Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst.

The introduction of added '3-dimensionality' through late-stage functionalisation of extended (hetero)aromatic systems is a powerful synthetic approach. The abundance of starting materials and cross-coupling methodologies to access the precursors allows for highly diverse products. Subsequent selective partial reduction can alter the core structure in a manner of interest to medicinal chemists. Herein, we describe the precise, partial reduction of multicyclic heteroaromatic systems using a simple heterogeneous catalyst. The approach can be extended to introduce deuterium (again at late-stage). Excellent yields can be obtained using simple reaction conditions.

Mediators of Ethnic Differences in Dropout Rates From a Randomized Controlled Treatment Trial Among Latinx and Non-Latinx White Primary Care Patients With Anxiety Disorders.

ABSTRACT: Disparities in treatment engagement and adherence based on ethnicity have been widely recognized but are inadequately understood. Few studies have examined treatment dropout among Latinx and non-Latinx White (NLW) individuals. Using Andersen's Behavioral Model of Health Service Use (A behavioral model of families' use of health services. 1968; J Health Soc Behav. 1995; 36:1-10) as a framework, we examine whether pretreatment variables (categorized as predisposing, enabling, and need factors) mediate the relationship between ethnicity and premature dropout in a sample of Latinx and NLW primary care patients with anxiety disorders who participated in a randomized controlled trial (RCT) of cognitive behavioral therapy. Data from a total of 353 primary care patients were examined; 96 Latinx and 257 NLW patients participated. Results indicated that Latinx patients dropped out of treatment more often than NLW patients, resulting in roughly 58% of Latinx patients failing to complete treatment compared with 42% of NLW, and approximately 29% of Latinx patients dropping out before engaging in modules related to cognitive restructuring or exposure, relative to 11% of NLW patients. Mediation analyses suggest that social support and somatization partially explained the relationship between ethnicity and treatment dropout, highlighting the importance of these variables in understanding treatment disparities.

Nucleophilicities and Nucleofugalities of Thio- and Selenoethers.

Rate constants for the reactions of dialkyl chalcogenides with laser flash photolytically generated benzhydrylium ions have been measured photometrically to integrate them into the comprehensive benzhydrylium-based nucleophilicity scale. Combining these rate constants with the previously reported equilibrium constants for the same reactions provided the corresponding Marcus intrinsic barriers and made it possible to quantify the leaving group abilities (nucleofugalities) of dialkyl sulfides and dimethyl selenide. Due to the low intrinsic barriers, dialkyl chalcogenides are fairly strong nucleophiles (comparable to pyridine and N-methylimidazole) as well as good nucleofuges; this makes them useful group-transfer reagents.

Addiction care in crisis: evidence should drive progressive policy and practice.

Addictions are challenging health and social problems that need to be addressed to preserve and promote good mental health and ensure that individuals within society lead healthy and productive lives. Tackling addictions is complex and requires communities, public health, specialist services, and local and national government to act in unison and implement evidence-based interventions. This editorial raises systemic issues that need attention and proposes a range of systemic options.

Off-the-shelf DFT-DISPersion methods: Are they now "on-trend" for organic molecular crystals?

Organic molecular crystals contain long-range dispersion interactions that can be challenging for solid-state methods such as density functional theory (DFT) to capture, and in some industrial sectors are overlooked in favor of classical methods to calculate atomistic properties. Hence, this publication addresses the critical question of whether dispersion corrected DFT calculations for organic crystals can reproduce the structural and energetic trends seen from experiment, i.e., whether the calculations can now be said to be truly "on-trend." In this work, we assess the performance of three of the latest dispersion-corrected DFT methods, in calculating the long-range, dispersion energy: the pairwise methods of D3(0) and D3(BJ) and the many-body dispersion method, MBD@rsSCS. We calculate the energetics and optimized structures of two homologous series of organic molecular crystals, namely, carboxylic acids and amino acids. We also use a classical force field method (using COMPASS II) and compare all results to experimental data where possible. The mean absolute error in lattice energies is 9.59 and 343.85 kJ/mol (COMPASS II), 10.17 and 16.23 kJ/mol (MBD@rsSCS), 10.57 and 18.76 kJ/mol [D3(0)], and 8.52 and 14.66 kJ/mol [D3(BJ)] for the carboxylic acids and amino acids, respectively. MBD@rsSCS produces structural and energetic trends that most closely match experimental trends, performing the most consistently across the two series and competing favorably with COMPASS II.

Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies.

OBJECTIVE: DNA methylation has been associated with both early life stress and depression. This study examined the combined association of DNA methylation at multiple CpG probes in five stress-related genes with depressive symptoms and tested whether these genes methylation mediated the association between childhood trauma and depression in two monozygotic (MZ) twin studies. METHODS: The current analysis comprised 119 MZ twin pairs (84 male pairs [mean = 55 years] and 35 female pairs [mean = 36 years]). Peripheral blood DNA methylation of five stress-related genes (BDNF, NR3C1, SLC6A4, MAOA, and MAOB) was quantified by bisulfite pyrosequencing or 450K BeadChip. We applied generalized Poisson linear-mixed models to examine the association between each single CpG methylation and depressive symptoms. The joint associations of multiple CpGs in a single gene or all five stress-related genes as a pathway were tested by weighted truncated product method. Mediation analysis was conducted to test the potential mediating effect of stress gene methylation on the relationship between childhood trauma and depressive symptoms. RESULTS: Multiple CpG probes showed nominal individual associations, but very few survived multiple testing. Gene-based or gene-set approach, however, revealed significant joint associations of DNA methylation in all five stress-related genes with depressive symptoms in both studies. Moreover, two CpG probes in the BDNF and NR3C1 mediated approximately 20% of the association between childhood trauma and depressive symptoms. CONCLUSIONS: DNA methylation at multiple CpG sites are jointly associated with depressive symptoms and partly mediates the association between childhood trauma and depression. Our results highlight the importance of testing the combined effects of multiple CpG loci on complex traits and may unravel a molecular mechanism through which adverse early life experiences are biologically embedded.

High expectancy and early response produce optimal effects in sertraline treatment for post-traumatic stress disorder.

BACKGROUND: Better indicators of prognosis are needed to personalise post-traumatic stress disorder (PTSD) treatments.AimsWe aimed to evaluate early symptom reduction as a predictor of better outcome and examine predictors of early response. METHOD: Patients with PTSD (N = 134) received sertraline or prolonged exposure in a randomised trial. Early response was defined as 20% PTSD symptom reduction by session two and good end-state functioning defined as non-clinical levels of PTSD, depression and anxiety. RESULTS: Early response rates were similar in prolonged exposure and sertraline (40 and 42%), but in sertraline only, early responders were four times more likely to achieve good end-state functioning at post-treatment (Number Needed to Treat = 1.8, 95% CI 1.28-3.00) and final follow-up (Number Needed to Treat = 3.1, 95% CI 1.68-16.71). Better outcome expectations of sertraline also predicted higher likelihood of early response. CONCLUSIONS: Higher expectancy of sertraline coupled with early response may produce a cascade-like effect for optimal conditions for long-term symptom reduction. Therefore, assessing expectations and providing clear treatment rationales may optimise sertraline effects. DECLARATION OF INTEREST: None.

Study Design and Rationale for the Mood and Methylation Study: A Platform for Multi-Omics Investigation of Depression in Twins.

Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome-wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future 'multi-omic' analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other 'omic' factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions.

Age Differences in Death and Suicidal Ideation in Anxious Primary Care Patients.

OBJECTIVES: The objective of this study was to examine age differences in the likelihood of endorsing of death and suicidal ideation in primary care patients with anxiety disorders. METHOD: Participants were drawn from the Coordinated Anxiety Learning and Management (CALM) Study, an effectiveness trial for primary care patients with panic disorder (PD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and/or social anxiety disorder (SAD). RESULTS: Approximately one third of older adults with anxiety disorders reported feeling like they were better off dead. Older adults with PD and SAD were more likely to endorse suicidal ideation lasting at least more than half the prior week compared with younger adults with these disorders. Older adults with SAD endorsed higher rates of suicidal ideation compared with older adults with other anxiety disorders. Multivariate analyses revealed the importance of physical health, social support, and comorbid MDD in this association. CONCLUSIONS: Suicidal ideation is common in anxious, older, primary care patients and is particularly prevalent in socially anxious older adults. Findings speak to the importance of physical health, social functioning, and MDD in this association. CLINICAL IMPLICATIONS: When working with anxious older adults it is important to conduct a thorough suicide risk assessment and teach skills to cope with death and suicidal ideation-related thoughts.

Cucurbit[7]uril-Dimethyllysine Recognition in a Model Protein.

Here, we provide the first structural characterization of host-guest complexation between cucurbit[7]uril (Q7) and dimethyllysine (KMe2 ) in a model protein. Binding was dominated by complete encapsulation of the dimethylammonium functional group. While selectivity for the most sterically accessible dimethyllysine was observed both in solution and in the solid state, three different modes of Q7-KMe2 complexation were revealed by X-ray crystallography. The crystal structures revealed also entrapped water molecules that solvated the ammonium group within the Q7 cavity. Remarkable Q7-protein assemblies, including inter-locked octahedral cages that comprise 24 protein trimers, occurred in the solid state. Cucurbituril clusters appear to be responsible for these assemblies, suggesting a strategy to generate controlled protein architectures.

Why Are Vinyl Cations Sluggish Electrophiles?

The kinetics of the reactions of the vinyl cations 2 [Ph2C═C+-(4-MeO-C6H4)] and 3 [Me2C═C+-(4-MeO-C6H4)] (generated by laser flash photolysis) with diverse nucleophiles (e.g., pyrroles, halide ions, and solvents containing variable amounts of water or alcohol) have been determined photometrically. It was found that the reactivity order of the nucleophiles toward these vinyl cations is the same as that toward diarylcarbenium ions (benzhydrylium ions). However, the reaction rates of vinyl cations are affected only half as much by variation of the nucleophiles as those of the benzhydrylium ions. For that reason, the relative reactivities of vinyl cations and benzhydrylium ions depend strongly on the nature of the nucleophiles. It is shown that vinyl cations 2 and 3 react, respectively, 227 and 14 times more slowly with trifluoroethanol than the parent benzhydrylium ion (Ph)2CH+, even though in solvolysis reactions (80% aqueous ethanol at 25 °C) the vinyl bromides leading to 2 and 3 ionize much more slowly (half-lives 1.15 yrs and 33 days) than (Ph)2CH-Br (half-life 23 s). The origin of this counterintuitive phenomenon was investigated by high-level MO calculations. We report that vinyl cations are not exceptionally high energy intermediates, and that high intrinsic barriers for the sp2 ⇌ sp rehybridizations account for the general phenomenon that vinyl cations are formed slowly by solvolytic cleavage of vinyl derivatives, and are also consumed slowly by reactions with nucleophiles.

Ambident Reactivity of Acetyl- and Formyl-Stabilized Phosphonium Ylides.

The kinetics and mechanism of the reactions of formyl-stabilized ylide Ph3P═CHCHO (1) and acetyl-stabilized ylide Ph3P═CHCOMe (2) with benzhydrylium ions (Ar2CH(+), 3) were investigated by UV-vis and NMR spectroscopy. As ambident nucleophiles, ylides 1 and 2 can react at oxygen as well as at the α-carbon. For some reactions, it was possible to determine the second-order rate constant for O-attack as well as for C-attack and to derive the nucleophile-specific parameters N and sN according to the correlation lg k (20 °C) = sN(E + N) for both nucleophilic sites. Generally, O-attack of benzhydrylium ions is faster than C-attack. However, the initially formed benzhydryloxyvinylphosphonium ions can only be observed by NMR spectroscopy when benzhydryl cations with high Lewis acidity are employed. In other cases, rearrangement to the thermodynamically more stable products arising from C-attack occurs. The results derived from our investigations are employed to rationalize the behavior of ambident nucleophiles 1 and 2 in reactions with carbon-centered electrophiles in general. It is shown that the principle of hard and soft acids and bases (HSAB) and the related Klopman-Salem concept of charge and orbital control lead to incorrect predictions of regioselectivity. We also show that the rate of the Wittig reaction of ylide 2 with aldehyde 14 is significantly faster than the rate of either C- or O-attack calculated using lg k (20 °C) = sN(E + N), thus indicating that the oxaphosphetane is formed by a concerted [2 + 2] cycloaddition.

Oxytocin neuron activation prevents hypertension that occurs with chronic intermittent hypoxia/hypercapnia in rats.

Hypertension is a common outcome associated with obstructive sleep apnea (OSA), a prevalent yet poorly treated cardiovascular disease. Recent studies showed oxytocin (OXT), released from hypothalamic paraventricular nucleus (PVN) neurons, activates cardiac vagal neurons in the dorsal motor nucleus of the vagus (DMNX) and may blunt cardiovascular responses to stress. This study tests whether the release of OXT from PVN fibers in the DMNX is diminished with chronic intermittent hypoxia-hypercapnia (CIH/H) exposure, an animal model of OSA, and whether activation of PVN OXT neurons restores OXT release in the DMNX and prevents the hypertension resulting from CIH/H. To assess OXT release from PVN fibers, Chinese hamster ovarian (CHO) cells were engineered to be highly sensitive to OXT by stable expression of the human recombinant OXT receptor and the calcium indicator R-GECO1. PVN fibers in the DMNX were selectively photoactivated in vitro by expression of channelrhodopsin. The release of OXT onto CHO cells in the DMNX was blunted in rats exposed to 21 days of CIH/H. Chronic activation of PVN OXT neurons in vivo, using designer receptors exclusively activated by designer drugs, restored the release of OXT onto CHO cells in the DMNX. Chronic PVN OXT neuron activation in vivo also prevented the hypertension that occurred in conscious unrestrained telemetry-equipped sham rats exposed to 3 wk of CIH/H. These results demonstrate that chronic activation of OXT neurons restores the release of OXT from PVN fibers in the DMNX and prevents the hypertension that occurs with 3 wk of CIH/H exposure.

The Mechanism of Phosphonium Ylide Alcoholysis and Hydrolysis: Concerted Addition of the O-H Bond Across the P=C Bond.

The previous work on the hydrolysis and alcoholysis reactions of phosphonium ylides is summarized and reviewed in the context of their currently accepted mechanisms. Several experimental facts relating to ylide hydrolysis and to salt and ylide alcoholysis are shown to conflict with those mechanisms. In particular, we demonstrate that the pKa values of water and alcohols are too high in organic media to bring about protonation of ylide. Therefore, we propose concerted addition of the water or alcohol O-H bond across the ylide P=C bond. In support of this, we provide NMR spectroscopic evidence for equilibrium between ylide and aclohol that does not require the involvement of phosphonium hydroxide. We report the first P-alkoxyphosphorane to be characterised by NMR spectroscopy that does not undergo exchange on an NMR timescale. Two-dimensional NMR spectroscopic techniques have been applied to the characterisation to P-alkoxyphosphoranes for the first time.

Improving outcomes for patients with medication-resistant anxiety: effects of collaborative care with cognitive behavioral therapy.

BACKGROUND: Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial. METHODS: Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [≥ 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6, 12, and 18 months. Within-group analyses examined outcomes by treatment choice (CBT vs. CBT plus medication management) and CBT dose. RESULTS: Approximately 58% of medication-resistant CALM-CBT patients responded and 46% remitted during the study. Relative to UC, CALM-CBT was associated with greater response at 6 months (AOR = 3.78, 95% CI 2.02-7.07) and 12 months (AOR = 2.49, 95% CI 1.36-4.58) and remission at 6, 12, and 18 months (AORs = 2.44 to 3.18). Patients in CBT plus medication management fared no better than those in CBT only. Some evidence suggested higher CBT dose produced better outcomes. CONCLUSIONS: CBT can improve outcomes for patients whose anxiety symptoms are resistant to standard pharmacotherapy.

The Association of Panic Disorder, Posttraumatic Stress Disorder, and Major Depression With Smoking in American Indians.

INTRODUCTION: Rates of cigarette smoking are disproportionately high among American Indian populations, although regional differences exist in smoking prevalence. Previous research has noted that anxiety and depression are associated with higher rates of cigarette use. We asked whether lifetime panic disorder, posttraumatic stress disorder, and major depression were related to lifetime cigarette smoking in two geographically distinct American Indian tribes. METHODS: Data were collected in 1997-1999 from 1506 Northern Plains and 1268 Southwest tribal members; data were analyzed in 2009. Regression analyses examined the association between lifetime anxiety and depressive disorders and odds of lifetime smoking status after controlling for sociodemographic variables and alcohol use disorders. Institutional and tribal approvals were obtained for all study procedures, and all participants provided informed consent. RESULTS: Odds of smoking were two times higher in Southwest participants with panic disorder and major depression, and 1.7 times higher in those with posttraumatic stress disorder, after controlling for sociodemographic variables. After accounting for alcohol use disorders, only major depression remained significantly associated with smoking. In the Northern Plains, psychiatric disorders were not associated with smoking. Increasing psychiatric comorbidity was significantly linked to increased smoking odds in both tribes, especially in the Southwest. CONCLUSIONS: This study is the first to examine the association between psychiatric conditions and lifetime smoking in two large, geographically diverse community samples of American Indians. While the direction of the relationship between nicotine use and psychiatric disorders cannot be determined, understanding unique social, environmental, and cultural differences that contribute to the tobacco-psychiatric disorder relationship may help guide tribe-specific commercial tobacco control strategies.

Suicide risk and associated demographic and clinical correlates among primary care patients with recent drug use.

BACKGROUND: There is an increased need to prepare primary care clinicians to effectively gauge the risk of suicidal behavior occurring within primary care patients who may abuse drugs, especially those served in safety-net settings. OBJECTIVES: The objectives of this paper were to explore suicide risk in a population of individuals endorsing recent drug use, and to describe patient demographic, medical, psychiatric, social, and substance use characteristics across different levels of suicide risk. METHODS: A total of 867 primary care patients with reported drug use in the previous 90 days were studied. Based upon their responses to two Addiction Severity Index questions, four suicide risk categories were constructed: (1) low risk; (2) moderate-low (suicidal ideation in the past 30 days); (3) moderate-high (history of a lifetime suicide attempt); and (4) high risk (history of a lifetime suicide attempt and suicidal ideation in the past 30 days). The association between suicide risk groups and demographic and clinical variables were assessed. RESULTS: A total of 40% of primary care patients endorsing recent drug use reported a lifetime suicide attempt. Compared to individuals in other suicide risk groups, individuals at high suicide risk had higher rates of substance use severity, recently used two or more substances, and were more likely to have a comorbid psychiatric condition. CONCLUSION: These findings indicate that the percentage of patients with suicide risk may be higher among patients with recent drug use. Primary care clinicians should be aware that they may be encountering patients with suicide risk among those with recent drug use.

Assessing Sexual Interest in Adolescents Who Have Sexually Offended.

Adolescents who have sexually offended have unique treatment needs. For mental health professionals to adequately address these unique needs, further research is necessary. To that end, we explored the assessment of sexual interest (which may play an integral role in understanding potential for sexual reoffending) in a sample of 103 male adolescents who have sexually offended. We compared results from a physiological assessment (MONARCH 21 penile plethysmography [PPG]) and an actuarial assessment (Screening Scale for Pedophilic Interest [SSPI]), plus data from an unobstrusive assessment (Affinity, a viewing time measure) in a smaller subsample of 16 male adolescents. One finding that has particular relevance for clinical assessment is that the SSPI may have limited utility with adolescents. We also found evidence for some overlap between data from PPG and viewing time assessments, although whether or not PPG data are ipsatized may affect relationships with other assessment modalities.

Barriers and Facilitators to Coordinating Care With High-Risk, High-Cost Disabled Medicaid Beneficiaries: Perspectives of Frontline Staff and Participating Clients.

This evaluation was designed to examine the perspectives of 15 frontline staff who implemented a managed care program and 154 high-risk, high-cost disabled Medicaid clients who were participants in the program. Results indicated that positive relationships between staff and clients played a key role in facilitating program implementation. Challenges included finding ways to provide a wide breadth of services including food, shelter, and transportation; handling difficulties following from staff turnover; and creating transitions of care for clients to community health clinics. Staff identified training in motivational interviewing and having both nurse care managers and social workers collaboratively deliver the intervention as among the most powerful components of the program. Staff and clients expressed high levels of satisfaction with the program, and clients believed they were experiencing positive impacts of the program. Lessons learned from this study may inform the design of services as the Affordable Care Act continues to unfold.