Pharmacological treatments for alcohol dependence: Evidence on uptake, inequalities and comparative effectiveness from a UK population-based cohort.

INTRODUCTION: We assessed the prevalence of prescribing of certain medications for alcohol dependence and the extent of any inequalities in receiving prescriptions for individuals with such a diagnosis. Further, we compared the effectiveness of two of the most prescribed medications (acamprosate and disulfiram) for alcohol dependence and assessed whether there is inequality in prescribing either of them. METHODS: We used a nationwide dataset on prescriptions and hospitalisations in Scotland, UK (N = 19,748). We calculated the percentage of patients receiving alcohol dependence prescriptions after discharge, both overall and by socio-economic groups. Binary logistic regressions were used to assess the odds of receiving any alcohol-dependence prescription and the comparative odds of receiving acamprosate or disulfiram. Comparative effectiveness in avoiding future alcohol-related hospitalisations (N = 11,239) was assessed using Cox modelling with statistical adjustment for potential confounding. RESULTS: Upto 7% of hospitalised individuals for alcohol use disorder received prescriptions for alcohol dependence after being discharged. Least deprived socio-economic groups had relatively more individuals receiving prescriptions. Inequalities in prescribing for alcohol dependence existed, especially across sex and comorbidities: males had 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81-0.96) and those with a history of mental health hospitalisations had 10% (OR 0.90, 95% CI 0.82-0.98) lower odds of receiving prescriptions after an alcohol-related hospitalisation. Prescribing disulfiram was superior to prescribing acamprosate in preventing alcohol-related hospitalisations (hazard ratio ranged between 0.60 and 0.81 across analyses). Disulfiram was relatively less likely prescribed to those from more deprived areas. DISCUSSION AND CONCLUSIONS: Inequalities in prescribing for alcohol dependence exists in Scotland with lower prescribing to men and disulfiram prescribed more to those from least deprived areas.

Assessing the performance of physician's prescribing preference as an instrumental variable in comparative effectiveness research with moderate and small sample sizes: a simulation study.

Aim: This simulation study is to assess the utility of physician's prescribing preference (PPP) as an instrumental variable for moderate and smaller sample sizes. Materials & methods: We designed a simulation study to imitate a comparative effectiveness research under different sample sizes. We compare the performance of instrumental variable (IV) and non-IV approaches using two-stage least squares (2SLS) and ordinary least squares (OLS) methods, respectively. Further, we test the performance of different forms of proxies for PPP as an IV. Results: The percent bias of 2SLS is around approximately 20%, while the percent bias of OLS is close to 60%. The sample size is not associated with the level of bias for the PPP IV approach. Conclusion: Irrespective of sample size, the PPP IV approach leads to less biased estimates of treatment effectiveness than OLS adjusting for known confounding only. Particularly for smaller sample sizes, we recommend constructing PPP from long prescribing histories to improve statistical power.

Comparing the performance of two-stage residual inclusion methods when using physician's prescribing preference as an instrumental variable: unmeasured confounding and noncollapsibility.

Aim: The first objective is to compare the performance of two-stage residual inclusion (2SRI), two-stage least square (2SLS) with the multivariable generalized linear model (GLM) in terms of the reducing unmeasured confounding bias. The second objective is to demonstrate the ability of 2SRI and 2SPS in alleviating unmeasured confounding when noncollapsibility exists. Materials & methods: This study comprises a simulation study and an empirical example from a real-world UK population health dataset (Clinical Practice Research Datalink). The instrumental variable (IV) used is based on physicians' prescribing preferences (defined by prescribing history). Results: The percent bias of 2SRI in terms of treatment effect estimates to be lower than GLM and 2SPS and was less than 15% in most scenarios. Further, 2SRI was found to be robust to mild noncollapsibility with the percent bias less than 50%. As the level of unmeasured confounding increased, the ability to alleviate the noncollapsibility decreased. Strong IVs tended to be more robust to noncollapsibility than weak IVs. Conclusion: 2SRI tends to be less biased than GLM and 2SPS in terms of estimating treatment effect. It can be robust to noncollapsibility in the case of the mild unmeasured confounding effect.

The Effect of Minimum Unit Pricing for Alcohol on Prescriptions for Treatment of Alcohol Dependence: A Controlled Interrupted Time Series Analysis.

In 2018, Scotland introduced a minimum unit price (MUP) for alcohol to reduce alcohol-related harms. We aimed to study the association between MUP introduction and the volume of prescriptions to treat alcohol dependence, and volume of new patients receiving such prescriptions. We also examined whether effects varied across different socio-economic groups. A controlled interrupted time series was used to examine variations of our two outcomes. The same prescriptions in England and prescriptions for methadone in Scotland were used as controls. There was no evidence of an association between MUP implementation and the volume of prescriptions for alcohol dependence (immediate change: 2.74%, 95% CI: -0.068 0.014; slope change: 0% 95%CI: -0.001 0.000). A small, significant increase in slope in number of new patients receiving prescriptions was observed (0.2% 95%CI: 0.001 0.003). However, no significant results were confirmed after robustness checks. We found also no variation across different socioeconomic groups. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-023-01070-6.

Anticipatory Stress Increases Deontological Inclinations: The Mediating Role of Emotional Valence.

Previous studies have explored the differences in moral judgments under normal situations and acute stress using the Trier Social Stress Test (TSST). The present study examined whether anticipatory stress (i.e., induced by an anticipated speech) could elicit similar effects and further explored the mediation of emotional responses between acute stress and moral judgments with a process-dissociation approach. Fifty-three undergraduate students (20 males and 33 females) were randomly assigned to the stress and control groups. In the first stage, they were instructed to prepare a public speech (the stress group) or just recall events during the previous vacation (the control group). In the second stage, they reported emotional valence and arousal for each moral dilemma in a set of 12 moral dilemmas, followed by judgments on moral acceptability of the agent's action. The manipulation check confirmed that anticipatory stress was reliably induced, as indicated in both self-reported and physiological data. The traditional dilemma analysis revealed that participants in the stress group would make fewer utilitarian judgments than those in the control group. The process dissociation (PD) analyses further revealed that the stress group exhibited higher deontological inclinations than the control group, but no significant differences in utilitarian inclinations. Emotional valence played a mediating role in the association between stress and deontological inclinations. To sum up, our study extended the investigation of the relationship between acute stress and moral judgment to anticipatory stress, clarified its distinct impact on deontological and utilitarian inclinations, and revealed the mediating effect of emotional valence.

Factor structure and longitudinal measurement invariance of the K6 among a national representative elder sample of China.

BACKGROUND: As the number of older people is rapidly growing, prevention, screening, and treatment of mental health problems (including anxiety and depression) in this population increasingly become a heavy burden to individuals, families, and even the whole society. The Kessler-6 screening measure (K6) is an efficient and effective instrument for general mental health problems. However, few studies have examined its measurement invariance across time, which is particularly important in longitudinal studies, such as exploring developmental trajectories of non-specific psychological distress and evaluating the effects of certain interventions. METHODS: The current study investigated the factor structure and the longitudinal measurement invariance of the K6 among a national representative elder sample of China. Longitudinal data in two survey waves (the year 2010, and the year 2014) from the China Family Panel Studies were drawn for secondary data analysis. A total of 3845 participants aged 60 years old and above (52.2% male, mean age = 66.99 years, SD = 5.93 years) responded to both waves of the survey. RESULTS: A comparison of four existing models with confirmatory factor analysis supported a two-factor solution of the K6. A series of multi-group confirmatory factor analyses further indicated that the K6 held strict longitudinal measurement invariance across time. Additionally, the internal consistency indices across time and the stability coefficients over time were acceptable. CONCLUSIONS: The findings further confirmed the psychometric defensibility of the K6 when used in the old Chinese population. The longitudinal measurement invariance justified comparisons of psychological distress scores among different measurement time points.

Progress on deuterated potassium dihydrogen phosphate (DKDP) crystals for high power laser system application.

In this review, we introduce the progress in the growth of large-aperture DKDP crystals and some aspects of crystal quality including determination of deuterium content, homogeneity of deuterium distribution, residual strains, nonlinear absorption, and laser-induced damage resistance for its application in high power laser system. Large-aperture high-quality DKDP crystal with deuteration level of 70% has been successfully grown by the traditional method, which can fabricate the large single-crystal optics with the size exceeding 400 mm. Neutron diffraction technique is an efficient method to research the deuterium content and 3D residual strains in single crystals. More efforts have been paid in the processes of purity of raw materials, continuous filtration technology, thermal annealing and laser conditioning for increasing the laser-induced damage threshold (LIDT) and these processes enable the currently grown crystals to meet the specifications of the laser system for inertial confinement fusion (ICF), although the laser damage mechanism and laser conditioning mechanism are still not well understood. The advancements on growth of large-aperture high-quality DKDP crystal would support the development of ICF in China.

Comparative effectiveness research considered methodological insights from simulation studies in physician's prescribing preference.

OBJECTIVES: To review comparative effectiveness research (CER) using physician's prescribing preference as an instrumental variable (PPP IV) in pharmacoepidemiology and to review methodological studies that use simulation to evaluate the performance of PPP IV in CER. STUDY DESIGN AND SETTING: We conducted a review of CER using PPP IV and studies evaluating the use of PPP IV by using simulation methods. We searched Ovid, PubMed, and Google Scholar databases from 2005 to 2020. RESULTS: We identified six simulation studies and 18 CER studies. The simulation studies explored the most suitable ways for using PPP IV in different settings (outcome types, sample size, and the prevalence of outcomes) which can be useful guidance for using PPP IV in CER. The CER studies identified show heterogeneity in terms of validation assumptions, estimation methods, and sample size. Not all applied studies used the methodological insights from the simulation studies. However, they all concluded that PPP is a valid IV. CONCLUSION: Future CER should consider a range of methodological issues to improve the validity of findings when using PPP IV. Specifically, studies should consider the impact of a different choice of statistical methods, forms of proxy for measuring preference, time-varying exposures, and the type of outcome.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

An infection-induced RhoB-Beclin 1-Hsp90 complex enhances clearance of uropathogenic Escherichia coli.

Host cells use several anti-bacterial pathways to defend against pathogens. Here, using a uropathogenic Escherichia coli (UPEC) infection model, we demonstrate that bacterial infection upregulates RhoB, which subsequently promotes intracellular bacteria clearance by inducing LC3 lipidation and autophagosome formation. RhoB binds with Beclin 1 through its residues at 118 to 140 and the Beclin 1 CCD domain, with RhoB Arg133 being the key binding residue. Binding of RhoB to Beclin 1 enhances the Hsp90-Beclin 1 interaction, preventing Beclin 1 degradation. RhoB also directly interacts with Hsp90, maintaining RhoB levels. UPEC infections increase RhoB, Beclin 1 and LC3 levels in bladder epithelium in vivo, whereas Beclin 1 and LC3 levels as well as UPEC clearance are substantially reduced in RhoB+/- and RhoB-/- mice upon infection. We conclude that when stimulated by UPEC infections, host cells promote UPEC clearance through the RhoB-Beclin 1-HSP90 complex, indicating RhoB may be a useful target when developing UPEC treatment strategies.

Self-assembling nitrilotriacetic acid nanofibers for tracking and enriching His-tagged proteins in living cells.

Specific and expeditious identification and enrichment of target proteins in living cells is often a challenging task. The hexahistidine (6His) tag is frequently used to label artificially engineered proteins produced in prokaryotic or eukaryotic cells. Utilizing the interaction between 6His-tag and nitrilotriacetic acid (NTA) mediated by divalent metal ions (Ni2+, Cu2+, Zn2+ or Co2+), we designed and synthesized a series of Nap-G/Biotin/ANA-FFpYGK-NTA probes that, assisted by alkaline phosphatase (ALP), self-assemble into nanofibers. The probe consists of an NTA group that specifically binds to 6His-tag, an FFpY group that promotes self-assembly facilitated by ALP, and a hydrophobic (Nap-G/ANA/Biotin) capping group for various applications. We demonstrate that the ANA-FFpYGK-NTA(Ni2+) nanofibers are fit for real-time tracking of His-tagged protein in living cells, and the Biotin-FFpYGK-NTA(Ni2+) nanofibers are for isolating His-tagged proteins and other proteins that they interact with.

Real-time monitoring of caspase-3/8 activity by self-assembling nanofiber probes in living cells.

Caspase-3/8 are key members of the cysteine-aspartyl protease family with pivotal roles in apoptosis. We have designed and synthesized self-assembling probes, Nap-GFFpYDEVD-AFC and Nap-GFFpYIETD-AFC, with fluorescence 'turn-on' properties for real-time monitoring of Caspase-3/8 activity in living cells.

Self-assembling peptide-etoposide nanofibers for overcoming multidrug resistance.

We developed a new strategy to overcome the MDR of etoposide using self-assembling nanofibers. Compared with the original etoposide, the inhibitory activity of Nap-GFFpYK-etoposide1/2 against murine Lewis lung cancer or breast cancer cells was increased 10 times, and 20 times on these cells with artificially overexpressed MDR1. Our method to synthesize and separate etoposide isomers provides a new strategy for the modification of this drug.

A Mokken scale analysis of the Kessler-6 screening measure among Chinese older population: findings from a national survey.

BACKGROUND: The aging population increases rapidly across the world. Timely and effective screening of their mental-health problems is important to individuals, families, and the whole society. The Kessler-6 screening measure (K6) is a very popular instrument for non-specific psychological distress. However, few studies have focused on the psychometric properties of this instrument in the older population. METHODS: The present study employed Mokken scale analysis to evaluate its dimensionality and structure. This study also used differential item functioning (DIF) to examine whether the same structure existed across sex in a national representative sample of old Chinese people. Data were drawn from a public data set, the 2010 China Family Panel Studies (CFPS2010), and responses from a total of 6450 participants aged 60 years old and above (3136 males and 3314 females) were included in the final analysis. RESULTS: Mokken scale analysis supported the unidimensional structure of the K6. Differential item functioning (DIF) analysis revealed that two of the six items ("Hopeless" and "Everything was an effort") were marked for DIF based on the Chi-square. However, their impacts were negligible in terms of McFadden's pseudo R2. CONCLUSIONS: The K6 demonstrates adequate psychometric properties in the old Chinese population. The sum of all six items can be used as an indicator of non-specific psychological distress. Differences in the indicator across sex should be considered as a real difference in psychological distress between the female and the male.

Compounds targeting YadC of uropathogenic Escherichia coli and its host receptor annexin A2 decrease bacterial colonization in bladder.

BACKGROUND: Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), and fimbrial tip adhesins, play important roles in UPEC colonization. Few fimbrial tip adhesins and their receptors on host cells, which have the potential to be the therapeutic targets, have been identified. METHODS: the UPEC wild-type strain CFT073, ΔyadC and the complemented strain were used to perform assays in vitro and in vivo. The effects of D-xylose targeting YadC on UPEC colonization were evaluated. A YadC receptor was identified by far-western blotting, LC-MS/MS and co-immunoprecipitation. The effects of compounds targeting the receptor on UPEC colonization were tested. FINDINGS: YadC was investigated for its mediation of UPEC adhesion and invasion to bladder epithelial cells in vitro; and its promotion of UPEC colonization in bladder in vivo. D-xylose, targeting YadC, showed prophylactic and therapeutic effects on UPEC colonization. Annexin A2 (ANXA2) was identified as a YadC receptor, involved in UPEC infection. ANXA2 inhibitors attenuated UPEC infections. The yadC gene was widely present in UPEC clinical isolates and phylogenetic analysis of yadC was performed. INTERPRETATION: YadC and its receptor ANXA2 play important roles in UPEC colonization in bladder, leading to novel treatment strategies targeting YadC or ANXA2 for acute UTIs. FUND: This study was supported by grants from the National Natural Science Foundation of China (NSFC) Programs (31670071 and 31970133), the National Key Technologies R&D Program, Intergovernmental international innovation cooperation (2018YFE0102000), Tianjin Science and Technology Commissioner Project (18JCZDJC36000), the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2017ZD12). The Science Foundation of Tianjin Medical University (2016KY2M08).

Comparison of hydrogen vacancies in KDP and ADP crystals: a combination of density functional theory calculations and experiment.

The hydrogen vacancy (VH) is the most common point defect that may lead to optical damage of potassium dihydrogen phosphate (KDP) and its analog ammonium dihydrogen phosphate (ADP), further limiting their practical application in high-power laser systems. In this work, we have grown KDP and ADP crystals by using a rapid growth method, and investigated the physical origin of the different stability of VH as well as the defect-induced electronic structure and optical absorption in KDP and ADP crystals. The inclusion of van der Waals correction to density functional theory calculations is found to have little influence on VH energetics of KDP whereas it largely reduces the charge transition level ε(+/-) of VH by >2 eV in ADP. It is found that hydrogen vacancies mainly contribute to the redshift of the measured absorption edges of both KDP and ADP crystals. Owing to the varied lattice environments and locations, the VH defects exhibit different stability, and electronic and optical properties in KDP and ADP crystals. Notably, the extra optical absorption caused by the positively-charged VH in KDP could be largely reduced by decreasing the defect concentration, whereas ADP exhibits defect-location dependence - the optical damage center of the VH in the NH4+ group could not be eliminated because of electron capture of its neighboring N atoms. The calculation results help us to better understand the origin of laser damage in KDP and ADP crystals.

Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor α membrane trafficking to promote breast cancer progression.

BACKGROUND: Epidermal growth factor receptor (EGFR) signalling is critical in epithelial cancer development. Human rhomboid family-1 (RHBDF1) facilitates the secretion of TGFα, an EGFR ligand, in breast cancer; however, the underlying mechanism remains unclear. We evaluated the role for RHBDF1 in clathrin-coated vesicle (CCV)-dependent pro-TGFα membrane trafficking in breast cancer cells upon stimulation by G-protein coupled receptor (GPCR) agonists. METHODS: RHBDF1 was silenced in various breast cancer cells using shRNA. TGFα levels, subcellular localization, and secretion were evaluated using ELISA, immunofluorescent staining, and coimmunoprecipitation. Phosphorylation and expression of relevant proteins were measured by western blotting. RHBDF1-dependent cell viability and invasion were measured. FINDINGS: RHBDF1 mediates GPCR agonist-induced EGFR phosphorylation by promoting TGFα secretion in various types of breast cancer cells. RHBDF1 not only mediates ADAM17-dependent shedding of TGFα, but is essential in membrane trafficking of pro-TGFα. RHBDF1 silencing results in blocking of clathrin uncoating from CCV, a crucial step for the plasma membrane release of pro-TGFα. Interaction of RHBDF1 with auxilin-2, a CCV protein, determines the recruitment of HSC70 to CCV to facilitate clathrin uncoating. RHBDF1 function is required for the proliferation and mobility of breast cancer cells upon stimulation by Sphingosine 1 Phosphate (S1P), a GPCR agonist. We demonstrate a significant correlation between RHBDF1 overexpression and EGFR activation in breast cancer tissues. INTERPRETATION: RHBDF1 is an indispensable component of the protein trafficking machinery involved in GPCR-mediated EGFR transactivation, and is an attractive therapeutic target for cancer. FUND: National Natural Science Foundation of China (81,672,740 to ZSZ, 81,272,356 and 81,330,029 to LYL).

Chronic Stress and Moral Decision-Making: An Exploration With the CNI Model.

Stress is prevalent in our daily life, and people often make moral decision-making in a stressful state. Several studies indicated the influence of acute stress on moral decision-making and behavior. The present study extended the investigation to chronic stress, and employed a new approach, the CNI model, to add new insights regarding the mechanism underlying the association between chronic stress and moral decision-making. A total of 197 undergraduates completed the Perceived Stress Scale and made moral decision-making on a series of deliberately designed moral dilemmas. The results indicated that higher chronic stress was related to more deontological moral choices. The process-dissociation analyses revealed that chronic stress was marginally significantly associated with deontological inclinations but not with utilitarian inclinations. And the CNI model analyses suggested that the high-stress group (above the median) showed a stronger general preference for inaction than the low-stress group (below the median) did, but there were no significant differences in sensitivity to consequences or sensitivity to moral norms between the two groups. Finally, the implications of the findings were discussed.

A novel Anti-Cancer Stem Cells compound optimized from the natural symplostatin 4 scaffold inhibits Wnt/ß-catenin signaling pathway.

Cancer stem cells (CSCs) are responsible for carcinogenesis, cancer progression, relapse, metastasis and drug resistance. Therefore, the development of drug molecules targeting CSCs plays a vital role in medicinal researching field. However, there are extremely rare molecules that selectively ablate CSCs. The research and development of drugs targeting CSCs is limited due to a lack of anti-CSCs lead compounds. In this study, an anti-CSCs lead compound 35b was discovered, which was derived from the natural chemical scaffold of Symplostatin 4. This compound exhibited a significantly suppressive effect on tumor growth both in vitro and in vivo. Additionally, 35b could significantly reduce the number of melanoma tumor spheres and decrease the percentage of ALDH+ melanoma cells. Further mechanism study illustrated that compound 35b could eliminate the melanoma CSCs by efficiently blocking Wnt/ß-catenin signaling pathway. Collectively, our findings would provide a novel chemical scaffold and alternative idea of molecular design for development of anti-CSCs drugs.