Toxic air pollution and cognitive decline: Untangling particulate matter.

There is increasing evidence indicating air pollution is an important factor influencing the aging brain. However, much of this work measures air pollution using particulate matter (PM). Yet we know that the chemical components of PM are not consistent across space or time. Rather, the possible chemical mixtures of PM vary and are therefore not reliably measuring the same thing across studies. In this study we attempt to disentangle the effects of the components of measured PM by using estimates of concurrent exposures of 415 industrial air toxics, as well as 44 neuro- and developmental toxics. Using bivariate latent curve models, we leverage individual level panel data from the bi-annual Health and Retirement Study to test how these exposures relate to cognitive score trajectories of respondents across the years 2002-2012. We find that more exposure to neurotoxics was associated with faster rate of cognitive decline by 1.09 points (p < 0.05).

Establishing Geriatric Opiate Use Patterns in Trauma.

Introduction: There is evidence that providers often overprescribe opiates in the postoperative period. Despite an ever-growing geriatric population, there is little research detailing current opiate usage in older patients after trauma. This population presents a unique set of challenges for pain management and prescription drug dependence due to sensitivity, a narrow therapeutic window, and high rates of pre-existing polypharmacy.Objective: Assess the use of narcotics in geriatric trauma patients with various injury patterns to establish a reference point for future intervention for reduction in narcotic dependence.Methods: We created a database of trauma patients' age ≥65 years admitted to a single level 1 trauma center in the Southeastern United States during the 2019 calendar year. Information gathered included patient factors, injury patterns, operative intervention, pain medications prescribed during hospitalization and at discharge, total and average daily morphine milligram equivalents (MME) inpatient and outpatient, and requests/prescriptions for narcotics at follow-up.Results: In 2019, there were 475 patients aged ≥65 admitted to our level 1 trauma center for acute traumatic injuries. 219 of those patients required operative intervention. Average total inpatient MME for this cohort was 169.0 with average daily MME of 22.89. The average total prescribed MME upon discharge was 79.27. There were 29 patients documented to request narcotic prescription refill at time of clinic follow-up, 27 of whom were prescribed a narcotic medication at follow-up.Conclusion: This dataset establishes a reference point for opiate use in geriatric trauma patients to facilitate further research for mitigation of risk in this population.

Can social media be used to increase fruit and vegetable consumption? A pilot intervention study.

Background: Exposure to social norms about fruit and vegetable intake has been shown to increase individuals' consumption of these foods. Further, exposure to socially endorsed 'healthy' food posts can increase consumption of low energy-dense (LED), relative to high energy-dense (HED) foods. The current pilot study aimed to investigate whether exposure to healthy eating (vs. control) social media accounts can shift normative perceptions about what others eat, eating intentions and self-reported food consumption. Methods: In a 2 (condition) × 2 (type of food consumed) mixed factorial design, 52 male and female students were asked to follow either healthy eating (intervention) or interior design (control) Instagram accounts over a two-week period. Baseline and post-intervention measures assessed normative perceptions of Instagram users' consumption of fruit and vegetables (LED foods), and energy dense snacks and sugar sweetened beverages (HED foods). Participants' intentions to consume, and self-reported consumption of these foods, were also measured. Results: There were no significant changes in perceptions about what others eat, or participants' own eating intentions (ps > 0.05). However, the intervention increased participants' self-reported consumption of LED foods by 1.37 servings (per day) and decreased consumption of HED foods by 0.81 items (per day), compared to the control condition (ps < 0.05). Conclusions: This novel pilot study demonstrates that a social norm-based social media intervention can successfully encourage healthier eating, with a large effect after two weeks. Certain social media platforms may therefore provide a viable tool for nudging healthy eating. Future work will aim to replicate these findings in a larger and more diverse sample.

The bacillithiol pathway is required for biofilm formation in Staphylococcus aureus.

Staphylococcus aureus is a major human pathogen that can cause infections that range from superficial skin and mucosal infections to life threatening disseminated infections. S. aureus can attach to medical devices and host tissues and form biofilms that allow the bacteria to evade the host immune system and provide protection from antimicrobial agents. To counter host-generated oxidative and nitrosative stress mechanisms that are part of the normal host responses to invading pathogens, S. aureus utilizes low molecular weight (LMW) thiols, such as bacillithiol (BSH). Additionally, S. aureus synthesizes its own nitric oxide (NO), which combined with its downstream metabolites may also protect the bacteria against specific host responses. We have previously shown that LMW thiols are required for biofilm formation in Mycobacterium smegmatis and Pseudomonas aeruginosa. Here, we show that the S. aureus bshC mutant strain, which is defective in the last step of the BSH pathway and lacks BSH, is impaired in biofilm formation. We also identify a possible S-nitrosobacillithiol reductase (BSNOR), similar in sequence to an S-nitrosomycothiol reductase found in M. smegmatis and show that the putative S. aureus bsnoR mutant strain has reduced levels of BSH and decreased biofilm formation. Our studies also show that NO plays an important role in biofilm formation and that acidified sodium nitrite severely reduces biofilm thickness. These studies provide insight into the roles of oxidative and nitrosative stress mechanisms on biofilm formation and indicate that BSH and NO are key players in normal biofilm formation in S. aureus.

Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical Matter─Compounds with Novel Mechanisms from High-Throughput Screening Profiles.

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries. Here, we outline a cheminformatics approach to identify a small set of compounds with likely novel mechanisms of action (MoAs), expanding the MoA search space for throughput limited phenotypic assays. Our approach is based on mining existing large-scale, phenotypic high-throughput screening (HTS) data. It enables the identification of chemotypes that exhibit selectivity across multiple cell-based assays, which are characterized by persistent and broad structure activity relationships (SAR). We validate the effectiveness of our approach in broad cellular profiling assays (Cell Painting, DRUG-seq, and Promotor Signature Profiling) and chemical proteomics experiments. These experiments revealed that the compounds behave similarly to known chemogenetic libraries, but with a notable bias toward novel protein targets. To foster collaboration and advance research in this area, we have curated a public set of such compounds based on the PubChem BioAssay dataset and made it available for use by the scientific community.

"I see it very much as an end-of-life food" - Barriers to oral nutritional supplement adherence, views from healthy older adults.

Malnutrition affects approximately one quarter of UK adults aged 65 years and over. As the global demographic shift continues, malnutrition is expected to increase. Oral nutritional supplements (ONS) are used both to prevent and to treat malnutrition. However, their effectiveness is compromised by poor adherence, and it is not well understood what contributes to this. Therefore, the current research was designed to explore ONS adherence from the parallel perspectives of ONS as a prescribed "medication" and as a food supplement/substitute. Eighteen older adults (13F, 5M; mean age = 73.4 yr; range: 70-80 yr) participated in focus groups (three in-person and one online), to investigate experiences of taking prescribed medications, including dietary supplements, and what should be factors to consider in supporting regular intake of ONS for trial development, as well as any potential improvements to products. Focus group sessions were recorded and then transcribed. Thematic Analysis was applied to the transcripts by the first author, and themes were discussed in depth, using exemplar quotes from participants. Five dominant themes were identified from the data: Disgust, Palatability and Acceptance; End-of-Life Care; Resistance to Medicines; Rituals and Reminders; and Real Food Displacement. Nutritional supplements were characterised as "disgusting", "manufactured", and associated with serious, chronic illness, as well as end-of-life care, in contrast to probiotics which were linked with health and wellness. The sweet taste of ONS was identified as a barrier to intake, given that it is generally associated with a signal to stop eating, and low hunger. As a group, participants tried to "avoid taking medicines", and viewed the need to have them negatively, yet most regularly took prescribed medication and/or vitamin supplements. Participants identified several, rituals and reminders to take medicines, including meal-based, or time-of-day-based prompts (e.g., before, with or after meals). To improve adherence, savoury products were suggested, as well as a more person-centred approach to individual nutritional needs and preferences. Overall, the group discussion mainly identified barriers to intake, but that improving taste, adding to "real food" (not replacing meals), and offering variety of flavour and form (e.g., savoury soups as well as sweet drinks) could be included in future trials to improve appeal and therefore intake. Future work should continue to explore how best to formulate, market and/or prescribe ONS, and how this might vary for malnutrition prevention vs treatment strategies.

Repeated exposure to models' positive facial expressions whilst eating a raw vegetable increases children's consumption of the modelled vegetable.

Exposing children to adults eating a raw vegetable with positive facial expressions ('positive modelling') increases children's consumption of the modelled vegetable. However, whether repeated versus a single exposure to positive modelling enhances this effect, and whether it generalises to a non-modelled vegetable, remains to be examined. Hence, this study examined the effect of a single exposure, versus repeated, exposure to positive modelling on children's acceptance and intake of a modelled and non-modelled vegetable. Children aged 5-6 years (N = 153; 81 males, 72 females) were randomised to one of three conditions in which they had i) a single or ii) repeated exposure to a video of adults eating raw broccoli with positive facial expressions or iii) were exposed to a no-food control video. Children's acceptance (measured as willingness to try and number of tastes), intake and liking of a modelled (raw broccoli) and non-modelled vegetable (raw mangetout) were measured. Children had greater raw broccoli consumption and liking if they had received repeated exposure to positive modelling, compared to children who had received a single exposure, but not compared to children in the control condition. Children's mangetout intake was greater in the single (versus repeated) positive condition, but this effect was not dependent on time. There was no effect on children's vegetable acceptance. Repeatedly exposing children to adults enjoying a vegetable encourages children's intake of the modelled vegetable in comparison to a single exposure. Thus, repeated exposure to others' food enjoyment may be a practical and useful strategy to encourage children's vegetable consumption.

Impact of minimally invasive lung transplantation on early outcomes and analgesia use: A matched cohort study.

BACKGROUND: Minimally invasive (MI) approaches to lung transplantation (LTx) offer the prospect of faster recovery compared to traditional incisions, however, little data exist describing the impact of surgical technique on early outcomes and analgesia use. METHODS: A prospectively maintained institutional registry identified 170 patients who underwent LTx between January, 2017 and June, 2022. Post-COVID acute respiratory distress syndrome, repeat, and multiorgan transplants were excluded (n = 27) leaving 37 MILTx and 106 traditional LTx patients. Propensity score matching by age, sex, body mass index, diagnosis, lung allocation score, double vs. single lung, hypertension, diabetes, and hospitalization status created 37 pairs. RESULTS: Before matching, MILTx patients were more often male (70% vs 43%) and more likely to receive grafts from younger (31 vs 42 years), circulatory death donors (19% vs 6%) compared with traditional LTx patients (all p < 0.05). After matching, there were no differences in graft warm ischemia or operative duration (both p > 0.05). Postoperatively, MILTx experienced shorter intensive care unit (ICU) (4.3 [IQR 3.1-5.5] vs 8.2 [IQR 3.7-10.8] days) and hospital lengths of stay (LOS) (13 [IQR 11-15] vs 17 [IQR 12-25] days) (both p < 0.05). Among patients surviving to discharge, MILTx patients required fewer opioid prescriptions at discharge (38% vs 66%, p = 0.008) and had improved pulmonary function at 3 months (Forced expiratory volume in 1 second 82 [IQR 72-102] vs 77 [IQR 52-88]% predicted; forced vital capacity 78 [IQR 65-92] vs 70 [IQR 62-80]% predicted] (both p < 0.05). CONCLUSION: Minimally invasive LTx techniques demonstrate potential advantages over traditional approaches, including reduced ICU and hospital LOS, lower opioid use on discharge, and improved early pulmonary function.

DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

Limited cumulative experience with ex vivo lung perfusion is associated with inferior outcomes after lung transplantation.

OBJECTIVE: Ex vivo lung perfusion (EVLP) allows for prolonged preservation and evaluation/resuscitation of donor lungs. We evaluated the influence of center experience with EVLP on lung transplant outcomes. METHODS: We identified 9708 isolated, first-time adult lung transplants from the United Network for Organ Sharing database (March 1, 2018-March 1, 2022), 553 (5.7%) involved using donor lungs after EVLP. Using the total volume of EVLP lung transplants per center during the study period, centers were dichotomized into low- (1-15 cases) and high-volume (>15 cases) EVLP centers. RESULTS: Forty-one centers performed EVLP lung transplants, including 26 low-volume and 15 high-volume centers (median volume, 3 vs 23 cases; P < .001). Recipients at low-volume centers (n = 109) had similar baseline comorbidities compared with high-volume centers (n = 444). Low-volume centers used numerically more donation after circulatory death donors (37.6 vs 28.4%; P = .06) and more donors with Pao2/Fio2 ratio <300 (24.8 vs 9.7%; P < .001). After EVLP lung transplants, low-volume centers had worse 1-year survival (77.8% vs 87.5%; P = .007), with an adjusted hazard ratio of 1.63 (95% CI, 1.06-2.50, adjusting for recipient age, sex, diagnosis, lung allocation score, donation after circulatory death donor, donor Pao2/Fio2 ratio, and total annual lung transplant volume per center). When compared to non-EVLP lung transplants, 1-year survival of EVLP lung transplants was significantly worse at low-volume centers (adjusted hazard ratio, 2.09; 95% CI, 1.47-2.97) but similar at high-volume centers (adjusted hazard ratio, 1.14; 95% CI, 0.82-1.58). CONCLUSIONS: The use of EVLP in lung transplantation remains limited. Increasing cumulative EVLP experience is associated with improved outcomes of lung transplantation using EVLP-perfused allografts.

Exposure to models' negative facial expressions whilst eating a vegetable decreases women's liking of the modelled vegetable, but not their desire to eat.

Introduction: Food enjoyment can be conveyed through facial expressions. Observing others' enjoyment of food has been found to influence adults' desirability of liked and disliked food. Exposing adults to other eaters enjoying nutritious foods that are typically disliked (e.g., vegetables) could enhance the consumption of vegetables by young adults. However, this remains to be examined in young adult populations. This study examined the effect of models' facial expressions towards raw broccoli on young adult women's change in liking and change in desire to eat a modelled vegetable (raw broccoli) and a non-modelled vegetable (cucumber). Methods: Young adult women (N = 205) were randomised to watch a video of unfamiliar adult models eating raw broccoli with a positive, negative, or neutral facial expression. Participants' change in liking and change in desire to eat the modelled and non-modelled vegetable was examined. Results: Observing models conveying negative facial expressions whilst eating raw broccoli resulted in a statistically significant reduction in liking ratings of broccoli, but not cucumber. There was no effect of models' facial expressions on the change in desire to eat foods. Discussion: These findings suggest that watching others express a negative facial expression whilst eating a raw vegetable reduces women's liking of the modelled vegetable, in the absence of a significant change to their desire to consume these foods. This highlights the power of others' negative facial expressions on food liking. Further work is needed to establish the effect of others' facial expressions on vegetable intake.