Pediatrician and Child Adolescent Psychiatrist Perspectives of Coordinated Care for Emerging Adults.

PURPOSE: To explore pediatrician and child/adolescent psychiatrists' perspectives of the role of coordinated care for emerging adults with serious mental health conditions, particularly as they transition to adult care. METHODS: Semi-structured individual interviews of a purposive sample of 10 pediatricians and 11 child/adolescent psychiatrists in Massachusetts were used to explore coordinated care for emerging adults. Following verbatim transcription and double coding, we conducted a thematic analysis to identify key themes. Care coordination concepts explored included a case discussion, teamwork, communication methods, medication management, transition to adult care, the healthcare home, and youth and family role. Organizational and societal barriers were also discussed. RESULTS: Providers described key barriers to continuous, coordinated care for youth with serious mental health conditions, including poor communication systems between providers, no organized process for the transition from pediatric to adult care, state licensing laws (particularly impacting college-age youth), inadequate connection to community supports, and poor reimbursement rates for psychiatric care. Termination of primary care in young adults and inadequate medication side effect monitoring were described as key gaps in care. DISCUSSION: The current system of coordinated care for emerging adults with serious mental health conditions is a perfect storm of challenges that creates a vicious cycle of interconnected barriers which lead to fragmented, discontinuous, and sub-par care for this population.

Established Outpatient Care and Follow-Up After Acute Psychiatric Service Use Among Youths and Young Adults.

OBJECTIVE: This study explored follow-up after hospitalization and emergency room (ER) use for mental health among youths and young adults with private insurance. METHODS: The IBM MarketScan commercial database (2013-2018) was used to identify people ages 12-27 with a mental health hospitalization (N=95,153) or ER use (N=108,576). Factors associated with outpatient mental health follow-up within 7 and 30 days of discharge were determined via logistic models with generalized estimating equations that accounted for state variation. RESULTS: Of those hospitalized, 42.7% received follow-up within 7 days (67.4% within 30 days). Of those with ER use, 28.6% received follow-up within 7 days (46.4% within 30 days). Type of established outpatient care predicted follow-up after hospitalization and ER use. Compared with people with no established care, the likelihood of receiving follow-up within 7 days was highest among those with mental health and primary care (hospitalization, adjusted odds ratio [AOR]=2.81, 95% confidence interval [CI]=2.68-2.94; ER use, AOR=4.06, 95% CI=3.72-4.42), followed by those with mental health care only (hospitalization, AOR=2.57, 95% CI=2.45-2.70; ER use, AOR=3.48, 95% CI=3.17-3.82) and those with primary care only (hospitalization, AOR=1.20, 95% CI=1.15-1.26; ER use, AOR=1.22, 95% CI=1.16-1.28). Similar trends were observed within 30 days of discharge. CONCLUSIONS: Follow-up rates after acute mental health service use among youths and young adults were suboptimal. Having established mental health care more strongly predicted receiving follow-up than did having established primary care. Improving engagement with outpatient mental health care providers may increase follow-up rates.

Healthcare use in commercially insured youth with mental health disorders.

BACKGROUND: The objective of this study is to describe age-related patterns of outpatient healthcare utilization in youth and young adults with mental health disorders. METHOD: We used the IBM® MarketScan® Commercial Database to identify 359,413 youth and young adults (12-27 years) with a mental health disorder continuously enrolled in private health insurance in 2018. Exploratory analysis was used to describe patterns of outpatient healthcare use (e.g., primary, reproductive, mental health care) and therapeutic management (e.g., medication prescriptions, psychotherapy) by age. Period prevalence and median number of visits are reported. Additional analysis explored utilization patterns by mental health disorder. RESULTS: The prevalence of outpatient mental health care and primary care decreased with age, with a larger drop in primary care utilization. While 74.0-78.4% of those aged 12-17 years used both outpatient mental health care and primary care, 53.1-59.7% of those aged 18-27 years did. Most 18-19-year-olds had a visit with an internal medicine or family medicine specialist, a minority had a pediatrician visit. The prevalence of medication management increased with age, while the prevalence of psychotherapy decreased. CONCLUSIONS: Taken together, this descriptive study illustrates age-related differences in outpatient healthcare utilization among those with mental health disorders. Additionally, those with the most severe mental health disorders seem to be least connected to outpatient care. This knowledge can inform efforts to improve utilization of healthcare across the transition to adulthood.

Be True to Our Schools-Models of Care in College Mental Health.

PURPOSE OF REVIEW: To review and synthesize the previous, current, and proposed models of care in college mental health in order to identify best practices that will address the mental health needs of today's students. To highlight data that supports existing or proposed models and describe areas where more data is needed. RECENT FINDINGS: Despite the potentially appealing attributes of integrated care, empirical evidence supporting these systems and structures in campus settings is mixed. Recent surveys show less than half of campuses have an integrated mental health care model. Overall, there is only partial consensus on optimal models of campus mental health care. Mental health needs in college student populations are greater and more complex than ever. While the resources available are vast and varied, there is limited evidence to support which models and programs can best meet students' needs.

Aligning Mental Health Treatments with the Developmental Stage and Needs of Late Adolescents and Young Adults.

Transitional age youth (TAY) are in a discrete developmental stage, different from both adolescents and mature adults. Serious mental illness can result in their delayed psychosocial development and morbidity. Systemic, provider, and individual barriers result in poor access to care for these youth, potentially impeding their transition to mature adulthood. Current strategies for TAY treatment include patient centered care, vocational and educational support, and shared decision making. There is a paucity of evidence-based practices to effectively treat this population or provide practice guidelines. The research required to do so should be a priority.

Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome.

Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1ß, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of EHEC-induced IL-1ß. Whereas EHEC-specific virulence factors were dispensable for NLRP3 activation, bacterial nucleic acids such as RNA:DNA hybrids and RNA gained cytosolic access and mediated inflammasome-dependent responses. Consistent with a direct role for RNA:DNA hybrids in inflammasome activation, delivery of synthetic EHEC RNA:DNA hybrids into the cytosol triggered NLRP3-dependent responses, and introduction of RNase H, which degrades such hybrids, into infected cells specifically inhibited inflammasome activation. Notably, an E. coli rnhA mutant, which is incapable of producing RNase H and thus harbors increased levels of RNA:DNA hybrid, induced elevated levels of NLRP3-dependent caspase-1 activation and IL-1ß maturation. Collectively, these findings identify RNA:DNA hybrids of bacterial origin as a unique microbial trigger of the NLRP3 inflammasome.

Enterohaemorrhagic Escherichia coli exploits a tryptophan switch to hijack host f-actin assembly.

Intrinsically disordered protein (IDP)-mediated interactions are often characterized by low affinity but high specificity. These traits are essential in signaling and regulation that require reversibility. Enterohaemorrhagic Escherichia coli (EHEC) exploit this situation by commandeering host cytoskeletal signaling to stimulate actin assembly beneath bound bacteria, generating "pedestals" that promote intestinal colonization. EHEC translocates two proteins, EspF(U) and Tir, which form a complex with the host protein IRTKS. The interaction of this complex with N-WASP triggers localized actin polymerization. We show that EspF(U) is an IDP that contains a transiently α-helical N-terminus and dynamic C-terminus. Our structure shows that single EspF(U) repeat forms a high-affinity trimolecular complex with N-WASP and IRTKS. We demonstrate that bacterial and cellular ligands interact with IRTKS SH3 in a similar fashion, but the bacterial protein has evolved to outcompete cellular targets by utilizing a tryptophan switch that offers superior binding affinity enabling EHEC-induced pedestal formation.

Enterohemorrhagic E. coli requires N-WASP for efficient type III translocation but not for EspFU-mediated actin pedestal formation.

Upon infection of mammalian cells, enterohemorrhagic E. coli (EHEC) O157:H7 utilizes a type III secretion system to translocate the effectors Tir and EspF(U) (aka TccP) that trigger the formation of F-actin-rich 'pedestals' beneath bound bacteria. EspF(U) is localized to the plasma membrane by Tir and binds the nucleation-promoting factor N-WASP, which in turn activates the Arp2/3 actin assembly complex. Although N-WASP has been shown to be required for EHEC pedestal formation, the precise steps in the process that it influences have not been determined. We found that N-WASP and actin assembly promote EHEC-mediated translocation of Tir and EspF(U) into mammalian host cells. When we utilized the related pathogen enteropathogenic E. coli to enhance type III translocation of EHEC Tir and EspF(U), we found surprisingly that actin pedestals were generated on N-WASP-deficient cells. Similar to pedestal formation on wild type cells, Tir and EspF(U) were the only bacterial effectors required for pedestal formation, and the EspF(U) sequences required to interact with N-WASP were found to also be essential to stimulate this alternate actin assembly pathway. In the absence of N-WASP, the Arp2/3 complex was both recruited to sites of bacterial attachment and required for actin assembly. Our results indicate that actin assembly facilitates type III translocation, and reveal that EspF(U), presumably by recruiting an alternate host factor that can signal to the Arp2/3 complex, exhibits remarkable versatility in its strategies for stimulating actin polymerization.

Insulin receptor tyrosine kinase substrate links the E. coli O157:H7 actin assembly effectors Tir and EspF(U) during pedestal formation.

Enterohemorrhagic Escherichia coli O157:H7 translocates 2 effectors to trigger localized actin assembly in mammalian cells, resulting in filamentous actin "pedestals." One effector, the translocated intimin receptor (Tir), is localized in the plasma membrane and clustered upon binding the bacterial outer membrane protein intimin. The second, the proline-rich effector EspF(U) (aka TccP) activates the actin nucleation-promoting factor WASP/N-WASP, and is recruited to sites of bacterial attachment by a mechanism dependent on an Asn-Pro-Tyr (NPY(458)) sequence in the Tir C-terminal cytoplasmic domain. Tir, EspF(U), and N-WASP form a complex, but neither EspF(U) nor N-WASP bind Tir directly, suggesting involvement of another protein in complex formation. Screening of the mammalian SH3 proteome for the ability to bind EspF(U) identified the SH3 domain of insulin receptor tyrosine kinase substrate (IRTKS), a factor known to regulate the cytoskeleton. Derivatives of WASP, EspF(U), and the IRTKS SH3 domain were capable of forming a ternary complex in vitro, and replacement of the C terminus of Tir with the IRTKS SH3 domain resulted in a fusion protein competent for actin assembly in vivo. A second domain of IRTKS, the IRSp53/MIM homology domain (IMD), bound to Tir in a manner dependent on the C-terminal NPY(458) sequence, thereby recruiting IRTKS to sites of bacterial attachment. Ectopic expression of either the IRTKS SH3 domain or the IMD, or genetic depletion of IRTKS, blocked pedestal formation. Thus, enterohemorrhagic E. coli translocates 2 effectors that bind to distinct domains of a common host factor to promote the formation of a complex that triggers robust actin assembly at the plasma membrane.

Hierarchical regulation of WASP/WAVE proteins.

Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.

Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U).

During infection, enterohaemorrhagic Escherichia coli (EHEC) takes over the actin cytoskeleton of eukaryotic cells by injecting the EspF(U) protein into the host cytoplasm. EspF(U) controls actin by activating members of the Wiskott-Aldrich syndrome protein (WASP) family. Here we show that EspF(U) binds to the autoinhibitory GTPase binding domain (GBD) in WASP proteins and displaces it from the activity-bearing VCA domain (for verprolin homology, central hydrophobic and acidic regions). This interaction potently activates WASP and neural (N)-WASP in vitro and induces localized actin assembly in cells. In the solution structure of the GBD-EspF(U) complex, EspF(U) forms an amphipathic helix that binds the GBD, mimicking interactions of the VCA domain in autoinhibited WASP. Thus, EspF(U) activates WASP by competing directly for the VCA binding site on the GBD. This mechanism is distinct from that used by the eukaryotic activators Cdc42 and SH2 domains, which globally destabilize the GBD fold to release the VCA. Such diversity of mechanism in WASP proteins is distinct from other multimodular systems, and may result from the intrinsically unstructured nature of the isolated GBD and VCA elements. The structural incompatibility of the GBD complexes with EspF(U) and Cdc42/SH2, plus high-affinity EspF(U) binding, enable EHEC to hijack the eukaryotic cytoskeletal machinery effectively.

Enterohaemorrhagic Escherichia coli Tir requires a C-terminal 12-residue peptide to initiate EspF-mediated actin assembly and harbours N-terminal sequences that influence pedestal length.

Enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) both utilize type III secretion systems that translocate the effector protein Tir into the plasma membrane of mammalian cells in order to stimulate localized actin assembly into 'pedestals'. The Tir molecule that EPEC delivers is phosphorylated within its C-terminus on tyrosine-474, and a clustered 12-residue phosphopeptide encompassing this residue initiates an efficient signalling cascade that triggers actin polymerization. In addition to Y474, tyrosine-454 of EPEC Tir is phosphorylated, although inefficiently, and promotes actin polymerization at low levels. In contrast to EPEC Tir, EHEC Tir lacks Y474 and triggers pedestal formation in a phosphotyrosine-independent manner by interacting with an additional effector protein, EspF(U). To identify EHEC Tir sequences that regulate localized actin assembly, we circumvented the strict requirements for type III translocation and directly expressed Tir derivatives in mammalian cells by transfection. Infection of Tir-expressing cells with a Tir-deficient EHEC strain demonstrated that ectopically expressed Tir localizes to the plasma membrane, is modified by mammalian serine-threonine kinases and is fully functional for actin pedestal formation. Removal of portions of the cytoplasmic N-terminus of Tir resulted in the generation of abnormally long pedestals, indicating that this region of EHEC Tir influences pedestal length. In the presence of the entire N-terminal domain, a 12-residue peptide from the C-terminus of EHEC Tir is both necessary and sufficient to recruit EspF(U) and initiate actin pedestal formation. This peptide encompasses the portion of EHEC Tir analogous to the EPEC Tir-Y454 region and is present within the Tir molecules of all pedestal-forming bacteria, suggesting that this sequence harbours a conserved signalling function.