Miracle-dz/UniFAR-FTUs huggingface dataset:
Predicting Environmental Risks of Pharmaceuticals from Wholesale Data: An Example from Norway

Environmental risk assessment (ERA) of pharmaceuticals relies on available measured environmental concentrations, but often such data are sparse. Predicted environmental concentrations (PECs), calculated from sales weights, are an attractive alternative but often cover only prescription sales. We aimed to rank, by environmental risk in Norway, approximately 200 active pharmaceutical ingredients (APIs) over 2016–2019, based on sales PECs. To assess the added value of wholesale and veterinary data, we compared exposure and risk predictions with and without these additional sources. Finally, we aimed to characterize the persistence, mobility, and bioaccumulation of these APIs. We compared our PECs to available Norwegian measurements, then, using public predicted‐no‐effect concentrations, we calculated risk quotients (RQs) and appended experimental and predicted persistence and bioaccumulation. Our approach overestimated environmental concentrations compared with measurements for 18 of 20 APIs with comparable predictions and measurements. Seventeen APIs had mean RQs >1, indicating potential risk, while the mean RQ was 2.05 and the median 0.001, driven by sex hormones, antibiotics, the antineoplastic abiraterone, and common painkillers. Some high‐risk APIs were also potentially persistent or bioaccumulative (e.g., levonorgestrel [RQ = 220] and ciprofloxacin [RQ = 56]), raising the possibility of impacts beyond their RQs. Exposure and risk were also calculated with and without over‐the‐counter sales, showing that prescriptions explained 70% of PEC magnitude. Likewise, human sales, compared with veterinary, explained 85%. Sales PECs provide an efficient option for ERA, designed to overestimate compared with analytical techniques and potentially held back by limited data availability and an inability to quantify uncertainty but, nevertheless, an ideal initial approach for identification and ranking of risks. Environ Toxicol Chem 2023;42:2253–2270. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state

Significance Preclinical evaluation of retinal pigment epithelial (RPE) cell–based therapy has largely been dependent on qualitative in vivo ophthalmic imaging techniques and ex vivo histological characterization of transplanted cells. However, these readouts do not provide a comprehensive picture of gene expression changes at single-cell resolution. In this study, we transplanted RPE monolayers in the subretinal space of immunocompetent rabbits and performed single-cell RNA sequencing. We observed unequivocal maturation toward the native adult human RPE state, and identified key regulons activated upon transplantation. These key regulons may confer RPE canonical functions important for retinal homeostasis and promote cell survival in vivo. These findings shed insights into the behavior of RPE after subretinal transplantation, with important implications for cell-based therapy for age-related macular degeneration.
Soluble and insoluble α-glucan synthesis in yeast by enzyme suites derived exclusively from maize endosperm

Abstract Molecular mechanisms that distinguish the synthesis of semi-crystalline α-glucan polymers found in plant starch granules from the synthesis of water-soluble polymers by nonplant species are not well understood. To address this, starch biosynthetic enzymes from maize (Zea mays L.) endosperm were isolated in a reconstituted environment using yeast (Saccharomyces cerevisiae) as a test bed. Ninety strains were constructed containing unique combinations of 11 synthetic transcription units specifying maize starch synthase (SS), starch phosphorylase (PHO), starch branching enzyme (SBE), or isoamylase-type starch debranching enzyme (ISA). Soluble and insoluble branched α-glucans accumulated in varying proportions depending on the enzyme suite, with ISA function stimulating distribution into the insoluble form. Among the SS isoforms, SSIIa, SSIII, and SSIV individually supported the accumulation of glucan polymer. Neither SSI nor SSV alone produced polymers; however, synergistic effects demonstrated that both isoforms can stimulate α-glucan accumulation. PHO did not support α-glucan production by itself, but it had either positive or negative effects on polymer content depending on which SS or a combination thereof was present. The complete suite of maize enzymes generated insoluble particles resembling native starch granules in size, shape, and crystallinity. Ultrastructural analysis revealed a hierarchical assembly starting with subparticles of approximately 50 nm diameter that coalesce into discrete structures of approximately 200 nm diameter. These are assembled into semi-crystalline α-glucan superstructures up to 4 μm in length filling most of the yeast cytosol. ISA was not essential for the formation of such particles, but their abundance was increased dramatically by ISA presence.
Sex differences in the characteristics of stimulant offenders with a history of substance use disorder treatment

We analyzed the results of a nationwide questionnaire administered to 699 stimulant offenders and examined sex differences in the association between various psychosocial problems and treatment history for substance use disorder. Based on their attributes, we predominantly evaluated the treatment and support provided to women with substance use disorder. The rates of childhood (before the age of 18) traumatic experiences (physical, psychological, and sexual abuse and neglect) and lifetime intimate partner violence were significantly higher in women than in men. The history of treatment for substance use disorder was also significantly higher in women than in men, at 15.8% for men and 42.4% for women [χ2(1) = 41.223, p < 0.001]. Logistic regression analysis was performed using the treatment history of substance use disorder as the dependent variable. The results showed that treatment history was significantly associated with the total drug abuse screening test‐20 score and suicidal ideation in men and with survivors of child abuse and eating disorders in women. A comprehensive assessment is required for several issues, such as child abuse, domestic violence, trauma symptoms, eating disorders, and drug problems. Moreover, an integrated treatment for substance use disorder, trauma, and eating disorders is required for female stimulant offenders.
Real-World Evidence of CAR T-cell Therapy in Older Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

The emergence of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for diffuse large B-cell lymphoma (DLBCL), however, real-world evidence reporting outcomes among older patients treated with CAR T-cell therapy is limited. We leveraged the 100% Medicare Fee-for-Service claims database and analyzed outcomes and cost associated with CAR T-cell therapy in 551 older patients (age ≥65) with DLBCL who received CAR T-cell therapy between 2018 and 2020. CAR T-cell therapy was used in third line and beyond in 19% of patients age 65-69, 22% among those age 70-74, compared to 13% of patients age ≥75. The majority of patients received CAR T-cell therapy in an inpatient setting (83%), with an average length of stay of 21 days. The median event-free survival (EFS) following CAR T-cell therapy was 7.2 months. Patients age ≥75 had significantly shorter EFS compared to patients age 65-69 and age 70-74 with 12-month EFS estimates of 34%, 43% and 52%, respectively (p = 0.002). The median overall survival was 17.1 months and there was no significant difference by age groups. The median total healthcare cost during the 90-day follow-up was $352,572 and was similar across all age groups. CAR T-cell therapy was associated with favorable effectiveness, but the CAR T-cell therapy use in older patients was very low especially in patients age ≥75 and this age group had a lower rate of EFS which illustrates the unmet need for more accessible, effective, and tolerable therapy in older patients, especially in patients age ≥75.
Subluxation of the first carpometacarpal joint and age are important factors in reduced hand strength in patients with hand osteoarthritis

Objective To investigate the determinants of hand strength in patients with hand osteoarthritis (OA). Method Pinch and cylinder grip strength were measured in 527 patients with hand OA diagnosed by their treating rheumatologist from the Hand OSTeoArthritis in Secondary care (HOSTAS) study. Radiographs of hands (22 joints) were scored 0–3 (scaphotrapeziotrapezoid and first interphalangeal joints 0–1) on osteophytes and joint space narrowing following the Osteoarthritis Research Society International atlas. The first carpometacarpal joint (CMC1) was scored 0–1 for subluxation. Pain was assessed with the Australian/Canadian Hand Osteoarthritis Index pain subscale, and health-related quality of life with the Short Form-36. Regression analysis served to investigate associations of hand strength with patient, disease, and radiographic features. Results Hand strength was negatively associated with female sex, age, and pain. Reduced hand strength was associated with reduced quality of life, although less after adjusting for pain. Radiographic features of hand OA were associated with reduced grip strength when solely adjusted for sex and body mass index, but only CMC1 subluxation in the dominant hand remained significantly associated with pinch grip adjusted additionally for age (−0.511 kg, 95% confidence interval −0.975; −0.046). Mediation analysis showed low and not significant percentages of mediation of hand OA in the association between age and grip strength. Conclusions Subluxation of CMC1 is associated with reduced grip strength, whereas associations with other radiographic features seem to be confounded by age. In the relationship between age and hand strength, radiographic hand OA severity is not an important mediator.
Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis

Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker.
CONSTRAINED AVERAGE COST MARKOV CONTROL PROCESSES IN BOREL SPACES

This paper considers constrained Markov control processes in Borel spaces, with un- bounded costs. The criterion to be minimized is a long-run expected average cost, and the constraints canbe imposed onsimilar average costs, or onaverage rewards ,o rdiscounted costs or rewards. We give conditions under which the constrained problem (CP) is solvable and equivalent to an equality constrained (EC) linear program. Furthermore, we show that there is no duality gap between EC and the dual program EC* and that in fact the strong duality condition holds. Finally, we introduce anexplicit procedure to solve CP insome cases which is illustrated with a detailed example.
Secreted phosphoprotein 1 regulates natural compound 3’,4’,5,7-tetrahydroxyflavone to inhibit mast cell-mediated allergic inflammation

Abstract Background Mast cells (MCs) are important effector cells in anaphylaxis and anaphylactic disease. 3’,4’,5,7-tetrahydroxyflavone (THF) presents in many medicinal plants and exerts a variety of pharmacological effects. In this study, we evaluated the effect of THF on C48/80-induced anaphylaxis and the mechanisms underlying its effects, including the role of secreted phosphoprotein 1 (SPP1), which has not been reported to IgE-independent MC activation. Results THF inhibited C48/80-induced Ca2+ flow and degranulation via the PLCγ/PKC/IP3 pathway in vitro. RNA-seq showed that THF inhibited the expression of SPP1 and downstream molecules. SPP1 is involved in pseudo-anaphylaxis reactions. Silencing SPP1 affects the phosphorylation of AKT and P38. THF suppressed C48/80-induced paw edema, hypothermia and serum histamine, and chemokines release in vivo. Conclusions Our results validated SPP1 is involved in IgE-independent MC activation anaphylactoid reactions. THF inhibited C48/80-mediated anaphylactoid reactions both in vivo and in vitro, suppressed calcium mobilization and inhibited SPP1-related pathways.
An exploratory analysis examining differences in physical activity and motor competence in children with and without asthma: brief report

Abstract Objective The purpose of this pilot study was to examine potential differences in motor competence (MC) and physical activity (PA) between children with and without asthma. Methods Thirty-seven children and adolescents completed the Exercises for a Healthy Asthma Lifestyle and Enjoyment study (46% with asthma, 51% female, 11.1 ± 0.4 years, and 46% White). Motor competence was assessed using the Movement Assessment Battery for Children 2nd edition (MABC-2). PA was assessed using accelerometry. Results Children with asthma had significantly lower MC in the domain of aiming and catching (with asthma: 8.2 ± 0.4 vs. without asthma: 9.9 ± 0.5; p = 0.03) and fewer daily minutes spent in moderate-to-vigorous PA (MVPA) (with asthma: 18.0 ± 2.3 min vs. without asthma: 27.2 ± 3.6 min; p = 0.047). There were no significant group differences in manual dexterity, balance, total MABC-2 score, or total daily PA (all ps > 0.05). Conclusions This study provides confirmatory evidence that children with asthma display lower MC and spend less time in MVPA compared to children without asthma. Because MC is a prerequisite for engaging in PA, future research should seek to determine if the differences observed in MC contribute to disparities in MVPA observed in this clinical population.
TEN-YEAR VISUAL OUTCOME AND CHANGE IN CHORIORETINAL ATROPHY AFTER INTRAVITREAL RANIBIZUMAB FOR MACULAR NEOVASCULARIZATION IN PATHOLOGIC MYOPIA

Best-corrected visual acuity in eyes with myopic macular neovascularization in pathologic myopia was maintained for 10 years after a single intravitreal ranibizumab injection followed by a pro re nata regimen without any drug-induced complications. Purpose: To investigate the 10-year visual outcome and chorioretinal atrophy after a single intravitreal ranibizumab injection followed by a pro re nata regimen for myopic macular neovascularization in pathologic myopia, and to identify the factors associated with 10-year best-corrected visual acuity (BCVA). Methods: This retrospective observational study evaluated 26 consecutive treatment-naïve eyes (26 patients) with myopic macular neovascularization in pathologic myopia who underwent a single intravitreal ranibizumab followed by a pro re nata regimen of intravitreal ranibizumab and/or intravitreal aflibercept injection and observed over 10 years. We assessed changes in BCVA and morphological parameters, including the META-PM Study category as a chorioretinal atrophy index. Results: The logarithm of the minimum angle of resolution BCVA changed from 0.36 (Snellen, 20/45) ± 0.39 to 0.39 (20/49) ± 0.36 over 10 years of observation. Compared to baseline, 1-year BCVA improved (P = 0.002), whereas 2 to 10-year BCVA was not significantly different. Total injection frequency was 3.8 ± 2.6. In none of the eyes, 10-year BCVA was 20/200 or less. Ten-year BCVA correlated with baseline BCVA (P = 0.01, r = 0.47). The META-PM Study category progressed in 60% of eyes. There were no drug-induced complications. Conclusion: Best-corrected visual acuity in eyes with myopic macular neovascularization in pathologic myopia was maintained for 10 years after a single intravitreal ranibizumab followed by a pro re nata regimen without drug-induced complications. The META-PM Study category progressed in 60% of eyes, especially those with older baseline age. Early diagnosis and treatment of myopic macular neovascularization are essential to maintain good long-term BCVA.
Retrieval of Ice Cloud Parameters Using the Advanced Microwave Sounding Unit

Abstract An algorithm is developed to derive cloud ice water path (IWP) and ice particle effective diameters De from the advanced microwave sounding unit (AMSU) measurements. In the algorithm, both IWP and De are related to the ice particle scattering parameters, which are determined from the AMSU 89- and 150-GHz measurements. The ratio of the scattering parameters measured at two frequencies provides a direct estimate of De. IWP is then derived from the scattering parameter at 150 GHz with the derived De and the constant bulk volume density. A screening procedure is developed to discriminate the scattering signatures between atmospheric clouds and surface materials. The major error sources affecting the retrievals are identified. The errors of retrieved effective diameter are primarily controlled by the errors in estimating cloud-base brightness temperatures at 89 and 150 GHz and the errors of the bulk volume density. It is shown that De possibly contains an error of 5%–20%. For the retrieval of cloud ic.
Lingering Effects of Legacy Industrial Pollution on Yellow Perch of the Detroit River

We used yellow perch (Perca flavescens) captured at four sites differing in legacy industrial pollution in the Lake St. Clair–Detroit River system to evaluate the lingering sublethal effects of industrial pollution. We emphasized bioindicators of direct (toxicity) and indirect (chronic stress, impoverished food web) effects on somatic and organ‐specific growth (brain, gut, liver, heart ventricle, gonad). Our results show that higher sediment levels of industrial contaminants at the most downstream Detroit River site (Trenton Channel) are associated with increased perch liver detoxification activity and liver size, reduced brain size, and reduced scale cortisol content. Trenton Channel also displayed food web disruption, where adult perch occupied lower trophic positions than forage fish. Somatic growth and relative gut size were lower in perch sampled at the reference site in Lake St. Clair (Mitchell's Bay), possibly because of increased competition for resources. Models used to determine the factors contributing to site differences in organ growth suggest that the lingering effects of industrial pollution are best explained by trophic disruption. Thus, bioindicators of fish trophic ecology may prove advantageous to assess the health of aquatic ecosystems. Environ Toxicol Chem 2023;42:2158–2170. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
A novel strategy for the study on molecular mechanism of prostate injury induced by 4,4′‐sulfonyldiphenol based on network toxicology analysis

The study aimed to investigate the underlying molecular mechanisms of prostate injury induced by 4,4′‐sulfonyldiphenol (BPS) exposure and propose a novel research strategy to systematically explore the molecular mechanisms of toxicant‐induced adverse health effects. By utilizing the ChEMBL, STITCH, and GeneCards databases, a total of 208 potential targets associated with BPS exposure and prostate injury were identified. Through screening the potential target network in the STRING database and Cytoscape software, we determined 21 core targets including AKT1, EGFR, and MAPK3. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses conducted through the DAVID database illustrated that the potential targets of BPS in prostatic toxicity were primarily enriched in cancer signaling pathways and calcium signaling pathways. These findings suggest that BPS may actively participate in the occurrence and development of prostate inflammation, prostatic hyperplasia, prostate cancer, and other aspects of prostate injury by regulating prostate cancer cell apoptosis and proliferation, activating inflammatory signaling pathways, and modulating prostate adipocytes and fibroblasts. This research provides a theoretical basis for understanding the molecular mechanism of underlying BPS‐induced prostatic toxicity and establishes a foundation for the prevention and treatment of prostatic diseases associated with exposure to plastic products containing BPS and certain BPS‐overwhelmed environments.
Nodding syndrome, a case-control study in Mahenge, Tanzania: Onchocerca volvulus and not Mansonella perstans as a risk factor

Background Nodding syndrome (NS) has been consistently associated with onchocerciasis. Nevertheless, a positive association between NS and a Mansonella perstans infection was found in South Sudan. We aimed to determine whether the latter parasite could be a risk factor for NS in Mahenge. Methods Cases of epilepsy were identified in villages affected by NS in Mahenge, Tanzania, and matched with controls without epilepsy of the same sex, age and village. We examined blood films of cases and controls to identify M. perstans infections. The participants were also asked for sociodemographic and epilepsy information, examined for palpable onchocercal nodules and onchocerciasis-related skin lesions and tested for anti-Onchocerca volvulus antibodies (Ov16 IgG4) by ELISA. Clinical characteristics of cases and controls, O. volvulus exposure status and relevant sociodemographic variables were assessed by a conditional logistic regression model for NS and epilepsy status matched for age, sex and village. Results A total of 113 epilepsy cases and 132 controls were enrolled, of which, respectively, 56 (49.6%) and 64 (48.5%) were men. The median age in cases and controls was 28.0 (IQR: 22.0–35.0) and 27.0 (IQR: 21.0–33.3) years. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria and 106 (93.8%) had onchocerciasis-associated epilepsy (OAE). M. perstans infection was absent in all participants, while Ov16 seroprevalence was positively associated with probable NS (odds ratio (OR): 5.05, 95%CI: 1.79–14.27) and overall epilepsy (OR: 2.03, 95%CI: 1–07–3.86). Moreover, onchocerciasis-related skin manifestations were only found in the cases (n = 7, p = 0.0040), including persons with probable NS (n = 4, p = 0.0033). Residing longer in the village and having a family history of seizures were positively correlated with Ov16 status and made persons at higher odds for epilepsy, including probable NS. Conclusion In contrast to O. volvulus, M. perstans is most likely not endemic to Mahenge and, therefore, cannot be a co-factor for NS in the area. Hence, this filaria is unlikely to be the primary and sole causal factor in the development of NS. The main risk factor for NS remains onchocerciasis.