Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

Stress Symptoms Among Children and Their Parents After ICU Hospitalization.

Objective: Child survival after intensive care unit (ICU) hospitalization has increased, yet many children experience acute stress that may precipitate mental/behavioral health comorbidities. Parents report stress after their child's hospitalization. Little is known about the individual and family characteristics that may moderate intergenerational relationships of acute stress. Design: Following ICU admission at a large academic medical center, a prospective cross-sectional cohort study assessed the associations between intergenerational characteristics and acute stress among children and families. Patients: Parent-child dyads (N = 88) were recruited from the pediatric ICU and pediatric cardiovascular ICU (CVICU) following ICU discharge. Eligible children were between 8 and 18 years old with ICU stays longer than 24 hours. Children with developmental delays were excluded. Caregivers were proficient in English or Spanish. Surveys were collected before hospital discharge. Measurements/Main Results: The primary outcome was "child stress" defined as a score≥17, measured by the Children's Revised Impact of Events Scale (CRIES-8). "Parent stress" was defined as an elevated composite score on the Stanford Acute Stress Reaction Questionnaire. We used validated scales to assess the child's clinical and family social characteristics. Acute stress was identified in 34 (39.8%) children and 50 (56.8%) parents. In multivariate linear regression analyses adjusting for social characteristics, parent stress was associated with increased risk of child stress (adjusted odds ratio 2.58, 95% confidence interval 0.69, 4.46, p < .01). In unadjusted analyses, Hispanic ethnicity was associated with greater child stress. In adjusted analyses, race, income, ICU length of stay, and language were not associated with child stress and did not moderate the parent-child stress relationship. Conclusions: Parent stress is closely correlated with child stress during ICU hospitalization. Hispanic ethnicity may be associated with increased risk for child stress, but further studies are required to define the roles of other social and clinical measures.

Home working and social and mental wellbeing at different stages of the COVID-19 pandemic in the UK: Evidence from 7 longitudinal population surveys.

BACKGROUND: Home working has increased since the Coronavirus Disease 2019 (COVID-19) pandemic's onset with concerns that it may have adverse health implications. We assessed the association between home working and social and mental wellbeing among the employed population aged 16 to 66 through harmonised analyses of 7 UK longitudinal studies. METHODS AND FINDINGS: We estimated associations between home working and measures of psychological distress, low life satisfaction, poor self-rated health, low social contact, and loneliness across 3 different stages of the pandemic (T1 = April to June 2020 -first lockdown, T2 = July to October 2020 -eased restrictions, T3 = November 2020 to March 2021 -second lockdown) using modified Poisson regression and meta-analyses to pool results across studies. We successively adjusted the model for sociodemographic characteristics (e.g., age, sex), job characteristics (e.g., sector of activity, pre-pandemic home working propensities), and pre-pandemic health. Among respectively 10,367, 11,585, and 12,179 participants at T1, T2, and T3, we found higher rates of home working at T1 and T3 compared with T2, reflecting lockdown periods. Home working was not associated with psychological distress at T1 (RR = 0.92, 95% CI = 0.79 to 1.08) or T2 (RR = 0.99, 95% CI = 0.88 to 1.11), but a detrimental association was found with psychological distress at T3 (RR = 1.17, 95% CI = 1.05 to 1.30). Study limitations include the fact that pre-pandemic home working propensities were derived from external sources, no information was collected on home working dosage and possible reverse association between change in wellbeing and home working likelihood. CONCLUSIONS: No clear evidence of an association between home working and mental wellbeing was found, apart from greater risk of psychological distress during the second lockdown, but differences across subgroups (e.g., by sex or level of education) may exist. Longer term shifts to home working might not have adverse impacts on population wellbeing in the absence of pandemic restrictions but further monitoring of health inequalities is required.

Tissue discrimination in head and neck cancer using image fusion of IR and optical microscopy.

A regression-based fusion algorithm has been used to merge hyperspectral Fourier transform infrared (FTIR) data with an H&E image of oral squamous cell carcinoma metastases in cervical lymphoid nodal tissue. This provides insight into the success of the ratio of FTIR absorbances at 1252 cm-1 and 1285 cm-1 in discriminating between these tissue types. The success is due to absorbances at these two wavenumbers being dominated by contributions from DNA and collagen, respectively. A pixel-by-pixel fit of the fused spectra to the FTIR spectra of collagen, DNA and cytokeratin reveals the contributions of these molecules to the tissue at high spatial resolution.

Metric-based analysis of FTIR data to discriminate tissue types in oral cancer.

A machine learning algorithm (MLA) has predicted the prognosis of oral potentially malignant lesions and discriminated between lymph node tissue and metastatic oral squamous cell carcinoma (OSCC). The MLA analyses metrics, which are ratios of Fourier transform infrared absorbances, and identifies key wavenumbers that can be associated with molecular biomarkers. The wider efficacy of the MLA is now shown in the more complex primary OSCC tumour setting, where it is able to identify seven types of tissue. Three epithelial and four non-epithelial tissue types were discriminated from each other with sensitivities between 82% and 96% and specificities between 90% and 99%. The wavenumbers involved in the five best discriminating metrics for each tissue type were tightly grouped, indicating that small changes in the spectral profiles of the different tissue types are important. The number of samples used in this study was small, but the information will provide a basis for further, larger investigations.

Characterising patterns of COVID-19 and long COVID symptoms: evidence from nine UK longitudinal studies.

Multiple studies across global populations have established the primary symptoms characterising Coronavirus Disease 2019 (COVID-19) and long COVID. However, as symptoms may also occur in the absence of COVID-19, a lack of appropriate controls has often meant that specificity of symptoms to acute COVID-19 or long COVID, and the extent and length of time for which they are elevated after COVID-19, could not be examined. We analysed individual symptom prevalences and characterised patterns of COVID-19 and long COVID symptoms across nine UK longitudinal studies, totalling over 42,000 participants. Conducting latent class analyses separately in three groups ('no COVID-19', 'COVID-19 in last 12 weeks', 'COVID-19 > 12 weeks ago'), the data did not support the presence of more than two distinct symptom patterns, representing high and low symptom burden, in each group. Comparing the high symptom burden classes between the 'COVID-19 in last 12 weeks' and 'no COVID-19' groups we identified symptoms characteristic of acute COVID-19, including loss of taste and smell, fatigue, cough, shortness of breath and muscle pains or aches. Comparing the high symptom burden classes between the 'COVID-19 > 12 weeks ago' and 'no COVID-19' groups we identified symptoms characteristic of long COVID, including fatigue, shortness of breath, muscle pain or aches, difficulty concentrating and chest tightness. The identified symptom patterns among individuals with COVID-19 > 12 weeks ago were strongly associated with self-reported length of time unable to function as normal due to COVID-19 symptoms, suggesting that the symptom pattern identified corresponds to long COVID. Building the evidence base regarding typical long COVID symptoms will improve diagnosis of this condition and the ability to elicit underlying biological mechanisms, leading to better patient access to treatment and services.

Oral cancer awareness and education within the pharmacy profession.

The incidence of oral cancers are rising in the UK, with early detection a significant positive prognostic factor. The Covid-19 pandemic has negatively impacted patients access to dental services, reducing a potential avenue to diagnosis. Community pharmacists are well positioned to play an expanded role in supporting earlier detection. This study seeks to identify levels of awareness and knowledge of oral cancer amongst community pharmacists, to inform development of educational resources.A cross-sectional digital survey was distributed via social media between August and September 2021. Data were collected on participant's demographics, oral cancer awareness and educational resources relevant to oral cancer. The results obtained were analysed using descriptive statistics in IBM SPSS software.61 pharmacists completed the survey. The majority were female (n = 40; 65.6%) aged 18-30 (n = 33; 54.1%). Less than half of respondents reported feeling confident in recognising risk factors (37.7%; n = 23). A substantial minority (n = 8; 13.1%) incorrectly selected fluoride toothpaste use as a risk factor for oral cancer. Most respondents correctly suggested signposting patients with signs or symptoms of oral cancer to a General Medical or General Dental Practitioner (GDP) (n = 35; 57.3%, n = 46; 75.4%). 91.8% of respondents (n = 56) would welcome an educational resource to support professional development.This study demonstrates a need for further educational resources regarding oral cancer, specifically aimed at community pharmacists. Community Pharmacists have a crucial role in efforts to improve rates of early detection of oral cancers. Work should be completed to explore the establishment of direct referral pathways from community pharmacy to secondary care.

The Danish-American Research Exchange (DARE): a cross-sectional study of a binational research education program.

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'. METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. RESULTS: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network. CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

Knowledge and perceptions of invasive plant biocontrol in Europe versus the rest of the world.

Biological control (BC) of invasive alien plants (IAP) can be an effective environmental management approach. It has only very recently been adopted in Europe and is underutilized compared to other continents where this method has been successfully implemented for over a century. This is in sharp contrast to the BC of invertebrate pests, which has been taken up widely within Europe. It has been suggested that this is related to the risk-adverse attitude of Europeans towards weed BC. Scientific and public perception have a major influence on environmental policy actions. Public perception and knowledge regarding BC is an understudied subject despite its relevance for the application of this management alternative. We aimed to assess the knowledge and perception of BC of IAP among European professionals compared with their peers from other continents. To this end we conducted an online survey including multiple choice and open questions among over 700 people professionally engaged with managing the natural environment, of which approximately half were from Europe (EU) and the others from outside (non-EU). We assessed relationships between the geographical location of the respondents and their knowledge, and perceptions of BC of weeds versus BC of invertebrate pests. We found that respondents' location influenced both perceptions and knowledge of BC for weeds. Compared to non-EU respondents, EU professionals showed less appreciation for BC (e.g., regarding safety, sustainability, and cost-effectiveness), and perceived it as a riskier method, particularly in the case of practitioners and researchers. More profoundly insect pest BC tended to be considered less safe than weed BC for non-EU respondents. Confidence in weed BC as a method, as well as in the validity of the associated pre-release risk assessments, strongly increased with the level of expertise in weed BC. While a much higher proportion of non-EU respondents were correctly aware of the presence/absence of BC in their own countries and identified successful examples of BC accurately, both groups of respondents were similarly aware of unsuccessful BC examples, including BC agents against animals, stressing the bias of EU respondents towards examples of BC failure. The appreciation of weed BC in Europe could be elevated by a combination of increasing knowledge of the technique and pre-release risk assessment and promoting successful examples of weed BC, which may bring major benefits for the management of IAP across the region.

Group Psychotherapy for Parents of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome.

Parents of children with diagnoses of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) may experience significant psychological distress related to their child's severe and relapsing illness and challenges with the traumatic nature of its treatment. No manualized or studied psychological interventions specifically for parents of youth with PANS have existed prior to this study. In this pilot study, we assessed the feasibility, satisfaction, and treatment fidelity of a brief 9-session group therapy intervention for parents based on principles of trauma-focused cognitive behavior therapy (CBT). We hypothesized that, if initially elevated, symptoms of depression, anxiety, and trauma would decrease and participants' utilization of positive coping mechanisms would increase post-intervention. We adapted an existing evidence-based group intervention developed for parents of children with premature infants to target sources of stress and coping in parents of children with PANS. Ten parents participated in the study. The 9-session intervention used a combination of techniques that included cognitive restructuring, coping skills, self-care, and a trauma narrative to address psychological stress, trust, grief, and unwanted emotions. Outcome measures included parental symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD), as well as rating of parental satisfaction with the intervention. The treatment was feasible and deliverable with high fidelity. The intervention was rated as useful and satisfactory by parents (overall average usefulness of 4.54 and satisfaction of 4.71 out of 5.0). Elevated symptoms of PTSD and depression decreased with large effect sizes (Cohen's d = 1.42 and Cohen's d = 1.38, respectively). Participating parents demonstrated significantly more active coping and acceptance behaviors and stances. A brief 9-session group therapy intervention based on principles of trauma-focused CBT was found to be effective in reducing symptoms of psychological distress in parents of children with PANS.

Preterm infant mental health in the neonatal intensive care unit: A review of research on NICU parent-infant interactions and maternal sensitivity.

Caregiving relationships in the postnatal period are critical to an infant's development. Preterm infants and their parents face unique challenges in this regard, with infants experiencing separation from parents, uncomfortable procedures, and increased biologic vulnerability, and parents facing difficulties assuming caregiver roles and increased risk for psychological distress. To better understand the NICU parent-infant relationship, we conducted a review of the literature and identified 52 studies comparing observed maternal, infant, and dyadic interaction behavior in preterm dyads with full-term dyads. Eighteen of 40 studies on maternal behavior found less favorable behavior, including decreased sensitivity and more intrusiveness in mothers of preterm infants, seven studies found the opposite, four studies found mixed results, and 11 studies found no differences. Seventeen of 25 studies on infant behavior found less responsiveness in preterm infants, two studies found the opposite, and the remainder found no difference. Eighteen out of 14 studies on dyad-specific behavior reported less synchrony in preterm dyads and the remainder found no differences. We identify confounding factors that may explain variations in results, present an approach to interpret existing data by framing differences in maternal behavior as potentially adaptive in the context of prematurity, and suggest future areas for exploration.

Las relaciones de prestación de cuidados en el período postnatal son críticas para el desarrollo del infante. Los infantes nacidos prematuramente y sus progenitores enfrentan retos únicos a este respecto, con los infantes que experimentan la separación de sus progenitores, procedimientos incómodos, así como un aumento en la vulnerabilidad biológica; y los progenitores enfrentando dificultades al asumir el papel de cuidadores y el aumento de riesgo de angustia sicológica. Para comprender mejor la relación progenitor-infante en la Unidad Neonatal de Cuidados Intensivos (NICU), llevamos a cabo una revisión de la literatura e identificamos 52 estudios que comparan la observada conducta de interacción materna, del infante y de la díada en díadas de infantes prematuros con díadas de infantes de gestación completa. Dieciocho de 40 estudios sobre la conducta materna encontraron una menos favorable conducta, incluyendo una baja en la sensibilidad y más intrusión en el caso de madres de infantes prematuros; 7 estudios encontraron que se daba la situación opuesta; 4 estudios presentaron resultados mixtos; y 11 estudios no encontraron diferencias. Diecisiete de 25 estudios sobre el comportamiento del infante encontraron una menor capacidad de respuesta en infantes prematuros; dos estudios encontraron que se daba la situación opuesta; y el resto de los estudios no encontró ninguna diferencia. Ocho de 14 estudios sobre el comportamiento específico de la díada reportaron menos sincronía en las díadas con infantes prematuros y el resto de los estudios no encontró ninguna diferencia. Identificamos factores confusos que pudieran explicar las variaciones en los resultados, presentamos un acercamiento para interpretar la información existente por medio de enmarcar las diferencias en la conducta materna como potencialmente adaptable en el contexto del nacimiento prematuro, y sugerimos futuras áreas para ser exploradas.

Les relations de soin dans la période postnatale sont critiques pour le développement du nourrisson. Les bébés nés avant terme et leurs parents font face à des défis uniques à cet égard, avec les bébés faisant l'expérience de la séparation des parents, des procédures désagréables et difficiles, et une vulnérabilité biologique accrue, et les parents faisant face aux difficultés assumant des rôles de soignants et étant à risque plus élevé de détresse psychologique. Afin de comprendre la relation parent-nourrisson USIN nous avons passé en revue toutes les recherches et identifié 52 études comparant le comportement d'interaction dyadique, maternel et du nourrisson chez des dyades prématurées avec des dyades à plein terme. 18 des 40 études sur le comportement maternel ont trouvé un comportement moins que favorable, y compris une sensibilité décrue et plus d'intrusion chez les mères de nourrissons prématurés, 7 études ont trouvé le contraire, 4 études ont trouvé des résultats mélangés, et 11 études n'ont trouvé aucune différence. 17 études sur 25 sur le comportement du nourrisson ont trouvé une réaction moindre chez les nourrissons prématurés deux études ont trouvé le contraire, et le reste n'a trouvé aucune différence. 8 études sur 14 sur le comportement spécifique à la dyade ont fait état de moins de synchronie chez les dyades avant terme et les autres études n'ont trouvé aucune différence. Nous identifions des facteurs confondants qui pourraient expliquer des variations dans les résultats et nous présentons une approche pour interpréter les données existantes en cadrant des différences dans le comportement maternel comme étant potentiellement adaptatives dans le contexte de la prématurité et nous suggérons des domaines futurs d'exploration.

Combining photoperiod and thermal responses to predict phenological mismatch for introduced insects.

A wide variety of organisms use the regular seasonal changes in photoperiod as a cue to align their life cycles with favorable conditions. Yet the phenological consequences of photoperiodism for organisms exposed to new climates are often overlooked. We present a conceptual approach and phenology model that maps voltinism (generations per year) and the degree of phenological mismatch that can arise when organisms with a short-day diapause response are introduced to new regions or are otherwise exposed to new climates. Our degree-day-based model combines continent-wide spatialized daily climate data, calculated date-specific and latitude-specific day lengths, and experimentally determined developmental responses to both photoperiod and temperature. Using the case of the knotweed psyllid Aphalara itadori, a new biological control agent being introduced from Japan to North America and Europe to control an invasive weed, we show how incorporating a short-day diapause response will result in geographic patterns of attempted voltinism that are strikingly different from the potential number of generations based on degree-days alone. The difference between the attempted and potential generations represents a quantitative measure of phenological mismatch between diapause timing and the end of the growing season. We conclude that insects moved from lower to higher latitudes (or to cooler climates) will tend to diapause too late, potentially resulting in high mortality from inclement weather, and those moved from higher to lower latitude (to warmer climates) may be prone to diapausing too early, therefore not fully exploiting the growing season and/or suffering from insufficient reserves for the longer duration in diapause. Mapped output reveals a central region with good phenology match that shifts north or south depending on the geographic source of the insect and its corresponding critical photoperiod for diapause. These results have direct relevance for efforts to establish populations of classical biocontrol agents. More generally, our approach and model could be applied to a wide variety of photoperiod- and temperature-sensitive organisms that are exposed to changes in climate, including resident and invasive agricultural pests and species of conservation concern.

Biases arising from linked administrative data for epidemiological research: a conceptual framework from registration to analyses.

Linked administrative data offer a rich source of information that can be harnessed to describe patterns of disease, understand their causes and evaluate interventions. However, administrative data are primarily collected for operational reasons such as recording vital events for legal purposes, and planning, provision and monitoring of services. The processes involved in generating and linking administrative datasets may generate sources of bias that are often not adequately considered by researchers. We provide a framework describing these biases, drawing on our experiences of using the 100 Million Brazilian Cohort (100MCohort) which contains records of more than 131 million people whose families applied for social assistance between 2001 and 2018. Datasets for epidemiological research were derived by linking the 100MCohort to health-related databases such as the Mortality Information System and the Hospital Information System. Using the framework, we demonstrate how selection and misclassification biases may be introduced in three different stages: registering and recording of people's life events and use of services, linkage across administrative databases, and cleaning and coding of variables from derived datasets. Finally, we suggest eight recommendations which may reduce biases when analysing data from administrative sources.

Left ventricular end-systolic volume response post-stress echocardiography: Dilation as a marker of multi-vessel coronary artery disease.

BACKGROUND: Transient ischemic dilation of the left ventricle (LV) during stress echocardiography indicates extensive myocardial ischemia. It remains unclear whether the change of LV end-systolic volume (ESV) or end-diastolic volume (EDV) better correlated with significant coronary artery disease (CAD). Meanwhile, the clinical significance of the extent of the volumetric change post-stress has not been investigated. METHODS: One hundred and five individuals (62 ± 12 years and 75% men) who underwent coronary angiography following exercise treadmill echocardiography were enrolled retrospectively. An additional 30 age- and sex-matched healthy subjects were included for comparison. LV dilation was defined as any increase in LV volume from rest to peak exercise. Patients who had at least two coronary arteries with significant stenosis were considered as having multi-vessel CAD. RESULTS: Thirty-four patients had ESV dilation during exercise echocardiography. On the contrary, ESV decreased at peak exercise in all healthy subjects. Forty-one patients had multi-vessel CAD, and its prevalence was higher in patients with ESV dilation (65% vs 27%, p = 0.001). The extent of ESV increase correlated with CAD severity. ESV dilation is associated with multi-vessel CAD (Odds ratio [OR] 5.02, 95% confidence interval [CI] 2.09 - 12.07, p < 0.001). After adjustment for EDV increase, clinical, electrocardiographic, and echocardiographic variables, the association remained significant (adjusted OR 5.57, 95% CI 1.37-22.64; p = 0.02). CONCLUSIONS: ESV dilation independently correlated with multi-vessel CAD, whereas EDV dilation did not. The amount of ESV increase correlated with the severity of CAD. Our findings provide a rationale for incorporating volume measurements into stress echocardiography practice.

Training Needs Assessment Survey in Pediatric Consultation-Liaison Psychiatry.

OBJECTIVE: Despite growing recognition of how curriculum modules can benefit child and adolescent psychiatry (CAP) training, there are few standardized teaching resources for pediatric consultation-liaison psychiatry (PCLP). A Special Interest Group (SIG) of the American Academy of Child and Adolescent Psychiatry Physically Ill Child Committee (PICC) conducted a needs assessment to establish interest in, and availability of, a library of online, self-paced learning modules specific to PCLP. METHOD: An email needs assessment survey was distributed to the PICC listserv in the fall of 2019 with four core areas of inquiry: (1) clinical service description, (2) teaching barriers, (3) interest in curriculum resources, and (4) interest in evaluation resources. RESULTS: Respondents were representative of typical academic PCLP programs. The response rate was 28% (n = 39). Programs endorsed barriers to teaching including high service obligations and limited protected teaching time. All respondents indicated that they would utilize high-quality, online learning modules. Psychiatric complications of medical illness, catatonia, and delirium were identified as priority topics in the care of pediatric patients with comorbid medical conditions. CONCLUSIONS: There are currently no published educational studies regarding the training needs for PCLP programs, even among tertiary care academic facilities. This training needs assessment is the first step in establishing a national PCLP training curriculum. New paradigms to develop standardized curriculum resources for PCLP are needed.

The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients.

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

Carotid Intima-Media Thickness: Novel Loci, Sex-Specific Effects, and Genetic Correlations With Obesity and Glucometabolic Traits in UK Biobank.

OBJECTIVE: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease. CONCLUSIONS: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

Situating agent-based modelling in population health research.

Today's most troublesome population health challenges are often driven by social and environmental determinants, which are difficult to model using traditional epidemiological methods. We agree with those who have argued for the wider adoption of agent-based modelling (ABM) in taking on these challenges. However, while ABM has been used occasionally in population health, we argue that for ABM to be most effective in the field it should be used as a means for answering questions normally inaccessible to the traditional epidemiological toolkit. In an effort to clearly illustrate the utility of ABM for population health research, and to clear up persistent misunderstandings regarding the method's conceptual underpinnings, we offer a detailed presentation of the core concepts of complex systems theory, and summarise why simulations are essential to the study of complex systems. We then examine the current state of the art in ABM for population health, and propose they are well-suited for the study of the 'wicked' problems in population health, and could make significant contributions to theory and intervention development in these areas.

Insight into metastatic oral cancer tissue from novel analyses using FTIR spectroscopy and aperture IR-SNOM.

A novel machine learning algorithm is shown to accurately discriminate between oral squamous cell carcinoma (OSCC) nodal metastases and surrounding lymphoid tissue on the basis of a single metric, the ratio of Fourier transform infrared (FTIR) absorption intensities at 1252 cm-1 and 1285 cm-1. The metric yields discriminating sensitivities, specificities and precision of 98.8 ± 0.1%, 99.89 ± 0.01% and 99.78 ± 0.02% respectively, and an area under receiver operator characteristic (AUC) of 0.9935 ± 0.0006. The delineation of the OSCC and lymphoid tissue revealed by the image formed from the metric is in better agreement with an immunohistochemistry (IHC) stained image than are either of the FTIR images obtained at the individual wavenumbers. Scanning near-field optical microscopy (SNOM) images of the tissue obtained at a number of key wavenumbers, with high spatial resolution, show variations in the chemical structure of the tissue with a feature size down to ∼4 µm. The image formed from the ratio of the SNOM images obtained at 1252 cm-1 and 1285 cm-1 shows more contrast than the SNOM images obtained at these or a number of other individual wavenumbers. The discrimination between the two tissue types is dominated by the contribution from the 1252 cm-1 signal, which is representative of nucleic acids, and this shows the OSCC tissue to be accompanied by two wide arcs of tissue which are particularly low in nucleic acids. Haematoxylin and eosin (H&E) staining shows the tumour core in this specimen to be ∼40 µm wide and the SNOM topography shows that the core centre is raised by ∼1 µm compared to the surrounding tissue. Line profiles of the SNOM signal intensity taken through the highly keratinised core show that the increase in height correlates with an increase in the protein signal. SNOM line profiles show that the nucleic acids signal decreases at the centre of the tumour core between two peaks of higher intensity. All these nucleic acid features are ∼25 µm wide, roughly the width of two cancer cells.