Search

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (low density lipoprotein cholesterol). Results: MK-0616 displayed high affinity ( K i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84–103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple–oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43–85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Study question Are alterations in the transcript levels of genes from the methionine cycle associated with maternal associated miscarriage risk? Summary answer Lower expression of AHCY is associated with a greater number of prior pregnancy losses What is known already Around 15% of pregnancies end in miscarriage, and the risk of recurrence increases with each pregnancy loss. Aberrant differentiation (decidualization) of endometrial stromal cells into specialised decidual cells to accommodate implantation is a key maternal factor for miscarriage risk. Our previous work identified secretory changes in cysteine and methionine metabolites upon decidualization. The methionine cycle contributes to vital cellular functions, including producing methionine for proliferation, regulating cell differentiation, and S-adenosylmethionine (SAM) production. SAM is required for protein, RNA and DNA methylation, thereby influencing pathways at the metabolic, epigenetic, and proteomic levels. AHCY clears S-adenosylhomocysteine (SAH), reducing its inhibition of methylation. Study design, size, duration Endometrial biopsies (n = 250) were collected during the luteal phase (LH + 6-11). Patients were grouped based on their miscarriage history. Accordingly, expression of genes from the methionine cycle were quantified using RT-qPCR. Participants/materials, setting, methods Endometrial biopsies were obtained, with written informed consent, from women attending the Implantation Clinic at University Hospitals Coventry and Warwickshire NHS Trust, following transvaginal ultrasounds to exclude uterine pathology. Isolated RNA was converted into cDNA. Expression of AHCY, AMD1, BHMT2, CBS, MAT2A, MAT2B, and MTR were normalised to L19. Statistical analysis was performed in Graphpad Prism; with significance accepted at p Main results and the role of chance This study reports a distinct reduction in expression of methionine cycle genes (MAT2A, AHCY, AMD1, MTR, BHMT2) in the late-luteal phase of the cycle consistent with a reduction in proliferation. By plotting percentile graphs based on the statistical distribution in gene expression for each day of the luteal phase, comparisons have been made between groups. AHCY expression is significantly reduced in patients with increasing number of prior miscarriages, particularly between 0-2 and 5+ previous miscarriages (p = 0.0334). Neither patient age nor BMI are a factor in this reduced expression. In contrast, there is a stromal specific increase in AHCY upon decidualization in vitro, suggesting it is required in the decidua. Silencing AHCY in an endometrial cell line significantly reduces PRL expression upon decidualization. Reduction in AHCY may lead to a decreased “methylation potential” as SAH cannot be cleared. SAH accumulation inhibits methylation, and limits SAM production, thus compounding its effect. Decreased methylation potential could prevent differentiation of the stromal compartment, resulting in lower levels of PRL, and altering decidual timing. Therefore, an embryo may implant into a tissue primed for disintegration, resulting a miscarriage. In summary, AHCY may contribute to aberrant decidualization augmenting the risk of miscarriage. Limitations, reasons for caution Results are based on endometrial biopsies from an implantation clinic, therefore studies into biopsies from women with normal reproductive histories should also be analysed. Further functional studies are needed to ascertain the mechanism of action of AHCY in miscarriage. Wider implications of the findings This study identified that a decrease in AHCY in whole endometrial tissue is associated with increased risk of miscarriage. Further, silencing AHCY perturbed decidual marker expression. Thus, AHCY may act as a biomarker for atypical decidualization, and the clearance of SAH may be a potential treatment. Trial registration number N/A

Reflecting upon the constructionist model "learning-bymaking," prototyping (prototype making) as a product design and research approach is well recognised for assured development of innovative concepts in individual or collaborative working environments. A prototype is typically used as a tool to support experiments or interventions and to evaluate research goals. It also facilitates participatory design and user-centred design. However, it carries both coded and tacit knowledge that we, design educators and practitioners, find problematic to explain and instruct, particularly to non-designers. This paper amalgamates and argues the characteristics of prototyping including types, formats, and principles through literature review. Reflecting upon the designer’s intentions and the dual coding cognitive learning process, the author proposes a descriptive model that illustrates the dual actions experienced by the designer which can enable study on the improvement of the prototyping process.

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant®), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

Arabidopsis thaliana L. ecotype Dijon-G (Di-G) showed a different symptom development during pathogenesis compared to ecotype Columbia-0 (Col-0). Previously, it has been shown that Di-G has a higher susceptibility to necrotrophic fungus Alternaria brassicicola than Col-0. In this study, Di-G showed enhanced disease susceptibility to necrotrophic fungi Botrytis cinerea, Sclerotinia sclerotiorum, and Sclerotium rolfsii known to secrete oxalic acid (OA) as a pathogenicity factor. Treatment with 50 and 100 mM OA resulted in a more leaf tissue collapse in Di-G than in Col-0. The OA also up-regulated expression of the salicylic acid (SA)-inducible pathogenesis-related gene 1 (PR1) and down-regulated expression of the jasmonic acid/ethylene-inducible defensin PDF1.2 gene in Di-G. By contrast, Di-G was resistant to hemibiotrophic fungus Colletotrichum higginsianum and biotrophic Turnip crinkle virus (TCV) infections. Application of 0.5 mM SA resulted in a higher accumulation of endogenous SA and in a preferential expression of SA-responsive genes in Di-G. Salicylic acid accelerated OA-triggered plant cell death and attenuated PDF1.2 expression in Di-G. These results suggest that the enhanced susceptibility of Di-G to necrotrophic pathogen infections might be mediated by attenuated JA-ethylene defence signalling and/or heightened SA-related defence signalling. Interaction of SA-signalling with OA secretion might be also involved in the enhanced susceptibility of Di-G.

To examine the effectiveness of breastfeeding education and peer support groups organized by International Board Certified Lactation Consultants (IBCLCs) during the first week (T1) and the fifth to sixth week postpartum (T2), in terms of breastfeeding self-efficacy and exclusive breastfeeding rate.A quasi-experimental design.A maternity ward of a medical center in northern Taiwan.214 postpartum women.The control group (n = 122) received standard care, while the intervention group (n = 92) received standard care and attended a support group at T1 and T2.Outcome measures were assessed through self-administered questionnaires: Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF) and exclusive breastfeeding rate. Demographic and obstetric data were collected from participants and from their medical records. A general estimating equation, t-tests, and chi-square tests were adopted to examine hypotheses.Before examining the hypotheses, homogeneous tests confirmed the equality between the groups at T1. There were significant differences in breastfeeding self-efficacy (B = 0.21, p 0.01) between the two groups from T1 to T2. The breastfeeding self-efficacy of participants in the intervention group was significantly higher than those in the control group (t = 3.26, p = 0.01) at T2. The exclusive breastfeeding rate (61%) in the intervention group at T2 was significantly higher than the rate (39%) in the control group (chi-square=11.28, p = 0.001).Attending IBCLC-organized breastfeeding education and support groups during early postpartum hospitalization may increase mothers' breastfeeding self-efficacy and exclusive breastfeeding rate.

Many biocontrol mechanisms including antimicrobial activity have been identified for control of plant diseases. However, the influence of various traits on the biocontrol performance of a specific biological control agent (BCA) remains to be revealed. In this study, to dissect the contribution of various traits to the biocontrol performance of a bacterial BCA, we performed genetic screening using a random transposon (Tn) mutant collection constructed from Pseudomonas parafulva JBCS1880 that shows strong antagonism against Xanthomonas axonopodis pv. glycines and Burkholderia glumae. Suppression of antibacterial activity by Tn insertion reduced the biocontrol performance of the strain. The disruption of viscosin-like lipopeptide, which is predicted to have D-Ser at the second position (called VILS2 hereafter), significantly suppressed not only antagonism, but also swarming motility and biofilm formation of P. parafulva JBCS1880. In addition, surface colonization with swarming motility and siderophore production also contributed to the biocontrol ability of the strain. The results indicate that the coordinated action of VILS2-mediated antibacterial activity and surface movement is critical for biocontrol activity of P. parafulva JBCS1880. Overall, our results suggest that antagonism, swarming motility, and siderophore production are important traits for the biocontrol performance of P. parafulva JBCS1880. This is the first report of the biocontrol of soybean bacterial pustules using a strain of P. parafulva, which is expected to produce a novel lipopeptide. The traits essential for biocontrol performance of the potential BCA were determined, but the functional roles of many genes in biocontrol remain a focus for further investigation.

HIV associated immune activation (IA) is associated with increased morbidity in people living with HIV (PLWH) on antiretroviral therapy, and remains a barrier for strategies aimed at reducing the HIV reservoir. The underlying mechanisms of IA have not been definitively elucidated, however, persistent production of Type I IFNs and expression of ISGs is considered to be one of the primary factors. Plasmacytoid DCs (pDCs) are a major producer of Type I IFN during viral infections, and are highly immunomodulatory in acute HIV and SIV infection, however their role in chronic HIV/SIV infection has not been firmly established. Here, we performed a detailed transcriptomic characterization of pDCs in chronic SIV infection in rhesus macaques, and in sooty mangabeys, a natural host non-human primate (NHP) species that undergoes non-pathogenic SIV infection. We also investigated the immunostimulatory capacity of lymph node homing pDCs in chronic SIV infection by contrasting gene expression of pDCs isolated from lymph nodes with those from blood. We observed that pDCs in LNs, but not blood, produced high levels of IFNα transcripts, and upregulated gene expression programs consistent with T cell activation and exhaustion. We apply a novel strategy to catalogue uncharacterized surface molecules on pDCs, and identified the lymphoid exhaustion markers TIGIT and LAIR1 as highly expressed in SIV infection. pDCs from SIV-infected sooty mangabeys lacked the activation profile of ISG signatures observed in infected macaques. These data demonstrate that pDCs are a primary producer of Type I IFN in chronic SIV infection. Further, this study demonstrated that pDCs trafficking to LNs persist in a highly activated state well into chronic infection. Collectively, these data identify pDCs as a highly immunomodulatory cell population in chronic SIV infection, and a putative therapeutic target to reduce immune activation., Author summary For people living with HIV (PLWH), persistent immune activation is an obstacle to optimal health. In this study, we investigate the immunostimulatory potential of plasmacytoid dendritic cells in chronic SIV infection using comparative RNA-Seq. We observed that pDCs from SIV-infected rhesus macaques have highly activated profiles relative to uninfected animals; in contrast, pDCs from SIV-infected natural host sooty mangabeys had expression profiles similar to cells from uninfected animals. In chronically infected RMs, pDCs from lymph nodes maintained activation profiles elevated at levels even higher than those in the blood. Further, transcripts for the immunostimulatory cytokine family IFNA were readily detected in LN homing pDCs, but not those from blood. These data confirm pDCs as a major producer of Type I IFN in chronic SIV infection, and identify them as a target for immunotherapy.

This work develops an artificially intelligent (AI) tokamak operation design algorithm that provides an adequate operation trajectory to control multiple plasma parameters simultaneously into different targets. An AI is trained with the reinforcement learning technique in the data-driven tokamak simulator, searching for the best action policy to get a higher reward. By setting the reward function to increase as the achieved β p, q 95, and l i are close to the given target values, the AI tries to properly determine the plasma current and boundary shape to reach the given targets. After training the AI with various targets and conditions in the simulation environment, we demonstrated that we could successfully achieve the target plasma states with the AI-designed operation trajectory in a real KSTAR experiment. The developed algorithm would replace the human task of searching for an operation setting for given objectives, provide clues for developing advanced operation scenarios, and serve as a basis for the autonomous operation of a fusion reactor.

This study aimed to examine the relationship between trait resilience and salivary cortisol in a group of Chinese undergraduates. The Chinese versions of the Brief Resilience Scale and a measure of optimism, the revised Life Orientation Test were administered to 49 Chinese undergraduates who provided self-collected saliva samples six times per day (immediately after waking; 0.5, 3, 6, and 12 h thereafter; and at bedtime) over 3 consecutive weekdays. The cortisol data were aggregated across the 3 days to examine the association between resilience and components of the diurnal rhythm of cortisol using multiple regression. The results showed that higher resilience was associated with a stronger cortisol response to awakening and a steeper diurnal decline in cortisol from waking to bedtime. Resilience was positively associated with cortisol output over the course of the day but this relationship was not significant (p = 0.065). This pattern of diurnal rhythm is consistent with that typically observed in better adjusted individuals. Generated by an intensive protocol with compliance objectively monitored, these findings clearly indicate the important role of the hypothalamic-pituitary-adrenocortical axis in health and adjustment and contribute to the growing literature on resilience and cortisol in humans.

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

SARS-CoV-2 induced hypercytokinemia and inflammation are critically associated with COVID-19 disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type-I IFN antiviral responses and SARS-CoV-2-specific T-cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib treated animals had a rapid and remarkably potent suppression of lung macrophages production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection., Highlights • SARS-CoV-2 infected RMs mimic signatures of inflammation seen in COVID-19 patients • Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages • Baricitinib limits recruitment of neutrophils to the lung and NETosis • Baricitinib preserves innate antiviral and SARS-CoV-2-specific T-cell responses, Using a rhesus macaque infection model it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.

Excessive use of smartphones or other electronic screen products and the associated symptoms of addiction among youngsters have sparked concerns. This study explores possibilities of preventing adolescents or young adults from excessive smartphone use via a character-based mobile application stimulating their imagination and reflection. The character responds contingently to a user’s act of switching on or off the screen, causing one to associate the effects on the character with excessive use. This approach, grounded in the embodied cognition thesis, combines behavior with imaginative consequences for one to experience, which combat the rewarding neural pathways activated in addictive behaviors. The application was deployed in a field trial. Each participant’s usage was tracked via automated logging, and cognitive responses were probed through in-depth interviews. Interview data were analyzed, followed by comparison with logged data. Overall, about half of the participants attributed imaginative consequences to their ways of using phones. One third of the participants showed evidence of positive change in using phones. These two groups substantially overlapped. The results suggest that experientially grounded association of virtual consequences with physical acts could correlate with behavior change. Using figurative representation as feedback could be promising in supporting individuals for healthy habits.

The rapid growth in the usage of mobile and screen-based products and the corresponding addiction of adolescents to such devices continue to cause great concerns among different stakeholders. Family, as a potential psychosocial support for reducing the likelihood of addiction development, can be weakened as a result of the deterioration of parent-adolescent relationships associated with mobile devices overuse. Based on the family functioning and gamification-enhanced concepts, positive and fun interactions between family members can be a vital component in fostering a supportive relationship. An innovative and alternative family-focused intervention strategy, the interactive play platform named “Lamb Lamp,” has been developed to facilitate fun and pleasurable parent-adolescent interactivities. The design aims to divert family members’ attention away from their phones, while facilitating joyful and cheerful engagements for the whole family, with the ultimate aim of fostering the development of a supportive relationship. This paper reports the initial results of a pilot study on 5 families recruited at a community-based treatment center, with at least one child aged between 12 and 19 who exhibited excessive Internet or mobile phone use problems. Daily patterns related to the adolescents’ Internet and mobile use and personal reflections on the perceptions of family interrelationships were recorded through lifestyle probes—a set of self-reporting home assignments—before the placement of the Lamb Lamp. Semi-structured interviews were conducted after the intervention to further solicit feedback from the families. The findings were then summarized and verified by parents and the counselors of the families engaged. Although the feedback collected from the families did not indicate an obvious reduction in mobile use behavior, they confirmed the benefits of this gamification-enhanced intervention in a family context. Collective play not only stimulated emotional connectivity between parents and adolescents, but also encouraged them to relive joyful memories of family activities while dealing with the problem of excessive mobile use.

Suppression or mitigation of edge-localized mode (ELM) crashes is necessary for ITER. The strategy to suppress all the ELM crashes by the resonant magnetic perturbation (RMP) should be applied as soon as the first low-to-high confinement (L–H) transition occurs. A control algorithm based on real-time machine learning (ML) enables such an approach: it classifies the H-mode transition and the ELMy phase in real-time and automatically applies the preemptive RMP. This paper reports the algorithm design, which is now implemented in the KSTAR plasma-control system, and the corresponding experimental demonstration of typical high-δ KSTAR H-mode plasmas. As a result, all initial ELM crashes are suppressed with an acceptable safety factor at the edge (q 95) and with RMP field adjustment. Moreover, the ML-driven ELM crash suppression discharges remain stable without further degradation due to the regularization of the plasma pedestal.

The World Health Organization (WHO) has declared COVID-19 a pandemic. We review and reduce the clinical literature on diagnosis of COVID-19 through symptoms that might be remotely detected as of early May 2020. Vital signs associated with respiratory distress and fever, coughing,and visible infections have been reported. Fever screening by temperature monitoring is currently popular. However, improved noncontact detection is sought. Vital signs including heart rate and respiratory rate are affected by the condition. Cough, fatigue, and visible infections are also reported as common symptoms. There are non-contact methods for measuring vital signs remotely that have been shown to have acceptable accuracy, reliability, and practicality in some settings. Each has its pros and cons and may perform well in some challenges but be inadequate in others. Our review shows that visible spectrum and thermal spectrum cameras offer the best options for truly noncontact sensing of those studied to date, thermal cameras due to their potential to measure all likely symptoms on a single camera, especially temperature, and video cameras due to their availability, cost, adaptability, and compatibility. Substantial supply chain disruptions during the pandemic and the widespread nature of the problem means that cost-effectiveness and availability are important considerations. Refereed/Peer-reviewed

In the first experiment, the effect of two novel Lactobacillus plantarum strains was studied on the fermentation of spent mushroom substrate (SMS) through 10d of ensiling. Based on lactic acid production and lactic acid bacteria population, L. plantarum KU5 was identified as the best strain for fermentation with a 5-L bag silo. Spent mushroom substrate was ensiled with 0.5% (v/w) L. plantarum KU5 without or with 5% molasses. Silages treated with microbial inoculant and molasses had the lowest pH and the highest fermentative odors. In a second set of experiments similar to the above 5-L silo study, the simultaneous application of L. plantarum KU5 inoculant and molasses to 80-L silos improved fermentability and aerobic stability of SMS silages. For similar treatment using ton-bag silos, aerobic stability decreased and NH3-N content increased dramatically. In conclusion, sawdust-based SMS for animal use was successfully ensiled with L. plantarum KU5 inoculant and molasses.

Alteration in cortisol response to acute social stressors has been hypothesized to mediate childhood adversities (CA) and increased morbidity in adulthood. However, the evidence supporting an association between CA and cortisol response to social stressors is inconclusive. The present review addressed this issue by reviewing the literature on CA and cortisol response to acute social stressors, with a focus on studies with adolescents or adults, using the Childhood Trauma Questionnaire (CTQ) to assess CA, and examining salivary cortisol response to the Trier Social Stress Test (TSST). Systematic searches of relevant articles in PsycINFO, PubMed, Web of Science and ScienceDirect in February and March 2020 identified 12 articles including 1196 participants with mean ages ranging from 15.3 to 52.3 yrs. across studies. CTQ scores were significantly associated with cortisol response in 2 studies. In addition, the physical abuse and emotional neglect subscales were associated with cortisol response respectively in 2 separate studies. The lack of association between CA and cortisol response calls for more longitudinal studies, and the use of formal records of maltreatment or informant reports in future research to complement information collected by retrospective measures. In addition, increased attention to biological mechanisms other than that associated with the regulation of cortisol in explaining the connection between CA and psychiatry morbidity is warranted.