Search Results (18)

Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental. Full article

This prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 adults with obesity. The percent total weight loss for the highest versus the lowest weight loss tertiles (T3 vs. T1) was 17.0 ± 1.3% and 11.1 ± 0.8%, p < 0.001. Serum metabolite alterations specific to T3 at three months included a decrease in methionine sulfoxide concentration as well as alterations to tryptophan and methionine metabolism (p < 0.03). Fecal metabolite changes specific to T3 included a decrease in taurine concentration and perturbations to arachidonic acid metabolism, and taurine and hypotaurine metabolism (p < 0.002). Preoperative metabolites were found to be highly predictive of weight loss outcomes in machine learning algorithms, with an average area under the curve of 94.6% for serum and 93.4% for feces. This comprehensive metabolomics analysis of weight loss outcome differences post-SG highlights specific metabolic alterations as well as machine learning algorithms predictive of weight loss. These findings could contribute to the development of novel therapeutic targets to enhance weight loss outcomes after SG. Full article

Lung and breast cancer are the two most common causes of malignant pleural effusion (MPE). MPE diagnosis plays a crucial role in determining staging and therapeutic interventions in these cancers. However, our understanding of the pathogenesis and progression of MPE at the molecular level is limited. Extracellular Vesicles (EVs) and their contents, including microRNAs (miRNAs), can be isolated from all bodily fluids, including pleural fluid. This study aims to compare EV-miRNA patterns of expression in MPE caused by breast (BA-MPE) and lung (LA-MPE) adenocarcinomas compared to the control group of heart-failure-induced effusions (HF-PE). We conducted an analysis of 24 pleural fluid samples (8 LA-MPE, 8 BA-MPE, and 8 HF-PE). Using NanoString technology, we profiled miRNAs within EVs isolated from 12 cases. Bioinformatic analysis demonstrated differential expression of miR-1246 in the MPE group vs. HF-PE group and miR-150-5p and miR-1246 in the BA-MPE vs. LA-MPE group, respectively. This difference was demonstrated and validated in an independent cohort using real-time PCR (RT-PCR). miRNA-1246 demonstrated 4-fold increased expression (OR: 3.87, 95% CI: 0.43, 35) in the MPE vs. HF-PE group, resulting in an area under the curve of 0.80 (95% CI: 0.60, 0.99). The highest accuracy for differentiating MPE vs. HF-PE was seen with a combination of miRNAs compared to each miRNA alone. Consistent with prior studies, this study demonstrates dysregulation of specific EV-based miRNAs in breast and lung cancer; pleural fluid provides direct access for the analysis of these EV-miRNAs as biomarkers and potential targets and may provide insight into the underlying pathogenesis of tumor progression. These findings should be explored in large prospective studies. Full article

People bereaved by suicide are affected psychologically and physically and may be at greater risk of taking their own lives. Whilst researchers have explored the impact of suicide on family members and friends, the area of colleague suicide has been neglected and postvention guidance for supporting surviving colleagues is often poorly developed. This critical integrative review explored the impact of colleague suicide on surviving co-workers and reviewed postvention guidance for workplaces. Systematic searches found 17 articles that met the inclusion criteria. Articles were appraised for quality and extracted data were analysed using a thematic network method. Article quality was moderate. Two global themes were developed: impact of a colleague suicide comprised themes of ‘suicide loss in the workplace’; ‘professional identities and workplace roles’; ‘perceptions of professional uniqueness’; and ‘professional abandonment and silencing’. Postvention following a colleague suicide comprised ‘individualised responses’; ‘the dual function of stigma’; and ‘complex pressure on managers’. A unifying global network ‘after a colleague suicide’ describes the relationships between all themes. A series of disconnects between existing postvention guidance and the needs of impacted workers are discussed. This review demonstrates the need for robust, systemic postvention for colleagues impacted by the complex issue of colleague suicide. Full article

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants. Full article

Introduction and aims: Associations between bar trading hours, a government lever for controlling alcohol availability, nightlife-goer intoxication levels and their likelihood of alcohol use disorder (AUD) have not been explored. We investigated whether: (i) participant AUD was associated with blood alcohol concentration (BAC); and, (ii) any association between AUD and BAC was moderated by participant preferred bar (i.e., venue spent most time at) closing time. Design and methods: A cross-sectional observational study using a sample of nightlife-goers who went out drinking in Perth, Western Australia, on weekends in 2015-16. Participants who reported alcohol use that night and spent most time in a bar (n = 667) completed street intercept surveys including AUDIT-C (n = 459) and provided a breath sample to estimate BAC (n = 651). We used gender-specific multinomial logistic regression models to explore associations between participant AUDIT-C score (1–4, lower risk; 5–7, hazardous; 8–12, active AUD), preferred bar type (standard vs. late closing time based on absence or presence of an extended trading permit) and BAC (male: 0–0.049, 0.05–0.099, ≥0.1 g/100 mL; female: 0–0.049, 0.05–0.079, ≥0.08 g/100 mL). Results: Males with active AUD (RR = 3.31; 95% CI 1.30–8.42; p = 0.01) and females with hazardous/active AUD (RR = 9.75; 95% CI 2.78–34.21; p < 0.001) were both more likely to have high-range BAC than their counterparts typically drinking at lower risk. We also found preferred bar type moderated the association between AUDIT-C score and BAC for some males but no females. Males with active AUD and high-range BAC were less likely to prefer late closing bars than males usually drinking at lower risk and high-range BAC (RR = 0.12; 95% CI 0.02–0.96; p = 0.046). Discussion and conclusions: Our study provides evidence of positive associations between AUD and acute intoxication among nightlife-goers and on the moderating effect of bar closing times among males. Full article

An effective vaccine against Chlamydia trachomatis is urgently needed as infection rates continue to rise and C. trachomatis causes reproductive morbidity. An obligate intracellular pathogen, C. trachomatis employs a type 3 secretion system (T3SS) for host cell entry. The tip of the injectosome is composed of the protein CT584, which represents a potential target for neutralization with vaccine-induced antibody. Here, we investigate the immunogenicity and efficacy of a vaccine made of CT584 epitopes coupled to a bacteriophage virus-like particle (VLP), a novel platform for Chlamydia vaccines modeled on the success of HPV vaccines. Female mice were immunized intramuscularly, challenged transcervically with C. trachomatis, and assessed for systemic and local antibody responses and bacterial burden in the upper genital tract. Immunization resulted in a 3-log increase in epitope-specific IgG in serum and uterine homogenates and in the detection of epitope-specific IgG in uterine lavage at low levels. By contrast, sera from women infected with C. trachomatis and virgin controls had similarly low titers to CT584 epitopes, suggesting these epitopes are not systemically immunogenic during natural infection but can be rendered immunogenic by the VLP platform. C. trachomatis burden in the upper genital tract of mice varied after active immunization, yet passive protection was achieved when immune sera were pre-incubated with C. trachomatis prior to inoculation into the genital tract. These data demonstrate the potential for antibody against the T3SS to contribute to protection against C. trachomatis and the value of VLPs as a novel platform for C. trachomatis vaccines. Full article

Introduction and aims: Associations between longer-term alcohol-related conditions and licensed outlet trading hours are not well understood. We investigated the association between nightlife-goers’ likelihood of an alcohol use disorder (AUD) and their preference for bars with special permits to remain open ‘late’ (i.e., spent more time there compared to any other venue) until 2 a.m. or 3 a.m. (Friday; Saturday) or midnight (Sunday) compared to bars with ‘standard’ closing times of midnight (Friday; Saturday) or 10 p.m. (Sunday). Design and methods: A cross-sectional observational study was conducted in four major nightlife areas of Perth, Australia, in 2015–2016. We conducted weekend street intercept surveys outside bars between 8 p.m. and 3 a.m. and screened participants who reported alcohol use prior to the survey and spent more time in a bar than any other venue type (n = 667) regarding their past year drinking pattern using AUDIT-C (n = 459). We used gender-specific logistic regression models to estimate associations between AUDIT-C categories (1–4, low risk; 5–7, hazardous; 8–12, active AUD) and preference for bars with different closing times (late vs. standard). Results: A large proportion of participants were hazardous drinkers or had active AUD (83% males; 65% females), and over half preferred a late to a standard closing bar. We found evidence of a positive association between preference for late closing bars and hazardous drinking females (OR = 3.48; 95% CI 1.47–8.23; p = 0.01), but not for females with active AUD, male hazardous drinkers, nor males with active AUD. Discussion and conclusions: Our study adds new evidence on associations between likelihood of AUD among nightlife-goers and trading hours. With increasing international relaxation of trading hours, evidence that late closing bars may be preferred by hazardous drinking females will be of concern to policymakers wanting to curb alcohol-related harms in the community. Full article

Rural communities are disproportionally affected by food insecurity, making them vulnerable to the consequences of supply disruptions caused by the COVID-19 pandemic. While access to food was initially diminished due to food supply disruptions, little is known about the mechanisms through which federal emergency assistance programs impacted food access in rural populations. Through a series of five focus groups in spring 2021, we examined the impact of the COVID-19 pandemic on food access in a rural Appalachian community in Kentucky. Data were analyzed using a Grounded Theory Approach. Findings revealed the following four primary themes: food scarcity in grocery stores; expanded federal food assistance; expanded community food resources; and expanded home gardening. Participants provided details regarding the way increased federal assistance, especially expanded benefits within the Supplemental Nutrition Assistance Program, allowed them to purchase greater quantities of nutritious food. This study unveils the specific impacts of the COVID-19 pandemic on one rural population, including the influence of some social determinants of health on food insecurity. Policymakers and stakeholders should recognize the layered protection of multiple federal emergency assistance programs against food insecurity and the potential for long-term population health promotion in rural areas. Full article

The global pandemic of coronavirus disease (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to an international thrust to study pathogenesis and evaluate interventions. Experimental infection of hamsters and the resulting respiratory disease is one of the preferred animal models since clinical signs of disease and virus shedding are similar to more severe cases of human COVID-19. The main route of challenge has been direct inoculation of the virus via the intranasal route. To resemble the natural infection, we designed a bespoke natural transmission cage system to assess whether recipient animals housed in physically separate adjacent cages could become infected from a challenged donor animal in a central cage, with equal airflow across the two side cages. To optimise viral shedding in the donor animals, a low and moderate challenge dose were compared after direct intranasal challenge, but similar viral shedding responses were observed and no discernible difference in kinetics. The results from our natural transmission set-up demonstrate that most recipient hamsters are infected within the system developed, with variation in the kinetics and levels of disease between individual animals. Common clinical outputs used for the assessment in directly-challenged hamsters, such as weight loss, are less obvious in hamsters who become infected from naturally acquiring the infection. The results demonstrate the utility of a natural transmission model for further work on assessing the differences between virus strains and evaluating interventions using a challenge system which more closely resembles human infection. Full article

Introduction and Aims: Past research indicates heavy episodic drinking (HED), trait aggression, male honour and conformity to masculine norms are risk factors for male barroom aggression (MBA) perpetration. However, little is known about the impact of these variables on experiences of MBA victimization. Further, data derived previously, particularly in relation to perpetration have come from relatively low-risk samples comprising university students, limiting the generalizability of findings to other, at-risk male groups. Thus, the present study assessed the impact of the aforementioned variables as well as personality constructs of impulsivity and narcissism on both the perpetration of and victimization from MBA among a high-risk sample sourced from male members of the Australian construction industry. Method: A purposive sample of Australian male construction workers aged 18 to 69 years (n = 476, M_age = 25.90, SD_age = 9.44) completed individual interviews at their current place of employment or while training at various trade schools in Geelong and Melbourne, Victoria, Australia. Items related to past month HED, past year experiences of verbal and physical MBA (perpetration and victimization), trait aggression’s four factors (physical, verbal, anger, hostility), impulsivity, narcissism, male honour and conformity to masculine norms. Results: Participants reported high levels of verbal (24.2%) and physical (21%) MBA perpetration and verbal (33.6%) and physical (31.1%) MBA victimization. Hierarchical binary logistic regression analyses identified HED as the strongest predictor of aggression involvement, while trait physical aggression, trait anger, narcissism and conformity to norms endorsing violence and a need to win were significantly and positively associated with MBA perpetration. Conclusions: The present study reinforces the key relationships between heavy drinking and aspects of personality and MBA, while also highlighting narcissism as a risk factor for barroom aggression perpetration. Indeed, personality profiles and HED appear to exert stronger influences on MBA perpetration than socially constructed masculinity factors, most of which were unrelated to aggression involvement in bars, clubs or pubs. Full article

The Breakthrough Series Quality Improvement Collaborative (QIC) initiative is a well-developed and widely used approach, but most of what we know about it has come from healthcare settings. In this article, those leading QICs to improve care in care homes provide detailed accounts of six QICs and share their learning of applying the QIC approach in the care home sector. Overall, five care home-specific lessons were learnt: (i) plan for the resources needed to support collaborative teams with collecting, processing, and interpreting data; (ii) create encouraging and safe working environments to help collaborative team members feel valued; (iii) recruit collaborative teams, QIC leads, and facilitators who have established relationships with care homes; (iv) regularly check project ideas are aligned with team members’ job roles, responsibilities, and priorities; and (v) work flexibly and accept that planned activities may need adapting as the project progresses. These insights are targeted at teams delivering QICs in care homes. These insights demonstrate the need to consider the care home context when applying improvement tools and techniques in this setting. Full article

Internet-based cognitive behavioral therapy (iCBT) may overcome barriers to mental health care and has proven efficacious. However, this approach currently exists outside the existing mental health care delivery system. Stepped care is a proposed framework for integrating digital mental health (DMH) into health systems by initiating iCBT and “stepping up” care to a more intensive intervention should iCBT prove ineffective. This study explores pre-treatment factors associated with reaching stepping criteria among patients receiving iCBT. This exploratory analysis of a stepped care arm of a larger randomized trial examined participants who were stepped to a more intensive intervention if they did not respond to iCBT. The association of pre-treatment factors on stepping were examined using Kruskal–Wallis and Chi-square tests. One-fifth of the 151 participants met criteria for stepping within the 20-week treatment period. Only pre-treatment depression severity and treatment preference were associated with increased likelihood of stepping (p = 0.049 and 0.048, respectively). The low number of individuals who stepped provides support for iCBT as an effective, low intensity treatment for depression. The modest association of pre-treatment depression and preference to not receive iCBT may be useful in identifying patients who are less likely to respond. Full article

Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide ω-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability. Full article