Current treatments for alcohol use disorders (AUD) have limited efficacy. Recently, Cannabidiol (CBD) has been examined in a multitude of clinical settings. Preclinical and clinical results suggest that CBD might be particularly well suited for the treatment of AUD and may reduce alcohol cue and stress-induced craving and alcohol seeking. This study aims to investigate this new pharmacotherapy with a particular focus on neurobiological and physiological indicators of craving. Methods: In this double-blind, within-subject, randomised, placebo-controlled, cross-over study, non-treatment seekers will be randomly allocated to three days of four 200 mg CBD gel capsules (800 mg/day) or placebo, with an 18-day washout period. Cognitive, clinical, and neuroimaging assessments will be completed during these three days. The CBD and placebo assessments will be compared. The primary outcomes are i) BOLD signal as a proxy for regional activity during a cue reactivity and a fear response task measured with functional magnetic resonance imaging (fMRI), ii) heart rate variability and skin conductance levels as a proxy for psychophysiological responses to alcohol stimuli. The secondary outcomes are: i) neurometabolite levels (γ-Aminobutyric acid, ethanol, glutathione, and glutamate + glutamine (combined signal)) using magnetic resonance spectroscopy (MRS); ii) functional connectivity using resting state fMRI (rsfMRI); iii) executive functioning task results; iv) clinical outcomes such as craving, anxiety, and sleep. Discussion: This study will improve the understanding of the mechanisms of action of CBD and provide early signals of efficacy regarding the therapeutic potential of CBD in the treatment of alcohol use disorder. ClinicalTrials.gov Identifier: NCT05387148.

BACKGROUND: Yajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear.
OBJECTIVE: The objective of this investigation is to explore how YJSB influences the TGF-β1/Smad signaling pathway as a strategy for reducing HF.
METHODS: The establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-β1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson\'s trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-β1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB\'s impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-β1/Smad signaling cascade.
RESULTS: In the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-β1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-β1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-β1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C.
CONCLUSIONS: YJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-β1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.

Hypertensive disorders of pregnancy (HDP) are the most common medical conditions in pregnancy and a leading cause of maternal morbidity and mortality in the United States. There are few interventions available to prevent HDP, and those currently available do not target underlying mechanisms of disease. Mindfulness training (MT) is effective at reducing blood pressure in non-pregnant patients with pre-hypertension and hypertension and has proven more effective at blood pressure reduction than other stress management interventions. MT thus holds great promise as a mind-body intervention to prevent HDP. This randomized trial will harness subjective and objective ecological momentary assessment methodology combined with wearable biosensor technology to capture psychological, physiological, and interpersonal processes through which MT may lead to improved maternal cardiovascular parameters. Pregnant women at risk for HDP will be randomized to an 8-week phone-delivered MT intervention or usual care. Through these methods, we will evaluate psychological, physiological, and interpersonal responses to daily experiences linking MT to cardiovascular parameters among women at risk for HDP.

The possibility of the formation of glycine (Gly) from fundamental gas molecules in cold interstellar media was studied using quantum chemical methods, transition state theory and microcanonical molecular dynamics simulations with surface hopping dynamics (NVE-MDSH). This theoretical study emphasized five photochemical pathways in the lowest singlet-excited (S 1) state, thermochemical processes after non-radiative S 1→S 0 relaxations, and photo-to-thermal energy conversion in the NVE ensemble. The optimized reaction pathways suggested that to generate a reactive singlet dihydroxy carbene (HOCOH) intermediate, photochemical pathways involving the H2O…CO van der Waals and H2O-OC hydrogen bond precursors (Ch (1)_Step (1)) possess considerably lower energy barriers than the S 0 state pathways. The Gibbs free energy barriers (∆G ǂ ) calculated after the non-radiative S 1 →S 0 relaxations indicated higher spontaneous temperatures (T s) for the formation of the HOCOH intermediate (Ch (1)_Step (1)) than for Gly formation (Ch (1)_Step (2) and Ch (4)). Although the termolecular reaction in Ch (4) possesses a low energy barrier, and is thermodynamically favourable, the high exothermic S 1 →S 0 relaxation energy leads to the separation of the weakly associated H2O…CH2NH…CO complex into single molecules. The NVE-MDSH results also confirmed that the molecular processes after the S 1 →S 0 relaxations are thermally selective, and because the non-radiative S 1 →S 0 relaxation temperatures are exceedingly higher than T s, the formation of Gly on consecutive reaction pathways is non-synergistic with low yields and several side products. Based on the theoretical results, photo-to-thermal control strategies to promote desirable photochemical products are proposed. They could be used as guidelines for future theoretical and experimental research on photochemical reactions.

BACKGROUND: Physiotherapeutic management is the first-line intervention for patients with entrapment neuropathies such as carpal tunnel syndrome (CTS). As part of physiotherapy, neurodynamic interventions are often used to treat people with peripheral nerve involvement, but their mechanisms of action are yet to be fully understood. The MONET (mechanisms of neurodynamic treatment) study aims to investigate the mechanisms of action of neurodynamic exercise intervention on nerve structure, and function.
METHODS: This mechanistic, randomised, single-blind, controlled trial will include 78 people with electrodiagnostically confirmed mild or moderate CTS and 30 healthy participants (N = 108). Patients will be randomly assigned into (1) a 6-week progressive home-based neurodynamic exercise intervention (n = 26), (2) a steroid injection (= 26), or (3) advice (n = 26) group. The primary outcome measure is fractional anisotropy of the median nerve at the wrist using advanced magnetic resonance neuroimaging. Secondary outcome measures include neuroimaging markers at the wrist, quantitative sensory testing, electrodiagnostics, and patient reported outcome measures. Exploratory outcomes include neuroimaging markers at the cervical spine, inflammatory and axonal integrity markers in serial blood samples and biopsies of median nerve innervated skin. We will evaluate outcome measures at baseline and at the end of the 6-week intervention period. We will repeat questionnaires at 6-months. Two-way repeated measures ANCOVAs, followed by posthoc testing will be performed to identify differences in outcome measures among groups and over time.
CONCLUSIONS: This study will advance our understanding of the mechanisms of action underpinning neurodynamic exercises, which will ultimately help clinicians to better target these treatments to those patients who may benefit from them. The inclusion of a positive control group (steroid injection) and a negative control group (advice) will strengthen the interpretation of our results.
BACKGROUND: NCT05859412, 20/4/2023.

The present investigation addresses the mechanical properties, wear behaviour, and high-temperature oxidation of cermets and hardmetals based on either Ti(C,N) or WC and a metal binder based on Fe15Ni or Fe15Ni10Cr. This study also includes a commercial-grade WC-Co for comparative purposes. The production of these materials involved a powder metallurgy and sinter-HIP processing route under identical conditions. It is found that WC-based materials have superior mechanical properties, including hardness, fracture toughness, transversal rupture strength (TRS), and wear response, compared to Ti(C,N)-based materials. However, the latter show better oxidation behaviour than the former. Notably, WC-FeNi exhibits a higher hardness and TRS than the commercial-grade material (an increase of 7% and 9%, respectively). The difference in wear behaviour is due to the difference in wear mechanisms. In this regard, cermets wear through a tribolayer of Ti and Fe oxides, while hardmetals primarily wear through abrasion from ploughing. Thus, hardmetals exhibit a lower coefficient of friction (COF) and wear rate than cermets. Furthermore, Ti(C,N)-based materials form a protective layer of TiO2, which enhances their integrity and reduces mass gain. The addition of Cr to the FeNi binder only appears to have a clear effect on the TRS of the materials.

UNASSIGNED: Social prescribing involves connecting individuals to community groups and activities, often to support their mental health and well-being. It has received increasing support in recent years across the NHS. There is a strong evidence base for the benefits of different types of community activities, including exercise groups, arts groups and nature interventions, on mental health outcomes, however, less is known about how these groups impact mental health and well-being. This study explores through what individual-level mechanisms (the \'how\') these groups support psychosocial well-being.
UNASSIGNED: An ethnographic study was conducted over 12-months to explore key shared, individual-level mechanisms across 4 social prescribing community groups: football, singing, gardening and reading. This study focused mostly on those with severe mental illness, whereas previously most social prescribing studies have focused on mild to moderate mental health problems. To frame the findings, a \'multi-level theoretical framework of mechanisms of action\' of leisure activities was used.
UNASSIGNED: Key shared psychological mechanisms were: increased self-confidence and self-esteem, increased purpose/meaning, increased sense of achievement, experience of pleasure; social mechanisms included: increased social support, formation of friendships and reduced loneliness, enhanced sense of community and belonging; behavioural mechanisms were: increased independence and openness to experience, reduction in addictive behaviours and building healthier habits, increased work-seeking behaviour, and provision of structure & routine.
UNASSIGNED: It is hoped that the findings of this study can help referring professionals increase their understanding of exactly how such groups support individuals\' mental health, thus enhancing referring practices.
This study uses ethnographic methods, wherein the lead researcher spent over a year participating in 4 different community groups, using interviews, conversations and observation to explore the mental health impact of such groups on individuals\' lives. The participants had moderate to severe mental health conditions, and the groups consisted of a reading, gardening, singing and football group. The study explored \'mechanisms\' underlying the mental health benefits of these groups. Key shared psychological mechanisms were: increased self-confidence and self-esteem, increased purpose/meaning, increased sense of achievement, experience of pleasure; social mechanisms included: increased social support, formation of friendships and reduced loneliness, enhanced sense of community and belonging; behavioural mechanisms were: increased independence and openness to experience, reduction in addictive behaviours and building healthier habits, increased work-seeking behaviour, and provision of structure & routine. It is hoped that the findings of this study can help referring professionals (e.g. GPs, social workers, link workers) increase their understanding of exactly how such groups support individuals’ mental health, thus improving referring skills.

Disparities in stroke may be due to socioeconomics, demographics, risk factors (RF) and ethnicity. Asian data are scant. This retrospective hospital-based study aimed to explore demographics, RF, stroke subtypes and mechanisms among the Chinese, Malays and Indians in Singapore. Stroke was subtyped into haemorrhagic stroke (HS) and ischaemic stroke (IS). For IS, the clinical syndrome was classified using the Oxfordshire Community Stroke Project (OCSP) classification while the stroke mechanism was categorised using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. During the study period 1 June 2015 to 31 December 2023, data were collected on 1165 patients, with a mean age of 65.6 ± 12.9 yr; 47.4% were female, 83% were Chinese and hypertension (63.5%) and hyperlipidaemia (60.3%) were the most common RF. HS comprised 23.5% (95%CI 21.1-26.1%) (intracerebral 21.7%, subarachnoid 1.3%) of the patients, while IS comprised 76.5% (95%CI 73.9-78.9%) (small artery occlusion 29.0%, cardioembolism 13.3%, large artery atherosclerosis 9.4%, stroke of other determined aetiology 6.2%, stroke of undetermined aetiology 18.6%); 55% of patients had lacunar syndrome. A multivariable analysis showed that HS was associated with ethnicity (p = 0.044), diabetes mellitus (OR 0.27, 95%CI 0.18-0.41, p < 0.001) and smoking (OR 0.47, 95%CI 0.34-0.64, p < 0.001). There were no significant inter-ethnic differences by the OCSP (p = 0.31) or TOAST (p = 0.103) classification. While differences in stroke subtype in Asia may be due to RF, ethnicity has a role. More studies are needed to further explore this.

Dissemination of digital cognitive behavioural therapy is a promising approach for treating insomnia in the broad population. Current evidence supports the effectiveness of the digital format, but clinical findings are often limited by the choice of control group and lack of in-depth therapeutic measures. This study was designed to investigate the specific effects of digital cognitive behavioural therapy in comparison to a self-monitoring application. Participants meeting criteria for insomnia were randomly allocated (1:1) to 8 weeks of digital cognitive behavioural therapy or 8 weeks of digital sleep monitoring (control application). The primary outcome, insomnia severity, was assessed at baseline, 8- and 16-weeks post-randomisation. Secondary outcomes included the assessment of sleep via application-integrated sleep diaries and actigraphy. Linear-mixed models were fitted to assess between-group differences. Fifty-six participants (48 females, mean age: M = 45.55 ± 13.70 years) were randomised to either digital cognitive behavioural therapy (n = 29) or digital sleep monitoring (n = 27). At 8- and 16-weeks post-randomisation, large treatment effects (d = 0.87-1.08) indicated robust reductions (-3.70 and -2.97, respectively; p ≤ 0.003) in insomnia severity in the digital cognitive behavioural therapy arm, relative to digital sleep monitoring. Treatment effects in favour of digital cognitive behavioural therapy were also found for self-reported and actigraphy-derived sleep continuity variables, indicating that sleep improved throughout the 8-week intervention period. Our study reinforces the role of digital cognitive behavioural therapy in achieving clinical improvements for patients with insomnia, affirming previous findings and supporting the specific effects of cognitive behavioural therapy.

UNASSIGNED: Recent studies have revealed a significant decrease in serum fetuin-A levels in atherosclerotic aneurysms, indicating that fetuin-A may play a protective role in the progression of arterial calcification. However, the specific mechanism behind this phenomenon remains unclear. We aimed to examine the association between fetuin-A levels in thoracic aortic aneurysms (TAAs) and risk of TAAs and to evaluate whether this association was causal.
UNASSIGNED: A total of 26 SNPs were selected as instrumental variables for fetuin-A in 9,055 participants of European ancestry from the CHARGE consortium, and their effects on thoracic aortic aneurysm and decreased descending thoracic aortic diameter were separately estimated in 353,049 and 39,688 individuals from FinnGen consortium. We used two-sample Mendelian randomization (MR) analysis to examine the causal association. At the same time, we employed various methods, including random-effects inverse variance weighting, weighted median, MR Egger regression, and MR PRESSO, to ensure the robustness of causal effects. We assessed heterogeneity using Cochran\'s Q value and examined horizontal pleiotropy through MR Egger regression and retention analysis.
UNASSIGNED: Fetuin-A level was associated with a significantly decreasing risk of thoracic aortic aneurysm (odds ratio (OR) 0.64, 95% CI 0.47 - 0.87, P = 0.0044). Genetically predicted fetuin-A was also correlated with the decreased descending thoracic aortic diameter (β = -0.086, standard error (SE) 0.036, P = 0.017).
UNASSIGNED: Serum fetuin-A level was negatively associated with risk of TTAs and correlated with the decreased descending thoracic aortic diameter. Mendelian randomization provides support for the potential causal relationship between fetuin-A and thoracic aortic aneurysm.