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Abstract PET and SPECT studies in treatment-resistant schizophrenia (TRS) have revealed significant alterations in regional cerebral blood flow (CBF) during clozapine treatment, which may vary according to the clinical response. Here, we used the more recent MRI approach of arterial spin labelling (ASL) to evaluate regional CBF in participants with TRS (N = 36) before starting treatment with clozapine compared to in healthy volunteers (N = 16). We then compared CBF in the TRS group, before and after 12 weeks of treatment with clozapine (N = 24); and examined the relationship of those differences against changes in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores over the treatment period. We observed widespread reductions in CBF in TRS compared to in healthy volunteers (p

Abstract The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p

To fight climate change, it is crucial to have a precise knowledge of greenhouse gas (GHG) concentrations in the atmosphere and to monitor sources and sinks of GHGs. On global scales, satellites are an appropriate monitoring tool. For the validation of the satellite measurements and to tie them to the World Meteorological Organization (WMO) trace gas scale, ground-based Fourier transform infrared (FTIR) networks are used, which provide reference data. To ensure the highest-quality validation data, the network must be scaled to the WMO trace gas scale and have a very small site-to-site bias. Currently, the Total Carbon Column Observing Network (TCCON) is the de facto standard FTIR network for providing reference data. Ensuring a small site-to-site bias is a major challenge for the TCCON. In this work, we describe the development and application of a new method to evaluate the site-to-site bias by using a remotely controlled portable FTIR spectrometer as a travel standard (TS) for evaluating the consistency of columnar GHG measurements performed at different TCCON stations, and we describe campaign results for the TCCON sites in Tsukuba (Japan), East Trout Lake (Canada) and Wollongong (Australia). The TS is based on a characterized portable EM27/SUN FTIR spectrometer equipped with an accurate pressure sensor which is operated in an automated enclosure. The EM27/SUN is the standard instrument of the Collaborative Carbon Column Observing Network (COCCON). The COCCON is designed such that all spectrometers are referenced to a common reference unit located in Karlsruhe, Germany. To evaluate the long-term stability of the TS instrument, it is placed side-by-side with the TCCON instrument in Karlsruhe (KA) and the COCCON reference unit (the EM27/SUN spectrometer SN37, which is operated permanently next to the TCCON-KA site) between deployments to collect comparing measurements. At each of the visited TCCON sites, the TCCON spectrometers collected low-resolution (LR) (0.5 cm−1) and high-resolution (HR) (0.02 cm−1) measurements in an alternating manner. Based on the TS as a portable standard, the measurements are compared to the Karlsruhe site as a common reference. For Tsukuba and Wollongong, the agreement with the reference in Karlsruhe found for XCO2 is on the 0.1 % level for both the LR and HR measurements. For XCH4, the agreement is at the 0.2 % level, with the low-resolution measurements showing a low bias at both sites and for both gases. For XCO, the deviations are up to 7 %. The reason for this is likely to be a known issue with the CO a priori profiles used by the TCCON over source regions. In East Trout Lake (ETL), the TCCON spectrometer broke down while the TS was en route to the station. Hence, no side-by-side comparison was possible there. An important auxiliary value for FTIR retrievals is the surface pressure. Using the pressure sensor in the TS, the surface pressure measurements at each site are also compared. The surface pressure analysis reveals excellent agreement (0.027, 0.135 and 0.094 hPa) for the Tsukuba, ETL and Wollongong sites.

The United States claims one of the highest rates of pregnancy-related mortality (PRM) and one of the highest rates of infant mortality (IM) among all high-income countries.1,2 Such findings are largely driven by the fact that almost one million U.S. pregnant individuals (i.e., 1 in 4) are affected by one or more chronic comorbid conditions, drastically increasing risk for mother and infant.3?7 Overall, the higher ages of pregnant individuals combined with a rising maternal chronic disease burden (e.g., hypertension, diabetes, mental health conditions, substance use disorders) and the growing impact of social determinants of health inequities have cumulatively increased the medical and social complexities faced by individuals during and after pregnancy.1 Importantly, non-Hispanic Black Americans are also more likely to face a complex pregnancy and/or a new onset complex condition after pregnancy than individuals of any other demographic group, leading to striking racial disparities in maternal and infant health.8?11 One complication that is considerably more common among mothers affected by a complex pregnancy is preterm birth (PTB) or birth of an infant before 37 weeks gestation. The United States has one of the highest PTB rates of all countries, affecting 1 in 10 pregnancies.12 Again, Black Americans bear a disproportionate burden of the complication, being 1.5???more likely to have a PTB and more than 2???more likely to have an early PTB13 PTBs (particularly early PTBs) are strong drivers of IM and racial disparities in IM.14,15 Mothers transitioning out of a pregnancy affected by PTB are also at higher risk for postpartum morbidity and mortality, new-onset chronic conditions, and a subsequent complicated pregnancy, highlighting the importance of maternal care after a complicated pregnancy. Indeed, longitudinal postpregnancy and interpregnancy clinical care can yield significant public health benefits, including a decreased chronic disease burden among the mother and reduced rates of subsequent PTB.16?18 Thus, longitudinal postpartum care is critical for both reducing current and future maternal disease severity and optimizing health for future pregnancies.19 Longitudinal postpartum and interpregnancy care serves as a compelling strategy to prevent recurrent adverse pregnancy outcomes, including PTB.20,21 For example, the American College of Obstetrics and Gynecology (ACOG) consensus guidelines recommend ongoing, multiepisode longitudinal postpartum and interpregnancy care, personalized to meet individual needs.16,22 Per ACOG, optimal interpregnancy care should be delivered by a multidisciplinary team of obstetric, primary care, and subspecialty clinicians, as a continuation of postpartum care to improve short and long-term health outcomes for individuals and their infants.16 Furthermore, primary care organizations, such as the Society of General Internal Medicine and the American Association of Family Physicians, have emphasized the importance of postpartum primary care in equitably addressing the health care needs of pregnant individuals across the life course.23,24 However, accumulating data has shed light on the inability of current U.S. postpartum health care models to deliver optimal postpartum and interpregnancy care, as the health care infrastructures needed to systematically connect individuals to longitudinal, multidisciplinary care after pregnancy are lacking. Moreover, existing care models often fail to address the needs of minoritized individuals who experience a higher burden of adverse social determinants of health, impeding their access to and utilization of postpartum preventive services.3,25?29 As such, few individuals receive any postpartum care and even fewer receive ongoing, longitudinal postpartum and interpregnancy care, even after high-risk pregnancy.30,31 Such data are particularly alarming considering that over half of PRM occurs during the year after childbirth,32 usually outside of the hospital setting.32 Poorly managed chronic conditions during the interpregnancy period also greatly increase risk for complications during subsequent pregnancies, including repeat PTB. Indeed, more than 80% of PRM is considered preventable,33 highlighting the significant gap in U.S. maternity care services that occurs during the months and even years after childbirth.34?36 Individuals transitioning out of a pregnancy affected by PTB have unique needs. The experience of PTB not only increases risk of subsequent PTB but also results in the need for intensive postpartum health care utilization.37 Individuals who experience PTB have a higher risk of postpartum depression, severe maternal morbidity, and all-cause mortality than those who carry pregnancies to term.38?42 Yet, they infrequently access primary care in the 12 months after delivery.43 Systematizing interpregnancy care after PTB not only has the potential to broadly address poor U.S. maternal health outcomes but also the unacceptable maternal health disparities embedded within these outcomes.44 While over 5 decades of research, policy, and practice has informed frameworks and evidence-based practice guidelines for the primary care of the preterm infant during the 1st year and beyond,45?51 interpregnancy and postpartum care of the mother after PTB remains a neglected topic.52?55 In their article, ?Integrating care for mother?infant dyads after preterm birth: A qualitative study of clinician perspectives on feasibility,? Gregory et al. elicit perspectives of multidisciplinary clinicians who provide care to postpartum individuals and infants after PTB to identify potential barriers and facilitators of using pediatric access points for maternal postpartum and interpregnancy care delivery through a dyadic mother?infant care model.56 The frequent (often ?6) pediatric visits in the year after birth has spurred development of focused professional guidelines and reimbursement structures to address maternal health needs for topics such as postpartum depression screening in pediatric settings. However, many unused opportunities remain to leverage infant care access points to address maternal postpartum care gaps.56 Some mother/infant dyadic care approaches exist for delivery by providers who care for both postpartum individuals and children, including family medicine, adolescent medicine, and dual internal medicine/pediatrics physicians.54,57?59 Importantly, Gregory et al. highlight that these models have limited application for mothers of the 80% of U.S. infants who receive primary care from pediatricians.56 Thus, leveraging pediatric care access points for postpartum and interpregnancy care require coordination across multiple settings and provider specialties, spanning pediatrics, neonatology, internal medicine, family medicine, and obstetrics and gynecology.56 Clinicians interviewed in the Gregory et al. qualitative study articulated multiple structural, systemic, and policy barriers to multispecialty, multisetting dyadic care.56 These barriers included inadequate care handoffs between specialties, communication barriers across health care settings, lack of care coordination between specialties, inconsistent access to counterparts in other specialties during clinical urgencies, privacy restrictions limiting communication between maternal and infant care teams, scheduling systems created to accommodate individuals instead of dyads, and lack of comprehensive electronic health record (EHR) access to both mother and infant charts.56 Clinicians in the Gregory et al. study also articulated concerns about pitfalls that could potentially arise from delivering care outside of one's area of licensure and expertise and described that responsibilities for maternal follow-up care across specialties were poorly delineated.56 Gregory et al. also noted that while their study recruited clinicians involved in the care of preterm infants, clinician-reported barriers were not restricted to dyads who experienced PTB.56 Multispecialty mother/infant dyadic care, leveraging pediatric well-child visit access points, may provide compelling opportunities to address postpartum and interpregnancy care gaps, including after PTB. Gregory et al. report many structural, policy, and practice barriers to implementation of this dyadic model for longitudinal interpregnancy care delivery,56 while also proposing some practical steps to facilitate collaborative care models. These include repurposing existing EHR team-based communication for handoffs, establishing clinician directories and call schedules to ease cross-dyad consultations, and clinically colocating dyad relevant medical specialties.56 Beyond these local interventions, these data can inform roadmaps guiding the policy changes and quality initiatives required to promote routine multispecialty interpregnancy dyadic care. First, incorporating longitudinal postpartum care, including primary care transition, into perinatal Medicaid programmatic, policy, and quality transformations may incentivize and resource the health system collaborative infrastructures needed for implementation of multispecialty dyadic programs.60 Prior transformations effected by Centers of Medicare and Medicaid Services (CMS) and select state Medicaid agencies have successfully improved obstetric postpartum visit attendance and quality.60 Broad adoption of postpartum Medicaid extension, with implementation or planned implementation in 46 states, provides national opportunities to apply similar approaches to incentivize optimal care after PTB and other high-risk pregnancies.61 Second, CMS can require that health systems with public-facing hospital designations (e.g., ?Birthing-Friendly? Hospital Designations) transition patients to established multidisciplinary interpregnancy care after PTB or high-risk pregnancy. The ?Birthing-Friendly? Hospital Designation was established in 2022 to help patients identify hospitals that have implemented maternal care best practices.62 CMS currently assigns ?Birthing-Friendly? Hospital Designation to systems that participate in state or national pregnancy quality collaboratives and act on their recommendations.63 There remain many opportunities to iteratively expand designation requirements over time to include transition to multidisciplinary, longitudinal postpartum care. Third, coalitions, such as the Alliance for Innovation in Maternal Health, can set priorities and establish consensus bundles to support state agencies and health systems in implementing the complex cross-sector strategies needed to ensure high-quality, evidence-based postpartum and interpregnancy care, especially after complex pregnancy.64,65 These interventions will help to overcome the barriers and facilitate the solutions proposed by Gregory et al.56 to improve postpartum maternal health outcomes through systematization of dyadic interpregnancy care after complex pregnancy, including PTB.

Background and objective: Real-world evidence of paediatric psoriasis (PsO) is lacking in Spain. The purpose of this study was to identify physician-reported disease burden and current treatment patterns in a real-world paediatric PsO patient cohort in Spain. This will enhance our understanding of the disease and contribute to the development of regional guidelines. Material and method: This retrospective analysis of a cross-sectional market research survey assessed the clinical unmet needs and treatment patterns in patients with paediatric PsO in Spain, as reported by their primary care and specialist physicians, using data collected as part of the Adelphi Real World Paediatric PsO Disease-Specific Program (DSP™) between February and October 2020. Results: Survey data from 57 treating physicians were included (71.9% [N = 41] dermatologists, 17.6% [N = 10] general practitioners/primary care physicians, and 10.5% [N = 6] paediatricians); the final analysis included 378 patients. At sampling, 84.1% (318/378) of patients had mild disease, 15.3% (58/378) had moderate disease and 0.5% (2/378) had severe disease. Retrospectively reported physician-judged severity at the time of PsO diagnosis recorded 41.8% (158/378) of patients with mild disease, 51.3% (194/378) with moderate disease and 6.9% (26/378) with severe disease. Overall, 89.3% (335/375) of patients were currently receiving topical PsO therapy, while 8.8% (33/375), 10.4% (39/375) and 14.9% (56/375) of patients were currently receiving phototherapy, conventional systemics and biologics, respectively. Conclusions: These real-world data reflect the current burden and treatment landscape of paediatric PsO in Spain. The management of patients with paediatric PsO could be improved by further educating healthcare professionals and developing regional guidelines. Resumen: Antecedente y objetivo: En España se carece de evidencia sobre psoriasis (PsO) pediátrica en el mundo real. El objetivo de este estudio fue identificar la carga de la enfermedad reportada por el facultativo y los patrones actuales de tratamiento en una cohorte de pacientes psoriásicos pediátricos en el mundo real. Ello ampliará nuestra comprensión de la enfermedad y contribuirá al desarrollo de directrices regionales. Material y método: Este análisis retrospectivo transversal de una encuesta de investigación mercado evaluó las necesidades clínicas no satisfechas y los patrones de tratamiento en pacientes con PsO pediátrica en España, según lo reportado por sus médicos de atención primaria y especialistas, utilizando datos recopilados como parte del Disease-specific program (DSP™) de Adelphi para PsO pediátrica en el mundo real, entre los meses de febrero y octubre de 2020. Resultados: Se incluyeron los datos de la encuesta realizada a 57 facultativos médicos tratantes (71,9% [N = 41] de dermatólogos, 17,6% [N = 10] de médicos generales de atención primaria y 10,5% [N = 6] de pediatras); el análisis final incluyó 378 pacientes. En la muestra, el 84,1% (318/378) de los pacientes padeció enfermedad leve, el 15,3% (58/378) enfermedad moderada y el 0,5% (2/378) enfermedad severa. De acuerdo con el reporte retrospectivo, la gravedad juzgada por el facultativo en el momento de diagnosticarse la PsO pediátrica registró un 41,8% (158/378) de pacientes con enfermedad leve, un 51,3% (194/378) con enfermedad moderada y un 6,9% (26/378) con enfermedad severa. En general, el 89,3% (335/375) de los pacientes recibía en la actualidad terapia tópica para PsO pediátrica, mientras que el 8,8% (33/375), el 10,4% (39/375) y el 14,9% (56/375) de los pacientes recibía en la actualidad fototerapia, sistémicos y biológicos convencionales, respectivamente. Conclusiones: Estos datos del mundo real reflejan la carga actual y el panorama de la PsO pediátrica en España. El manejo de los pacientes pediátricos podría mejorar, formando aún más a los profesionales sanitarios y desarrollando directrices regionales.

IntroductionPatients are stakeholders in their own pain management. Factors motivating individuals to seek or use opioids therapeutically for treatment of acute pain are not well characterized but could be targeted to reduce incident iatrogenic opioid use disorder (OUD). Emergency departments (EDs) commonly encounter patients in acute pain for whom decisions regarding opioid therapy are required. Decision-making is necessarily challenged in episodic, unscheduled care settings given time pressure, limited information, and lack of pre-existing patient provider relationship. Patients may decline to take prescribed opioids or conversely seek opioids from other providers or non-medical sources.MethodsUsing a framework analysis approach, we qualitatively analyzed transcripts from 29 patients after discharge from an ED visit for acute pain at a large, urban, academic hospital in the midwestern United States to describe motivating factors influencing patient decisions regarding opioid use for acute pain. A semi-structured interview guide framed participant discussion in either a focus group or interview transcribed and analyzed with conventional content analysis.ResultsFour major themes emerged from our analysis including a) pain management literacy, b) control preferences, c) risk tolerance, and d) cues to action.DiscussionOur findings suggest targets for future intervention development and a framework to guide the engagement of patients as stakeholders in their own acute pain management.

Abstract Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition.

Background Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing. Aims Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness. Method This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.

Abstract Background While benefits of greenness to health have been reported, findings specific to child respiratory health are inconsistent. Methods We utilized a prospective birth cohort followed from birth to age 7 years (n = 617). Residential surrounding greenness was quantified via Normalized Difference Vegetation Index (NDVI) within 200, 400, and 800 m distances from geocoded home addresses at birth, age 7 years, and across childhood. Respiratory health outcomes were assessed at age 7 years, including asthma and lung function [percent predicted forced expiratory volume in the first second (%FEV1), percent predicted forced vital capacity (%FVC), and percent predicted ratio of forced expiratory volume in the first second to forced vital capacity (%FEV1/FVC)]. We assessed associations using linear and logistic regression models adjusted for community deprivation, household income, and traffic-related air pollution. We tested for effect measure modification by atopic status. Results We noted evidence of positive confounding as inverse associations were attenuated upon adjustment in the multivariable models. We found evidence of effect measure modification of NDVI and asthma within 400 m at age 7 years by atopic status (p = 0.04), whereby children sensitized to common allergens were more likely to develop asthma as exposure to greenness increased (OR = 1.3, 95% CI: 0.9, 2.0) versus children not sensitized to common allergens (OR = 0.8, 95% CI: 0.5, 1.2). We found consistently positive associations between NDVI and %FEV1 and %FVC which similarly evidenced positive confounding upon adjustment. In the adjusted regression models, NDVI at 7 years of age was associated with %FEV1 (200 m: β = 2.1, 95% CI: 0.1, 3.3; 400 m: β = 1.6, 95% CI: 0.3, 2.9) and %FVC (200 m: β = 1.8, 95% CI: 0.7, 3.0; 400 m: β = 1.6, 95% CI: 0.3, 2.8; 800 m: β = 1.5, 95% CI: 0.1, 2.8). Adjusted results for %FEV1/FVC were non-significant except exposure at birth in the 400 m buffer (β = 0.81, 95% CI: 0.1, 1.5). We found no evidence of effect measure modification of NDVI by atopic status for objective measures of lung function. Conclusion Sensitivity to allergens may modify the effect of greenness on risk for asthma in children but greenness is likely beneficial for concurrent lung function regardless of allergic status.

Resumen: Antecedente y objetivo: En España se carece de evidencia sobre psoriasis (PsO) pediátrica en el mundo real. El objetivo de este estudio fue identificar la carga de la enfermedad reportada por el facultativo y los patrones actuales de tratamiento en una cohorte de pacientes psoriásicos pediátricos en el mundo real. Ello ampliará nuestra comprensión de la enfermedad y contribuirá al desarrollo de directrices regionales. Material y método: Este análisis retrospectivo transversal de una encuesta de investigación mercado evaluó las necesidades clínicas no satisfechas y los patrones de tratamiento en pacientes con PsO pediátrica en España, según lo reportado por sus médicos de atención primaria y especialistas, utilizando datos recopilados como parte del Disease-Specific Program (DSP™) de Adelphi para PsO pediátrica en el mundo real, entre los meses de febrero y octubre de 2020. Resultados: Se incluyeron los datos de la encuesta realizada a 57 facultativos médicos tratantes (71,9% [n = 41] de dermatólogos, 17,6% [n = 10] de médicos generales de atención primaria y 10,5% [n = 6] de pediatras); el análisis final incluyó 378 pacientes. En la muestra, 84,1% (318/378) de los pacientes padeció enfermedad leve, 15,3% (58/378) enfermedad moderada y 0,5% (2/378) enfermedad severa. De acuerdo con el reporte retrospectivo, la gravedad juzgada por el facultativo en el momento de diagnosticarse la PsO pediátrica registró 41,8% (158/378) de pacientes con enfermedad leve, 51,3% (194/378) con enfermedad moderada y 6,9% (26/378) con enfermedad severa. En general, 89,3% (335/375) de los pacientes recibía en la actualidad terapia tópica para PsO pediátrica, mientras que 8,8% (33/375), 10,4% (39/375) y 14,9% (56/375) de los pacientes recibían en la actualidad fototerapia, sistémicos y biológicos convencionales, respectivamente. Conclusiones: Estos datos del mundo real reflejan la carga actual y el panorama de la PsO pediátrica en España. El manejo de los pacientes pediátricos podría mejorar, formando aún más a los profesionales sanitarios y desarrollando directrices regionales. Abstract: Background and objective: Real-world evidence of paediatric psoriasis (PsO) is lacking in Spain. The purpose of this study was to identify physician-reported disease burden and current treatment patterns in a real-world paediatric PsO patient cohort in Spain. This will enhance our understanding of the disease and contribute to the development of regional guidelines. Material and method: This retrospective analysis of a cross-sectional market research survey assessed the clinical unmet needs and treatment patterns in patients with paediatric PsO in Spain, as reported by their primary care and specialist physicians, using data collected as part of the Adelphi Real World Paediatric PsO Disease-Specific Program (DSP™) between February and October 2020. Results: Survey data from 57 treating physicians were included (71.9% [N = 41] dermatologists, 17.6% [N = 10] general practitioners/primary care physicians, and 10.5% [N = 6] paediatricians); the final analysis included 378 patients. At sampling, 84.1% (318/378) of patients had mild disease, 15.3% (58/378) had moderate disease and 0.5% (2/378) had severe disease. Retrospectively reported physician-judged severity at the time of PsO diagnosis recorded 41.8% (158/378) of patients with mild disease, 51.3% (194/378) with moderate disease and 6.9% (26/378) with severe disease. Overall, 89.3% (335/375) of patients were currently receiving topical PsO therapy, while 8.8% (33/375), 10.4% (39/375) and 14.9% (56/375) of patients were currently receiving phototherapy, conventional systemics and biologics, respectively. Conclusions: These real-world data reflect the current burden and treatment landscape of paediatric PsO in Spain. The management of patients with paediatric PsO could be improved by further educating healthcare professionals and developing regional guidelines.

Experimental tasks comparing participants’ performance for categorising, remembering, and recognising positive and negative words are widely used in the emotional cognitive domain. Such tasks are commonly used in experimental psychology and psychiatry research, and have been shown to be sensitive biomarkers of depression and antidepressant drug action [1,2]. In addition, several of these tasks investigate self-referential processing i.e., the processing of information relevant to oneself; this has been shown to modify the way emotional words are encoded and remembered and may be a target that is amenable to treatment [3,4].In practice, the development of such tasks for implementation in research studies often depends on the selection and matching of words according to characteristics such as valence or arousal, imageability, word frequency and word length to investigate differences in a chosen domain of interest whilst keeping important confounds constant. This introduces a need for ratings covering a range of word attributes that have been shown to affect processing. In particular, ratings of self-referential valence (how positively or negatively subjects feel about a word when this is used to describe themselves/their circumstances) have been seldom included in databases, despite the frequent investigation of the concept in research [1,5]. Other important attributes often considered in the process of matching and selection are word imageability and subjective frequency [6,7].To facilitate the word selection and matching process required in cognitive-emotional task development, the present dataset provides subjective ratings for 150 positive and 150 negative adjectives describing personality characteristics. Across four online surveys, the 300 words were rated on self-referential valence, imageability and subjective frequency by representative samples of 200 UK-based, English-speaking adults. Basic demographics and data on depressive symptoms and state anxiety were collected from all participants.Comprehensive descriptive statistics and word length were calculated for each of the 300 words. All data cleaning and statistical analysis was performed in R.Our work is based on years of experience using the Oxford Emotional Task Battery [1,5] and may be particularly relevant for researchers using self-referential cognitive tasks with UK-based samples.

ABSTRACTSevere acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1–3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.

Background: Inflammatory bowel disease (IBD) involves an increase in T effector cells in the intestines that disrupts the normal balance with T regulatory cells (Tregs). A therapy that restores this balance has the potential to treat IBD. We have shown that epicutaneous exposure to OVA induces Tregs that are able to induce tolerance. The Tregs also migrate to the intestines where they alleviate colitis in mice, demonstrating the potential for skin induced Tregs to treat intestinal inflammation. We investigated the role of Foxp3, IL-10, and TGF-β in the suppression of colitis by epicutaneous immunotherapy (ET).Methods: RAG1−/− mice were transferred with CD4+CD45RBhi T cells from wild type mice to induce colitis. To determine whether Foxp3+ Tregs, IL-10-, or TGF-β-producing Tregs were necessary, Foxp3-DTR, IL-10−/−, or CD4-dnTGFBRII mice were immunized with OVA and OVA TCR enriched T cells were added. As control groups, some mice were given OVA TCR enriched T cells from wild type mice or no OVA TCR enriched T cells. Half of the mice in each group were then exposed on the skin to Viaskin patches containing OVA weekly for 3 weeks. Mice given OVA TCR enriched T cells from Foxp3-DTR mice were given diphtheria toxin (DT) or not in addition to ET. Mice were assessed for weight loss, colon length, colonic cytokine production, and histological inflammation.Results: ET, after injection with OVA TCR enriched T cells derived from wild type mice, prevented weight loss, decreased colonic inflammatory cytokine production and histological colitis. ET in the absence of the OVA TCR enriched T cells did not alleviate colitis. ET, after injection with OVA TCR enriched T cells derived from Foxp3-DTR mice, prevented weight loss, decreased colonic inflammatory cytokine production, and histological colitis. Ablation with DT did not impair the ability of ET to alleviate colitis. ET failed to alleviate colitis when OVA TCR enriched T cells were derived from IL-10−/− or CD4-dnTGFBRII mice.Conclusions: ET through induction of Tregs, which produce IL-10 and TGF-β, could be a promising treatment for IBD.

Abstract Background The post-disaster mental health crisis intervention (MHCI) system in China remains immature and unsystematic. We aim to report the perceptions of a large sample of MHCI workers and government administrators and provide recommendations for developing a national mental health disaster response management plan in China. Methods An in-depth qualitative study was conducted, collecting data from 20 focus-group discussions and 25 key stakeholder interviews. These recruited participants who had been involved in different types of disaster rescue across 7 provinces/cities where disasters have recently occurred. We used thematic analysis to analyze the data and relevant findings were extracted for policy recommendation. Results Mental health workers’ perspectives were examined in detailed according to four core themes: forms of organization, intervention pathway, intervention strategy and technique, and public health information. Post-disaster MHCI should be approached in teams that are integrated with emergency medicine systems, and be led by unified command management. All levels of local health and family planning commission should prepare post-disaster MHCI work plans and build response teams/emergency centres. Future training for MHCI workers should focus on: building a sense of trust within the team; clarifying each member’s role; strengthening the screening, assessment and referrals training for psychological professionals; and providing psychological intervention training for Chinese psychiatrists. It is necessary to set up guiding principles for disaster research ethics, mental health rehabilitation and media interaction. Conclusions Through exploring and analyzing the perceptions of current disaster response mental health workers and government administrators, our findings provide essential recommendations for developing a national to county level post-disaster MHCI emergency management plan and can guide the formulation of relevant laws and regulation in China.

Premise Microsatellite markers were developed for Labrador tea (Rhododendron groenlandicum, Ericaceae) to facilitate downstream genetic investigation of this species and the extremely closely related, circumboreal Rhododendron subsect. Ledum. Methods and Results Forty‐eight primer pairs were designed using Illumina data and screened for excellent amplification. Sixteen successful pairs were developed as microsatellite markers using fluorescently labeled amplification to generate chromatogram data. These data were evaluated for intrapopulation and interpopulation variability in three populations from Alaska and Maine, USA, and the Northwest Territories, Canada. Fourteen polymorphic markers genotyped reliably, each with one to eight alleles. Cluster analysis indicates that across the range, populations can be easily discriminated. Cross‐amplification in other Rhododendron subsect. Ledum species shows broad application of the developed markers within this small, well‐supported clade. Conclusions These microsatellite markers exhibit significant variability and will be useful in population genetics within R. groenlandicum and for investigation of species boundaries across Rhododendron subsect. Ledum.

Premise Microsatellite markers were developed for sandmyrtle, Kalmia buxifolia (Ericaceae), to facilitate phylogeographic studies in this taxon and possibly many of its close relatives. Methods and Results Forty‐eight primer pairs designed from paired‐end Illumina MiSeq data were screened for robust amplification. Sixteen pairs were amplified again, but with fluorescently labeled primers to facilitate genotyping. Resulting chromatograms were evaluated for variability using three populations from Tennessee, North Carolina, and New Jersey, USA. Eleven primer pairs were reliable and polymorphic (mean 3.92 alleles), one was reliable but monomorphic, and four were not reliable. The markers exhibited lower heterozygosity (mean 0.246) than expected (mean 0.464). Cross‐amplification in the remaining nine Kalmia species exhibited a phylogenetic pattern, suggesting broad applicability of the markers across the genus. Conclusions These microsatellite markers will be useful in population genetics and species boundaries studies of K. buxifolia, K. procumbens, and likely all other Kalmia species.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released from intestinal enteroendocrine (EE) cells and have well-established glucose-lowering actions. Lactic acid bacteria (LAB) colonise the human intestine, but it is unknown whether LAB and EE cells interact. Acute co-culture of LAB with EE cells showed that certain LAB strains elicit GLP-1 and GIP secretion (13-194-fold) and upregulate their gene expression. LAB-induced incretin hormone secretion did not appear to involve nutrient mechanisms, nor was there any evidence of cytolysis. Instead PCR array studies implicated signalling agents of the toll-like receptor system, e.g. adaptor protein MyD88 was decreased 23-fold and cell surface antigen CD14 was increased 17-fold. Mechanistic studies found that blockade of MyD88 triggered significant GLP-1 secretion. Furthermore, blocking of CD14 completely attenuated LAB-induced secretion. A recent clinical trial clearly shows that LAB have potential for alleviating type 2 diabetes, and further characterisation of this bioactivity is warranted.

Dendritic cells (DC) are well-known modulators of immunity. This heterogeneous population is composed of defined subsets that exhibit functional specialization and are critical in initiating responses to pathogens. As such, many infectious agents employ strategies to disrupt DC functioning in attempts to evade the immune system. In some instances, this manifests as an outright loss of these cells. Previous work has suggested that, in the absence of an efficient natural killer (NK) cell response, murine cytomegalovirus (MCMV) induces large amounts of interferon (IFN)-I. This heightened IFN-I response is thought to contribute to conventional DC (cDC) loss and delayed development of T cell immunity. However, the precise role of IFN-I in such cDC loss remains unclear. We investigated the effects of licensed NK cells and IFN-I signaling on splenic cDC subsets during MCMV infection and found that a licensed NK cell response partially protects cDC numbers, but does not prevent increases in serum IFN-I. This suggested that high residual IFN-I could contribute to cDC loss. Therefore, we used multiple strategies to modulate IFN-I signaling during MCMV infection including plasmacytoid DC depletion, IFN-I receptor (IFNAR) blockade, and genetic ablation of IFNAR expression. Interestingly, restriction of IFN-I signals did not substantially preserve either CD8+ or CD4+ DC total numbers, but resulted in significant retention and/or accumulation of the splenic CD8− CD4− [double negative (DN)] subset. However, the DN DC effect manifested in a DC-extrinsic manner since IFNAR-deficient cells were not preferentially retained over their IFNAR wild-type counterparts in a mixed-chimera setting. Our results show that IFN-I signaling is not responsible for overt cDC toxicity in the setting of acute MCMV infection and emphasize that additional mechanisms contribute to DC loss and require exploration.

Plant secondary metabolites are protective dietary constituents and rol genes evidently increase the synthesis of these versatile phytochemicals. This study subjected a globally important vegetable, lettuce (Lactuca sativa) to a combination of untargeted metabolomics (LC-QTof-MS) and in vitro bioactivity assays. Specifically, we examined the differences between untransformed cultured lettuce (UnT), lettuce transformed with either rolABC (RA) or rolC (RC) and commercially grown (COM) lettuce. Of the 5333 metabolite features aligned, deconvoluted and quantified 3637, 1792 and 3737 significantly differed in RA, RC and COM, respectively, compared with UnT. In all cases the number of downregulated metabolites exceeded the number increased. In vitro bioactivity assays showed that RA and RC (but not COM) significantly improved the ability of L. sativa to inhibit α-glucosidase, inhibit dipeptidyl peptidase-4 (DPP-4) and stimulate GLP-1 secretion. We putatively identified 76 lettuce metabolites (sesquiterpene lactones, non-phenolic and phenolic compounds) some of which were altered by several thousand percent in RA and RC. Ferulic acid levels increased 3033–9777%, aminooxononanoic acid increased 1141–1803% and 2,3,5,4′tetrahydroxystilbene-2-O-β-d-glucoside increased 40,272–48,008%. Compound activities were confirmed using commercially obtained standards. In conclusion, rol gene transformation significantly alters the metabolome of L.sativa and enhances its antidiabetic properties. There is considerable potential to exploit rol genes to modulate secondary metabolite production for the development of novel functional foods. This investigation serves as a new paradigm whereby genetic manipulation, metabolomic analysis and bioactivity techniques can be combined to enable the discovery of novel natural bioactives and determine the functional significance of plant metabolites.

The mier family consists of three related genes encoding ELM2-SANT containing proteins. MIER1 has been well characterized and is known to function in transcriptional repression through its ability to recruit HDAC1 and 2. Little is known about MIER2 or MIER3 function and no study characterizing these two proteins has been published. In this report, we investigate MIER2 and MIER3 localization and function. Confocal analysis revealed that, while MIER2 and MIER3 are mainly nuclear proteins, a substantial proportion (32%) of MIER2 is localized in the cytoplasm. Co-immunoprecipitation experiments demonstrated that the MIER proteins do not dimerize; that MIER2, but not MIER3, can recruit HDACs; and that recruitment is cell line-dependent. MIER2 was associated with HDAC1 and HDAC2 in HEK293 cells, but only with HDAC1 in MCF7 and HeLa cells. Little or no MIER3 co-immunoprecipitated with either HDAC1 or 2 in any of the three cell lines tested. By contrast, HDAC1 and 2 were readily detected in MIER1α complexes in all three cell lines. Histone deacetylase assays confirmed that MIER2, but not MIER3 complexes, have associated deacetylase activity, leading to the conclusion that MIER3 does not function in HDAC recruitment in these cell lines. In contrast to what has been reported for other ELM2-SANT associated HDACs, addition of D-myo-inositol-1,4,5,6-tetrakisphosphate led to only a small increase in MIER1α associated deacetylase activity and no effect on that associated with MIER2. Deletion analysis revealed that HDAC recruitment occurs through the ELM2 domain. Finally, using site-directed mutagenesis, we show that, like MIER1, 228W in the ELM2 domain is a critical residue for HDAC recruitment by MIER2.