC lower limit was 9.91 g/dL [90% CI, 9.70-10.13 g/dL] vs 10.00 g/dL [90% CI, 9.78-10.23 g/dL] for RC). For males, lower OC limits were higher than lower RC limits until age 20 months (eg, at 6 months, the OC lower limit was 9.74 g/dL [90% CI, 9.46-10.02 g/dL] vs 9.28 g/dL [90% CI, 8.94-9.63 g/dL] for RC) and were similar afterwards. Differences in the upper limits were minimal for both sexes. WHO hemoglobin thresholds were consistently higher than lower limits of OCs across all ages but exceeded the 5th percentile curve only among children aged 5 through 10 years for both sexes (eg, for males aged 1 year, the OC lower limit was 10.06 g/dL [90% CI, 9.92-10.21 g/dL] vs the 10.5 g/dL WHO threshold). This cross-sectional study estimated sex-specific pediatric RCs for hemoglobin, modeled as a continuous function of age, to eliminate the need for age partitioning and overcome the associated sample size limitations. OCs, developed using health-based criteria, offered additional clinical context beyond traditional RIs. The findings highlight potential misalignments with existing WHO thresholds, particularly at younger ages.
The complement system is a key driver of geographic atrophy (GA), a disease that leads to progressive, irreversible vision loss. Pharmacological preclinical studies characterizing an antibody fragment, which is a novel complement C3 inhibitor under investigation for GA treatment, are presented. Kinetic parameters were determined for the antibody fragment binding to C3, C3b, and C3 variants associated with GA. Inhibition of membrane attack complex (MAC) formation after classical (CP), alternative (AP), and lectin (LP) pathway activation was determined. Comparisons with the second-generation compstatin derivative (APL-1) were made because of the expected similarity of binding behavior and in vitro potency with pegcetacoplan (which could not be sourced at the time of the study). Diffusion through Bruch's membrane (BrM) was investigated for the antibody fragment and a pegcetacoplan-similar (PEG-s) molecule using enriched porcine BrM in Ussing chamber devices. The antibody fragment showed high (picomolar) affinity for all tested C3 ligands. APL-1 showed lower (single-digit nanomolar) affinity than the antibody fragment, comparable with published values. The antibody fragment exhibited dose-dependent inhibition of MAC formation via CP (half-maximal inhibitory concentration [IC50] 79 nM), AP (344 nM), and LP (67 nM), with enhanced potency for inhibiting CP- and LP-mediated complement activation vs. APL-1. More efficient permeation of the BrM was observed with the antibody fragment than with the PEG-s molecule. The antibody fragment is a potent and specific C3 inhibitor that displays dose-dependent inhibition of MAC formation across all three complement pathways and effectively crosses the BrM. In line with these results, the antibody fragment is being investigated in patients with GA. Graphical abstract available for this article. Geographic atrophy is the late stage of age-related macular degeneration. Geographic atrophy is a disease that causes damage to the retina in the eye and can cause loss of vision and reduce a person’s quality of life. There are currently only a few medicines approved to treat geographic atrophy. The development and progression of geographic atrophy is linked to the components of the immune system that are responsible for inflammation and the formation of destructive protein complexes. This preclinical study used laboratory experiments to investigate how a potential new therapy called an antibody fragment affects these immune system components and to see if it is suitable for the treatment for geographic atrophy. The study found that the antibody fragment bound strongly to its target immune components, and it may prevent the formation of destructive protein complexes. The antibody fragment was also able to readily pass through the membrane found in the eye where the immune components need to be targeted. These promising preclinical results support further investigation of the antibody fragment in people with geographic atrophy.
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.
Bismuth subsalicylate is a widely available over-the-counter medication commonly used for gastrointestinal symptoms. Although generally considered safe, prolonged use can result in systemic toxicity, including severe neurological manifestations that are often underrecognized. We report the case of a 77-year-old man with microscopic colitis, lymphocytic subtype, who developed progressive encephalopathy, proximal muscle weakness, tremor, and gait instability after more than two years of daily bismuth subsalicylate use. His clinical course was marked by fluctuating neurological symptoms, multiple hospitalizations, extensive negative diagnostic evaluations, and an initial misdiagnosis of a Parkinsonian disorder. Serum testing ultimately revealed markedly elevated bismuth levels. Discontinuation of bismuth subsalicylate and supportive care resulted in gradual clinical improvement, with normalization of serum bismuth levels and gradual neurological recovery over several months. This case highlights the diagnostic challenges associated with bismuth-induced neurotoxicity and underscores the importance of thorough medication reconciliation, including over-the-counter agents. Increased clinician awareness is critical, as prompt recognition and discontinuation of bismuth-containing products can lead to substantial neurological recovery and prevent unnecessary diagnostic interventions.