Explore the vast range of titles available.

Substantial production and wide applications of engineered nanomaterials (ENMs) have raised concerns over their potential influences on the environment and humans. However, regulations of products containing ENMs are scarce, even in countries with the greatest volume of ENMs produced, such as the United States and China. After a comprehensive review of life cycles of ENMs, five major challenges to regulators posed by ENMs are proposed in this review: (a) ENMs exhibit variable physicochemical characteristics, which makes them difficult for regulators to establish regulatory definition; (b) Due to diverse sources and transport pathways for ENMs, it is difficult to monitor or predict their fates in the environment; (c) There is a lack of reliable techniques for quantifying exposures to ENMs; (d) Because of diverse intrinsic properties of ENMs and dynamic environmental conditions, it is difficult to predict bioavailability of ENMs on wildlife and the environment; and (e) There are knowledge gaps in toxicity and toxic mechanisms of ENMs from which to predict their hazards. These challenges are all related to issues in conventional assessments of risks that regulators rely on. To address the fast-growing nanotechnology market with limited resources, four ENMs (nanoparticles of Ag, TiO 2 , ZnO and Fe 2 O 3 ) have been prioritized for research. Compulsory reporting schemes (registration and labelling) for commercial products containing ENMs should be adopted. Moreover, to accommodate their potential risks in time, an integrative use of quantitative structure-activity relationship and adverse outcome pathway (QSAR-AOP), together with qualitative alternatives to conventional risk assessment are proposed as tools for decision making of regulators.

Background Several disparities in healthcare utilisation and delivery are reported in inflammatory bowel disease (IBD). We examined disparities for delays in biologic administration. Methods This is a tertiary centre, retrospective, cohort study of consecutive adult IBD outpatients referred to the biologics clinic (BC) for initiation of therapy over 2 years. We collected patient-, disease- and service-related data in addition to adverse clinical outcomes (primary non-response, corticosteroid prescription, IBD hospital admission and surgery) within 6 months of the first dose of therapy. The primary outcome was time-to-therapy (TTT): time interval from referral to the first drug dose. Univariate and multivariate regression analyses examined associations between variables and TTT. Results 240 patients started biologics: 87 (36%) ulcerative colitis (UC) and 153 (64%) Crohn’s disease (CD). Median referral age was 43 years (IQR 34–56) and 128 (53%) were male. Charlson Comorbidity Index was ≤ 1 in 185 patients (77%) and 141 (59%) were biologic naïve. 91 (37.9%) were White British, 88 (36.7%) Asian (Indian or Pakistani), 61 (25.4%) were from other ethnic groups. Median TTT was 76 (IQR 56–97) days. In multivariable analysis, longer TTT was associated with CD, other ethnic groups and Adalimumab. Lack of funding at the time of BC and referral age were of borderline statistical significance. Adverse outcomes at 6 months was significantly associated with C-reactive protein level > 10 mg/L (OR 2.13; p  = 0.03) but not with longer TTT. Conclusions Delays in initiating biologic therapy are significantly associated with IBD type, ethnicity and therapy type. Unwarranted variation in IBD care can be mitigated by concerted initiatives to address modifiable factors for timely access to effective therapies. Key messages ∙ What is already known on this topic? Disparities are reported in inflammatory bowel disease (IBD) care. Delays in therapy leads to adverse clinical outcomes. Disparities in administration of biologic therapy affects quality of care. ∙ What does this study add? Sociodemographic characteristics, such as ethnicity, disease and biologic type were significantly associated with delays in initiation of therapy. ∙ How does this study affect research, practice or policy? Specific patient-related factors and patient profiles were identified that may benefit from focused multi-disciplinary input, and service-related factors may be modified to mitigate delays in starting biologic therapy.

Adult Refsum disease (ARD, OMIM #266510) is an autosomal recessive condition, resulting in phytanic acid (PA) accumulation in plasma and tissue. The management of ARD relies on a low PA diet, but the importance of adequate energy and carbohydrate provision in reducing circulating PA levels and preventing metabolic crisis is less well described. Two patients recently diagnosed with ARD initiated on the low PA diet leading to a 65% reduction in circulating PA levels, one case achieving this reduction in 5 months. Four patients already established on the low PA diet for > 10 years experienced a rapid rise in circulating PA levels due to weight loss and/or inadequate carbohydrate intakes, despite adherence to a low PA diet. Circulating PA levels more than doubled in all four of these cases. Implementing dietary interventions to ensure adequate energy, carbohydrates and weight stabilisation resulted in a decrease in circulating PA levels by 47%–84% in the outpatient setting. The reduction in circulating PA occurred within 1.6–5 months. These cases demonstrate that PA restriction, and weight and carbohydrate management have integral roles in ensuring metabolic stability in ARD. This case series highlights that circulating PA levels can be reduced more rapidly with dietary interventions than previously shown in case series of chronic management.

Rationale. Retinoic acids (RAs) are crucial to the development of various animals. However, exposure to excessive concentrations of RAs can lead to teratogenic effects in aquatic species during their developmental stages. Some urbanised coastal marine environments receive a large amount of partially treated wastewater effluent and occasionally suffer from algal bloom incidents, both of which are considered important sources of RAs in the marine environment. Yet information on degradation and transformation of RAs in seawater is currently unavailable for assessment of their environmental risk. This study, therefore, aimed to investigate the degradation and transformation of all-trans-RA (at-RA), which is the most abundant and widely distributed RA in the marine environment. Methodology. A laboratory experiment was conducted to examine the degradation and transformation of at-RA in six different types of seawater (i.e. artificial seawater, unfiltered and filtered natural seawater, each with or without autoclave treatment). Degradation and transformation products of at-RA were analysed using high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Results. The experiment showed that at-RA could be instantly degraded and transformed into other isomers such as 9-cis-RA and 13-cis-RA when entering seawater. Over 80% of at-RA was degraded in the first 48 h regardless of the type of seawater. Discussion. The presence of microorganisms and suspended organic matters could jointly facilitate the degradation and removal of at-RA from the water column. Further investigation is encouraged to reveal the influence of other factors (e.g. temperature, solar radiation, aeration) on the transformation and degradation of at-RA in seawater.

Background: Special low-protein foods are essential in the dietary treatment of phenylketonuria (PKU). In the UK, these are available on prescription through the General Practitioners (GPs) and distributed via nutritional home delivery companies or pharmacies. Methods: A 58-item online non-validated semi-structured questionnaire was emailed to British Inherited Metabolic Disease Group (BIMDG) dietitians and dietetic support workers (DSW)/administrators working in PKU to ascertain the main system issues and errors with the supply of low-protein prescription foods (LPPF). Results: 73% (n = 53/73) of dietitians and 72% (n = 18/25) of DSW/administrators responded. A total of 80 questionnaires (representing 44 paediatric and 36 adult PKU centres) were completed. A total of 50% (n = 40/80) of respondents reported patient/caregiver problems accessing LPPF at least weekly. The most common problems were unavailable products (82%), missing LPPF in deliveries (79%), and delayed deliveries (66%). For 64% of respondents, >25% of their patients had recurring problems accessing LPPF, and 69% of respondents spent ≥1 h/week and 11% >5 h/week correcting LPPF patient supply issues. The most common foods patients experienced supply issues with were bread (96%), pasta/rice (41%) and milk replacements (35%). This was associated with GP prescription errors (65%), LPPF prescriptions sent to incorrect dispensers/suppliers (60%), and manufacturer supply issues (54%). Problems with patients/caregivers included not ordering LPPF in a timely way (81%), not responding to messages from home delivery companies (73%) and poor understanding of the ordering process (70%). The majority (93%) of respondents reported that prescription issues impacted their patients’ blood Phe control. Suggestions for improving access to LPPF included centralisation of the system to one supplier (76%) and apps for ordering LPPF (69%). Conclusions: The supply of LPPF for PKU in the UK is problematic; it may adversely affect the ability of patients to adhere to dietary management, and a review investigating patient access to LPPF is urgently required.

ObjectiveUpadacitinib is the first Janus kinase inhibitor and oral advanced therapy licensed for Crohn’s disease (CD). Following NICE approval in 2023, real-world data on outcomes are limited. The effectiveness and safety of upadacitinib in a cohort of patients with CD was assessed.MethodsA multicentre retrospective cohort analysis across 19 UK hospitals. Adult patients with active CD who started upadacitinib between April 2023 and October 2023 were included. Outcomes were reviewed over 24 weeks. The primary endpoint was clinical remission (Harvey Bradshaw Index (HBI) <4) at 12 and 24 weeks. Biochemical remission (faecal calprotectin <200 μg/g and C-reactive protein ≤5) and endoscopic remission (Simple Endoscopic Score for Crohn’s Disease ≤3) were assessed at the same intervals. Adverse events (AEs) were recorded until 24 weeks or drug withdrawal.Results312 patients were included, with a minimum follow-up of 12 weeks. The cohort had difficult-to-treat disease; 64% failing 3 or more biologics, 51% exhibiting penetrating or stricturing disease and 41% requiring prior resection. 50% (113/227) of patients achieved clinical remission at 12 weeks and 45% (77/172) at 24 weeks. Patients with colonic disease had higher remission rates at 24 weeks compared with other disease locations. At 24 weeks, 51 patients (16%) had discontinued upadacitinib. Treatment persistence was 90.3% at 12 weeks and 84.1% at 24 weeks. 28% had AEs, with 18% experiencing serious AEs and 16.6% requiring hospitalisation.ConclusionThis is a large real-world study reporting outcomes in patients with CD treated with upadacitinib. Our data demonstrated good short-term effectiveness and tolerance in a clinically refractory population.

Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with respect to the potential impact of pathogenic bacteria on host genomic and epigenomic abnormalities remain poorly studied. In this study, the mucosal bacterial community, host genome-wide transcriptome and DNA CpG methylation were simultaneously profiled in tumors and their adjacent normal tissues of OSCC patients. Significant enrichment in the relative abundance of seven bacteria species (Fusobacterium nucleatum, Treponema medium, Peptostreptococcus stomatis, Gemella morbillorum, Catonella morbi, Peptoanaerobacter yurli and Peptococcus simiae) were observed in OSCC tumor microenvironment. These tumor-enriched bacteria formed 254 positive correlations with 206 up-regulated host genes, mainly involving signaling pathways related to cell adhesion, migration and proliferation. Integrative analysis of bacteria-transcriptome and bacteria-methylation correlations identified at least 20 dysregulated host genes with inverted CpG methylation in their promoter regions associated with enrichment of bacterial pathogens, implying a potential of pathogenic bacteria to regulate gene expression, in part, through epigenetic alterations. An in vitro model further confirmed that Fusobacterium nucleatum might contribute to cellular invasion via crosstalk with E-cadherin/β-catenin signaling, TNFα/NF-κB pathway and extracellular matrix remodeling by up-regulating SNAI2 gene, a key transcription factor of epithelial-mesenchymal transition (EMT). Our work using multi-omics approaches explored complex host-microbiota interactions and provided important insights into genetic and functional basis in OSCC tumorigenesis, which may serve as a precursor for hypothesis-driven study to better understand the causational relationship of pathogenic bacteria in this deadly cancer.

Alzheimer’s Disease (AD) is the leading type of dementia worldwide. Despite an increasing burden of disease due to a rapidly ageing population, there is still a lack of complete understanding of the precise pathological mechanisms which drive its progression. Glutamate is the main excitatory neurotransmitter in the brain and plays an essential role in the normal function and excitability of neuronal networks. While previous studies have shown alterations in the function of the glutamatergic system in AD, the underlying etiology of beta amyloid (Aβ1-42) induced changes has not been explored. Here we have investigated the acute effects of stereotaxic hippocampal Aβ1-42 injection on specific glutamatergic receptors and transporters in the mouse hippocampus, using immunohistochemistry and confocal microscopy 3 days after Aβ1-42 injection in aged male C57BL/6 mice before the onset of neuronal cell death. We show that acute injection of Aβ1-42 is sufficient to induce cognitive deficits 3 days post-injection. We also report no significant changes in glutamate receptor subunits GluA1, GluA2, VGluT1, and VGluT2 in response to acute injection of Aβ1-42 when compared with the ACSF-vehicle injected mice. However, we observed increased expression in the DG hilus and ventral stratum (str.) granulosum, CA3 str. radiatum and str. oriens, and CA1 str. radiatum of the GluN1 subunit, and increased expression within the CA3 str. radiatum and decreased expression within the DG str. granulosum of the GluN2A subunit in Aβ1-42 injected mice compared to NC, and a similar trend observed when compared to ACSF injected mice. We also observed alterations in expression patterns of glutamatergic receptor subunits and transporters within specific layers of hippocampal subregions in response to a microinjection stimulus. These findings indicate that the pathological alterations in the glutamatergic system observed in AD are likely to be partially a result of both acute and chronic exposure to Aβ1-42 and implies a much more complex circuit mechanism associated with glutamatergic dysfunction than simply glutamate-mediated excitotoxic neuronal death.

Coronavirus disease 2019 (COVID-19) is increasing worldwide, with complications due to frequent viral mutations, an intricate pathophysiology, and variable host immune responses. Biomarkers with predictive and prognostic value are crucial but lacking. Serum samples from authentic and D614G variant (non-Omicron), and Omicron-SARS-CoV-2 infected patients were collected for METRNβ detection and longitudinal cytokine/chemokine analysis. Correlation analyses were performed to compare the relationships between serum METRNβ levels and cytokines/chemokines, laboratory parameters, and disease severity. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were used to evaluate the predictive value of METRNβ in COVID-19. The serum level of METRNβ was highly elevated in non-Omicron-SARS-CoV-2 infected patients compared to healthy individuals, and the non-survivor displayed higher METRNβ levels than survivors among the critical ones. METRNβ concentration showed positive correlation with viral load in NAPS. ROC curve showed that a baseline METRNβ level of 1886.89 pg/ml distinguished COVID-19 patients from non-infected individuals with an AUC of 0.830. Longitudinal analysis of cytokine/chemokine profiles revealed a positive correlation between METRNβ and pro-inflammatory cytokines such as IL6, and an inverse correlation with soluble CD40L (sCD40L). Higher METRNβ was associated with increased mortality. These findings were validated in a second and third cohort of COVID-19 patients identified in a subsequent wave. Our study uncovered the precise role of METRNβ in predicting the severity of COVID-19, thus providing a scientific basis for further evaluation of the role of METRNβ in triage therapeutic strategies.