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Abstract Clinical studies from WHO have demonstrated that only 50–70% of patients adhere properly to prescribed drug therapy. Such adherence failure can impact therapeutic efficacy for the patients in question and compromises data quality around the population-level efficacy of the drug for the indications targeted. In this study, we applied various ensemble learning and deep learning models to predict medication adherence among patients. Our contribution to this endeavour involves targeting the problem of adherence prediction for a particularly challenging class of patients who self-administer injectable medication at home. Our prediction pipeline, based on event history, comprises a connected sharps bin which aims to help patients better manage their condition and improve outcomes. In other words, the efficiency of interventions can be significantly improved by prioritizing the patients who are most likely to be non-adherent. The collected data comprising a rich event feature set may be exploited for the purposes of predicting the status of the next adherence state for individual patients. This paper reports on how this concept can be realized through an investigation using a wide range of ensemble learning and deep learning models on a real-world dataset collected from such a system. The dataset investigated comprises 342,174 historic injection disposal records collected over the course of more than 5 years. A comprehensive comparison of different models is given in this paper. Moreover, we demonstrate that the selected best performer, long short-term memory (LSTM), generalizes well by deploying it in a true future testing dataset. The proposed end-to-end pipeline is capable of predicting patient failure in adhering to their therapeutic regimen with 77.35 % accuracy (Specificity: 78.28 %, Sensitivity: 76.42%, Precision: 77.87%,F1 score: 0.7714, ROC AUC: 0.8390).

Abstract GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit a shift from a diurnal anxiety state to a nocturnal normal or anxiolytic-like state. Overexpression of NEK4 also affects the circadian fluctuations in dendritic spine morphology and synaptic structure. Furthermore, we show that treatment with lithium ameliorates the effects of NEK4 overexpression in male mice. We then perform phosphoproteomic analyses to demonstrate that the diurnal and nocturnal phosphoproteomic profiles of male control and NEK4 overexpressing mice are different. These results suggest that male mice with different NEK4 expression levels may recapitulate some of the core features observed in patients with bipolar disorder, indicating that interruption of the homeostatic dynamics of synapses may underlie the emotional swings in bipolar disorder.

ABSTRACT: This study aims to identify lactic acid bacteria (LAB) isolates possessing physiological characteristics suitable for use as probiotics in yogurt fermentation. Following acid and bile salt tolerance tests, Lactiplantibacillus plantarum (NUC08 and NUC101), Lacticaseibacillus rhamnosus (NUC55 and NUC201), and Lacticaseibacillus paracasei (NUC159, NUC216, and NUC351) were shortlisted based on intraspecies distribution for further evaluation. Their physiological probiotic properties, including transit tolerance, adhesion, autoaggregation, surface hydrophobicity, biofilm formation, and antibacterial activity, were assessed. Principal component analysis indicated that Lactiplantibacillus plantarum NUC08 was the preferred choice among the evaluated strains. Subsequent investigations revealed that co-culturing Lactiplantibacillus plantarum NUC08 with 2 yogurt starter strains resulted in a cooperative and synergistic effect, enhancing the growth of mixed strains and increasing their tolerance to simulated gastric and intestinal conditions. Additionally, when Vibrio harveyi bioluminescent reporter strain was used, the 3 cocultured strains cooperated to induce the activity of a quorum sensing (QS) molecule autoinducer-2 (AI-2), hinting a potential connection between phenotypic traits and QS in the cocultured strains. Importantly, LAB viable counts were significantly higher in yogurt co-fermented with Lactiplantibacillus plantarum NUC08, consistently throughout the storage period. In conclusion, the study demonstrates that the probiotic strain Lactiplantibacillus plantarum NUC08 can be employed in synergy with yogurt starter strains, affirming its potential for use in the development of functional fermented dairy products.

The fifth wave of COVID-19, driven by the Omicron variant, started to surge in Hong Kong in December 2021. Previous studies have shown that younger adults, compared to older adults, are vulnerable to increased risks of side effects after vaccination. However, little is known about the COVID-19 vaccination behavior among younger adults, especially university students, in Hong Kong. Therefore, the present online survey study aimed to investigate the predictors of COVID-19 vaccination intention among university students in Hong Kong using the Health Belief Model (HBM) as a framework. Two other potential predictors, the previous influenza vaccine uptake frequency and the Hong Kong SAR government vaccination lottery program, were also examined. The intention to receive another dose of the COVID-19 vaccine was low (36.4%). Multivariate binomial logistic regression analysis showed that, after controlling for demographic and baseline characteristics, the perceived susceptibility (OR = 2.98, CI = 1.18–7.53) and previous influenza vaccine uptake frequency (OR = 1.54, CI = 1.08–2.19) significantly and positively predicted the COVID-19 vaccination intention. However, the government vaccination lottery program (i.e., wining prizes for being vaccinated) (OR = 0.87, CI = 0.34–2.26) was not a significant motivator of COVID-19 vaccination. Future public health campaigns should focus on the individual susceptibility to COVID-19 and past influenza vaccination history to promote increased vaccination uptake among university students.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6–9.5 μm in diameter, average diameter > 4.2 μm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.

Cordyceps fumosorosea is a common species within the Cordyceps genus. In this study, the protective effect of Cordyceps fumosorosea mycelium was investigated to clarify the potential mechanism of alleviating acute lung injury in mice using serum metabolomic analysis, which could provide a theoretical basis for the clinical application of C. fumosorosea. Sixty mice were divided into six groups (NS, LPS, MIX, COR, COC and DMX). Lung cell nuclei were analyzed using hematoxylin and eosin staining and cellular changes were observed using transmission electron microscopy (TEM). Metabolomic analyses using liquid chromatography-mass spectrometry (LC-MS) were used to identify various compounds. In all six groups, lung nuclear inflammation was observed in the COR, COC and DMX groups, whereas the NS, LPS and MIX groups showed no cellular changes, indicating good health. Metabolomic analysis using LC-MS identified 1607 compounds across various classes. Statistical analyses, including the coefficient of variation and OPLS-DA, revealed distinct metabolic proles, indicating significant changes after the consumption of C. fumosorosea mycelia. Lipids constituted the largest proportion (30.37%) of the 30 identified classes and subclasses of metabolites. A total of 617 differentially accumulated metabolites (DAMs) were identified, both unique and shared between comparisons. Metabolite analysis identified 617 differentially accumulated metabolites, with 493 common to the LPS vs. MIX group, 75 in the LPS vs. NS group and 49 in the LPS vs. NS group and LPS vs. MIX group. This comprehensive investigation suggests that C. fumosorosea mycelia treatment holds promise as a therapeutic intervention for lung injury, influencing both the histopathological (lung) features and serum metabolic profiles.

The accumulation of isothiocyanate in germinated broccoli under ZnSO4-melatonin treatment was optimized. The isothiocyanate content, bud length and fresh weight of broccoli during germination were used as indices to study the effects of germination temperature, germination time, ZnSO4 and melatonin treatment concentration on isothiocyanate by single factor experiment first, and on this basis, it was further optimized by response surface experiment. Meanwhile, the changes of isothiocyanate metabolism related indexes were analyzed. The results showed that germination temperature, germination time, ZnSO4 and melatonin treatment concentration all had significant effects on isothiocyanate enrichment. Response surface optimization experiment showed that when the broccoli was treated with 4.69 mmol/L ZnSO4 combined with 13.18 μmol/L melatonin at 30 ℃ for 3 days, the isothiocyanate content was up to the highest, which was 451.27 mg/100 g mf. The contents of glucosinolates and sulforapenin and the activity of myrosinase in broccoli sprouts under ZnSO4 combined with melatonin treatment were significantly higher than those in the control group(P

Ophiocordyceps sinensis is a fungus with medicinal value in treating lung diseases, but no study has reported how to prevent acute lung injury using this fungus. The mice were divided into normal, model, positive control, and O. sinensis groups to observe lung histopathological sections and transmission electron microscopy, along with liquid chromatography-mass spectrometry and hematoxylin and eosin (H&E) staining to closely identify structural differences resulting from destruction between the groups. The results of the H&E staining showed that, compared with the normal group, the model group showed alveolar collapse. Compared with the model group, the infiltration of inflammatory cells in the alveolar cavity of the O. sinensis group was significantly reduced. Mitochondrial plate-like cristae were observed in type II alveolar cells of the normal group, with normal coloration of the mitochondrial matrix. Type II alveolar cells in the model group showed obvious edema. The statuses of type II alveolar cells in the O. sinensis and positive groups were similar to that in the normal group. Twenty-nine biomarkers and 10 related metabolic pathways were identified by serum metabolomics screening. The results showed that O. sinensis mycelia had a significant effect on the prevention of lipopolysaccharide-induced inflammation.

Identification of meat authenticity is a matter of increasing concerns due to religious, economical, legal, and public health reasons. However, little is known about the inspection of eight meat species in one tube reaction due to technological challenge of multiplex polymerase chain reaction (PCR) techniques. Here, a developed multiplex PCR method can simultaneously authenticate eight meat species including ostrich (753 bp), cat (564 bp), goose (391 bp), duck (347 bp), chicken (268 bp), horse (227 bp), dog (190 bp), and sheep (131 bp). The detectable deoxyribonucleic acid (DNA) contents for each target species was as low as 0.01 ng in both raw and heat-treated meat or target meat down to 0.1% (w/w) of total meat weight reflecting high stability of the assay in heat processing condition, indicating that this method is adequate for tracing meat origin in real-world meat products, which has been further validated by authenticity assays of commercial meat products. Overall, this method is a powerful tool for accurate evaluation of meat origin with a good application foreground.

Background: Malignant fibrous histiocytoma (MFH) is a common type of soft tissue sarcoma and a serious threat to human health. MFH often relapses locally after the curettage is related to the residual cancer stem cells (CSCs). Currently, the dysregulation of microRNA (miRNA) has been found to be closely related to the recurrence of CSCs. However, whether dysregulations of miRNAs exist in MFH, CSCs remained unknown.Methods: In this study, miRNAs in MFH CSCs and MFH common cells were examined by gene probe. Then, target genes and their functions involved in the signal pathway were predicted by the relevant database. Finally, the miRNAs’ target regulatory network was constructed. Furthermore, the miRNAs and target genes were identified by quantitative polymerase chain reaction, whereas miRNA analogs and antagonists were transfected in tumor cells to investigate cell proliferation ability further.Results: Results showed that a total of 47 miRNAs were found, including 16 that were upregulated and 31 that were downregulated. The screened differential miRNA showed a different expression in the cell resistant strains compared with the control group. Quantitative polymerase chain reaction analysis confirmed that the relative abundance of seven miRNAs and four target genes varied significantly. The encouraging issue is that we found Hsa-miR-206 significantly inhibited MFH proliferative activity.Conclusion: Hsa-miR-206 played a key role in regulating MFH CSC properties that might be a representative marker and target for the diagnosis and treatment of MFH in the future.

Background: Knowledge of how intrinsic capacity (IC) and neighbourhood physical environment shape functional ability (FA) trajectories in later life remains understudied. We investigated four-year trajectories of IC and their impact on FA trajectories and the association between neighbourhood physical environment and FA trajectories among community-dwelling older adults in Hong Kong, China. Methods: We conducted a four-wave longitudinal study from 2014 to 2017 in Hong Kong with 2,081 adults aged 65 and above. FA was assessed by The Chinese Lawton Instrumental Activities of Daily Living Scale. We used cognition, affect, locomotion, sensory capacity, and vitality to capture the multiple domains of IC. Neighbourhood physical environment attributes included green space, land use diversity, and availability of facilities, assessed within 200- and 500-meter buffers of respondents’ homes. We used the parallel process of latent growth curve model. Findings: IC (Unstandardized coefficient, β = −0.02, p

Callose is a β‐1,3‐glucan commonly found in higher plants that plays an important role in regulating plant pollen development. It is synthesized by glucan synthase‐like (GSL) and is degraded by the enzyme endo‐1,3‐β‐glucosidase. However, genome‐wide analyses of callose GSL and endo‐1,3‐β‐glucosidase enzymes in fertile and sterile flower buds of Chinese cabbage have not yet been reported. Here, we show that delayed callose degradation at the tetrad stage may be the main cause of microspore abortion in Chinese cabbage with nuclear sterility near‐isogenic line ‘10L03’. Fifteen callose GSLs and 77 endo‐1,3‐β‐glucosidase enzymes were identified in Chinese cabbage. Phylogenetic, gene structural and chromosomal analyses revealed that the expansion occurred due to three polyploidization events of these two gene families. Expression pattern analysis showed that the GSL and endo‐1,3‐β‐glucosidase enzymes are involved in the development of various tissues and that the genes functionally diverged during long‐term evolution. Relative gene expression analysis of Chinese cabbage flowers at different developmental stages showed that high expression of the synthetic enzyme BraA01g041620 and low expression of AtA6‐homologous genes (BraA04g008040, BraA07g009320, BraA01g030220 and BraA03g040850) and two other genes (BraA10g020080 and BraA05g038340) for degrading enzymes in the meiosis and tetrad stages may cause nuclear sterility in the near‐isogenic line ‘10L03’. Overall, our data provide an important foundation for comprehending the potential roles of the callose GSL and endo‐1,3‐β‐glucosidase enzymes in regulating pollen development in Chinese cabbage.

Bin1/Amphiphysin/Rvs (BAR) domain-containing proteins mediate fundamental cellular processes, including membrane remodeling and endocytosis. Nematode-trapping (NT) fungi can differentiate to form trapping structures through highly reorganized cell membranes and walls. In this study, we identified the NT fungus Arthrobotrys oligospora ortholog of yeast Rvs167 and documented its involvement in membrane bending and endocytosis. We further confirmed that the deletion of AoRvs167 makes the fungus more hypersensitive to osmotic salt (Nacl), higher temperatures (28 to 30 °C), and the cell wall perturbation agent Congo red. In addition, the disruption of AoRvs167 reduced the trap formation capacity. Hence, AoRvs167 may regulate fungal pathogenicity through the integrity of plasma membranes and cell walls.

Objectives This study examined the interaction effects of individual and neighbourhood socioeconomic status (SES) in older adults in Hong Kong, considering all-cause and cause-specific mortality from respiratory disease, cancer, cardiovascular diseases, ischaemic heart disease, stroke, nonmedical disease and suicide.Design A retrospective follow-up study.Setting Hong Kong Special Administrative Region, a rapidly ageing society with 16.1% residents aged 65 years or older in 2020.Participants 43 910 people aged 65 years or older were enrolled at baseline. They had participated in health check-ups during 2000–2003 in one of the Elderly Health Centres. Observation periods started on the date of the participant’s first health check-up, and ended at death, or 31 December 2011, whichever occurred first.Outcome measures All-cause and cause-specific mortality over the study timeframe.Analysis Cox’s proportional hazards regression models were applied to estimate the adjusted HRs of mortality, by including covariates at neighbourhood (deprivation) and individual levels (poverty, education and type of housing).Results The ‘double tragedy theory’ (ie, lower SES persons living in lower SES neighbourhoods have worst health outcomes) was more related to cancer, while the ‘psychosocial comparison theory’ (ie, lower SES persons living in higher SES neighbourhoods have poorer health outcomes) was more related to cardiovascular, ischaemic heart disease, and stroke.Conclusion There were important interaction effects between neighbourhood and individual factors on mortality. Policies based on the interaction between individual and neighbourhood SES should be considered. For instance, for cancer, targeted services (ie, free consultation, relevant treatment information, health check-up, etc) could be allocated in socioeconomically deprived areas to support individuals with low SES. On the other hand, more free public services to reduce psychological stresses (ie, psychological support services, recreational services, health knowledge information, etc) could be provided for those individuals with low SES living in higher SES areas to reduce stroke, cardiovascular and ischaemic heart diseases.

Lactobacillus are normal inhabitants of the gastrointestinal tract and confer a variety of health effects. Lipoteichoic acid (LTA), an amphiphilic substance located in the cell membrane, is a key molecule in probiotic–host crosstalk. Through the characterization of structural characteristics of LTA molecules derived from Lactobacillus plantarum A3, Lactobacillus reuteri DMSZ 8533, and Lactobacillus acidophilus CICC 6074, there exists some heterogeneity in LTA molecules, which perhaps contributes to the distinguishable adhesion properties of Lactobacillus strains based on fluorescence microscopy observations. In LPS-induced RAW 264.7 cells, LTAs derived from three Lactobacillus strains obviously alleviated inflammatory responses as evidenced by the altered inflammatory cytokine levels of TNF-α, IL-6, and IL-10. Western blotting demonstrated that L. reuteri LTA blocked LPS-triggered expression of the MAPK and NF-κB pathways. The findings further validated that LTA is an important effector molecule and deserves further consideration as an alternative therapeutic for ulcerative colitis treatment.

Cryo-electron microscopy was exploited to reveal and study the influence of pyruvate dehydrogenase (E[sub 1]) occupancy on the conformational states of the Saccharomyces cerevisiae pyruvate dehydrogenase complex (PDC). Structures representative of PDC preparations with ≈40% and full E[sub 1] occupancy were determined after the electron microscopy images from each preparation were classified according to their sizes. The reconstructions derived from two size groups showed that the deposition of the E[sub 1] molecules associated with the larger complex is, unexpectedly, not icosahedrally arranged, whereas in the smaller complex the E[sub 1] molecules have an arrangement and architecture similar to their more ordered deposition in the WT bovine kidney PDC. This study also shows that the linker of dihydrolipamide acetyltransferase (E[sub 2]) that tethers E[sub 1] to the E[sub 2] core increases in length from ≈50 to 75 Å, accounting largely for the size difference of the smaller and larger structures, respectively. Extensive E[sub 1] occupancy of its 60 E[sub 2] binding sites favors the extended conformation of the linker associated with the larger complex and appears to be related to the loss of icosahedral symmetry of the E[sub 1] molecules. However, the presence of a significant fraction of larger molecules also in the WT PDC preparation with low E[sub 1] occupancy indicates that the conformational variability of the linker contributes to the overall protein dynamics of the PDC and the variable deposition of E[sub 1]. The flexibility of the complex may enhance the catalytic proficiency of this macromolecular machine by promoting the channeling of the intermediates of catalysis between the active sites. [ABSTRACT FROM AUTHOR]

Previous investigations of geographic concentration of urban poverty indicate the contribution of a variety of factors, such as economic restructuring and class-based segregation, racial segregation, demographic structure, and public policy. However, the models used by most past research do not consider the possibility that poverty concentration may take different forms in different locations across a city, and most studies have been conducted in Western settings. We investigated the spatial patterning of neighborhood poverty and its correlates in Hong Kong, which is amongst cities with the highest GDP in the region, using the city-wide ordinary least square (OLS) regression model and the local-specific geographically weighted regression (GWR) model. We found substantial geographic variations in small-area poverty rates and identified several poverty clusters in the territory. Factors found to contribute to urban poverty in Western cities, such as socioeconomic factors, ethnicity, and public housing, were also mostly associated with local poverty rates in Hong Kong. Our results also suggest some heterogeneity in the associations of poverty with specific correlates (e.g. access to hospitals) that would be masked in the city-wide OLS model. Policy aimed to alleviate poverty should consider both city-wide and local-specific factors.

There has been a marked rise in suicide by charcoal burning (CB) in some East Asian countries but little is known about its incidence in mainland China. We examined media-reported CB suicides and the availability of online information about the method in mainland China.We extracted and analyzed data for i) the characteristics and trends of fatal and nonfatal CB suicides reported by mainland Chinese newspapers (1998-2014); ii) trends and geographic variations in online searches using keywords relating to CB suicide (2011-2014); and iii) the content of Internet search results.109 CB suicide attempts (89 fatal and 20 nonfatal) were reported by newspapers in 13 out of the 31 provinces or provincial-level-municipalities in mainland China. There were increasing trends in the incidence of reported CB suicides and in online searches using CB-related keywords. The province-level search intensities were correlated with CB suicide rates (Spearman's correlation coefficient = 0.43 [95% confidence interval: 0.08-0.68]). Two-thirds of the web links retrieved using the search engine contained detailed information about the CB suicide method, of which 15% showed pro-suicide attitudes, and the majority (86%) did not encourage people to seek help.The incidence of CB suicide was based on newspaper reports and likely to be underestimated.Mental health and suicide prevention professionals in mainland China should be alert to the increased use of this highly lethal suicide method. Better surveillance and intervention strategies need to be developed and implemented.

Mammalian reoviruses are internalized into cells by receptor-mediated endocytosis. Within the endocytic compartment, the viral outer capsid undergoes acid-dependent proteolysis resulting in removal of the or3 protein and proteolytic cleavage of the μ1/μ1C protein. Ammonium chloride (AC) is a weak base that blocks disassembly of reovirus virions by inhibiting acidification of intracellular vacuoles. To identify domains in reovirus proteins that influence pH-sensitive steps in viral disassembly, we adapted strain type 3 Dearing (T3D) to growth in murine L929 cells treated with AC. In comparison to wild-type (wt) T3D, AC-adapted (ACA-D) variant viruses exhibited increased yields in AC-treated cells. AC resistance of reassortant viruses generated from a cross of wt type 1 Lang and ACA-D variant ACA-D1 segregated with the σ3-encoding S4 gene. The deduced σ3 amino acid sequences of six independently derived ACA-D variants contain one or two mutations each, affecting a total of six residues. Four of these mutations, 1180T, A246G, I347S, and Y354H, cluster in the virion-distal lobe of σ3. Linkage of these mutations to AC resistance was confirmed in experiments using reovirus disassembly intermediates recoated with wt or mutant σ3 proteins. In comparison to wt virions, ACA-D viruses displayed enhanced susceptibility to proteolysis by endocytic protease cathepsin L. Image reconstructions of cryoelectron micrographs of three ACA-D viruses that each contain a single mutation in the virion-distal lobe of σ3 demonstrated native capsid protein organization and minimal alterations in σ3 structure. These results suggest that mutations in σ3 that confer resistance to inhibitors of vacuolar acidification identify a specific domain that regulates proteolytic disassembly. [ABSTRACT FROM AUTHOR]