Air pollution, traffic noise, mental health, and cognitive development: A multi-exposure longitudinal study of London adolescents in the SCAMP cohort.

BACKGROUND: There is increasing evidence that air pollution and noise may have detrimental psychological impacts, but there are few studies evaluating adolescents, ground-level ozone exposure, multi-exposure models, or metrics beyond outdoor residential exposure. This study aimed to address these gaps. METHODS: Annual air pollution and traffic noise exposure at home and school were modelled for adolescents in the Greater London SCAMP cohort (N=7555). Indoor, outdoor and hybrid environments were modelled for air pollution. Cognitive and mental health measures were self-completed at two timepoints (baseline aged 11-12 and follow-up aged 13-15). Associations were modelled using multi-level multivariate linear or ordinal logistic regression. RESULTS: This is the first study to investigate ground-level ozone exposure in relation to adolescent executive functioning, finding that a 1 interquartile range increase in outdoor ozone corresponded to -0.06 (p < 0.001) z-score between baseline and follow-up, 38 % less improvement than average (median development + 0.16). Exposure to nitrogen dioxide (NO2), 24-hour traffic noise, and particulate matter < 10 µg/m3 (PM10) were also significantly associated with slower executive functioning development when adjusting for ozone. In two-pollutant models, particulate matter and ozone were associated with increased externalising problems. Daytime and evening noise were associated with higher anxiety symptoms, and 24-hour noise with worse speech-in-noise perception (auditory processing). Adjusting for air pollutants, 24-hour noise was also associated with higher anxiety symptoms and slower fluid intelligence development. CONCLUSIONS: Ozone's potentially detrimental effects on adolescent cognition have been overlooked in the literature. Our findings also suggest harmful impacts of other air pollutants and noise on mental health. Further research should attempt to replicate these findings and use mechanistic enquiry to enhance causal inference. Policy makers should carefully consider how to manage the public health impacts of ozone, as efforts to reduce other air pollutants such as NO2 can increase ozone levels, as will the progression of climate change.

Risk it for a biscuit: Food safety behaviours and food insecurity of older adults.

Foodborne disease presents a significant public health issue, costing the UK economy £9 billion annually, with many incidences being due to food-related behaviours in the home. Adults aged 60 and over account for around a quarter of the population in England and Wales and are at a greater risk of foodborne disease and may suffer a much higher burden. Research into risky food behaviours has previously focused on larger cohorts and typically treats the over 60's as one homogenous group. The current paper aims to identify the characteristics associated with risky food-related practices related to cooking, cleaning, chilling, cross-contamination, and use-by date adherence. The current research analysed data from the Official Statistics survey, Food and You 2: Wave 6 (2022-23). A series of binary logistic regression models examined the characteristics associated with risky food-related practices. We demonstrate that the characteristics associated with risky behaviours are not uniform, with different factors being associated with specific behaviours. We suggest that risky behaviours cannot be targeted efficiently with a one size fits all approach. This research provides an evidence base for policy makers to target risky food behaviours in this understudied vulnerable group.

Real-world experience in treatment of donor-derived Hepatitis C virus in kidney transplant recipients with delayed initiation, shortened course glecaprevir/pibrentasvir versus standard of care.

BACKGROUND: There is limited literature describing the real-world practice of delayed initiation and shortened duration direct-acting antiviral (DAA) in kidney transplant recipients. We compared Hepatitis C virus (HCV) cure rates among kidney transplant recipients who received an HCV nucleic acid test positive (NAT +) kidney and were treated with sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks or glecaprevir/pibrentasvir (G/P) for 8 weeks, a duration that is 4 weeks shorter than the guideline recommendation for treatment delay beyond 1-week post-transplant. METHODS: Retrospective study of HCV-negative adult patients who received a kidney transplant from an HCV NAT+ donor between April 2019 and April 2022 treated with either SOF/VEL for 12 weeks or G/P for 8 weeks. The primary outcome was sustained virologic response 12 weeks after completion of therapy (SVR12). Secondary outcomes included time to DAA initiation, renal function, graft loss, patient death, liver function tests, and opportunistic infections. RESULTS: 102 kidney transplant recipients were included with 36 treated with G/P and 66 treated with SOF/VEL. All 36 (100%) treated with G/P achieved SVR12. One patient in the SOF/VEL group failed to achieve SVR12 but received additional therapy and was cured. Time to DAA initiation was similar with a mean of 4 weeks. There was no difference in AST/ALT > 3x ULN or renal function. One rejection occurred in each group. No patient death or graft loss was observed. There was no difference in cytomegalovirus and BK viremia between groups.  CONCLUSION: Delayed initiation of DAA therapy with 12 weeks of SOF/VEL or 8 weeks of G/P achieves SVR12 in kidney transplant recipients without significant adverse effects.

Virtual stimulation of the interictal EEG network localizes the EZ as a measure of cortical excitability.

Introduction: For patients with drug-resistant epilepsy, successful localization and surgical treatment of the epileptogenic zone (EZ) can bring seizure freedom. However, surgical success rates vary widely because there are currently no clinically validated biomarkers of the EZ. Highly epileptogenic regions often display increased levels of cortical excitability, which can be probed using single-pulse electrical stimulation (SPES), where brief pulses of electrical current are delivered to brain tissue. It has been shown that high-amplitude responses to SPES can localize EZ regions, indicating a decreased threshold of excitability. However, performing extensive SPES in the epilepsy monitoring unit (EMU) is time-consuming. Thus, we built patient-specific in silico dynamical network models from interictal intracranial EEG (iEEG) to test whether virtual stimulation could reveal information about the underlying network to identify highly excitable brain regions similar to physical stimulation of the brain. Methods: We performed virtual stimulation in 69 patients that were evaluated at five centers and assessed for clinical outcome 1 year post surgery. We further investigated differences in observed SPES iEEG responses of 14 patients stratified by surgical outcome. Results: Clinically-labeled EZ cortical regions exhibited higher excitability from virtual stimulation than non-EZ regions with most significant differences in successful patients and little difference in failure patients. These trends were also observed in responses to extensive SPES performed in the EMU. Finally, when excitability was used to predict whether a channel is in the EZ or not, the classifier achieved an accuracy of 91%. Discussion: This study demonstrates how excitability determined via virtual stimulation can capture valuable information about the EZ from interictal intracranial EEG.

Supporting Timor-Leste midwives and nurses through an educational program: An evaluative study.

Little is currently known about the impacts of participation in a five-week Australian maternal and newborn health training program for Timorese midwives and nurses. BACKGROUND: The maternal mortality rate in Timor-Leste is estimated to be around 204 per 100,000 live births, and there is a correlation between safe and quality maternal and newborn health services. Hence, there is a need to develop the nation's maternity workforce. Whilst numerous training programs have been geared towards improving the knowledge and skills of Timorese midwives and nurses, to date, no published study has evaluated their impact on participants. AIM: To describe satisfaction of an Australian maternal and newborn health training program for Timorese midwives and nurses and its impact based upon the participants survey and qualitative evaluations. METHODS: An evaluative study was conducted using a survey to explore the impacts of a five-week Australian residential training program on 12 Timorese midwives and one nurse. FINDINGS: The survey data demonstrated an increase in the participants knowledge and skills required to provide enhanced maternal and newborn care; post-training, most participants demonstrated increased knowledge of obstetric emergencies. The participants showed the most pronounced increase in Advanced Clinical Skills in the subjects of fetal assessment, neonatal resuscitation and obstetric emergencies. The qualitative data identified two main themes and six subthemes related to professionalism, communication, and connections. CONCLUSION: An Australian residential training program, provided in collaboration with local Rotary clubs can enhance the development of maternal and newborn healthcare skills for midwives and nurses from Timor-Leste.

Vivifying Outbreaks: Investigating the Influence of a Forecast Visual on Risk Perceptions, Time-Urgency, and Behavioral Intentions.

Although visual depictions of epidemiological data are not new in public health, the US public saw more of them during the COVID-19 pandemic than ever before. In this study, we considered visualizations of forecasts (i.e. predictions of how a disaster will unfold over time) formatted as line charts. We investigated how two choices scientists make when creating a forecast visual - the outcome of focus (cases or deaths) and the amount of data provided (more or less data) about the past or the potential future - shape behavioral intentions via risk-related appraisals (e.g. threat and efficacy). In an online experiment, participants (N = 236) viewed a written health alert about a novel airborne virus, with one of the eight versions of a forecast visual or no visual (text only). The results of the experiment showed that exposing people to a health alert with a forecast visual in it may be less effective than anticipated. Reading a written health alert with a forecast visual was, at best, equal to outcomes from reading an alert without it, and sometimes it performed worse: participants appraised the novel virus as a less urgent threat and the recommended solutions as less efficacious. Implications of the findings for theories of risk and visual health communication and practical considerations for future health communicators were discussed.

COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

OBJECTIVES: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy. METHODS: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database. RESULTS: In the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT. CONCLUSIONS: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Rethinking the Three Rs: Growing Momentum Toward a New Gold Standard in Australian Research.

Recent years have seen increasing recognition of the scientific, economic and ethical benefits of the use of non-animal models in advancing preclinical research, giving reason to rethink the application and framework of the Three Rs. However, to benefit from the economic advantages of shifting to such alternative methods, and to realise Australia's drug development potential, legislative reform is essential. Such reform should be responsive to international regulations that encourage the use of animal-free methods, and be coupled with a corresponding re-evaluation of current Three Rs frameworks and principles. If these supportive changes, and the recommendations from the 2023 Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) Futures Non-animal models report, are implemented concurrently - with government support paramount- then a new gold standard for scientific research in Australia could be created in which the use of non-animal models and animal-free methods is the default.

Network excitability of stimulation-induced spectral responses helps localize the seizure onset zone.

OBJECTIVE: While evoked potentials elicited by single pulse electrical stimulation (SPES) may assist seizure onset zone (SOZ) localization during intracranial EEG (iEEG) monitoring, induced high frequency activity has also shown promising utility. We aimed to predict SOZ sites using induced cortico-cortical spectral responses (CCSRs) as an index of excitability within epileptogenic networks. METHODS: SPES was conducted in 27 epilepsy patients undergoing iEEG monitoring and CCSRs were quantified by significant early (10-200 ms) increases in power from 10 to 250 Hz. Using response power as CCSR network connection strengths, graph centrality measures (metrics quantifying each site's influence within the network) were used to predict whether sites were within the SOZ. RESULTS: Across patients with successful surgical outcomes, greater CCSR centrality predicted SOZ sites and SOZ sites targeted for surgical treatment with median AUCs of 0.85 and 0.91, respectively. We found that the alignment between predicted and targeted SOZ sites predicted surgical outcome with an AUC of 0.79. CONCLUSIONS: These findings indicate that network analysis of CCSRs can be used to identify increased excitability of SOZ sites and discriminate important surgical targets within the SOZ. SIGNIFICANCE: CCSRs may supplement traditional passive iEEG monitoring in seizure localization, potentially reducing the need for recording numerous seizures.

A transient brain endothelial translatome response to endotoxin is associated with mild cognitive changes post-shock in young mice.

Sepsis-associated encephalopathy (SAE) is associated with increased risk of long-term cognitive impairment. SAE is driven, at least in part, by brain endothelial dysfunction in response to systemic cytokine signaling. However, the mechanisms driving SAE and its consequences remain largely unknown. Here, we performed translating ribosome affinity purification and RNA-sequencing (TRAP-seq) from the brain endothelium to determine the transcriptional changes after an acute endotoxemic (LPS) challenge. LPS induced a strong acute transcriptional response in the brain endothelium that partially correlates with the whole brain transcriptional response and suggested an endothelial-specific hypoxia response. Consistent with a crucial role for IL-6, loss of the main regulator of this pathway, SOCS3, leads to a broadening of the population of genes responsive to LPS, suggesting that an overactivation of the IL-6/JAK/STAT3 pathway leads to an increased transcriptional response that could explain our prior findings of severe brain injury in these mice. To identify any potential sequelae of this acute response, we performed brain TRAP-seq following a battery of behavioral tests in mice after apparent recovery. We found that the transcriptional response returns to baseline within days post-challenge, but reductions in gene expression regulating protein translation and respiratory electron transport remained. We observed that mice that recovered from the endotoxemic shock showed mild, sex-dependent cognitive impairment, suggesting that the acute brain injury led to sustained effects. A better understanding of the transcriptional and non-transcriptional changes in response to shock is needed in order to prevent and/or revert the devastating consequences of septic shock.

A Randomized Controlled Trial Testing the Effects of a Social Needs Navigation Intervention on Health Outcomes and Healthcare Utilization among Medicaid Members with Type 2 Diabetes.

Health systems are increasingly assessing and addressing social needs with referrals to community resources. The objective of this randomized controlled trial was to randomize adult Medicaid members with type 2 diabetes to receive usual care (n = 239) or social needs navigation (n = 234) for 6 months and compare HbA1c (primary outcome), quality of life (secondary outcome), and other exploratory outcomes with t-tests and mixed-effects regression. Eligible participants had an HbA1c test in claims in the past 120 days and reported 1+ social needs. Data were collected from November 2019 to July 2023. Surveys were completed at baseline and at 3-, 6-, and 12-month follow-up. Health plan data included care management records and medical and pharmacy claims. The sample was from Louisiana, USA, M = 51.6 (SD = 9.5) years old, 76.1% female, 66.5% Black, 29.4% White, and 3.0% Hispanic. By design, more navigation (91.5%) vs. usual care (6.7%) participants had a care plan. Social needs persisted for both groups. No group differences in HbA1c tests and values were observed, though the large amount of missing HbA1c lab values reduced statistical power. No group differences were observed for other outcomes. Proactively eliciting and attempting to provide referrals and resources for social needs did not demonstrate significant health benefits or decrease healthcare utilization in this sample.

Random interval schedule of reinforcement influences punishment resistance for cocaine in rats.

In an animal model of compulsive drug use, a subset of rats continues to self-administer cocaine despite footshock consequences and is considered punishment resistant. We recently found that punishment resistance is associated with habits that persist under conditions that typically encourage a transition to goal-directed control. Given that random ratio (RR) and random interval (RI) schedules of reinforcement influence whether responding is goal-directed or habitual, we investigated the influence of these schedules on punishment resistance for cocaine or food. Male and female Sprague Dawley rats were trained to self-administer either intravenous cocaine or food pellets on a seeking-taking chained schedule of reinforcement, with the seeking lever requiring completion of either an RR20 or RI60 schedule. Rats were then given four days of punishment testing with footshock administered at the completion of seeking on a random one-third of trials. For cocaine-trained rats, the RI60 schedule led to greater punishment resistance (i.e., more trials completed) than the RR20 schedule in males and females. For food-trained rats, the RI60 schedule led to greater punishment resistance (i.e., higher reward rates) than the RR20 schedule in female rats, although male rats showed punishment resistance on both RR20 and RI60 schedules. For both cocaine and food, we found that seeking responses were suppressed to a greater degree than reward rate with the RI60 schedule, whereas response rate and reward rate were equally suppressed with the RR20 schedule. This dissociation between punishment effects on reward rate and response rate with the RI60 schedule can be explained by the nonlinear relation between these variables on RI schedules, but it does not account for the enhanced resistance to punishment. Overall, the results show greater punishment resistance with the RI60 schedule as compared to the RR20 schedule, indicating that schedules of reinforcement are an influencing factor on resistance to negative consequences.

Oyster Restoration to Recover Ecosystem Services.

Oyster reef loss represents one of the most dramatic declines of a foundation species worldwide. Oysters provide valuable ecosystem services (ES), including habitat provisioning, water filtration, and shoreline protection. Since the 1990s, a global community of science and practice has organized around oyster restoration with the goal of restoring these valuable services. We highlight ES-based approaches throughout the restoration process, consider applications of emerging technologies, and review knowledge gaps about the life histories and ES provisioning of underrepresented species. Climate change will increasingly affect oyster populations, and we assess how restoration practices can adapt to these changes. Considering ES throughout the restoration process supports adaptive management. For a rapidly growing restoration practice, we highlight the importance of early community engagement, long-term monitoring, and adapting actions to local conditions to achieve desired outcomes.

The ecology of giant kelp colonization and its implications for kelp forest restoration.

The success and cost-effectiveness of kelp forest restoration hinges on understanding the colonization ecology of kelps, particularly with respect to dispersal potential, recruitment success, and subsequent establishment. To gain needed insight into these processes we examined spatial patterns and temporal trajectories of the colonization of a large artificial reef by the giant kelp Macrocystis pyrifera. The 151 ha artificial reef complex was constructed in three phases over 21 years, enabling dispersal, recruitment, and subsequent establishment to be examined for a wide range of environmental conditions, dispersal distances, and source population sizes. Natural colonization of all phases of the artificial reef by giant kelp was rapid (within 1 year) and extended across the entire 7-km-long reef complex. Colonization density declined with distance from the nearest source population, but only during the first phase when the distance from the nearest source population was ≤3.5 km. Despite this decline, recruitment on artificial reef modules farthest from the source population was sufficient to produce dense stands of kelp within a couple of years. Experimental outplanting of the artificial reef with laboratory-reared kelp embryos was largely successful but proved unnecessary, as the standing biomass of kelp resulting from natural recruitment exceeded that observed on nearby natural reefs within 2-3 years of artificial reef construction for all three phases. Such high potential for natural colonization following disturbance has important implications for kelp forest restoration efforts that employ costly and logistically difficult methods to mimic this process by active seeding and transplanting.

Aerosol exposure at air-liquid-interface (AE-ALI) in vitro toxicity system characterisation: Particle deposition and the importance of air control responses.

Experimental systems allowing aerosol exposure (AE) of cell cultures at the air-liquid-interface (ALI) are increasingly being used to assess the toxicity of inhaled contaminants as they are more biomimetic than standard methods using submerged cultures, however, they require detailed characterisation before use. An AE-ALI system combining aerosol generation with a CULTEX® exposure chamber was characterised with respect to particle deposition and the cellular effects of filtered air (typical control) exposures. The effect of system parameters (electrostatic precipitator voltage, air flowrate to cells and insert size) on deposition efficiency and spatial distribution were investigated using ICP-MS and laser ablation ICP-MS, for an aerosol of CeO2 nanoparticles. Deposition varied with conditions, but appropriate choice of operating parameters produced broadly uniform deposition at suitable levels. The impact of air exposure duration on alveolar cells (A549) and primary small airway epithelial cells (SAECs) was explored with respect to LDH release and expression of selected genes. Results indicated that air exposures could have a significant impact on cells (e.g., cytotoxicity and expression of genes, including CXCL1, HMOX1, and SPP1) at relatively short durations (from 10 mins) and that SAECs were more sensitive. These findings indicate that detailed system characterisation is essential to ensure meaningful results.