Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts.

Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

Hardwiring tissue-specific AAV transduction in mice through engineered receptor expression.

The development of transgenic mouse models that express genes of interest in specific cell types has transformed our understanding of basic biology and disease. However, generating these models is time- and resource-intensive. Here we describe a model system, SELective Expression and Controlled Transduction In Vivo (SELECTIV), that enables efficient and specific expression of transgenes by coupling adeno-associated virus (AAV) vectors with Cre-inducible overexpression of the multi-serotype AAV receptor, AAVR. We demonstrate that transgenic AAVR overexpression greatly increases the efficiency of transduction of many diverse cell types, including muscle stem cells, which are normally refractory to AAV transduction. Superior specificity is achieved by combining Cre-mediated AAVR overexpression with whole-body knockout of endogenous Aavr, which is demonstrated in heart cardiomyocytes, liver hepatocytes and cholinergic neurons. The enhanced efficacy and exquisite specificity of SELECTIV has broad utility in development of new mouse model systems and expands the use of AAV for gene delivery in vivo.

KLF transcription factors in bone diseases.

Krüppel-like factors (KLFs) are crucial in the development of bone disease. They are a family of zinc finger transcription factors that are unusual in containing three highly conserved zinc finger structural domains interacting with DNA. It has been discovered that it engages in various cell functions, including proliferation, apoptosis, autophagy, stemness, invasion and migration, and is crucial for the development of human tissues. In recent years, the role of KLFs in bone physiology and pathology has received adequate attention. In addition to regulating the normal growth and development of the musculoskeletal system, KLFs participate in the pathological process of the bones and joints and are intimately linked to several skeletal illnesses, such as osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP) and osteosarcoma (OS). Consequently, targeting KLFs has emerged as a promising therapeutic approach for an array of bone disorders. In this review, we summarize the current literature on the importance of KLFs in the emergence and regulation of bone illnesses, with a particular emphasis on the pertinent mechanisms by which KLFs regulate skeletal diseases. We also discuss the need for KLFs-based medication-targeted treatment. These endeavours offer new perspectives on the use of KLFs in bone disorders and provide prognostic biomarkers, therapeutic targets and possible drug candidates for bone diseases.

Label-Free and Real-Time Optical Detection of Affinity Binding of the Antibody on Adherent Live Cells.

Oblique-incidence reflectivity difference (OIRD) is a novel real-time, label-free, and nondestructive optical detection method and exhibits encouraging application in the detection of antibody/DNA microarrays. In this study, for the first time, an OIRD label-free immunoassay was achieved by using adherent live cells as the probe. The cells were cultured on glass cells, and the affinity binding of antibodies targeted on the HLA class I antigen of the cell surface was detected with an OIRD. The results show that an OIRD is able to detect the binding process of anti-human HLA-A, B, and C antibodies on MDA-MB-231 cells and HUVEC cells. Control experiments and complementary fluorescence analysis confirmed the high detection specificity and good quantitative virtue of the OIRD label-free immunoassay. Label-free OIRD imaging analysis of cell microarrays was further demonstrated successfully, and the underlying optical mechanism was revealed by combining the theoretical modeling. This work explores the use of live cells as probes for an OIRD immunoassay, thus expanding the potential applications of the OIRD in the field of pathological analysis, disease diagnosis, and drug screening, among others.

Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives.

The anteroposterior axial identity of motor neurons (MNs) determines their functionality and vulnerability to neurodegeneration. Thus, it is a crucial parameter in the design of strategies aiming to produce MNs from human pluripotent stem cells (hPSCs) for regenerative medicine/disease modelling applications. However, the in vitro generation of posterior MNs corresponding to the thoracic/lumbosacral spinal cord has been challenging. Although the induction of cells resembling neuromesodermal progenitors (NMPs), the bona fide precursors of the spinal cord, offers a promising solution, the progressive specification of posterior MNs from these cells is not well defined. Here, we determine the signals guiding the transition of human NMP-like cells toward thoracic ventral spinal cord neurectoderm. We show that combined WNT-FGF activities drive a posterior dorsal pre-/early neural state, whereas suppression of TGFß-BMP signalling pathways promotes a ventral identity and neural commitment. Based on these results, we define an optimised protocol for the generation of thoracic MNs that can efficiently integrate within the neural tube of chick embryos. We expect that our findings will facilitate the comparison of hPSC-derived spinal cord cells of distinct axial identities.

Compartmentalized ciliation changes of oligodendrocytes in aged mouse optic nerve.

Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1+ /Olig2+ oligodendrocytes in aged mice compared with young mice. Thus, the prevalence of primary cilia in oligodendrocytes in the visual pathway and the age-related changes in ciliation suggest that they may play important roles in white matter and age-associated optic neuropathies.

Sex differences in 3- to 5-year-old children's motor competence: A pooled cross-sectional analysis of 6241 children.

There is some, albeit inconsistent, evidence supporting sex differences in preschoolers' motor competence (MC), with these observations not uniform when analyzed by age, and cultural groups. Thus, this study examined sex differences across ages in 3- to 5-year-old children's MC. A cross-country pooled sample of 6241 children aged 3-5 years (49.6% girls) was assessed for MC using the Test of Gross Motor Development-2nd/3rd edition, and children were categorized into groups of age in months. Multiple linear regression models and predictive margins were calculated to explore how sex and age in months affect scores of MC (i.e., locomotor and ball skills), with adjustments for country and BMI. The Chow's Test was used to test for the presence of a structural break in the data. Significant differences in favor of girls were seen at 57-59 and 66-68 months of age for locomotor skills; boys performed better in ball skills in all age periods, except for 42-44 and 45-47 months of age. The higher marginal effects were observed for the period between 45-47 and 48-50 months for locomotor skills (F = 30.21; and F = 25.90 for girls and boys, respectively), and ball skills (F = 19.01; and F = 42.11 for girls and boys, respectively). A significantly positive break point was seen at 45-47 months, highlighting the age interval where children's MC drastically improved. The identification of this breakpoint provides an evidence-based metric for when we might expect MC to rapidly increase, and an indicator of early delay when change does not occur at that age.

Sirt1 Protects Subventricular Zone-Derived Neural Stem Cells from DNA Double-Strand Breaks and Contributes to Olfactory Function Maintenance in Aging Mice.

DNA damage is assumed to accumulate in stem cells over time and their ability to withstand this damage and maintain tissue homeostasis is the key determinant of aging. Nonetheless, relatively few studies have investigated whether DNA damage does indeed accumulate in stem cells and whether this contributes to stem cell aging and functional decline. Here, we found that, compared with young mice, DNA double-strand breaks (DSBs) are reduced in the subventricular zone (SVZ)-derived neural stem cells (NSCs) of aged mice, which was achieved partly through the adaptive upregulation of Sirt1 expression and non-homologous end joining (NHEJ)-mediated DNA repair. Sirt1 deficiency abolished this effect, leading to stem cell exhaustion, olfactory memory decline, and accelerated aging. The reduced DSBs and the upregulation of Sirt1 expression in SVZ-derived NSCs with age may represent a compensatory mechanism that evolved to protect stem cells from excessive DNA damage, as well as mitigate memory loss and other stresses during aging.

Regulation and therapy, the role of JAK2/STAT3 signaling pathway in OA: a systematic review.

Osteoarthritis (OA) is a multifactorial chronic disease primarily characterized by the degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA other than surgery. The exploration of the mechanisms of occurrence is important in exploring other new and effective treatments for OA. The current evidence shows that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a vital role in cytogenesis and is involved in OA progression. The terms "JAK2", "STAT3", and "Osteoarthritis"were used in a comprehensive literature search in PubMed to further investigate the relationship between the JAK2/STAT3 signaling pathway and OA. This review focuses on the role and mechanism of JAK2/STAT3 signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation. In addition, this review summarizes recent evidence of therapeutic approaches to treat OA by targeting the JAK2/STAT3 pathway to accelerate the translation of evidence into the progression of strategies for OA treatment. Video abstract.

Hsa_circ_0007380 silencing restrains the growth and enhances radiosensitivity in esophagus cancer by miR-644a/Spindlin 1 axis.

Circular RNAs are frequently dysregulated and show important regulatory function of tumorigenesis in cancers. Hsa_circ_0007380 was found to be elevated in human radioresistant esophageal cancer cells. Here, this study aimed to investigate the action and mechanism of hsa_circ_0007380 in esophageal cancer carcinogenesis and radiosensitivity. Quantitative real-time PCR and western blotting were performed to detect levels of genes and proteins. Functional experiments were conducted using MTT assay, EdU assay, clonogenic survival assay, flow cytometry and murine xenograft model assay, respectively. The binding between miR-644a and hsa_circ_0007380 or spindlin1 (SPIN1) was validated using dual-luciferase activity assay. Hsa_circ_0007380 was highly expressed in esophagus cancer tissues and cells, knockdown of hsa_circ_0007380 suppressed esophagus cancer cell proliferation, induced apoptosis and enhanced radiosensitivity in vitro, and the same effects were also confirmed in nude mice. Mechanistically, hsa_circ_0007380 sequestered miR-644a to release SPIN1 expression, implying the hsa_circ_0007380/miR-644a/SPIN1 competing endogenous RNA network esophagus cancer cells. miR-644a was decreased in esophagus cancer, re-expression of miR-644a restrained cell growth and conferred radiosensitivity in esophagus cancer, which were reversed by SPIN1 overexpression. Besides that, inhibition of miR-644a abolished the promoting action of hsa_circ_0007380 knockdown on esophagus cancer apoptosis and radiosensitivity. Hsa_circ_0007380 silencing impedes cell growth and reinforces radiosensitivity in esophagus cancer by miR-644a/SPIN1 axis, suggesting a promising therapeutic target for esophagus cancer combined treatment.

Withdrawn: 'Downregulation of circPPFIA1 elevates radiosensitivity via miR-1299-mediated TXNRD1 inhibition in oesophageal squamous cell carcinoma', Weihui Yu, Ke Ning, Jincheng Xiao, Qiwen Bai and Chenyang Guo. (https://onlinelibrary.wiley.com/doi/10.1111/1440-1681.13751).

The above article, published online on 16 February 2023 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the journal Editor in Chief, Yang Yang, and John Wiley & Sons Ltd. The withdrawal has been agreed following no response from the authors to requests to sign the journal's publishing license agreement.

Study on the use and effectiveness of malaria preventive measures reported by employees of chinese construction companies in Western Africa in 2021.

BACKGROUND: As malaria continues to be a significant global public health concern, especially in Sub-Saharan Africa, Chinese workers in Africa are at increased risk of malaria. The effectiveness of malaria prevention measures implemented by Chinese companies and workers is a question that may correlate with the malaria infection rate in this population. This study explored the use and effectiveness of malaria prevention measures for Chinese employees in West Africa to provide a reference for companies and individuals on improving malaria prevention and control. METHODS: Using a cross-sectional approach, we surveyed 256 participants in 2021, mainly from Nigeria, Mali, Côte d'Ivoire, Ghana, Guinea, Sierra Leone, and Senegal in West Africa. The survey duration is from July to the end of September 2021. We selected two companies from the 2020 ENR "World's Largest 250 International Contractors" list, which featured 6 Chinese companies, all of which are state-owned and have a 61.9% market share in Africa. The participants were Chinese workers with more than a year of work experience in construction companies in Africa. A 20-minute WeChat-based structured online questionnaire was used to obtain information on malaria infection status and malaria prevention measures. Descriptive statistical analysis, chi-square test, principal components analysis, and ordinal logistic regression analysis are used to analyze the data obtained. The difference in Statistical significance was set at P < 0.05. RESULTS: Ninety six (37.5%) participants contracted malaria more than once within a year. The principal components analysis found a low correlation between public and individual preventive measures. No significant correlation was found between public preventive measures and malaria infection (p > 0.05), while standardized use of mosquito nets (P = 0.016) and pesticide spraying (P = 0.047) contributed significantly to fewer malaria infections at the individual level, but the removal of vegetation around houses (P = 0.028) at the individual level related to higher malaria infection. CONCLUSIONS: In our sample of Chinese construction workers going to Africa, some individual preventive measures had a stronger association with malaria prevention than a variety of public environmental measures. Furthermore, individual and public preventive measures were not associated with each other. Both of these findings are surprising and require further investigation in larger and more diverse samples. This- study provides important clues about the challenges that risk reduction programs face for migrant workers from China and elsewhere.

Association of liver function with health-related physical fitness: a cross-sectional study.

BACKGROUND: In this study, by analyzing the correlation between various components of health-related physical fitness (HPF) and liver function indicators, the indicators of physical fitness that were highly correlated with liver function and could be monitored at home were screened to prevent more serious liver disease in the future, and to provide experimental basis for prescribing personalized exercise. METHODS: A total of 330 faculties (female = 198) of a university were recruited. The indicators of HPF and liver function were measured. Spearman correlation analysis, multivariate linear regression, and cross-lagged panel model was used to data statistics. RESULTS: In males, body fat (BF) was positively correlated with alanine aminotransferase (ALT); vital capacity and the vital capacity index were positively correlated with albumin; and vertical jump was positively correlated with globulin and negatively correlated with the albumin-globulin ratio (P < 0.05). However, there was no significant correlation among all indicators controlled confounding factors. In females, BF was negatively correlated with direct bilirubin; VO2max was positively correlated with indirect bilirubin; and vertical jump was positively correlated with the albumin-globulin ratio and significantly negatively correlated with globulin (P < 0.05). Controlled confounding factors, body fat percentage was positively correlated with globulin (ß = 0.174) and negatively correlated with direct bilirubin (ß = -0.431), and VO2max was positively correlated with indirect bilirubin (ß = 0.238, P < 0.05). Cross-lagged panel analysis showed that BF percentage can negatively predict direct bilirubin levels with great significance (ß = -0.055, P < 0.05). CONCLUSIONS: HPF may play a crucial role in liver function screening, particularly for female faculty members. For males, BF, vertical jump, vital capacity and vital capacity index could be associated with liver function but are susceptible to complex factors such as age, smoking, diabetes, and hypertension. In females, BF percentage is an important predictor of abnormal liver function in addition to VO2max and vertical jump, which are not affected by complex factors.

Uptake of an App-Based Case Management Service for HIV-Positive Men Who Have Sex With Men in China: Process Evaluation Study.

BACKGROUND: Men who have sex with men (MSM) in China are disproportionately affected by the HIV epidemic, and medication adherence to antiretroviral treatment in this vulnerable population is suboptimal. To address this issue, we developed an app-based case management service with multiple components, informed by the Information Motivation Behavioral skills model. OBJECTIVE: We aimed to conduct a process evaluation for the implementation of an innovative app-based intervention guided by the Linnan and Steckler framework. METHODS: Process evaluation was performed alongside a randomized controlled trial in the largest HIV clinic in Guangzhou, China. Eligible participants were HIV-positive MSM aged ≥18 years planning to initiate treatment on the day of recruitment. The app-based intervention had 4 components: web-based communication with case managers, educational articles, supportive service information (eg, information on mental health care and rehabilitation service), and hospital visit reminders. Process evaluation indicators of the intervention include dose delivered, dose received, fidelity, and satisfaction. The behavioral outcome was adherence to antiretroviral treatment at month 1, and Information Motivation Behavioral skills model scores were the intermediate outcome. Logistic and linear regression was used to investigate the association between intervention uptake and outcomes, controlling for potential confounders. RESULTS: A total of 344 MSM were recruited from March 19, 2019, to January 13, 2020, and 172 were randomized to the intervention group. At month 1 follow-up, there was no significant difference in the proportion of adherent participants between the intervention and control groups (66/144, 45.8% vs 57/134, 42.5%; P=.28). In the intervention group, 120 participants engaged in web-based communication with case managers and 158 accessed at least 1 of the delivered articles. The primary concern captured in the web-based conversation was the side effects of the medication (114/374, 30.5%), which was also one of the most popular educational articles topics. The majority (124/144, 86.1%) of participants that completed the month 1 survey rated the intervention as "very helpful" or "helpful." The number of educational articles accessed was associated with adequate adherence in the intervention group (odds ratio 1.08, 95% CI 1.02-1.15; P=.009). The intervention also improved the motivation score after adjusting for baseline values (ß=2.34, 95% CI 0.77-3.91; P=.004). However, the number of web-based conversations, regardless of conversation features, was associated with lower motivation scores in the intervention group. CONCLUSIONS: The intervention was well-received. Delivering educational resources of interest may enhance medication adherence. The uptake of the web-based communication component could serve as an indicator of real-life difficulties and could be used by case managers to identify potential inadequate adherence. TRIAL REGISTRATION: Clinicaltrial.gov NCT03860116; https://clinicaltrials.gov/ct2/show/NCT03860116. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12889-020-8171-5.

Mediating mechanisms of the relationship between exposure to deprivation and threat during childhood and adolescent psychopathology: evidence from the Millennium Cohort Study.

The key aim of our study was to examine pathways from exposure to childhood adversities (i.e., deprivation and threat) to adolescent psychopathology. The assessed mediating mechanisms included cognitive ability and emotion regulation, as proposed by the Dimensional Model of Adversity and Psychopathology (DMAP). The study comprised participants from the nationally representative Millennium Cohort Study. Latent scores for deprivation and threat were derived using confirmatory factor analysis from indicators collected when participants were at age of 9 months, 3 and 5 years. Cognitive ability was measured using the Verbal Similarities subscale of the British Ability Scales II at age 11, and emotion regulation was measured using emotion dysregulation subscale of the Child Social Behavioural Questionnaire at age 7. Psychopathology, defined as psychological distress, was assessed using the Kessler 6 scale at age 17. We conducted causal mediation analysis adjusting for multiple confounding factors. We did not find total effect of either exposure to deprivation or threat on psychological distress, but we did find significant indirect effects of exposure to deprivation on psychological distress via cognitive ability (- 0.11, 95% CI - 0.20 to - 0.05) and emotion regulation (0.03, 0.02 to 0.12), and exposure to threat on psychological distress via cognitive ability (- 0.04, - 0.07 to - 0.01) and emotion regulation (0.09, 0.03 to 0.15). The lack of associations between deprivation or threat and psychological distress may be due to reporting bias or developmental period of psychopathology. Results of mediation analysis partially support the DMAP but indicate limited benefits to reduce adolescent psychological distress by targeting cognitive ability or emotion regulation to those exposed to childhood adversities.

Recapitulating the Drifting and Fusion of Two-Generation Spheroids on Concave Agarose Microwells.

Cells with various structures and proteins naturally come together to cooperate in vivo. This study used cell spheroids cultured in agarose micro-wells as a 3D model to study the movement of cells or spheroids toward other spheroids. The formation dynamics of tumor spheroids and the interactions of two batches of cells in the agarose micro-wells were studied. The results showed that a concave bottom micro-well (diameter: 2 mm, depth: 2 mm) prepared from 3% agarose could be used to study the interaction of two batches of cells. The initial tumor cell numbers from 5 × 103 cells/well to 6 × 104 cells/well all could form 3D spheroids after 3 days of incubation. Adding the second batch of DU 145 cells to the existing DU 145 spheroid resulted in the formation of satellite cell spheroids around the existing parental tumor spheroid. Complete fusion of two generation cell spheroids was observed when the parental spheroids were formed from 1 × 104 and 2 × 104 cells, and the second batch of cells was 5 × 103 per well. A higher amount of the second batch of cells (1 × 104 cell/well) led to the formation of independent satellite spheroids after 48 h of co-culture, suggesting the behavior of the second batch of cells towards existing parental spheroids depended on various factors, such as the volume of the parental spheroids and the number of the second batch cells. The interactions between the tumor spheroids and Human Umbilical Vein Endothelial Cells (HUVECs) were modeled on concave agarose micro-wells. The HUVECs (3 × 103 cell/well) were observed to gather around the parental tumor spheroids formed from 1 × 104, 2 × 104, and 3 × 104 cells per well rather than aggregate on their own to form HUVEC spheroids. This study highlights the importance of analyzing the biological properties of cells before designing experimental procedures for the sequential fusion of cell spheroids. The study further emphasizes the significant roles that cell density and the volume of the spheroids play in determining the location and movement of cells.

Comprehensive Analysis of Cellular Senescence-Related Genes in Prognosis, Molecular Characterization and Immunotherapy of Hepatocellular Carcinoma.

BACKGROUND: Cellular senescence is a tumor suppressive response in which the cell cycle is in a state of permanent arrest and can inhibit tumor cell proliferation. In recent years, induction of cellular senescence has been shown to be important for antitumor therapy, and the link between cellular senescence and clinical prognosis and immunotherapy of hepatocellular carcinoma is still unknown. METHODS: We performed enrichment analysis of genes in three cellular senescence gene sets, screened for gene sets significantly enriched in hepatocellular carcinoma and extracted genes from them. Signature were constructed using senescence-related genes, and their expression was verified at the protein and RNA levels. Survival, clinical staging and grading, immune infiltration, immunotherapy, and drug sensitivity were also analyzed between risk groups. RESULTS: The q-PCR and immunohistochemistry results revealed significant differences in the expression of the signature genes between normal and tumor tissues. Significant differences in clinicopathological features, prognosis and immune infiltration were observed between risk groups. In the low-risk group, better OS and lower TMB scores were demonstrated, while the high-risk group had higher immune checkpoint expression, as well as lower risk of immune escape. In addition, we found that the High-risk group was more sensitive to sorafenib. CONCLUSION: In summary, the signature constructed using aging-related genes can reliably predict patient prognosis and immunotherapy efficacy, providing a new idea for immune system therapy of hepatocellular carcinoma.

Study of the scavenger and vector roles of microplastics for polyhalocarbazoles under simulated gastric fluid conditions.

Microplastics entering the digestive system of living organisms can serve as a carrier of hydrophobic organic pollutants (HOPs), increasing their exposure levels and the health risks they pose to both humans and animals. The desorption kinetics of six polyhalocarbazoles (PHCZs) from 5 mm and 0.15 mm polypropylene (PP) and polyvinyl chloride (PVC) microplastic particles were assessed using a combined microplastics and food system, representing the gastric system of vertebrates and invertebrates. Results showed that the chemical transfer of PHCZs is biphasic and reversible, with rapid exchange occurring within 2-48 h, followed by a period of slow transfer, which continues for weeks to months. The desorption capacity of PHCZs loaded on 0.15 mm microplastic particles was greater than that of 5 mm particles. The bioavailability percentage of PHCZ congeners for PP (24.2%-65.3%) and PVC (43.5%-57.2%) in the vertebrate fluid system were all lower than those in the invertebrate system (34.2%-70.7% for PP and 56.3%-72.7% for PVC, respectively). These findings indicate that physiological conditions, such as polarity, ingestion fluid, and microplastic affect the desorption of PHCZs from microplastics. In addition, desorption from PP was inhibited by the presence of foodstuff loaded with PHCZs due to competition, while desorption from PVC was not significantly affected by the presence of PHCZs contaminant food. Microplastics could provide a cleaning function in gastric fluid systems containing contaminated foodstuff, especially PP, which was capable of competitive adsorption of PHCZs from food. Few investigations have focused on the adverse effects of microplastic ingestion on human health, particularly in their role as vectors for HOPs, compared to other routes of exposure and transport. Therefore, these findings provide valuable insight into the health risks associated with dietary intake of microplastics and HOPs.

Early life mental health and problematic drinking in mid-adulthood: evidence from two British birth cohorts.

PURPOSE: Accumulating evidence suggests that externalising problems are consistently associated with alcohol use behaviours, but findings are inconsistent regarding the role of internalising problems. We investigate whether externalising and internalising problems are associated with problematic drinking in mid-adulthood, and whether potential associations are modified by age, sex and cohort. METHODS: The National Child Development Study (NCDS58, n = 17,633) and 1970 British Cohort Study (BCS70, n = 17,568) recruited new-borns in Great Britain in a single week in 1958 and 1970. Mental health was assessed with the Rutter Behaviour Questionnaire at ages 7, 11, and 16 in NCDS58 and ages 5, 10 and 16 in BCS70. Problematic drinking was measured with the CAGE questionnaire at age 33 in NCDS58 and age 34 in BCS70, and the AUDIT scale at age 44/45 in NCDS58 and age 46 in BCS70. Latent scores of externalising and internalising problems were added chronologically into lagged logistic regression models. RESULTS: Externalising and internalising problems were associated in opposite directions with problematic drinking in mid-adulthood. Externalising was a risk factor (OR [95% CI] ranging from 1.06 [1.03, 1.10] to 1.11 [1.07, 1.15] for different ages), and internalising was a protective factor (OR [95% CI] ranging from 0.95 [0.92, 0.99] to 0.90 [0.86, 0.94] for different ages). Associations between early life mental health and mid-adulthood problematic drinking did not differ by developmental timing but were stronger in males. CONCLUSION: Our study provides new insights on links of externalising and internalising difficulties with alcohol use and has implications for public policy in the UK.

HPV/p16-positive oropharyngeal cancer treated with transoral robotic surgery: The roles of margins, extra-nodal extension and adjuvant treatment.

PURPOSE: Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treatment outcomes are re-defining management. Traditional margins, the role of extranodal extension (ENE) and adjuvant treatment intensity continue to be debated. This study aimed to determine the impact of margins, ENE and adjuvant therapy on survival following transoral robotic surgery (TORS). METHODS: Patients treated with TORS at an academic center were retrospectively identified (2013-2019). Survival outcomes were evaluated using Kaplan-Meier curves. RESULTS: 48 patients were included. 40 (83%) were male. Mean age was 61.2 years. 43 (90%) were stage I. 22 (45.8%) had ENE. 31 (65%) had margins >1 mm. 38 (79%) had indications for radiation therapy; 9 (24%) refused. Chemotherapy was recommended in 36 (75%) patients; 24 (67%) refused. Locoregional control was 98%, metastasis-free survival was 96%, and disease-specific survival was 100% at 5-years. Overall survival was 95%. CONCLUSIONS: Given the high survival rate seen after TORS, it is likely that margins, ENE and adjuvant treatment may not significantly contribute to outcomes.