The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies.

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Association between Shift Work and Health Outcomes in the General Population in China: A Cross-Sectional Study.

Shift work may adversely affect individuals' health, thus, the current study aimed to investigate the association between shift work and health outcomes in the general population. A total of 41,061 participants were included in this online cross-sectional survey, among which 9612 (23.4%) individuals engaged in shift work and 31,449 (76.6%) individuals engaged in non-shift work. Multiple logistic regression analyses were conducted to explore the association between shift work and health outcomes (psychiatric disorders, mental health symptoms, and physical disorders). In addition, associations between the duration (≤1 year, 1-3 years, 3-5 years, 5-10 years, ≥10 years) and frequency of shift work (<1 or ≥1 night/week) and health outcomes were also explored. The results showed that compared to non-shift workers, shift workers had a higher likelihood of any psychiatric disorders (odds ratios [OR] = 1.80, 95% CI = 1.56-2.09, p < 0.001), mental health symptoms (OR = 1.76, 95% CI = 1.68-1.85, p < 0.001), and physical disorders (OR = 1.48, 95% CI = 1.39-1.57, p < 0.001). In addition, inverted U-shaped associations were observed between the duration of shift work and health outcomes. These results indicated that shift work was closely related to potential links with poor health outcomes. The findings highlighted the importance of paying attention to the health conditions of shift workers and the necessity of implementing comprehensive protective measures for shift workers to reduce the impact of shift work.

Minor Changes in Response Modules Leading to a "U-Shaped" Conversion Rate of Docetaxel Prodrug Nanoassemblies.

The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONß, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.

Association of Caffeine Consumption and Brain Amyloid Positivity in Cognitively Normal Older Adults.

BACKGROUND: Several epidemiological studies have reported the protective role of caffeine on health outcomes; however, it remained debatable on caffeine consumption and brain amyloid positivity. OBJECTIVE: We aimed to determine the relationship between caffeine consumption and brain amyloid pathology in cognitively normal older adults. METHODS: The dataset used for analysis in this cross-sectional study was selected from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. Multivariable logistic regression analyses were performed to explore the association between caffeine consumption and amyloid positivity using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In total, 4,394 participants were included in the final analysis. No significant association between caffeine consumption and amyloid positivity was observed in the whole participants (OR, 0.95; 95% CI, 0.78-1.14; p = 0.558). Subgroup analysis showed that caffeine intake was significantly associated with decreased amyloid positivity in males (OR, 0.72; 95% CI, 0.54-0.97; p = 0.032) but not in females (OR, 1.14; 95% CI, 0.90-1.46; p = 0.280), and the association between caffeine and amyloid positivity was not affected by age or APOE genotypes. In addition, different levels of caffeine were not associated with amyloid positivity. CONCLUSION: The findings suggest that caffeine consumption was not significantly associated with amyloid positivity in the whole sample. However, caffeine consumption may be inversely associated with amyloid positivity among males but not females. More studies are needed to explore the mechanisms underlying caffeine consumption and brain amyloid positivity.

Critical roles of linker length in determining the chemical and self-assembly stability of SN38 homodimeric nanoprodrugs.

Homodimeric prodrug nanoassemblies (HDPNs) have been widely studied for efficient cancer therapy by virtue of their ultra-high drug loading and distinct nanostructure. However, the development of SN38 HDPNs is still a great challenge due to the rigid planar aromatic ring structure. Improving the structural flexibility of homodimeric prodrugs by increasing the linker length may be a potential strategy for constructing SN38 HDPNs. Herein, three SN38 homodimeric prodrugs with different linker lengths were synthesized. The number of carbon atoms from the disulfide bond to the adjacent ester bond is 1 (denoted as α-SN38-SS-SN38), 2 (ß-SN38-SS-SN38), and 3 (γ-SN38-SS-SN38), respectively. Interestingly, we found that α-SN38-SS-SN38 exhibited extremely low yield and poor chemical stability. Additionally, ß-SN38-SS-SN38 demonstrated suitable chemical stability but poor self-assembly stability. In comparison, γ-SN38-SS-SN38 possessed good chemical and self-assembly stability, thereby improving the tumor accumulation and antitumor efficacy of SN38. We developed the SN38 HDPNs for the first time and illustrated the underlying molecular mechanism of increasing the linker length to enhance the chemical and self-assembly stability of homodimeric prodrugs. These findings would provide new insights for the rational design of HDPNs with superior performance.

Long-term psychological profile of general population following COVID-19 outbreak: symptom trajectories and evolution of psychopathological network.

AIMS: COVID-19 has long-term impacts on public mental health, while few research studies incorporate multidimensional methods to thoroughly characterise the psychological profile of general population and little detailed guidance exists for mental health management during the pandemic. This research aims to capture long-term psychological profile of general population following COVID-19 by integrating trajectory modelling approaches, latent trajectory pattern identification and network analyses. METHODS: Longitudinal data were collected from a nationwide sample of 18 804 adults in 12 months after COVID-19 outbreak in China. Patient Health Questionnaire-9, Generalised Anxiety Disorder-7 and Insomnia Severity Index were used to measure depression, anxiety and insomnia, respectively. The unconditional and conditional latent growth curve models were fitted to investigate trajectories and long-term predictors for psychological symptoms. We employed latent growth mixture model to identify the major psychological symptom trajectory patterns, and ran sparse Gaussian graphical models with graphical lasso to explore the evolution of psychopathological network. RESULTS: At 12 months after COVID-19 outbreak, psychological symptoms generally alleviated, and five psychological symptom trajectories with different demographics were identified: normal stable (63.4%), mild stable (15.3%), mild-increase to decrease (11.7%), mild-decrease to increase (4.0%) and moderate/severe stable (5.5%). The finding indicated that there were still about 5% individuals showing consistently severe distress and approximately 16% following fluctuating psychological trajectories, who should be continuously monitored. For individuals with persistently severe trajectories and those with fluctuating trajectories, central or bridge symptoms in the network were mainly 'motor abnormality' and 'sad mood', respectively. Compared with initial peak and late COVID-19 phase, aftermath of initial peak might be a psychologically vulnerable period with highest network connectivity. The central and bridge symptoms for aftermath of initial peak ('appetite change' and 'trouble of relaxing') were totally different from those at other pandemic phases ('sad mood'). CONCLUSIONS: This research identified the overall growing trend, long-term predictors, trajectory classes and evolutionary pattern of psychopathological network of psychological symptoms in 12 months after COVID-19 outbreak. It provides a multidimensional long-term psychological profile of the general population after COVID-19 outbreak, and accentuates the essentiality of continuous psychological monitoring, as well as population- and time-specific psychological management after COVID-19. We believe our findings can offer reference for long-term psychological management after pandemics.

A systematic review and meta-analysis on prevalence of and risk factors associated with depression, anxiety and insomnia in infectious diseases, including COVID-19: a call to action.

Infectious disease epidemics have become more frequent and more complex during the 21st century, posing a health threat to the general public and leading to psychological symptoms. The current study was designed to investigate the prevalence of and risk factors associated with depression, anxiety and insomnia symptoms during epidemic outbreaks, including COVID-19. We systematically searched the PubMed, Embase, Web of Science, OVID, Medline, Cochrane databases, bioRxiv and medRxiv to identify studies that reported the prevalence of depression, anxiety or insomnia during infectious disease epidemics, up to August 14th, 2020. Prevalence of mental symptoms among different populations including the general public, health workers, university students, older adults, infected patients, survivors of infection, and pregnant women across all types of epidemics was pooled. In addition, prevalence of mental symptoms during COVID-19 was estimated by time using meta-regression analysis. A total of 17,506 papers were initially retrieved, and a final of 283 studies met the inclusion criteria, representing a total of 948,882 individuals. The pooled prevalence of depression ranged from 23.1%, 95% confidential intervals (95% CI: [13.9-32.2]) in survivors to 43.3% (95% CI: [27.1-59.6]) in university students, the pooled prevalence of anxiety ranged from 25.0% (95% CI: [12.0-38.0]) in older adults to 43.3% (95% CI: [23.3-63.3]) in pregnant women, and insomnia symptoms ranged from 29.7% (95% CI: [24.4-34.9]) in the general public to 58.4% (95% CI: [28.1-88.6]) in university students. Prevalence of moderate-to-severe mental symptoms was lower but had substantial variation across different populations. The prevalence of mental problems increased over time during the COVID-19 pandemic among the general public, health workers and university students, and decreased among infected patients. Factors associated with increased prevalence for all three mental health symptoms included female sex, and having physical disorders, psychiatric disorders, COVID infection, colleagues or family members infected, experience of frontline work, close contact with infected patients, high exposure risk, quarantine experience and high concern about epidemics. Frequent exercise and good social support were associated with lower risk for these three mental symptoms. In conclusion, mental symptoms are common during epidemics with substantial variation across populations. The population-specific psychological crisis management are needed to decrease the burden of psychological problem and improve the mental wellbeing during epidemic.

Comparative Efficacy of Fish Meal Replacement With Enzymatically Treated Soybean Meal on Growth Performance, Immunity, Oxidative Capacity and Fecal Microbiota in Weaned Pigs.

This study investigated the growth performance, immunity, antioxidant capacity and fecal microbiota of weaned pigs by partially or completely replacing dietary fish meal with enzymatically treated soybean meal. A total of 144 piglets (initial body weight of 7.19 ± 0.11 kg) weaned at 28 d were allotted to 3 dietary treatments (6 replicates per treatment): 4% fish meal diet (FM); 2% fishmeal plus 6% enzymatically treated soybean meal (ESBM1); and 6% enzymatically treated soybean meal without fish meal (ESBM2). The experimental period was 28 d, serum was collected at day 14 and day 28 for biochemical parameters analysis, feces was obtained for microbiota analysis at 28d. The body weight, average daily gain and average daily feed intake of piglets in the ESBM2 group were significantly increased compared with those in the FM and ESBM1 groups from 0 to 28 d, respectively (P < 0.05). The diets with enzymatically treated soybean meal in ESBM1 and ESBM2 groups decreased the diarrhea rate (P < 0.05). Compared with FM, ESBM1 and ESBM2 decreased 5-hydroxytryptamine (5-HT) (P < 0.05). ESBM1 decreased diamine oxidase (DAO) and Interleukin 6 (IL-6) compared with FM and ESBM2 (P < 0.05). ESBM1 decreased serum Interleukin 1ß (IL-1ß) compared with FM at d 14 (P < 0.05). The serum Immunoglobulin E (IgE), secretory curl associated protein 5 (sFRP-5) were higher in ESBM1 compared with FM and ESBM2 (P < 0.05). ESBM2 increased super oxidase dismutase (SOD) level and decreased malondialdehyde (MDA) content compared with FM and ESBM1, the concentration of SOD in ESBM1was higher than that in FM (P < 0.05). ESBM1 decreased cortisol and caspase 3 (Casp-3) (P < 0.05). FM showed a higher content of tri-iodothyronine (T3) (P < 0.05) and a lower thyroxine/ tri-iodothyronine ratio compared with those in the other two groups (P < 0.05). The concentration of leptin was lower in ESBM2 (P < 0.05). ESBM1 had a higher α-diversity than ESBM2 (P < 0.05). The microbiota composition was different among three treatments (difference between FM and ESBM1, p = 0.005; FM and ESBM2, p = 0.009; ESBM1 and ESBM2, p = 0.004). ESBM2 tend to increase the abundance of Firmicutes (P = 0.070) and decrease Bacteroidetes (P = 0.069). ESBM2 decreased the abundance of Parabacteroides and increased SMB53 compared with FM (P < 0.05). The spearman correlation analysis revealed that the abundance of Parabacteroides enriched in FM group was negatively correlated with SOD, Megasphaera enriched in ESBM2 group were positively correlated with SOD. The abundance of Lachnospira enriched in ESBM2 group were negatively correlated with serum concentration of D-lactate, DAO, IL-6, and NO. In conclusion, under the conditions of this study, diet with only ESBM demonstrate the beneficial impact on intestinal microbiota developments, antioxidant capacity as well as growth performance for weaned pigs.

The effect of perceived stress on cognition is mediated by personality and the underlying neural mechanism.

Perceived stress impairs cognitive function across the adult lifespan, but the extent to which cognition decline is variable across individuals. Individual differences in the stress response are described as personality traits. Substantial individual differences in the magnitude of cognitive impairment that is induced by short-term perceived stress are poorly understood. The present study tested the hypothesis that the relationship between short-term perceived stress and different aspects of cognition is mediated by personality traits. The study included 1066 participants with behavior and neuroimaging data from the Human Connectome Project after excluding individuals with missing variables. In the result, the parallel multiple mediation model demonstrated that the influence of perceived stress on the total and crystalized cognition is mainly mediated by neuroticism (indirect effect = -0.04, p < 0.05) and conscientiousness (indirect effect = 0.05, p < 0.05) in adults. Cortical thickness value (n = 1066) of the right superior frontal gyrus (SFG) showed not only positive correlations with short-term perceived stress and neuroticism, but negative associations with cognition. The chain mediation model found that the right SFG and neuroticism play a small but significant chain mediating effect between stress and total cognition. The strength of the resting-state functional connectivity (n = 968) between the left orbitofrontal cortex versus the left superior medial frontal cortex was positively correlated with crystallized cognition and negatively associated with conscientiousness. These results extend previous findings by the impacts of short-term perceived stress on cognitive function is mediated by neuroticism and the right SFG was the underlying neural mechanism.

Accessibility to Digital Mental Health Services among the General Public throughout COVID-19: Trajectories, Influencing Factors and Association with Long-Term Mental Health Symptoms.

Digital mental health services (DMHSs) have great potential for mitigating the mental health burden related to COVID-19, but public accessibility (ease of acquiring services when needed) to DMHSs during the pandemic is largely unknown. Accessibility to DMHSs was tracked longitudinally among a nationwide sample of 18,804 adults in China from before to one year after COVID-19 outbreak. Unconditional and conditional latent growth curve models and latent growth mixture models were fitted to explore the overall growth trend, influencing factors, and latent trajectory classes of accessibility to DMHSs throughout COVID-19. Generalized estimating equation models and generalized linear mixed models were employed to explore the association between accessibility to DMHSs and long-term mental health symptoms. We found that people generally reported increased difficulty in accessing DMHSs from before to one year after COVID-19 outbreak. Males, youngsters, individuals with low socioeconomic status, and individuals greatly affected by COVID-19 reported greater difficulty in accessing DMHSs. Four DMHS accessibility trajectory classes were identified: "lowest-great increase" (6.3%), "moderate low-slight increase" (44.4%), "moderate high-slight decrease" (18.1%) and "highest-great decrease" (31.2%). Trajectory classes reporting greater difficulty in accessing DMHSs were at higher risk for long-term mental symptoms. In conclusion, an overall increase in difficulty in accessing DMHSs is observed throughout COVID-19, and heterogeneity exists in DMHS accessibility trajectories. Our results suggest that easy access to DMHSs should be consistently facilitated. Moreover, access gaps should be reduced across demographic groups, and target populations for service allocation should alter as the pandemic evolves.

A systematic review and meta-analysis on the prevalence of stigma in infectious diseases, including COVID-19: a call to action.

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.

COVID-19 Vaccine-Related Psychological Stress Among General Public in China.

Background: The COVID-19 pandemic is our generation's greatest global challenge to our public health system. Vaccines are considered one of the most effective tools available for preventing COVID-19 infection and its complications and sequelae. Understanding and addressing the psychological stress related to COVID-19 vaccination may promote acceptance of these vaccines. Methods: We conducted an online survey from January 29 to April 26, 2021 to explore stress levels related to COVID-19 vaccination among the general public in China. Participants were asked to evaluate their psychological stress of considering whether or not to get vaccinated at the beginning period of the COVID-19 mass vaccination, after getting access to the information about the vaccine, as well as after getting vaccinated, using visual analog stress scale. Multiple linear regression analysis was performed to explore factors potentially associated with COVID-19-related psychological stress levels before and after getting vaccinated. Results: A total of 34,041 participants were included in the final analysis. The mean stress score concerning COVID-19 vaccination was 3.90 ± 2.60 among all participants, and significantly decreased over time. In addition, the vaccine-related stress level significantly decreased after accessing information about the COVID-19 vaccine (N = 29,396), as well as after getting vaccinated (N = 5,103). Multivariable regression analysis showed higher stress levels related to COVID-19 vaccination in participants who were younger, having lower education level, having history of chronic diseases, mistrusting vaccine's efficacy, experience of vaccine allergy events, being affected by the COVID-19 epidemic, and having mental illness symptoms. Moreover, mistrust in vaccine efficacy and experience of vaccine allergy events had a long-term impact on psychological stress levels about COVID-19 vaccination even after getting vaccinated. Conclusions: The current findings profiled the COVID-19 vaccine-related psychological stress among the general public in China. Population-specific management and interventions targeting the stress related to COVID-19 vaccination are needed to help governments and policy makers promote individual's willingness to get vaccinations for public well-being during the COVID-19 pandemic.