Stress and inflammation target dorsolateral prefrontal cortex function: Neural mechanisms underlying weakened cognitive control.

Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and the thoughtful regulation of attention, action and emotion. For example, schizophrenia, depression, long-COVID and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often focused in layer III. The dlPFC has extensive top-down projections: e.g. to the posterior association cortices to regulate attention, and the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state, and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors in most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research, and are summarized in this review. For example, the layer III dlPFC circuits generating working memory-related neuronal firing have unusual neurotransmission, depending on NMDAR and nicotinic-α7R actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A-AR and mGluR3 signaling, but dysregulated by inflammation and/or chronic stress exposure, contributing to spine loss. Treatments that strengthen dlPFC, via pharmacological (the α2A-AR agonist, guanfacine) or rTMS manipulation, provide a rational basis for therapy.

Comparing times of self-harm presentations to hospital emergency departments in children, adolescents, young adults and adults: a national registry study 2007-2019.

PURPOSE: The few studies that have explored self-harm presentation times at hospital emergency departments (EDs) - an important factor that can determine if a patient receives a mental health assessment - primarily focus on adult samples. This study examined the times of self-harm presentations to EDs, self-harm methods used, mental health assessments, and admission data across different age-groups. METHODS: Using data from the National Self-Harm Registry Ireland over a 13-year timeframe (2007-2019), this study compared times, days, seasons, methods of self-harm, and admission data for children (8-12 years), adolescents (13-17 years), young adults (18-25 years) and adults (> 25 years). RESULTS: The majority of the 152,474 self-harm presentations (78.6%) for all ages occurred out-of-hours (outside the standard working hours or in-hours times of 09:00-17:00, Monday-Friday). The four hours before midnight had the highest proportions of self-harm presentations for adolescents (27.9%) and adults (23.1%), whereas the four hours after midnight had the highest proportion of self-harm presentations for young adults (22.9%). The 16:00-midnight timeframe had highest proportion of self-harm presentations in children (52.3%). Higher proportions of patients received a mental health assessment in-hours compared to out-of-hours among young adults (78.2% vs. 73.3%) and adults (76.1% vs. 72.0%). Self-harm presentations were lowest during summer months in children and adolescents. DISCUSSION: Hospitals should ensure that adequate resources are available for individuals presenting with self-harm, especially in the case of overcrowded EDs, and protocols need to be designed for those presenting with self-harm due to intoxication. In line with national policy, protocols for patients presenting during out-of-hours should be designed that can incorporate services from allied health multidisciplinary teams, social work, addiction services and counselling organisations. Given the lower rates of self-harm during school holidays for children and adolescents, the school environment must be considered in the context of mental health and self-harm public health prevention interventions.

Discharged from the emergency department following hospital-presented self-harm: referral patterns and risk of repeated self-harm.

BACKGROUND: Presentation to the emergency department (ED) with self-harm provides an important opportunity for intervention. AIMS: To investigate characteristics and self-harm repetition risk of those discharged from the ED without a referral for mental health-related aftercare. METHOD: Data on consecutive self-harm presentations to EDs for the years 2013-2019 (n = 55,770) were obtained from the National Self-Harm Registry Ireland. Multilevel Poisson and Cox regression models were estimated. RESULTS: Half of the self-harm presenters were discharged from the ED (49.8%) and almost half of them did not receive a mental health-related referral (46.8%). Receipt of a psychosocial assessment was associated with a 50% reduced risk of non-referral (IRR 0.54; 95% CI 0.51-0.57). Non-referral was also less likely for young people (< 18 years), presentations involving attempted hanging, persons with previous self-harm presentations, and in the latter half of the study period (2017-2019 vs. 2013-2016), but was more likely for those brought by ambulance, presenting outside 9 am-5 pm and admitted to an ED medical assessment unit. Of those not referred, 19.3% had a repeat presentation within 12 months, compared to 22.4% of those referred. No difference in repetition risk between these two groups was evident in adjusted analyses. Self-harm history had the strongest association with repetition, with highest risk among individuals with four or more previous presentations (HR 9.30, 95% CI 8.14-10.62). CONCLUSIONS: The findings underline the importance of assessing all individuals who present with self-harm and highlight the need for comprehensively resourced 24hr services providing mental health care in the ED.

The meso-connectomes of mouse, marmoset, and macaque: network organization and the emergence of higher cognition.

The recent publications of the inter-areal connectomes for mouse, marmoset, and macaque cortex have allowed deeper comparisons across rodent vs. primate cortical organization. In general, these show that the mouse has very widespread, "all-to-all" inter-areal connectivity (i.e. a "highly dense" connectome in a graph theoretical framework), while primates have a more modular organization. In this review, we highlight the relevance of these differences to function, including the example of primary visual cortex (V1) which, in the mouse, is interconnected with all other areas, therefore including other primary sensory and frontal areas. We argue that this dense inter-areal connectivity benefits multimodal associations, at the cost of reduced functional segregation. Conversely, primates have expanded cortices with a modular connectivity structure, where V1 is almost exclusively interconnected with other visual cortices, themselves organized in relatively segregated streams, and hierarchically higher cortical areas such as prefrontal cortex provide top-down regulation for specifying precise information for working memory storage and manipulation. Increased complexity in cytoarchitecture, connectivity, dendritic spine density, and receptor expression additionally reveal a sharper hierarchical organization in primate cortex. Together, we argue that these primate specializations permit separable deconstruction and selective reconstruction of representations, which is essential to higher cognition.

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders.

Importance: The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders. Objective: To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices. Design, Setting, and Participants: The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques. Main Outcomes and Measures: Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments. Results: Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by ß1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or ß1-adrenoceptor antagonist protected working memory from stress. Conclusions and Relevance: The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration.

INTRODUCTION: Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217-tau levels in plasma. RESULTS: pT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

Disparities in the association between ambient temperature and preterm birth according to individual and regional characteristics: a nationwide time-stratified case-crossover study.

BACKGROUND: Several studies have reported that climate change elevates heat exposure in pregnant women and high temperatures during pregnancy are associated with preterm births (PTBs). Although the association might be disproportionate, related evidence remains sparse. We evaluated the disproportionate risk of PTB associated with ambient temperature during pregnancy by individual and regional characteristics in South Korea. METHODS: We collected data on birth certificates and daily mean temperatures during the period from 2011 to 2019. A time-stratified case-crossover design was used to investigate the association between temperature and PTB and stratified analyses were conducted to examine the effect modification of individual and regional characteristics. RESULTS: A total of 160,067 singleton PTBs were recorded in Korea from 2011 to 2019. A 5℃ increase in the mean temperature during the last four weeks before delivery was associated with an increased risk of PTB with an odds ratio (OR) of 1.03 (95% confidence interval [CI]: 1.02, 1.05), and the association was more evident in mothers aged ≥35 years (OR: 1.06 [95% CI: 1.03, 1.10]) and with low education levels (OR: 1.04 [95% CI: 1.02, 1.05]). Additionally, the estimated risk was evident in districts with lower medical resources and more prominent disparities were shown by individual and regional characteristics in rural areas than in urban areas. CONCLUSIONS: This study provides evidence that the risk of PTB related to ambient temperature is disproportionate by individual and regional characteristics and suggests the need for public health policies to alleviate the disparities, especially in rural areas.

A cost-analysis of managing secondary and apparent treatment-resistant hypertension in a specialist multidisciplinary hypertension clinic.

OBJECTIVES: A knowledge gap exists around the costs and budget impact of specialist hypertension clinics. This study reports on the cost of providing care in a multidisciplinary hypertension clinic staffed by nephrologist, endocrinologist and cardiologist, which manages patients with suspected secondary hypertension and/or apparent treatment-resistant hypertension. The aim of this study is to provide the evidence required to inform policy and planning care pathways for this patient group. METHODS: A cost analysis from a healthcare provider perspective using micro-costing techniques was conducted to estimate the direct implementation costs of existing standard practice for the care pathway of patients attending the multidisciplinary hypertension clinic. Sixty-five patients originally recruited for a study of medication adherence in hypertension were included in the sample. RESULTS: The total care-pathway cost per patient, taking into account clinic visits, clinical reviews, investigations and MDT discussion, was estimated to be €3277, on average. For the patient subgroups, the average cost was €5644 for patients diagnosed with primary aldosteronism and €1446 for patients diagnosed with essential hypertension. CONCLUSION: There is significant cost associated with providing specialized hypertension care for patients with apparent treatment-resistant hypertension. Given the high rates of nonadherence in this population, it is likely that some of this cost could be avoided with better detection and management of medication adherence in this challenging population. Future studies should consider the cost-effectiveness of this or similar models of care by exploring the benefit to patients and the wider healthcare context of providing care of this type.

Untangling the association between COVID-19 health literacy, trust in the pandemic response, and mental distress, during the COVID-19 pandemic in Ireland: a repeated cross-sectional study.

BACKGROUND: The impact of the COVID-19 pandemic on rates of mental distress is well described. However, the contribution of poor health literacy and low levels of trust in state institutions to mental distress is less well defined. This study aimed to assess the impact of COVID-19 health literacy and trust in the pandemic response (Trust) on mental distress during the COVID-19 pandemic in Ireland. METHODS: We did this nationally representative cross-sectional survey of adult Irish residents during three study periods: from May 26 to June 17, 2020 (n=947); from July 1 to July 23, 2020 (n=995); and from Sept 5 to Sept 28, 2020 (n=972). Participants were contacted using random-digit-dialling and interviewed by a professional market research organisation (Ipsos MRBI' about 80% via mobile phone, 20% via landline). Mental distress was assessed by the Patient Health Questionnaire Anxiety Depression Scale (PHQ-ADS), for which a score of 10 or higher indicated mental distress. Heath literacy and trust were each assessed with three questions, which defined three categories: low, moderate, and high (appendix). Descriptive analysis and multivariate (MVA) Poisson regression were conducted in STATA17, Incidence Rate Ratios (IRR) are reported. FINDINGS: 2914 participants completed the survey across three study periods (median age 46 years, 1510 [51·8%] women, 1401 [48·1%] men, three [0·1%] non-binary). 804 (27·6%) of 2914 participants experienced mental distress (n=804). More women experienced mental distress than men (508 [34%] of women vs 294 [21%] of men). Mental distress was inversely associated with age (from 43% in those aged <30 years [n=232/539] to 19% in those aged >70 years [n=66/349]). Most participants had high health literacy (n=2,530, 86·8%). While health literacy was positively and significantly associated with trust, it was not associated with mental distress and it was therefore excluded from the MVA. Level of trust was captured for 2693 adults; 42·2% participants reported low trust (n=457) or moderate trust (n=679). The prevalence of mental distress was inversely associated with trust; increasing from 24% in those with high trust (n=374/1557), 30% in those with moderate trust (n=202/679), to 36% in those with low trust (n=166/457). In MVA higher rates of mental distress were associated with low trust (IRR 1·45, 95% CI 1·20-1·75; p=0·000) and moderate trust (IRR 1·24, 1·04-1·47, p=0·016) compared with high trust when adjusted for age, sex, employment status, and income,. INTERPRETATION: In Ireland, low levels of trust in the COVID-19 pandemic response were associated with higher levels of mental distress. Although poor health literacy was associated with low levels of trust, it was not independently associated with mental distress. Inference on the nature and direction of causal effects must be cautious given the cross-sectional study design. FUNDING: Health Research Board.

Causal relationship between particulate matter 2.5 and diabetes: two sample Mendelian randomization.

Backgrounds: Many studies have shown particulate matter has emerged as one of the major environmental risk factors for diabetes; however, studies on the causal relationship between particulate matter 2.5 (PM2.5) and diabetes based on genetic approaches are scarce. The study estimated the causal relationship between diabetes and PM2.5 using two sample mendelian randomization (TSMR). Methods: We collected genetic data from European ancestry publicly available genome wide association studies (GWAS) summary data through the MR-BASE repository. The IEU GWAS information output PM2.5 from the Single nucleotide polymorphisms (SNPs) GWAS pipeline using pheasant-derived variables (Consortium = MRC-IEU, sample size: 423,796). The annual relationship of PM2.5 (2010) were modeled for each address using a Land Use Regression model developed as part of the European Study of Cohorts for Air Pollution Effects. Diabetes GWAS information (Consortium = MRC-IEU, sample size: 461,578) were used, and the genetic variants were used as the instrumental variables (IVs). We performed three representative Mendelian Randomization (MR) methods: Inverse Variance Weighted regression (IVW), Egger, and weighted median for causal relationship using genetic variants. Furthermore, we used a novel method called MR Mixture to identify outlier SNPs. Results: From the IVW method, we revealed the causal relationship between PM2.5 and diabetes (Odds ratio [OR]: 1.041, 95% CI: 1.008-1.076, P = 0.016), and the finding was substantiated by the absence of any directional horizontal pleiotropy through MR-Egger regression (ß = 0.016, P = 0.687). From the IVW fixed-effect method (i.e., one of the MR machine learning mixture methods), we excluded outlier SNP (rs1537371) and showed the best predictive model (AUC = 0.72) with a causal relationship between PM2.5 and diabetes (OR: 1.028, 95% CI: 1.006-1.049, P = 0.012). Conclusion: We identified the hypothesis that there is a causal relationship between PM2.5 and diabetes in the European population, using MR methods.

Effect of nebuliser and patient interface type on fugitive medical aerosol emissions in adult and paediatric patients.

BACKGROUND: Open circuit aerosol therapy is associated with the potential for fugitive emissions of medical aerosol. Various nebulisers and interfaces are used in respiratory treatments, including the recent consideration of filtered interfaces. This study aims to quantify fugitive medical aerosols from various nebuliser types, in conjunction with different filtered and non-filtered interfaces. METHODS: For both simulated adult and paediatric breathing, four nebuliser types were assessed including; a small volume jet nebuliser (SVN), a breath enhanced jet nebuliser (BEN), a breath actuated jet nebuliser (BAN) and a vibrating mesh nebuliser (VMN). A combination of different interfaces were used including filtered and unfiltered mouthpieces, as well as open, valved and filtered facemasks. Aerosol mass concentrations were measured using an Aerodynamic Particle Sizer at 0.8 m and 2.0 m. Additionally, inhaled dose was assessed. RESULTS: Highest mass concentrations recorded were 214 (177, 262) µg m-3 at 0.8 m over 45-minute run. The highest and lowest fugitive emissions were observed for the adult SVN facemask combination, and the adult BAN filtered mouthpiece combination respectively. Fugitive emissions decreased when using breath-actuated (BA) mode compared to continuous (CN) mode on the BAN for the adult and paediatric mouthpiece combination. Lower fugitive emissions were observed when a filtered facemask or mouthpiece was used, compared to unfiltered scenarios. For the simulated adult, highest and lowest inhaled dose were 45.1 (42.6, 45.6)% and 11.0 (10.1,11.9)% for the VMN and SVN respectively. For the simulated paediatric, highest and lowest inhaled dose were 44.0 (42.4, 44.8)% and 6.1 (5.9, 7.0)% for the VMN and BAN CN respectively. Potential inhalation exposure of albuterol was calculated to be up to 0.11 µg and 0.12 µg for a bystander and healthcare worker respectively. CONCLUSION: This work demonstrates the need for filtered interfaces in clinical and homecare settings to minimise fugitive emissions and to reduce the risk of secondary exposure to care givers.

Air Pollution and Acute Kidney Injury in the U.S. Medicare Population: A Longitudinal Cohort Study.

BACKGROUND: Recent studies have reported the association between air pollution exposure and reduced kidney function. However, it is unclear whether air pollution is associated with an increased risk of acute kidney injury (AKI). OBJECTIVES: To address this gap in knowledge, we investigated the effect estimates of long-term exposures to fine particulate matter [PM ≤2.5µm in aerodynamic diameter (PM2.5)], nitrogen dioxide (NO2), and ozone (O3) on the risk of first hospital admission for AKI using nationwide Medicare data. METHODS: This nationwide population-based longitudinal cohort study included 61,300,754 beneficiaries enrolled in Medicare Part A fee-for-service (FFS) who were ≥65 years of age and resided in the continental United States from the years 2000 through 2016. We applied Cox-equivalent Poisson models to estimate the association between air pollution and first hospital admission for AKI. RESULTS: Exposure to PM2.5, NO2, and O3 was associated with increased risk for first hospital admission for AKI, with hazard ratios (HRs) of 1.17 (95% CI: 1.16, 1.19) for a 5-µg/m3 increase in PM2.5, 1.12 (95% CI: 1.11, 1.13) for a 10-ppb increase in NO2, and 1.03 (95% CI: 1.02, 1.04) for a 10-ppb increase in summer-period O3 (June to September). The associations persisted at annual exposures lower than the current National Ambient Air Quality Standard. DISCUSSION: This study found an association between exposures to air pollution and the risk of the first hospital admission with AKI, and this association persisted even at low concentrations of air pollution. Our findings provide beneficial implications for public health policies and air pollution guidelines to alleviate health care expenditures and the disease burden attributable to AKI. https://doi.org/10.1289/EHP10729.

Subgenual and Hippocampal Pathways in Amygdala Are Set to Balance Affect and Context Processing.

The amygdala, hippocampus, and subgenual cortex area 25 (A25) are engaged in complex cognitive-emotional processes. Yet pathway interactions from hippocampus and A25 with postsynaptic sites in amygdala remain largely unknown. In rhesus monkeys of both sexes, we studied with neural tracers how pathways from A25 and hippocampus interface with excitatory and inhibitory microcircuits in amygdala at multiple scales. We found that both hippocampus and A25 innervate distinct as well as overlapping sites of the basolateral (BL) amygdalar nucleus. Unique hippocampal pathways heavily innervated the intrinsic paralaminar basolateral nucleus, which is associated with plasticity. In contrast, orbital A25 preferentially innervated another intrinsic network, the intercalated masses, an inhibitory reticulum that gates amygdalar autonomic output and inhibits fear-related behaviors. Finally, using high-resolution confocal and electron microscopy (EM), we found that among inhibitory postsynaptic targets in BL, both hippocampal and A25 pathways preferentially formed synapses with calretinin (CR) neurons, which are known for disinhibition and may enhance excitatory drive in the amygdala. Among other inhibitory postsynaptic sites, A25 pathways innervated the powerful parvalbumin (PV) neurons which may flexibly regulate the gain of neuronal assemblies in the BL that affect the internal state. In contrast, hippocampal pathways innervated calbindin (CB) inhibitory neurons, which modulate specific excitatory inputs for processing context and learning correct associations. Common and unique patterns of innervation in amygdala by hippocampus and A25 have implications for how complex cognitive and emotional processes may be selectively disrupted in psychiatric disorders.SIGNIFICANCE STATEMENT The hippocampus, subgenual A25, and amygdala are associated with learning, memory, and emotions. We found that A25 is poised to affect diverse amygdalar processes, from emotional expression to fear learning by innervating the basal complex and the intrinsic intercalated masses. Hippocampal pathways uniquely interacted with another intrinsic amygdalar nucleus which is associated with plasticity, suggesting flexible processing of signals in context for learning. In the basolateral (BL) amygdala, which has a role in fear learning, both hippocampal and A25 interacted preferentially with disinhibitory neurons, suggesting a boost in excitation. The two pathways diverged in innervating other classes of inhibitory neurons, suggesting circuit specificities that could become perturbed in psychiatric diseases.

In vitro evaluation of the potential use of snake-derived peptides in the treatment of respiratory infections using inhalation therapy: A proof of concept study.

Inhalation therapy using nebulisers is an attractive non-invasive route for drug delivery, particularly for the treatment of lung infections with anti-inflammatory and anti-microbial compounds. This study evaluated the suitability of three snake-derived peptides (termed Sn1b, SnE1 and SnE1-F), which we have recently shown have potent anti-inflammatory and bacteriostatic activities, for nebulisation using a vibrating mesh nebuliser (VMN). The effect of nebulisation on peptide concentration, stability and function were assessed, prior to progression to aerodynamic particle size distribution, and in vitro drug delivery in simulated adult spontaneous breathing and mechanical ventilated patient models. When nebulised, all three peptides exhibited similar functions to their non-nebulised counterparts and were found to be respirable during simulated mechanical ventilation. Based on the assessment of the droplet distributions of nebulised peptides using a Next Generation Impactor (NGI) demonstrated that if administered in vivo each peptide would likely be delivered to the lower airways. These data suggest that nebulisation using a VMN is a viable means of anti-microbial / anti-inflammatory peptide delivery targeting microbial respiratory infections, and possibly even systemic infections.

An evaluation of the skills group component of DBT-A for parent/guardians: a mixed methods study.

OBJECTIVES: Previous research indicates that dialectical behaviour therapy for adolescents (DBT-A) is effective in treating emotionally dysregulated adolescents with self-harm and/or suicidal ideation. As part of the DBT-A programme, parents attend the weekly skills group with their child. However, few studies have evaluated parental outcomes in DBT-A. This multi-site study aims to explore the outcomes and experiences of parents who participated in a 16-week DBT-A programme in Ireland. METHODS: This study was conducted in community-based child and adolescent mental health services (CAMHS) in the national public health system in Ireland. Participants were parent/guardians of adolescents attending a DBT-A programme in their local CAMHS. Participants attended the group skills component of the DBT-A programme. This study utilised a mixed methods approach where both quantitative and qualitative data were collected from participants. Self-report measures of burden, grief and parental stress were completed at pre-intervention, post-intervention and 16-week follow-up. Qualitative written feedback was obtained at post-intervention. The data were analysed using multi-level linear mixed-effects models and content analysis. RESULTS: One hundred participants (76% female) took part in this study. Significant decreases were reported for objective burden, subjective burden, grief and parental stress from pre- to post-intervention (p < 0.01). Participants reported that the skills component of DBT-A was useful in meeting their own needs and the needs of their child. DISCUSSION: DBT-A shows promise for parents as well as their adolescent child. Future studies should evaluate changes to family relationships following completion of the programme and also include controlled comparison groups.

The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion.

ARNSTEN, A.F.T., M.K.P. Joyce and A.C. Roberts. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. NEUROSCI BIOBEHAV REV XXX-XXX, 2022. The symptoms of major-depressive-disorder include psychic pain and anhedonia, i.e. seeing the world through an "aversive lens". The neurobiology underlying this shift in worldview is emerging. Here these data are reviewed, focusing on how activation of subgenual cingulate (BA25) induces an "aversive lens", and how higher prefrontal cortical (PFC) areas (BA46/10/32) provide top-down regulation of BA25 but are weakened by excessive dopamine and norepinephrine release during stress exposure, and dendritic spine loss with chronic stress exposure. These changes may generate an attractor state, which maintains the brain under the control of BA25, requiring medication or neuromodulatory treatments to return connectivity to a more flexible state. In line with this hypothesis, effective anti-depressant treatments reduce the activity of BA25 and restore top-down regulation by higher circuits, e.g. as seen with SSRI medications, ketamine, deep brain stimulation of BA25, or rTMS to strengthen dorsolateral PFC. This research has special relevance in an era of chronic stress caused by the COVID19 pandemic, political unrest and threat of climate change.

Time of self-harm presentations to hospital emergency departments: a scoping review.

BACKGROUND: The time at which a self-harm presentation occurs has been shown to be a significant factor as to whether a patient receives a psychiatric assessment or not, which may benefit the patient's future care. This scoping review sought to identify studies that report on the peak time of day for self-harm presentations to hospital Emergency Departments (EDs). This could help hospital managers to properly allocate the appropriate services for self-harm patients when they are needed the most. METHODS: A scoping review of the literature from the year 2000 until 30th June 2021 was carried out using the PubMed, Web of Science, Embase and the Cochrane library databases. RESULTS: There were 22 studies that were included for data extraction. The findings from 20 of these studies indicate that self-harm presentations tend to occur outside of working hours (09:00-17:00, Monday to Friday). The majority of studies found that the peak time for self-harm presentations was in the hours before and after midnight. CONCLUSIONS: While this scoping review identified a satisfactory number of studies for data extraction, examination of time of day of presentation was a secondary outcome across most studies. Given that the majority of studies focused on adult samples, further research is necessary to investigate peak times for other age cohorts. More research on this topic is also needed in low- and middle-income countries. Consideration should be given to ensure that the necessary resources to treat hospital presenting self-harm are allocated outside of typical working hours.

An in vitro study of the effects of respiratory circuit setup and parameters on aerosol delivery during mechanical ventilation.

Introduction: Aerosol therapy is often prescribed concurrently during invasive mechanical ventilation (IMV). This study determines the effects of nebuliser position, circuit humidification source, and most importantly, lung health on the delivery of aerosol in simulated adult and paediatric IMV patients. Furthermore, the influence of closed suction catheters on aerosol delivery is also addressed. Methods: A vibrating mesh nebuliser was used to deliver Albuterol to simulated adult and paediatric IMV patients with differing states of lung health. Four different nebuliser positions and two types of humidification were analysed. Closed suction catheter mounts, a mainstay in IMV therapy, were incorporated into the circuits. The mean ± SD dose of aerosol (%) was assayed from a filter at the distal end of the endotracheal tube. Results: Nebuliser placement and circuit humidification source had no effect on the delivered dose (%) in adults, yet both significantly did in the simulated paediatric patients. The use of closed suction catheter mounts significantly reduced the delivered dose (%) in adults but not in paediatric patients. A simulated healthy lung state generated the largest delivered dose (%), irrespective of nebuliser position in the adult. However, different lung health and nebuliser positions yielded higher delivered doses (%) in paediatrics. Conclusion: Lung health and respiratory circuit composition significantly affect aerosol delivery in both adult and paediatric IMV patients. Nebuliser placement and respiratory circuit humidification source do not affect the delivered dose in adult but do in paediatric IMV patients.

In vitro model for investigating aerosol dispersion in a simulated COVID-19 patient during high-flow nasal cannula treatment.

The use of high-flow nasal cannula in the treatment of COVID-19 infected patients has proven to be a valuable treatment option to improve oxygenation. Early in the pandemic, there were concerns for the degree of risk of disease transmission to health care workers utilizing these treatments that are considered aerosol generating procedures. This study developed an in vitro model to examine the release of simulated patient-derived bioaerosol with and without high-flow nasal cannula at gas flow rates of 30 and 50 L/min. Aerosol dispersion was evaluated at 30 and 90 cm distances. Reduction of transmission risk was assessed using a surgical facemask on the manikin. Results indicated that the use of a facemask facilitated a 94-95% reduction in exhaled aerosol concentration at 30 cm and 22-60% reduction for 90 cm distance across both gas flow rates. This bench study confirms that this in vitro model can be used as a tool to assess the risk of disease transmission during aerosol generating procedures in a simulated patient and to test factors to mitigate the risk.

Associations of biomarkers for exposure to tobacco smoke with lung cancer risk in Korea.

BACKGROUND: Nicotine metabolite ratio (NMR) can be used to predict total nicotine clearance. However, it is unknown whether NMR could be used as a marker of lung cancer risk. OBJECTIVE: To evaluate the blood metabolites of nicotine relating to the risk of developing lung cancer and investigate the combined effects of NMR and cigarette per day on the risk of lung cancer. METHODS: Among the 1,054 eligible subjects from the Korean Cancer Prevention Study-II biobank cohort, those with cotinine values below 0 ng/ml were excluded. Slow and fast metabolizer groups were defined using the median value of the NMR, calculated with the control group data, as the cut-point. RESULTS: The multivariable Cox proportional hazard models demonstrated that, the fast metabolizer group had a significantly higher risk of lung cancer than the slow metabolizer group (Adjusted HR: 2.02, 95% CI: 1.32-3.10). Fast metabolizers who smoked more than 15 cigarettes per day had an even higher risk of lung cancer (Adjusted HR: 3.51, 95% CI: 1.96-6.29) than the slow metabolizers who smoked less than 15 cigarettes per day. CONCLUSIONS: In summary, the NMR may be an effective marker for estimating tobacco-related disease risks such as lung cancer.