Meaningful Engagement in Depression and Anxiety Collaborative Care: Associations With Systematic Case Review.

BACKGROUND: Collaborative care (CC) is an evidence-based model of care for treating behavioral health conditions in primary care settings. The CC team consists of a primary care provider, behavioral health care manager (CM), and a consultant psychiatrist who collaborate to create treatment plans. To date, there is limited data on factors associated with meaningful engagement in CC programs. OBJECTIVE: To identify the proportion of patients who were meaningfully engaged and to investigate the factors associated with meaningful engagement in a CC program. METHODS: Data was collected from a CC program implemented across 27 adult primary care clinics in a Midwestern, U.S. academic medical system. Logistic regression (n = 5218) was used to estimate the odds of receiving meaningful engagement. RESULTS: Data was collected from 6437 individuals with 68% being female and a mean age of 45 years old (standard deviation 17.6). Overall, 57% of patients were meaningfully engaged; however, this proportion differed based on demographic and clinical factors. Among modifiable clinical factors, systematic case reviews between the CM and psychiatrist (odds ratio: 10.2, 95% confidence interval: 8.6-12.1) and warm handoffs (odds ratio: 1.3, 95% confidence interval: 1.1-1.5) were associated with a higher likelihood of receiving meaningful engagement. CONCLUSIONS: The presence of systematic case reviews between the behavioral health CM and the consultant psychiatrist was highly associated with meaningful engagement. When implementing such programs, high fidelity to the core principles including regularly scheduled systematic case reviews should be pursued.

Machine vision reveals micronucleus rupture as a potential driver of the transcriptomic response to aneuploidy.

Micronuclei are aberrant nuclear compartments that trap a portion of a cell's chromatin in a distinct organelle separate from the nucleus and are drivers of inflammation, DNA damage, chromosome instability, and chromothripsis. Many of the consequences of micronucleus formation stem from micronucleus rupture: the sudden loss of micronucleus compartmentalization, resulting in mislocalization of nuclear factors and the exposure of chromatin to the cytosol for the remainder of interphase. Micronuclei form primarily from segregation errors during mitosis, errors that also give rise to other, non-exclusive phenotypes, including aneuploidy and chromatin bridges. The stochastic formation of micronuclei and phenotypic overlap confounds the use of population-level assays or hypothesis discovery, requiring labor-intensive techniques to visually identify and follow micronucleated cells individually. In this study, we present a novel technique for automatically identifying and isolating micronucleated cells generally and cells with ruptured micronuclei specifically using a de novo neural net combined with Visual Cell Sorting. As a proof of concept, we compare the early transcriptomic responses to micronucleation and micronucleus rupture with previously published responses to aneuploidy, revealing micronucleus rupture to be a potential driver of the aneuploidy response.

Insomnia in primary care: Considerations for screening, assessment, and management.

Insomnia, including insomnia disorder, is a common but often overlooked complaint in primary care settings. It is a risk factor for various medical and psychiatric diagnoses and is associated with substantial health care costs. While cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia disorder, access to CBT-I is limited. This article provides a pragmatic approach to screening, assessment, and treatment of insomnia in the primary care setting, promoting a population health approach. The authors review the role of CBT-I, treatment of comorbid conditions, and pharmacologic recommendations in working with primary care patients with insomnia. In addition, the authors highlight the potential utility of technology in improving access to insomnia care.

Demystifying borderline personality disorder in primary care.

Borderline personality disorder (BPD) is a common mental health diagnosis observed in the primary care population and is associated with a variety of psychological and physical symptoms. BPD is a challenging disorder to recognize due to the limitations of accurate diagnosis and identification in primary care settings. It is also difficult to treat due to its complexity (e.g., interpersonal difficulties and patterns of unsafe behaviors, perceived stigma) and healthcare professionals often feel overwhelmed when treating this population. The aim of this article is to describe the impact of BPD in primary care, review current state of knowledge, and provide practical, evidence-based treatment approaches for these patients within this setting. Due to the lack of evidence-based pharmacological treatments, emphasis is placed on describing the framework for treatment, identifying psychotherapeutic opportunities, and managing responses to difficult clinical scenarios. Furthermore, we discuss BPD treatment as it relates to populations of special interest, including individuals facing societal discrimination and adolescents. Through this review, we aim to highlight gaps in current knowledge around managing BPD in primary care and provide direction for future study.

Treating Bipolar Disorder in Primary Care: Diagnosis, Pharmacology, and Management.

Bipolar disorder is a chronic mental illness associated with early mortality, elevated risk of comorbid cardiovascular disease, enormous burden of disability, and large societal costs. Patients often seek treatment for symptoms of bipolar disorder in the primary care setting but are frequently misdiagnosed. This article provides primary care providers with an evidence-based approach to the screening, diagnosis, and pharmacological management of bipolar disorder. Guidance is also provided for helping patients connect with higher levels of specialty psychiatric care when clinically indicated.

Collaborative care implementation: lessons learned.

The authors drafted a "Shared Values of Collaborative Care" document with fundamental principles to make better group decisions in implementing collaborative care.

Chromosome length and gene density contribute to micronuclear membrane stability.

Micronuclei are derived from missegregated chromosomes and frequently lose membrane integrity, leading to DNA damage, innate immune activation, and metastatic signaling. Here, we demonstrate that two characteristics of the trapped chromosome, length and gene density, are key contributors to micronuclei membrane stability and determine the timing of micronucleus rupture. We demonstrate that these results are not due to chromosome-specific differences in spindle position or initial protein recruitment during post-mitotic nuclear envelope assembly. Micronucleus size strongly correlates with lamin B1 levels and nuclear pore density in intact micronuclei, but, unexpectedly, lamin B1 levels do not completely predict nuclear lamina organization or membrane stability. Instead, small gene-dense micronuclei have decreased nuclear lamina gaps compared to large micronuclei, despite very low levels of lamin B1. Our data strongly suggest that nuclear envelope composition defects previously correlated with membrane rupture only partly explain membrane stability in micronuclei. We propose that an unknown factor linked to gene density has a separate function that inhibits the appearance of nuclear lamina gaps and delays membrane rupture until late in the cell cycle.

Management of SIADH-related hyponatremia due to psychotropic medications - An expert consensus from the Association of Medicine and Psychiatry.

OBJECTIVE: Hyponatremia is the most common electrolyte imbalance encountered in clinical practice and is associated with negative healthcare outcomes and cost. SIADH is thought to account for one third of all hyponatremia cases and is typically an insidious process. Psychotropic medications are commonly implicated in the etiology of drug induced SIADH. There is limited guidance for clinicians on management of psychotropic-induced SIADH. METHODS: After an extensive review of the existing literature, clinical-educators from the Association of Medicine and Psychiatry developed expert consensus recommendations for management of psychotropic-induced SIADH. A risk score was proposed based on risk factors for SIADH to guide clinical decision-making. RESULTS: SSRIs, SNRIs, antipsychotics, carbamazepine, and oxcarbazepine have moderate to high level of evidence demonstrating their association with SIADH. Evaluation for an avoidance of medications that cause hyponatremia is particularly important. Substitution with medication that is less likely to cause SIADH should be considered when appropriate. We propose an algorithmic approach to monitoring hyponatremia with SIADH and corresponding treatment depending on symptom severity. CONCLUSIONS: The proposed algorithm can help clinicians in determining whether psychotropic medication should be stopped, reduced or substituted where SIADH is suspected with recommendations for sodium (Na+) monitoring. These recommendations preserve a role for clinical judgment in the management of hyponatremia with consideration of the risks and benefits, which may be particularly relevant for complex patients that present with medical and psychiatric comorbidities. Further studies are needed to determine whether baseline and serial Na+ monitoring reduces morbidity and mortality.

PKC downregulation upon rapamycin treatment attenuates mitochondrial disease.

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. Mechanistic target of rapamycin (mTOR) inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 knock-out (KO) mouse); however, the mechanism of rescue is unknown. Here we identify protein kinase C (PKC) downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice, we find that rapamycin restores mitochondrial protein levels, inhibits signalling through both mTOR complexes and reduces the abundance and activity of multiple PKC isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.

High-throughput, microscope-based sorting to dissect cellular heterogeneity.

Microscopy is a powerful tool for characterizing complex cellular phenotypes, but linking these phenotypes to genotype or RNA expression at scale remains challenging. Here, we present Visual Cell Sorting, a method that physically separates hundreds of thousands of live cells based on their visual phenotype. Automated imaging and phenotypic analysis directs selective illumination of Dendra2, a photoconvertible fluorescent protein expressed in live cells; these photoactivated cells are then isolated using fluorescence-activated cell sorting. First, we use Visual Cell Sorting to assess hundreds of nuclear localization sequence variants in a pooled format, identifying variants that improve nuclear localization and enabling annotation of nuclear localization sequences in thousands of human proteins. Second, we recover cells that retain normal nuclear morphologies after paclitaxel treatment, and then derive their single-cell transcriptomes to identify pathways associated with paclitaxel resistance in cancers. Unlike alternative methods, Visual Cell Sorting depends on inexpensive reagents and commercially available hardware. As such, it can be readily deployed to uncover the relationships between visual cellular phenotypes and internal states, including genotypes and gene expression programs.

QTc monitoring in adults with medical and psychiatric comorbidities: Expert consensus from the Association of Medicine and Psychiatry.

OBJECTIVE: Several psychiatric medications have the potential to prolong the QTc interval and subsequently increase the risk for ventricular arrhythmias such as torsades de pointes (TdP). There is limited guidance for clinicians to balance the risks and benefits of treatments. METHODS: After a review of the existing literature, clinical-educators from the Association of Medicine and Psychiatry developed expert consensus guidelines for ECG monitoring of the QTc interval for patients with medical and psychiatric comorbidities who are prescribed medications with the potential to prolong the QTc interval. A risk score was developed based on risk factors for QTc prolongation to guide clinical decision-making. RESULTS: A baseline ECG may not be necessary for individuals at low risk for arrythmia. Those individuals with a risk score of two or more should have an ECG prior to the start of a potentially QTc-prolonging medication or be started on a lower risk agent. Antipsychotics are not equivalent in causing QTc prolongation. A consensus-based algorithm is presented for the management of those identified at high (QTc >500 msec), intermediate (males with QTc 450-499 msec or females with QTc > 470-499 msec), or low risk. CONCLUSIONS: The proposed algorithm can help clinicians in determining whether ECG monitoring should be considered for a given patient. These guidelines preserve a role for clinical judgment in selection of treatments that balance the risks and benefits, which may be particularly relevant for complex patients with medical and psychiatric comorbidities. Additional studies are needed to determine whether baseline and serial ECG monitoring reduces mortality.

Approach to Evaluating and Managing Adult Attention-Deficit/Hyperactivity Disorder in Primary Care.

Requests for the evaluation of potential adult attention-deficit/hyperactivity disorder (ADHD) is on the rise across primary care clinics. Many health care providers, however, may feel ill equipped to diagnose and manage adults presenting with inattention and impulsivity. The diagnosis of ADHD is often complicated by medical and psychiatric conditions that can contribute to inattention symptoms. In this article, the authors provide a pragmatic clinical approach for evaluating and managing adult ADHD in the primary care setting.

Corrigendum: Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

[This corrects the article on p. 113 in vol. 8, PMID: 28919908.].

Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

The inactivation of ribosomal protein S6 kinase 1 (S6K1) recapitulates aspects of caloric restriction and mTORC1 inhibition to achieve prolonged longevity in invertebrate and mouse models. In addition to delaying normative aging, inhibition of mTORC1 extends the shortened lifespan of yeast, fly, and mouse models with severe mitochondrial disease. Here we tested whether disruption of S6K1 can recapitulate the beneficial effects of mTORC1 inhibition in the Ndufs4 knockout (NKO) mouse model of Leigh Syndrome caused by Complex I deficiency. These NKO mice develop profound neurodegeneration resulting in brain lesions and death around 50-60 days of age. Our results show that liver-specific, as well as whole body, S6K1 deletion modestly prolongs survival and delays onset of neurological symptoms in NKO mice. In contrast, we observed no survival benefit in NKO mice specifically disrupted for S6K1 in neurons or adipocytes. Body weight was reduced in WT mice upon disruption of S6K1 in adipocytes or whole body, but not altered when S6K1 was disrupted only in neurons or liver. Taken together, these data indicate that decreased S6K1 activity in liver is sufficient to delay the neurological and survival defects caused by deficiency of Complex I and suggest that mTOR signaling can modulate mitochondrial disease and metabolism via cell non-autonomous mechanisms.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

What is integrated care?

Increasing awareness of mental illness's impact on medical and psychiatric health has accelerated global efforts to integrate medical and behavioural health services. As the field of integration has advanced, numerous integrated programmes have been implemented. In examining the impact of these programmes, it is important to maintain a standardized vocabulary to describe the various components of their integration. Additionally important is examination of how these programmes impact elements of patient care and the healthcare system. Specifically, what value do they bring? This article will discuss the importance of carefully assessing the value integrated services bring to patients, and questioning whether they do so in ways in which today's segregated world of medical and behavioural health cannot. This article will also explore the various settings in which medical and behavioural integration can bring added value.

A restrictive element 1 (RE-1) in the VIP gene modulates transcription in neuronal and non-neuronal cells in collaboration with an upstream tissue specifier element.

The vasoactive intestinal peptide (VIP) gene has been studied extensively as a prototype neuronal gene containing multiple cis-active elements that confer responsiveness to cell lineage, neurotrophic, and activity-dependent intrinsic and extrinsic cues. However, reporter genes containing the presumptive complete regulatory region 5' to the start of transcription do not confer tissue-specific gene expression in vivo. We therefore sought cis-regulatory elements downstream of the transcriptional start that might confer additional tissue-specific and tissue-restrictive properties to the VIP transcriptional unit. We report here a repressor element, similar to the canonical restrictive element-1 (RE-1), located within the first non-coding exon of the human VIP gene. The ability of this element to regulate VIP reporter gene expression in neuroblastoma and fibroblastic cells was examined. Endogenous VIP expression is high in SH-EP neuroblastoma cells, low but inducible in SH-SY5Y cells, and absent in HeLa cells. Endogenous RE-1 silencer factor (REST) expression was highest in SH-EP and HeLa cells, and significantly lower in SH-SY5Y cells. Transient transfection of a VIP reporter gene containing a mutated RE-1 sequence revealed an RE-1-dependent regulation of VIP gene expression in all three cell types, with regulation greatest in cells (SH-EP, HeLa) with highest levels of REST expression. Serial truncation of the VIP reporter gene further revealed a specific interaction between the RE-1 and a tissue-specifier element located 5 kb upstream in the VIP gene. Thus, REST can regulate VIP gene expression in both neuroblastic and non-neuronal cells, but requires coupling to the upstream tissue specifier element.