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Background: Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology., Methods: Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55). Specifically, we tested whether mGlu5 availability in frontolimbic regions of interest (ROIs; dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) differed as a function of CU status., Results: Past-year CU (n = 22) was associated with 18.62%-19.12% higher mGlu5 availability in frontal and 14.24%-16.55% higher mGlu5 in limbic ROIs relative to participants with no recent CU. Similarly, past-month or monthly CU (n = 16) was associated with higher mGlu5 availability in frontal (18.05%-20.62%) and limbic (15.53%-16.83%) ROIs. mGlu5 availability in the orbitofrontal cortex and amygdala was negatively associated with depressive symptoms in the past-year CU group. In both CU groups, exploratory analyses showed negative correlations between mGlu5 availability and sadness across all ROIs and with perceptions of worthlessness and past failures (r's = -.47 to .66, P's = .006-.033) in the ventromedial prefrontal cortex. Participants with CU reported lower mean depressive symptoms (P's = .006-.037) relative to those without CU., Conclusions: These findings have substantial implications for our understanding of interactions between CU and glutamatergic neurotransmission in trauma-related psychopathology, underscoring the need for treatment development efforts to consider the effects of CU in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Background: The national opioid crisis continues to intensify, despite the fact that opioid use disorder (OUD) is treatable and opioid overdose deaths are preventable through first-line treatment with medications for opioid use disorder (MOUD). This study identifies and categorizes payment-related barriers that impact MOUD access and retention from both the provider and patient perspectives and provides insight into how these barriers can be addressed., Methods: We performed a critical review of the literature (peer-reviewed studies and relevant documents from the gray literature) to identify payment-related access and retention barriers to MOUD. We used the results of this review to develop an analytic framework to understand how payment impacts MOUD access and retention for both providers and patients. In addition, we reviewed action plans developed by Massachusetts communities that participated in the Healing Communities Study (HCS) to analyze which payment-related barriers were addressed through the study., Results: We identified 18 payment-related barriers that patients or providers face when initiating or continuing MOUD with either methadone or buprenorphine in Opioid Treatment Programs (OTP) and non-OTP settings. Patient-related barriers mainly relate to health insurance coverage or the design of health plans (e.g., cost sharing, covered benefits) resulting in direct (medical and non-medical) and indirect costs that can affect both access and retention, especially as they relate to services provided in OTPs. Provider-related barriers include low reimbursement and administrative burden and are most likely to impact access to MOUD. Evidence-based strategies to expand MOUD as part of the HCS in Massachusetts targeted about half of the patient and provider payment-related barriers identified., Conclusion: Patients and providers face an array of payment-related barriers that impact access to and retention on MOUD, most of which relate to inadequate health insurance coverage, features of health plans, and key federal and state policies. As new regulatory policies are enacted that expand access to MOUD, such as greater flexibility in OTPs and MOUD delivered via telehealth, it will be important to align these delivery changes with payment reform involving payers, providers, and policymakers., Competing Interests: Declaration of competing interest No conflicts declared., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mothers with a history of childhood maltreatment (CM) are particularly vulnerable to postpartum mental health changes. Variability in mental health trajectories is present over the first 18-months postpartum. Little is known about the potentially unique impacts of post-traumatic change or resilience on later postpartum mental health., Methods: Participants (N = 97) completed questionnaires over the first 18-months postpartum measuring demographic risk, mental health symptoms, traumatic experiences, and resilience. Mothers also completed an interview measure coded for post-traumatic changes at 6-months postpartum. Multinomial logistic regression models examined post-traumatic change and resilience factors as predictors of mothers' longitudinal latent mental health trajectory., Results: Three classes of latent postpartum mental health emerged: low-symptom, vulnerable, and chronic high-risk. Mothers reporting stronger positive post-traumatic changes were more likely to be in the low-symptom class than the chronic high-risk class (B = -1.082, p = .01). Mothers reporting stronger negative post-traumatic changes were more likely to be in the vulnerable class (B = 0.778, p = .006) or chronic high-risk class (B = 0.906, p = .046) than the low-symptom class. Resilience was not predictive of mental health class., Limitations: Findings are correlational, and causal effects between post-traumatic growth and mental health symptoms cannot be assumed. Mothers who consented to the interview may not be fully representative of all women who have experienced CM, limiting generalizability of findings., Conclusions: Positive post-traumatic change is associated with reduced psychopathology. These findings may assist in identification of mothers at greater risk of adverse postpartum outcomes and futher inform interventions focused on enhancing positive changes in post-traumatic cognitions., Competing Interests: Declaration of competing interest The authors have no disclosures to make., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD., Methods: Positron emission tomography (PET) with [ 18 F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25)., Results: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028)., Limitations: The modest sample size is the primary limitation., Conclusions: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: People with substance use disorders (SUD) face many barriers to receiving evidence-based treatments including access to and cost of treatment. People who use drugs face stigma that limits access to traditional office-based clinics. With the goal of reducing morbidity and mortality, mobile clinics reduce many of these barriers by providing harm reduction and on-demand low-threshold medical care., Methods: In 2020 Massachusetts Department of Public Health (DPH) Mobile Addiction Services Program expanded a program called Community Care in Reach building on its success in reducing barriers to care and increasing patient encounters. In the current evaluation we conducted site visits to the four new mobile clinics and conducted one individual semi-structured provider interview at each of the four clinics. In addition, we supported a monthly learning collaborative of staff in four agencies involved with this initiative. The current evaluation used the RE-AIM framework to analyze the implementation of the mobile clinics., Results: Clinicians described many challenges and opportunities. The typical patient is unhoused, having a substance use disorder, and disconnected from traditional pathways to care. Clinicians are able to initiate people on buprenorphine largely due to the trust they establish with patients. Referral networks are facilitated by established community linkages. The philosophy of care is patient-centered. Mobile clinics provide a wide range of healthcare services including harm reduction, although finding a location to park and relations with police can be challenging. The workflow is uneven due to the model that is built on unscheduled visits., Conclusion: This study provides insight into how mobile clinics address the gaps in care for persons with OUD and fatal opioid overdoses. Harm reduction services are a critical intervention and financial sustainability of mobile clinics has to be tested., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [ 11 C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease., Competing Interests: Competing interests statement:J.H.K.: (consultations less than $5,000/y) Aptinyx, Inc., BioXcel, Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cerevel Pharmaceuticals, Epiodyne, Inc., Esai, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., PsychoGenics, Inc., Sunovion Pharmaceuticals, Inc., Takeda Pharmaceuticals (Stock/Options) Biohaven Pharmaceuticals, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, Inc., EpiVario, Inc., Freedom Biosciences, Neumora Therapeutics, Inc., Response Pharmaceuticals, Rest Therapeutics, Spring Health, Inc., Tempero Bio, Inc., Terran Biosciences, Tetricus Inc. (nonmonetary support, i.e., provision of drug) Cerevel Pharmaceuticals, Novartis. J.H.K. stands to benefit from patents held by Yale University that were licensed to Janssen Pharmaceuticals (ketamine), Biohaven Pharmaceuticals (riluzole), Freedom Biosciences (NMDA-R antagonist plus MTORC inhibitor), and Spring Health (precision medicine strategy).

Atrial fibrillation (AFib) is the most common cardiac rhythm disturbance, often treated via electrical cardioversion. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs, suggesting that defects in contractility occur in AFib and are revealed upon restoration of rhythm. This project aims to define the contractile remodeling that occurs in AFib. To assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared with sinus rhythm atria. Atrial cardiomyocytes show reduced force of contraction, decreased resting tension, and increased calcium sensitivity in skinned single cardiomyocyte studies. These alterations correlated with degradation of myofilament proteins including myosin heavy chain altering force of contraction, titin altering resting tension, and troponin I altering calcium sensitivity. We measured degradation of other myofilament proteins, including cardiac myosin binding protein C and actinin, that show degradation products in the AFib samples that are absent in the sinus rhythm atria. Many of the degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. These results provide an understanding of the contractile remodeling that occurs in AFib and provide insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib. NEW & NOTEWORTHY Atrial fibrillation is the most common cardiac rhythm disorder, and remodeling during atrial fibrillation is highly variable between patients. This study has defined the biophysical changes in contractility that occur in atrial fibrillation along with identifying potential molecular mechanisms that may drive this remodeling. This includes proteolysis of several myofilament proteins including titin, troponin I, myosin heavy chain, myosin binding protein C, and actinin, which is consistent with the observed contractile deficits.

Since the inception of the Higher Education Opportunity Act in 2008, there has been an increase in the number of post-secondary education institutions in the United States that have established inclusive postsecondary programs for individuals with intellectual disabilities to attend college and achieve higher levels of employment. Previous studies have investigated the development and outcomes of these programs, however, less has been explored related to professors' experiences and perceptions regarding this unique student population, particularly within Hispanic Serving Institutions (HSI). The current study focused on professors teaching inclusive courses within a new Comprehensive Transition and Postsecondary Program at a HSI and aimed to identify their perceptions and experiences related to instructing students with intellectual disabilities. Six professors participated in pre- and post-semester in-depth interviews. Findings from applied thematic analysis included: (a) barriers to success; (b) academic supports and strategies; (c) successful outcomes and (d) considerations for future, related programming.

EBNA1 is an Epstein Barr virus (EBV) protein expressed in all EBV-associated cancers. EBNA1 plays a critical role in the replication and maintenance of EBV episomes in latently infected cells. VK-2019 was developed as a highly specific inhibitor of EBNA1 DNA binding activity and is currently in phase 1 development as a treatment for EBV-associated carcinomas. A sensitive and reliable method was developed to quantify VK-2019 in human plasma using liquid chromatography with tandem mass spectrometry to perform detailed pharmacokinetic studies. VK-2019 was extracted from plasma using protein precipitation with acetonitrile. Separation of VK-2019, two purported metabolites, and the internal standard, VK-2019-d6, was achieved with a Zorbax XDB C 18 column using a gradient flow over 6 min. VK-2019 was detected using a SCIEX 4500 triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The assay range was 0.5-500 ng/mL and proved to be accurate and precise. Dilutions of 1:10 were accurately quantified. VK-2019 was stable in plasma at -70°C for approximately 18 months. The method was applied to assess the total plasma concentrations of VK-2019 in a patient who received a single and multiple oral daily doses of 120 mg., (© 2023 John Wiley & Sons Ltd.)

Background: Understanding distinct neurobiological mechanisms underlying bipolar disorder (BD) and major depressive disorder (MDD) is crucial for accurate diagnosis and the discovery of novel and more effective targeted treatments. Previous diffusion-weighted MRI studies have suggested some common frontotemporal corticolimbic system white matter (WM) abnormalities across the disorders. However, critical to the development of more precise diagnosis and treatment is identifying distinguishing abnormalities. Promising candidates include more prominent frontotemporal WM abnormalities observed in BD in the uncinate fasciculus (UF) that have been associated with frontal-amygdala functional dysconnectivity, and with suicide that is especially high in BD. Prior work also showed differentiation in metabotropic glutamate receptor 5 (mGlu5) abnormalities in BD versus MDD, which could be a mechanism affected in the frontotemporal system. However, associations between WM and mGlu5 have not been examined previously as a differentiator of BD. Using a multimodal neuroimaging approach, we examined WM integrity alterations in the disorders and their associations with mGluR5 levels., Methods: Individuals with BD ( N  = 21), MDD ( N  = 10), and HC ( N  = 25) participated in structural and diffusion-weighted MRI scanning, and imaging with [ 18 F]FPEB PET for quantification of mGlu5 availability. Whole-brain analyses were used to assess corticolimbic WM matter fractional anisotropy (FA) across BD and MDD relative to HC; abnormalities were tested for associations with mGlu5 availability., Results: FA corticolimbic reductions were observed in both disorders and altered UF WM integrity was observed only in BD. In BD, lower UF FA was associated with lower amygdala mGlu5 availability ( p  < .05)., Conclusions: These novel preliminary findings suggest important associations between lower UF FA and lower amygdala mGlu5 levels that could represent a disorder-specific neural mechanism in which mGluR5 is associated with the frontotemporal dysconnectivity of the disorder., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Borderline personality disorder (BPD) is a serious and understudied mental health condition associated with profound personal and public health consequences. Methodological differences in characterizing BPD may limit understanding the scope of the disorder's prevalence and effect. For example, using different diagnostic rules for BPD can affect apparent prevalence, comorbidity, and clinical presentation. This study examined how differences in diagnostic rules used to assign BPD diagnosis impacted its prevalence and associations with clinically relevant variables (e.g., demographics, comorbidity, treatment-seeking). Participants were a nationally representative sample of 36,309 noninstitutionalized U.S. adults. All variables were assessed via clinical interview (Alcohol Use Disorder and Associated Disabilities Interview Schedule-5). Six diagnostic rules determined BPD status. We used frequencies to examine prevalence rates of and associations between BPD and other clinical variables, and logistic regressions to examine the associations between each BPD variable and the other outcomes. The prevalence of BPD ranged widely-from 0.5% to 11.4%-per the diagnostic rule used. Associations between BPD diagnosis and various outcomes and clinical variables generally remained stable across all diagnostic rules, though effects became more extreme as diagnostic rules became more restrictive. Additionally, meaningful differences emerged as a function of the number of items used (30 vs. 18 items) even with no other changes to diagnostic rules. The field examining BPD and associated problem behaviors should critically consider how to most effectively characterize BPD to understand these problems more accurately and optimize the generalizability of findings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Structural and functional studies of heart muscle are important to gain insights into the physiological bases of cardiac muscle contraction and the pathological bases of heart disease. While fresh muscle tissue works best for these kinds of studies, this is not always practical to obtain, especially for heart tissue from large animal models and humans. Conversely, tissue banks of frozen human hearts are available and could be a tremendous resource for translational research. It is not well understood, however, how liquid nitrogen freezing and cryostorage may impact the structural integrity of myocardium from large mammals. In this study, we directly compared the structural and functional integrity of never-frozen to previously frozen porcine myocardium to investigate the consequences of freezing and cryostorage. X-ray diffraction measurements from hydrated tissue under near-physiological conditions and electron microscope images from chemically fixed porcine myocardium showed that prior freezing has only minor effects on structural integrity of the muscle. Furthermore, mechanical studies similarly showed no significant differences in contractile capabilities of porcine myocardium with and without freezing and cryostorage. These results demonstrate that liquid nitrogen preservation is a practical approach for structural and functional studies of myocardium., (© 2023 Ma et al.)

Background: Understanding the neurobiology underlying bipolar disorder (BD) versus major depressive disorder (MDD) is crucial for accurate diagnosis and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography., Methods: Individuals with BD (n = 17 depressed; n = 10 euthymic) or MDD (n = 17) and healthy control (HC) individuals (n = 18) underwent imaging with [ 18 F]FPEB positron emission tomography to quantify mGluR5 availability in regions of the prefrontal cortex, which was compared across groups and assessed in relation to depressive symptoms and cognitive function., Results: Prefrontal cortex mGluR5 availability was significantly different across groups (F 6,116  = 2.18, p = .050). Specifically, mGluR5 was lower in BD versus MDD and HC groups, with no difference between MDD and HC groups. Furthermore, after dividing the BD group, mGluR5 was lower in both BD-depression and BD-euthymia groups versus both MDD and HC groups across regions of interest. Interestingly, lower dorsolateral prefrontal cortex mGluR5 was associated with worse depression in MDD (r = -0.67, p = .005) but not in BD. Significant negative correlations were observed between mGluR5 and working memory in MDD and BD-depression groups., Conclusions: This work suggests that mGluR5 could be helpful in distinguishing BD and MDD as a possible treatment target for depressive symptoms in MDD and for cognitive alterations in both disorders. Further work is needed to confirm differentiating roles for mGluR5 in BD and MDD and to probe modulation of mGluR5 as a preventive/treatment strategy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Health plans are key players in substance use treatment in the United States, and the opioid crisis presents new challenges for them. This article is part of the HEALing Communities Study (HCS) funded by NIH, which seeks to facilitate communities' adoption of activities that might reduce overdose deaths, including overdose prevention education and naloxone distribution, medication for opioid use disorder, and safer opioid prescribing. We examine how health plans in one state (Massachusetts) are adapting to encourage and sustain activities that help communities to address opioid use disorder (OUD)., Methods: We conducted semi-structured interviews with managers of behavioral health services at eight health plans in Massachusetts that that have Medicare, Medicaid, and commercial lines of business. Two plans in this sample contract with a specialized behavioral health organization ("carve-out"). The interviewees also completed a survey on policies regarding access to treatment and opioid prescribing. Interviews were recorded and transcribed and analyzed using thematic analysis. Analysis of the data included intended influence of the policies at three levels: member level (micro), group or community level (meso), and system or institutional level (macro)., Results: All health plans developed strategies to increase access to treatment for OUD, primarily through eliminating or decreasing cost-sharing, eliminating pre-authorization for MOUD, and increasing supply of providers. Health plans encourage qualified practitioners to offer MOUD, but most do not provide incentives or training. Identifying high risk populations is a focus of health plans in this sample. Naloxone is a covered benefit in all health plans, although with variation in monthly limits and cost-sharing. Most health plans take measures to influence opioid prescribing. Health plans' activities are predominately aimed at the micro (member) level with little ability to influence at the macro (wider system-level changes)., Conclusion: This study provides insight into how health plans develop strategies to address the rise in OUD and fatal opioid overdoses, many of which are key in the HCS initiative. How active a role health plans play in addressing the opioid crisis varies, even within the insurance industry in one state (Massachusetts)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In species with vocal learning, acquiring species-typical vocalizations relies on early social orienting. In songbirds, for example, learning song requires dynamic social interactions with a "tutor" during an early sensitive period. Here, we hypothesized that the attentional and motivational processes that support song learning recruit the oxytocin system, which is well-understood to play a role in social orienting in other species. Juvenile male zebra finches naïve to song were each tutored by two unfamiliar adult males. Before exposure to one tutor, juveniles were injected subcutaneously with oxytocin receptor antagonist (OTA; ornithine vasotocin) and before exposure to the other, saline (control). Treatment with OTA reduced behaviors associated with approach and attention during tutoring sessions. Using a novel operant paradigm to measure preference while balancing exposure to the two tutor songs, we showed that the juveniles preferred to hear the song of the control tutor. Their adult songs more closely resembled the control tutor's song, and the magnitude of this difference was predicted by early preference for control over OTA song. Overall, oxytocin antagonism during exposure to a tutor seemed to bias juveniles against that tutor and his song. Our results suggest that oxytocin receptors are important for socially-guided vocal learning., (© 2023. The Author(s).)

With overdose deaths increasing, improving access to harm reduction and low barrier substance use disorder treatment is more important than ever. The Community Care in Reach ®  model uses a mobile unit to bring both harm reduction and clinical care for addiction to people experiencing barriers to office-based care. These mobile units provide many resources and services to people who use drugs, including safer consumption supplies, naloxone, medication for substance use disorder treatment, and a wide range of primary and preventative care. This protocol outlines the evaluation plan for the Community in Care ® model in MA, USA. Using the RE-AIM framework, this evaluation will assess how mobile services engage new and underserved communities in addiction services and primary and preventative care.

Metabotropic glutamate receptor 5 (mGluR5) dysregulation has been implicated in the pathophysiology of many psychiatric disorders, as well as nicotine use and dependence. We used positron emission tomography with [ 18 F]FPEB to measure mGluR5 availability in vivo in 6 groups: (1) nicotine users (NUs) without other psychiatric comorbidities ( n  =   23); (2) comparison controls (CCs) without nicotine use or psychiatric comorbidities ( n  =   38); (3) major depressive disorder subjects with concurrent nicotine use (MDD-NU; n  =   19); (4) MDD subjects without concurrent nicotine use (MDD-CC; n  =   20); (5) posttraumatic stress disorder subjects with concurrent nicotine use (PTSD-NU; n  =   17); and (6) PTSD subjects without concurrent nicotine use (PTSD-CC; n  =   16). The goal of the study was to test the hypothesis that mGluR5 availability in key corticolimbic regions of interest (ROIs) is different in NU with versus without comorbid psychiatric disorders (ROI: dorsolateral prefrontal cortex [dlPFC], orbitofrontal cortex [OFC], ventromedial prefrontal cortex [vmPFC], anterior cingulate cortex [ACC], amygdala, hippocampus). We found that NU had 11%-13% lower mGluR5 availability in OFC, vmPFC, dlPFC, and ACC as compared with CC, while PTSD-NU had 9%-11% higher mGluR5 availability in OFC, dlPFC, and ACC compared with PTSD. Furthermore, relationships between mGluR5 availability and psychiatric symptoms varied as a function of psychiatric diagnosis among NUs. NU showed a negative correlation between mGluR5 and smoking cravings and urges ( r's = -0.58 to -0.70, p's = 0.011 - 0.047), while PTSD-NU had the reverse relationship ( r's = 0.60-0.71, p's = 0.013-0.035 in ACC, vmPFC, and dlPFC). These findings have substantial implications for our understanding of glutamate homeostasis in psychiatric subgroups and for identifying key neural phenotypes among NU. mGluR5 is a potential treatment target for precision medicine in individuals with nicotine use., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Eutrophication of the planet's aquatic systems is increasing at an unprecedented rate. In freshwater systems, nitrate-one of the nutrients responsible for eutrophication-is linked to biodiversity losses and ecosystem degradation. One of the main sources of freshwater nitrate pollution in New Zealand is agriculture. New Zealand's pastoral farming system relies heavily on the application of chemical fertilisers. These fertilisers in combination with animal urine, also high in nitrogen, result in high rates of nitrogen leaching into adjacent aquatic systems. In addition to nitrogen, livestock waste commonly carries human and animal enteropathogenic bacteria, many of which can survive in freshwater environments. Two strains of enteropathogenic bacteria found in New Zealand cattle, are K99 and Shiga-toxin producing Escherichia coli (STEC). To better understand the effects of ambient nitrate concentrations in the water column on environmental enteropathogenic bacteria survival, a microcosm experiment with three nitrate-nitrogen concentrations (0, 1, and 3 mg NO 3 -N /L), two enteropathogenic bacterial strains (STEC O26-human, and K99-animal), and two water types (sterile and containing natural microbiota) was run. Both STEC O26 and K99 reached 500 CFU/10 ml in both water types at all three nitrate concentrations within 24 hours and remained at those levels for the full 91 days of the experiment. Although enteropathogenic strains showed no response to water column nitrate concentrations, the survival of background Escherichia coli , imported as part of the in-stream microbiota did, surviving longer in 1 and 3 mg NO 3 -N/Lconcentrations ( P  < 0.001). While further work is needed to fully understand how nitrate enrichment and in-stream microbiota may affect the viability of human and animal pathogens in freshwater systems, it is clear that these two New Zealand strains of STEC O26 and K99 can persist in river water for extended periods alongside some natural microbiota., Competing Interests: The authors declare there are no competing interests., (©2022 Davis et al.)

Background: A robust literature supports the role of the metabotropic glutamate receptor type 5 (mGluR5) in cognitive functioning. mGluR5 is also implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), which are characterized by cognitive alterations. However, the relationship between mGluR5 and cognition in MDD and PTSD has not yet been directly investigated. To address this gap, we examined the relationship between in vivo mGluR5 availability and cognition in PTSD, MDD, and matched healthy adults (HA)., Methods: Individuals with PTSD ( N  = 28) and MDD ( N  = 21), and HA ( N  = 28) were matched for age, gender, and smoking status. Participants completed 18 F-FPEB positron emission tomography (PET) scan, psychiatric and cognitive assessments., Results: Across models examining the relationship between mGluR5 availability and different domains of cognition across diagnostic groups, only the interaction of diagnosis*attention was significant ( F 4,64  = 3.011, P  = .024). Higher mGluR5 availability was associated with poorer attention in PTSD in 4 frontolimbic regions of interests (ROI's: OFC ( r  = -.441, P  = .016), vmPFC ( r  = -.408, P  = .028), dlPFC ( r  = -.421, P  = .023), hippocampus ( r  = -.422, P  = .025). By contrast, mGluR5 availability in the MDD group was positively related to Attention (ATTN) in the OFC ( r  = .590, P  = .006), vmPFC ( r  = .653, P  = .002), and dlPFC ( r  = .620, P  = .004). Findings in the hippocampus for MDD followed the same pattern but did not survive correction for multiple comparisons ( r  = .480, P  = .036). ATTN and mGluR5 availability were not significantly related in the HA group. Of note, in MANOVA analyses group*ATTN interaction results in the OFC did not survive multiple comparisons ( P  = .046). All other findings survived correction for multiple comparisons and remained significant when covarying for potential confounds (eg, depressed mood)., Conclusions: We observed a significant relationship between frontolimbic mGluR5 availability and performance on tests of attention in individuals with MDD and PTSD. This finding aligns with animal work showing dysregulation in mGluR5 in cognitive functioning, and differed as a function of diagnosis. Results suggest interventions targeting mGluR5 may help bolster cognitive difficulties, highlighting the importance of employing different mGluR5 directed treatment strategies in MDD and PTSD., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Maruff is a full-time employee of Cogstate Ltd He reports no other potential conflicts of interest. All other authors report no conflicts of interest, and have nothing further to disclose., (© The Author(s) 2022.)

Like human language, song in songbirds is learned during an early sensitive period and is facilitated by motivation to seek out social interactions with vocalizing adults. Songbirds are therefore powerful models with which to understand the neural underpinnings of vocal learning. Social motivation and early social orienting are thought to be mediated by the oxytocin system; however, the developmental trajectory of oxytocin receptors in songbirds, particularly as it relates to song learning, is currently unknown. This gap in knowledge has hindered the development of songbirds as a model of the role of social orienting in vocal learning. In this study, we used quantitative PCR to measure oxytocin receptor expression during the sensitive period of song learning in zebra finches (Taeniopygia guttata). We focused on brain regions important for social motivation, attachment, song recognition, and song learning. We detected expression in these regions in both sexes from posthatch day 5 to adulthood, encompassing the entire period of song learning. In this species, only males sing; we found that in regions implicated in song learning specifically, oxytocin receptor mRNA expression was higher in males than females. These sex differences were largest during the developmental phase when males attend to and memorize tutor song, suggesting a functional role of expression in learning. Our results show that oxytocin receptors are expressed in relevant brain regions during song learning, and thus provide a foundation for developing the zebra finch as a model for understanding the mechanisms underlying the role of social motivation in vocal development., (© 2021 Wiley Periodicals LLC.)

Intravenous (IV) subanesthetic doses of ketamine have been shown to reduce psychiatric distress in both major depressive (MDD) and posttraumatic stress disorder (PTSD). However, the effect of ketamine on cognitive function in these disorders is not well understood. To address this gap, we examined the effect of a single dose of IV ketamine on cognition in individuals with MDD and/or PTSD relative to healthy controls (HC). Psychiatric (n = 29; 15 PTSD, 14 MDD) and sex- age- and IQ matched HC (n = 29) groups were recruited from the community. A single subanesthetic dose of IV ketamine was administered. Mood and cognitive measures were collected prior to, 2 h and 1 day post-ketamine administration. MDD/PTSD individuals evidenced a large-magnitude improvement in severity of depressive symptoms at both 2-hours and 1 day post-ketamine administration (p's < .001, Cohen d's = 0.80-1.02). Controlling for baseline performance and years of education, IV ketamine induced declines in attention (ATTN), executive function (EF), and verbal memory (VM) 2 h post-administration, all of which had resolved by 1 day post-ketamine across groups. The magnitude of cognitive decline was significantly larger in MDD/PTSD relative to HC on attention only (p = .012, d = 0.56). Ketamine did not affect working memory (WM) performance. Cognitive function (baseline, change from baseline to post-ketamine) was not associated with antidepressant response to ketamine. Results suggest that while ketamine may have an acute deleterious effect on some cognitive domains in both MDD/PTSD and HC individuals, most notably attention, this reduction is transient and there is no evidence of ketamine-related cognitive dysfunction at 1 day post-administration.

Introduction: Many people drop out of substance use disorder (SUD) treatment within the first few sessions, which suggests the need for innovative strategies to address this. We examined the effectiveness of incentive-based contracting for Maine's publicly funded outpatient (OP) and intensive outpatient (IOP) SUD treatment, to determine its potential for improving treatment engagement and retention., Methods: Maine's incentive-based contract with federally block grant-funded OP and IOP treatment agencies created a natural experiment, in which we could compare treatment engagement and retention with a group of state-licensed treatment agencies that were not part of the incentive-based contract. We used administrative data for OP (N = 18,375) and IOP (N = 5986) SUD treatment admissions from FY2005-FY2011 to capture trends prior to and after the FY2008 contract implementation date. We performed multivariable difference-in-difference logistic regression models following propensity score matching of clients., Results: Two-thirds (66%) of OP admissions engaged in treatment, defined as 4+ treatment sessions, and 85% of IOP admissions satisfied the similar criteria of 4+ treatment days. About 40-45% of OP admissions reached the threshold for retention, defined as 90 days in treatment. IOP treatment completion was attained by 50-58% of admissions. For OP, the incentive and nonincentive groups had no significant differences in percentages with treatment engagement (AOR = 1.28, DID = 5.9%, p = .19), and 90-day retention was significant in the opposite direction of what we hypothesized (AOR = 0.80, DID = -4.6%, p = .0003). For IOP, the incentive group had a significant, but still small, increase in percentage with treatment engagement (AOR = 1.52, DID = 5.5%, p = .003), but the corresponding increase in treatment completion was not similarly significant (AOR = 1.12, DID = 2.7%, p = .53). In all models, individual-level variables were strong predictors of outcomes., Conclusion: We found little to no impact of the incentive-based contract on the treatment engagement, retention, and completion measures, adding to the body of evidence that shows few or null results for value-based purchasing in SUD treatment programs. The limited success of such efforts is likely to reflect the bandwidth that providers and programs have to focus on new endeavors, the importance of the incentive funding to their bottom line, and forces beyond their immediate control., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Summary: As states plan to implement system-wide change of any kind, it is important to understand program directors' perspectives on challenges they face. This is especially true with quality improvement reforms. Much research has focused on quality improvement in medicine, but there is a gap in our knowledge about programs that treat individuals with drug or alcohol use. From 2007 to 2016, Maine contracted with selected substance use treatment programs using financial incentives to improve quality, with focus on treatment access, engagement, retention, and completion as measures of quality. Using surveys and in-depth interviews, this research documents strategies that programs used to improve performance and challenges faced in implementing reforms. Only programs that received federal block grant funding through the state to provide substance use treatment were eligible for an incentive contract, creating a natural experiment with non-block grant programs (non-incentive). Directors were interviewed in incentive (n= 13) and non-incentive programs (n=12)., Findings: Thematic analysis revealed that: 1) programs focused on QI, but those eligible for incentives focused on different quality measures, 2) most of the reforms in both groups targeted improving treatment access and retention, and 3) programs faced substantial challenges in undertaking reforms. Despite efforts, many programs could not meet quality measures consistently over time and faced barriers over which they had little control., Applications: Policy makers and program administrators will benefit from knowing the challenges of undertaking QI initiatives and provide support for the programs., Competing Interests: Conflict of Interest: The authors claim they have no competing interest with any content in this paper.

The metabotropic glutamate receptor 5 (mGluR5) is a promising treatment target for psychiatric disorders due to its modulatory effects on glutamate transmission. Using [ 11 C]ABP688, we previously showed that the rapidly acting antidepressant ketamine decreases mGluR5 availability. The mGluR5 radioligand [ 18 F]FPEB offers key advantages over [ 11 C]ABP688; however, its suitability for drug challenge studies is unknown. We evaluated whether [ 18 F]FPEB can be used to capture ketamine-induced effects on mGluR5. Seven healthy subjects participated in three [ 18 F]FPEB scans: a baseline, a same-day post-ketamine, and a 24-h post-ketamine scan. The outcome measure was V T / f P , obtained using a two-tissue compartment model and a metabolite-corrected arterial input function. Dissociative symptoms, heart rate and blood pressure increased following ketamine infusion. [ 18 F]FPEB V T / f P decreased by 9% across the cortex after ketamine infusion, with minimal difference between baseline and 24-h scans. Compared to our previous work using [ 11 C]ABP688, the magnitude of the ketamine-induced change in mGluR5 was smaller using [ 18 F]FPEB; however, effect sizes were similar for the same-day post-ketamine vs. baseline scan (Cohen's d = 0.75 for [ 18 F]FPEB and 0.88 for [ 11 C]ABP688). [ 18 F]FPEB is therefore able to capture some of the effects of ketamine on mGluR5, but [ 11 C]ABP688 appears to be more suitable in drug challenge paradigms designed to probe glutamate transmission.

Four microbes (Campylobacter spp., Escherichia coli, Cryptosporidium spp. and Giardia spp.) were monitored in 16 waterways that supply public drinking water for 13 New Zealand towns and cities. Over 500 samples were collected from the abstraction point at each study site every three months between 2009 and 2019. The waterways represent a range from small to large, free flowing to reservoir impoundments, draining catchments of entirely native vegetation to those dominated by pastoral agriculture. We used machine learning algorithms to explore the relative contribution of land use, catchment geology, vegetation, topography, and water quality characteristics of the catchment to determining the abundance and/or presence of each microbe. Sites on rivers draining predominantly agricultural catchments, the Waikato River, Oroua River and Waiorohi Stream had all four microbes present, often in high numbers, throughout the sampling interval. Other sites, such as the Hutt River and Big Huia Creek in Wellington which drain catchments of native vegetation, never had pathogenic microbes detected, or unsafe levels of E. coli. Boosted Regression Tree models could predict abundances and presence/absence of all four microbes with good precision using a wide range of potential environmental predictors covering land use, geology, vegetation, topography, and nutrient concentrations. Models were more accurate for protozoa than bacteria but did not differ markedly in their ability to predict abundance or presence/absence. Environmental drivers of microbe abundance or presence/absence also differed depending on whether the microbe was protozoan or bacterial. Protozoa were more prevalent in waterways with lower water quality, higher numbers of ruminants in the catchment, and in September and December. Bacteria were more abundant with higher rainfall, saturated soils, and catchments with greater than 35% of the land in agriculture. Although modern water treatment protocols will usually remove many pathogens from drinking water, several recent outbreaks of waterborne disease due to treatment failures, have highlighted the need to manage water supplies on multiple fronts. This research has identified potential catchment level variables, and thresholds, that could be better managed to reduce the potential for pathogens to enter drinking water supplies., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

The long-term behavioral, psychological, and neurobiological effects of exposure to potentially traumatic events vary within the human population. Studies conducted on trauma-exposed human subjects suggest that differences in trauma type and extent of exposure combine to affect development, maintenance, and treatment of a variety of psychiatric syndromes. The serotonin 1-A receptor (5-HT1A) is an inhibitory G protein-coupled serotonin receptor encoded by the HTR1A gene that plays a role in regulating serotonin release, physiological stress responding, and emotional behavior. Studies from the preclinical and human literature suggest that dysfunctional expression of 5-HT1A is associated with a multitude of psychiatric symptoms commonly seen in trauma-exposed individuals. Here, we synthesize the literature, including numerous preclinical studies, examining differences in alterations in 5-HT1A expression following trauma exposure. Collectively, these findings suggest that the impact of trauma exposure on 5-HT1A expression is dependent, in part, on trauma type and extent of exposure. Furthermore, preclinical and human studies suggest that this observation likely applies to additional molecular targets and may help explain variation in trauma-induced changes in behavior and treatment responsivity. In order to understand the neurobiological impact of trauma, including the impact on 5-HT1A expression, it is crucial to consider both trauma type and extent of exposure.

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [ 11 C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.

There is little research about trauma, financial stress, and social service needs emanating from the experience of parenting grandchildren caused by the opioid crisis in the United States. We conducted a qualitative study with 15 grandparents who currently or in the past had custodial care of their grandchildren. We also interviewed nine issue-related stakeholders in Eastern Massachusetts. Specific inquiries centered on events leading up to a change in guardianship, stressors related to legal, financial, and family issues, and system-wide response to the grandparents' needs. Results indicate that the opioid crisis presents distinct challenges for the grandparent-led families and for the systems that serve the new family arrangement. Crisis triggers a change in guardianship and continues throughout the years. The continued crises stem from events related to the parent's opioid use disorder (OUD) and from expenses related to raising a young family, especially when the grandchild has adverse childhood experiences. Our analysis shows that systems break down on a number of levels, and the fluidity of custodial arrangements due to parents' OUD status does not map onto existing support or benefit systems. Policy responses must focus on the immediate and long-term needs of grandparent caretakers, especially since the opioid crisis is likely to continue.

Citation data have remained hidden behind proprietary, restrictive licensing agreements, which raises barriers to entry for analysts wishing to use the data, increases the expense of performing large-scale analyses, and reduces the robustness and reproducibility of the conclusions. For the past several years, the National Institutes of Health (NIH) Office of Portfolio Analysis (OPA) has been aggregating and enhancing citation data that can be shared publicly. Here, we describe the NIH Open Citation Collection (NIH-OCC), a public access database for biomedical research that is made freely available to the community. This dataset, which has been carefully generated from unrestricted data sources such as MedLine, PubMed Central (PMC), and CrossRef, now underlies the citation statistics delivered in the NIH iCite analytic platform. We have also included data from a machine learning pipeline that identifies, extracts, resolves, and disambiguates references from full-text articles available on the internet. Open citation links are available to the public in a major update of iCite (https://icite.od.nih.gov)., Competing Interests: The authors have declared that no competing interests exist.

Fundamental scientific advances can take decades to translate into improvements in human health. Shortening this interval would increase the rate at which scientific discoveries lead to successful treatment of human disease. One way to accomplish this would be to identify which advances in knowledge are most likely to translate into clinical research. Toward that end, we built a machine learning system that detects whether a paper is likely to be cited by a future clinical trial or guideline. Despite the noisiness of citation dynamics, as little as 2 years of postpublication data yield accurate predictions about a paper's eventual citation by a clinical article (accuracy = 84%, F1 score = 0.56; compared to 19% accuracy by chance). We found that distinct knowledge flow trajectories are linked to papers that either succeed or fail to influence clinical research. Translational progress in biomedicine can therefore be assessed and predicted in real time based on information conveyed by the scientific community's early reaction to a paper., Competing Interests: Since the authors work in the Division of Program Coordination, Planning, and Strategic Initiatives at the National Institutes of Health, our work could have policy implications for how research portfolios are evaluated.

Recent evidence implicates dysregulation of metabotropic glutamatergic receptor 5 (mGluR5) in pathophysiology of PTSD and suicidality. Using positron emission tomography and [ 18 F]FPEB, we quantified mGluR5 availability in vivo in individuals with PTSD ( n = 29) and MDD ( n = 29) as a function of suicidal ideation (SI) to compare with that of healthy comparison controls (HC; n = 29). Volume of distribution was computed using a venous input function in the five key frontal and limbic brain regions. We observed significantly higher mGluR5 availability in PTSD compared with HC individuals in all regions of interest ( P 's = 0.001-0.01) and compared with MDD individuals in three regions ( P 's = 0.007). mGluR5 availability was not significantly different between MDD and HC individuals ( P = 0.17). Importantly, we observed an up-regulation in mGluR5 availability in the PTSD-SI group ( P 's = 0.001-0.007) compared with PTSD individuals without SI. Findings point to the potential role for mGluR5 as a target for intervention and, potentially, suicide risk management in PTSD., Competing Interests: The authors declare no conflict of interest.

Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [ 11 C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.

The shift from a multiaxial system of diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) brought forth the discontinuation of the Global Assessment of Functioning (GAF). DSM-5 proposes the use of a more reliable method for assessing and describing disability, the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). The WHODAS 2.0 is widely-used within the Department of Veterans Affairs (VA) and the Veterans Benefits Administration to guide clinical decision making and assist in decisions pertaining to financial compensation. While the WHODAS 2.0 purports to be well-validated for adults cross-culturally in clinical and non-clinical samples, research is limited pertaining to the factor structure of the WHODAS 2.0 in non-compensation seeking U.S. Veteran populations. This study evaluated the factor structure of the WHODAS 2.0 in a sample of 464 Veterans receiving VA mental healthcare. Exploratory and confirmatory factor analyses of the WHODAS 2.0 data were conducted. Analyses confirmed the hardiness of the WHODAS 2.0 for use with Veterans. However, exploratory analyses pointed to several items that may reduce the functioning of the questionnaire in clinical Veteran samples. Exploratory and confirmatory analyses indicated better model fit can be achieved., (Published by Elsevier B.V.)

Program-level financial incentives are used by some payers as a tool to improve quality of substance use treatment. However, evidence of effectiveness is mixed and performance contracts may have unintended consequences such as creating barriers for more challenging clients who are less likely to meet benchmarks. This study investigates the impact of a performance contract on waiting time for substance use treatment and client selection. Admission and discharge data from publicly funded Maine outpatient (OP) and intensive outpatient (IOP) substance use treatment programs (N = 38,932 clients) were used. In a quasi-experimental pre-post design, pre-period (FY 2005-2007) admission data from incentivized (IC) and non-incentivized (non-IC) programs were compared to post-period (FY 2008-2012) using propensity score matching and multivariate difference-in-difference regression. Dependent variables were waiting time (incentivized) and client selection (severity: history of mental disorders and substance use severity, not incentivized). Despite financial incentives designed to reduce waiting time for substance use treatment among state-funded outpatient programs, average waiting time for treatment increased in the post period for both IC and non-IC groups, as did client severity. There were no significant differences in waiting time between IC and non-IC groups over time. Increases in client severity over time, with no group differences, indicate that programs did not restrict access for more challenging clients. Adequate funding and other approaches to improve quality may be beneficial., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Flory-Huggins (F-H) solubility equation has been widely used to describe the solubility of a small-molecule drug in a polymeric carrier and thus determine the design space available for formulating a stable amorphous solid dispersion. The F-H interaction parameter (χ) describes the thermodynamic properties of drug-polymer solutions and accounts for any enthalpic and entropic changes in solubility. Many studies have found that for a limited compositional range, χ varies proportionally to the inverse of the melting temperature of the drug. We explored this relationship using a highly sensitive DSC technique to detect remaining residual crystalline active pharmaceutical ingredients (APIs) following annealing of ball milled mixtures of crystalline itraconazole (ITZ) and either Soluplus or hydroxypropyl methylcellulose phthalate (HPMCP) at temperatures near the estimated solubility curve. Depending on the experimental approach taken, the measurement of drug-polymer solubility can be restricted to mixtures with a high proportion of drug, but in this study, solubility was experimentally determined for mixtures with API content as low as 10 wt %. Results suggest that the proposed linear relationship does not extend to compositions with smaller amounts of API, instead indicating that χ was both temperature- and composition-dependent for the systems studied. The feasibility of this technique to measure interactions in a ternary system containing itraconazole and both polymers was also determined; ITZ-HPMCP exhibited the most favorable values of χ, while ITZ-Soluplus and ITZ-Soluplus-HPMCP demonstrated similar interaction parameters.

There is limited study of suicidal behaviors among veterans identifying as sexual and gender minorities (SGMs), despite previous research indicating rates of suicide attempts are high within civilian SGM populations. Further, some research incorporating military service members suggests those identifying as SGMs are disproportionately exposed to military sexual trauma (MST), an additional risk factor for negative psychiatric sequelae. To address health care research disparities among minority veterans (i.e., women, those endorsing MST, SGMs), we examined presentations of veterans (N = 277) who attended initial consultation appointments for MST-related treatment and completed a semistructured clinical interview including demographic characteristics, history of suicide attempts (HSA), and a diagnostic evaluation. Twenty-eight (10.1%) veterans identified as SGMs. SGM/non-SGM groups were contrasted on suicidal and psychiatric morbidity outcomes. Overall, endorsement of HSA was high (30.7%). Despite similar clinical profiles, 53.6% of veterans who identified as SGM endorsed HSA in contrast with 28.1% of peers identifying as heterosexual and nontransgender, a significant effect of small-to-moderate size. Findings suggest assessment and clinical management of suicidality is of critical importance for clinicians providing services to veterans pursuing recovery from MST, generally, and may be especially so when delivering care to SGM. Further, results underscore the need for culturally competent delivery of trauma-focused interventions. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Downstream processing aspects of a stable form of amorphous itraconazole exhibiting enhanced dissolution properties were studied. Preparation of this ternary amorphous solid dispersion by either spray drying or hot melt extrusion led to significantly different powder processing properties. Particle size and morphology was analysed using scanning electron microscopy. Flow, compression, blending and dissolution were studied using rheometry, compaction simulation and a dissolution kit. The spray dried material exhibited poorer flow and reduced sensitivity to aeration relative to the milled extrudate. Good agreement was observed between differing forms of flow measurement, such as Flow Function, Relative flow function, Flow rate index, Aeration rate, the Hausner ratio and the Carr index. The stability index indicated that both powders were stable with respect to agglomeration, de-agglomeration and attrition. Tablet ability and compressibility studies showed that spray dried material could be compressed into stronger compacts than extruded material. Blending of the powders with low moisture, freely-flowing excipients was shown to influence both flow and compression. Porosity studies revealed that blending could influence the mechanism of densification in extrudate and blended extrudate formulations. Following blending, the powders were compressed into four 500 mg tablets, each containing a 100 mg dose of amorphous itraconazole. Dissolution studies revealed that the spray dried material released drug faster and more completely and that blending excipients could further influence the dissolution rate., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The white-throated sparrow (Zonotrichia albicollis) represents a powerful model in behavioral neuroendocrinology because it occurs in two plumage morphs that differ with respect to steroid-dependent social behaviors. Birds of the white-striped (WS) morph engage in more territorial aggression than do birds of the tan-striped (TS) morph, and the TS birds engage in more parenting behavior. This behavioral polymorphism is caused by a chromosomal inversion that has captured many genes, including estrogen receptor alpha (ERα). In this study, we tested the hypothesis that morph differences in aggression might be explained by differential sensitivity to estradiol (E2). We administered E2 non-invasively to non-breeding white-throated sparrows and quantified aggression toward a conspecific 10 min later. E2 administration rapidly increased aggression in WS birds but not TS birds, consistent with our hypothesis that differential sensitivity to E2 may at least partially explain morph differences in aggression. To query the site of E2 action in the brain, we administered E2 and quantified Egr-1 expression in brain regions in which expression of ERα is known to differ between the morphs. E2 treatment decreased Egr-1 immunoreactivity in nucleus taeniae of the amygdala, but this effect did not depend on morph. Overall, our results support a role for differential effects of E2 on aggression in the two morphs, but more research will be needed to determine the neuroanatomical site of action.

This study used the interpersonal-psychological theory of suicide to explore the relationships among DSM-5 posttraumatic stress disorder (PTSD) symptom clusters derived from the six-factor anhedonia model and facets of acquired capability for suicide (ACS). In a sample of 373 trauma-exposed undergraduates, most PTSD symptom clusters were negatively associated with facets of ACS in bivariate correlations, but the anhedonia cluster was positively associated with ACS in regression models. Structure coefficients and commonality analysis indicated that anhedonia served as a suppressor variable for the other symptom clusters. Our findings further elucidate the complex relationship between specific PTSD symptom clusters and ACS., (© 2017 The American Association of Suicidology.)

Trauma-related beliefs have salient relationships to the development and maintenance of Posttraumatic Stress Disorder (PTSD) following stress exposure. The Posttraumatic Cognitions Inventory (PTCI) has the potential to be a standard assessment of this critical construct. However, some critical aspects of validity and reliability appear to vary by population. To date, the PTCI has not been psychometrically evaluated for use with military-specific traumas such as combat and military sexual trauma (MST). Based on exploratory and confirmatory analyses with 949 Veterans seeking trauma-focused treatment for military traumas, we found a four factor model (negative view of the self, negative view of the world, self-blame, and negative beliefs about coping competence) provided the best fit. In contrast, the original three factor model was not confirmed. Both models demonstrated convergent and discriminative validity. Although gender was associated with PTCI total and factor scores, differences did not persist after controlling for trauma type. MST was associated with higher PTCI scores even when controlling for gender, though the clinical magnitude of these differences is likely negligible. Internal reliability validity was demonstrated with PTCI total and subscale scores., (Published by Elsevier B.V.)

Background: Neuroimaging studies have revealed that disturbances in network organization of key brain regions may underlie cognitive and emotional dysfunction in posttraumatic stress disorder (PTSD). Examining both brain structure and function in the same population may further our understanding of network alterations in PTSD., Methods: We used tensor-based morphometry (TBM) and intrinsic connectivity distribution (ICD) to identify regions of altered volume and functional connectivity in unmedicated individuals with PTSD (n=21) and healthy comparison (HC) participants (n=18). These regions were then used as seeds for follow-up anatomical covariance and functional connectivity analyses., Results: Smaller volume in the cerebellum and weaker structural covariance between the cerebellum seed and middle temporal gyrus were observed in the PTSD group. Individuals with PTSD also exhibited lower whole-brain connectivity in the cerebellum, dorsolateral prefrontal cortex (dlPFC) and medial prefrontal cortex (mPFC). Functional connectivity in the cerebellum and grey matter volume in the dlPFC were negatively correlated with PTSD severity as measured by the DSM-5 PTSD checklist (PCL-5; r= -.0.77, r=-0.79). Finally, seed connectivity revealed weaker connectivity within nodes of the central executive network (right and left dlPFC), and between nodes of the default mode network (mPFC and cerebellum) and the supramarginal gyrus, in the PTSD group., Conclusion: We demonstrate structural and functional alterations in PTSD converging on the PFC and cerebellum. Whilst PFC alterations are relatively well established in PTSD, the cerebellum has not generally been considered a key region in PTSD. Our findings add to a growing evidence base implicating cerebellar involvement in the pathophysiology of PTSD., Competing Interests: Declaration of Conflicting Interests Dr. Krystal acknowledges the following relevant financial interests. He is a co-sponsor of a patent for the intranasal administration of ketamine for the treatment of depression that was licensed by Janssen Pharmaceuticals, the maker of s-ketamine. He has a patent related to the use of riluzole to treat anxiety disorders that was licensed by Biohaven Medical Sciences. He has stock or stock options in Biohaven Medical Sciences, ARett Pharmaceuticals, Blackthorn Therapeutics, and Luc Therapeutics. He consults broadly to the pharmaceutical industry, but his annual income over the past year did not exceed $5,000 for any organization. He receives over $5,000 in income from the Society of Biological Psychiatry for editing the journal Biological Psychiatry. He has fiduciary responsibility for the International College of Neuropsychopharmacology as president of this organization. The other authors declare no conflict of interest.

The aim of this study was to evaluate a novel combination of hydroxypropyl methylcellulose phthalate (HPMCP-HP-50) and Soluplus ® polymers for enhanced physicochemical stability and solubility of the produced amorphous solid dispersions (ASDs). This was achieved using hot melt extrusion (HME) to convert the crystalline active pharmaceutical ingredient (API) into a more soluble amorphous form within the ternary systems. Itraconazole (ITZ), a Biopharmaceutics Classification System class II (BCS II) API, was selected as the model drug. The ASDs were characterized by Powder X-Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) spectroscopy, Solid State Nuclear Magnetic Resonance (ssNMR) and dissolution studies. The data showed that the ASDs were physically and chemically stable at 20°C and 50% RH over 12 months. PXRD results indicated that the ITZ in the ASDs was in the amorphous state and no recrystallization occurred. DSC scans confirmed that each formulation exhibited a single intermediate glass transition (T g ), around 96.4°C, indicating that ITZ was completely miscible in the polymeric blends of HPMCP and Soluplus ® at up to 30% (w/w) drug loading and that the two polymers were miscible with each other in the presence of ITZ. The FTIR analysis indicated the formation of strong hydrogen bonding between ITZ, HPMCP and Soluplus ® . The dissolution end-point of the ASDs was determined to be approximately 10 times greater than that of the crystalline ITZ., (Copyright © 2017 Elsevier B.V. All rights reserved.)