Collaborative Care for Depression and Anxiety: Racial-Ethnic Differences in Treatment Engagement and Outcomes.

OBJECTIVE: This study aimed to examine racial-ethnic differences in engagement with and clinical outcomes of a collaborative care model (CoCM) implemented in primary care outpatient clinics in an urban academic medical center. METHODS: Adult patients (N=4,911) who screened positive for symptoms of depression, anxiety, or both on the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 scale and who identified as non-Hispanic Black, Hispanic, or non-Hispanic White were offered participation in a CoCM implementation. The primary outcome was treatment engagement, defined as receipt of any follow-up visit, minimally adequate 4-week follow-up (at least one visit), and minimally adequate 16-week follow-up (at least three visits) after initial assessment. Secondary outcomes were response and remission of depression or anxiety. RESULTS: After adjustment of analyses for sociodemographic covariates, Black and Hispanic participants were significantly less likely than White participants to have received any or minimally adequate follow-up. Black and Hispanic participants who received any or minimally adequate 16-week follow-up were more likely than White participants to demonstrate depression symptom response and remission of anxiety symptoms. CONCLUSIONS: This CoCM implementation appears to have been effective in treating depression and anxiety among Black and Hispanic patients. However, significant disparities in receipt of follow-up care were observed. Efforts must be made to improve the retention of patients from racial-ethnic minority groups in collaborative care.

Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.

The approaching pilot for One Health governance index.

BACKGROUND: One Health approach advocates realizing the best health and harmonious symbiosis of human, animal and natural environment through cross-border, multi-sectoral and interdisciplinary cooperation. The good governance model is the leading factor for the performance of One Health governance. In order to tackle the complex problems in the One Health governance at the global level, the variation of One Health governance in different countries was analyzed by a set of indicators within the One Health system. METHOD: The capacity of One Health governance was assessed after establishment of a set of indicators for the One Health governance index (OHGI) following the methodology of the global One Health index. The data to calculate OHGI was collected from various database sources, including the Food and Agriculture Organization, the World Health Organization, the World Organization for Animal Health, and official health-related institutions of various countries. Eight indicators (including 19 sub-indicators) were employed in the OHGI system to comprehensively evaluate the capacity of One Health governance in 146 countries of the world. RESULTS: Among the 146 countries scored in the OHGI system, the average score was 34.11, with a median score of 31.49, ranged from 8.50 to 70.28. Most countries with higher OHGI scores come from Europe and Central Asia, East Asia and the Pacific and North America, while countries with the lower OHGI scores are almost from sub-Saharan Africa. Six countries scored more than 65 points, including Australia, Sweden, Germany, Netherlands, the United States of America and Finland, indicating that these countries are relatively mature in most aspects of One Health governance. However, there were some developing countries with OHGI scored lower than 15. Therefore, the gap between countries with higher OHGI scores and those with lower OHGI scores is more than 60. CONCLUSIONS: Good governance on One Health is an important indicator to measure One Health's governance capacity. The political stability, the level of rule of law and economic conditions in different regions are significantly correlated with the One Health governance capacity. Actions need to be taken urgently to close the gap of One Health governance between different regions.

Impact of Virtual Seminars on Hepatitis B Knowledge and Attitudes Among Preclinical-Year Medical Students.

Background A limited understanding of hepatitis B virus (HBV) disease transmission contributes to fear of routine contact and can stigmatize affected individuals. To reduce potential HBV-related discrimination, there is a need to increase awareness among medical students on HBV knowledge and transmission. We aimed to assess the impact of virtual education seminars on first- and second-year medical students' understanding of HBV and their attitudes toward HBV infection. Methods Pre- and post-seminar surveys were designed and administered to first- and second-year medical students in the February and August 2021 virtual HBV seminars to assess basic knowledge and attitudes toward HBV infection. The seminars consisted of a lecture on HBV followed by case study discussions. Paired samples t-test and McNemar's test for paired proportional differences were used for analysis. Results This study included 24 first-year and 16 second-year medical students who completed both pre- and post-seminar surveys. After attending the seminar, participants demonstrated an increase in correct responses to transmission modes including vertical transmission (p≤0.001) and sharing razors or toothbrushes (p=0.031) rather than sharing utensils or shaking hands (p<0.01). Using 5-point Likert means, improved attitudes were observed in concerns of shaking hands or hugging (pre=2.4, post=1.3, p<0.001) and caring for someone with infection (pre=1.55, post=1.18, p=0.009), and acceptance of an HBV-infected coworker in the same workplace (pre = 4.13, post= 4.78, p<0.001). Conclusion The virtual education seminars clarify misconceptions about transmission and bias towards individuals with HBV infection. Implementation of educational seminars in medical students' training is important to improve overall knowledge of HBV infection.

Expression of membrane Hsp90 is a molecular signature of T cell activation.

Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified a membrane expressed form of Hsp90 (mHsp90) that previously appeared to be restricted to rapidly proliferating cells exhibiting a metastatic phenotype. Here, we used HS-131, a fluor-tethered mHsp90 inhibitor, to quantify the effect of T cell activation on the expression of mHsp90 in human and mouse T cells. In cell-based assays, stimulation of human T cells induced a 20-fold increase in mHsp90 expression at the plasma membrane, suggesting trafficking of mHsp90 is regulated by TCR and inflammatory mediated signaling. Following injection of HS-131 in mouse models of human rheumatoid arthritis and inflammatory bowel disease, we detected localization of the probe at sites of active disease, consistent with immune cell invasion. Moreover, despite rapid hepatobiliary clearance, HS-131 demonstrated efficacy in reducing the mean clinical score in the CIA arthritis model. Our results suggest mHsp90 expression on T cells is a molecular marker of T cell activation and potentially a therapeutic target for chronic diseases such as rheumatoid arthritis.

Relationship between adverse childhood experiences and symptom severity in adult men with Tourette Syndrome.

Childhood adversity is associated with the development or expression of many neuropsychiatric disorders, including those with strong genetic underpinnings. Despite reported associations between perceived stress and tic severity, the relationship between potentially traumatic events in childhood and Tourette Syndrome (TS), a highly heritable neuropsychiatric disorder, is unknown. This study aimed to assess whether exposure to eight categories of adverse childhood experiences (ACEs) is associated with TS severity and impairment, and whether TS genetic risk modifies this association. Online survey data were collected from 351 adult males with TS who previously participated in genetic studies. Participants completed the ACE questionnaire and a lifetime version of the Yale Global Tic Severity Scale (YGTSS). Demographic and relevant health data were assessed; polygenic risk scores (PRS) measuring aggregated TS genetic risk were derived using genome-wide association data. Univariable and multivariable linear regressions examined the relationships between childhood adversity and retrospectively recalled worst-ever tic severity and impairment, adjusting for covariates. Potential gene-by-environment (GxE) interactions between ACE and PRS were estimated. After covariate adjustment, there was a significant graded dose-response relationship between ACE Scores and increases in lifetime worst-ever tic severity and impairment. There was some evidence that TS genetic risk moderated the relationship between ACE Score and tic impairment, but not tic severity, particularly for individuals with higher TS polygenic risk. We provide evidence that childhood adversity is associated with higher lifetime TS severity and impairment, although future longitudinal studies with genetically-sensitive designs are needed to determine whether these relationships are causal and/or directional.

Racial and Ethnic Disparities in Childhood ADHD Treatment Access and Utilization: Results From a National Study.

OBJECTIVE: The study examined racial-ethnic disparities in access to and utilization of treatment for attention-deficit hyperactivity disorder (ADHD) and other psychiatric diagnoses among children with ADHD. METHODS: Nationally representative, cross-sectional data from the Household Component of the Medical Expenditure Panel Survey 2011-2019 were used to examine racial-ethnic disparities in access to and utilization of treatment by children ages 5-17 with ADHD (N=5,838). Logistic regression models were estimated for access outcomes, and generalized linear models were estimated for utilization outcomes. Multivariable regression models adjusted for race-ethnicity, age, sex, and treatment need in accordance with the Institute of Medicine definition of health care disparities. RESULTS: In adjusted analyses, compared with White children with ADHD, Black, Hispanic, and Asian children with ADHD had significantly lower rates of any past-year treatment visit for ADHD or for other psychiatric diagnoses. They also had lower rates of having accessed ADHD medication. Compared with White children, Black and Asian children with ADHD used fewer ADHD medications, and Black and Hispanic children with ADHD had lower overall mental health treatment expenditures. CONCLUSIONS: Disparities in ADHD treatment among children from racial-ethnic minority populations may be driven primarily by disparities in access rather than in utilization. Once treatment had been accessed, disparities in utilization were largely accounted for by differences in socioeconomic status. These findings suggest that interventions targeting access to treatment among children from racial-ethnic minority populations may help close existing care gaps.

Association Between Hospital Private Equity Acquisition and Outcomes of Acute Medical Conditions Among Medicare Beneficiaries.

Importance: As private equity (PE) acquisitions of short-term acute care hospitals (ACHs) continue, their impact on the care of medically vulnerable older adults remains largely unexplored. Objective: To investigate the association between PE acquisition of ACHs and access to care, patient outcomes, and spending among Medicare beneficiaries hospitalized with acute medical conditions. Design, Setting, and Participants: This cross-sectional study used a generalized difference-in-differences approach to compare 21 091 222 patients admitted to PE-acquired vs non-PE-acquired short-term ACHs between January 1, 2001, and December 31, 2018, at least 3 years before to 3 years after PE acquisition. The analysis was conducted between December 28, 2020, and February 1, 2022. Differences were estimated using both facility and hospital service area fixed effects. To assess the robustness of findings, regressions were reestimated after including fixed effects of patient county of origin to account for geographic differences in underlying health risks. Two subset analyses were also conducted: (1) an analysis including only hospitals in hospital referral regions with at least 1 PE acquisition and (2) an analysis stratified by participation in the Hospital Corporation of America 2006 acquisition. The study included Medicare beneficiaries 66 years and older who were hospitalized with 1 of 5 acute medical conditions: acute myocardial infarction (AMI), acute stroke, chronic obstructive pulmonary disease exacerbation, congestive heart failure exacerbation, and pneumonia. Exposures: Acquisition of hospitals by PE firms. Main Outcomes and Measures: Comorbidity burden (measured by Elixhauser comorbidity score), hospital length of stay, in-hospital mortality, 30-day mortality, 30-day readmission, and 30-day episode payments. Results: Among 21 091 222 total Medicare beneficiaries admitted to ACHs between 2001 and 2018, 20 431 486 patients received care at non-PE-acquired hospitals, and 659 736 received care at PE-acquired hospitals. Across all admissions, the mean (SD) age was 79.45 (7.95) years; 11 727 439 patients (55.6%) were male, and 4 550 012 patients (21.6%) had dual insurance; 2 996 560 (14.2%) patients were members of racial or ethnic minority groups, including 2 085 128 [9.9%] Black and 371 648 [1.8%] Hispanic; 18 094 662 patients (85.8%) were White. Overall, 3 083 760 patients (14.6%) were hospitalized with AMI, 2 835 777 (13.4%) with acute stroke, 3 674 477 (17.4%) with chronic obstructive pulmonary disease exacerbation, 5 868 034 (27.8%) with congestive heart failure exacerbation, and 5 629 174 (26.7%) with pneumonia. Comorbidity burden decreased slightly among patients admitted with acute stroke (difference, -0.04 SDs; 95% CI, -0.004 to -0.07 SDs) at acquired hospitals compared with nonacquired hospitals but was unchanged across the other 4 conditions. Among patients with AMI, a greater decrease in in-hospital mortality was observed in PE-acquired hospitals compared with non-PE-acquired hospitals (difference, -1.14 percentage points, 95% CI, -1.86 to -0.42 percentage points). In addition, a greater decrease in 30-day mortality (difference, -1.41 percentage points; 95% CI, -2.26 to -0.56 percentage points) was found at acquired vs nonacquired hospitals. However, 30-day spending and readmission rates remained unchanged across all conditions. The extent and directionality of estimates were preserved across all robustness assessments and subset analyses. Conclusions and Relevance: In this cross-sectional study using a difference-in-differences approach, PE acquisition had no substantial association with the patient-level outcomes examined, although it was associated with a moderate improvement in mortality among Medicare beneficiaries hospitalized with AMI.

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.

Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited over the lifetime of the patient due to the development of antidrug antibodies that preclude proper therapeutic benefits. As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects. Thus, there is an unmet medical need to develop alternative treatments enabling patients to regain the benefits of selectively targeting TNF functions in vivo. The protein kinase TAK1 is a critical signaling node in TNF-mediated intracellular signaling, regulating downstream NF-κß activation, leading to the transcription of inflammatory cytokines. TAK1 inhibitors have been developed but have been limited in their clinical advancement due to the lack of selectivity within the human kinome and, most importantly, lack of oral bioavailability. Using a directed medicinal chemistry approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276, a potent (Ki = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor. Following oral administration in normal mice, HS-276 is well tolerated (MTD >100 mg/Kg), displaying >95% bioavailability with µM plasma levels. The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics.

Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.

ABSTRACT: Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent discovery of membrane bound ectopic Hsp90 (eHsp90) on tumor cells has shown that Hsp90 induction to the plasma membrane can stabilize disease-relevant proteins. Here, we characterize eHsp90 expression in a mouse model of inflammation and demonstrate its role in nociception and pain. We found that intraplantar complete Freund adjuvant (CFA) induced robust expression of eHsp90 on the cell membranes of primary afferent nociceptors located in the L3-L5 dorsal root ganglia (DRG), bilaterally, with minimal to no expression in other tissues. Complete Freund adjuvant-induced increases in eHsp90 expression on lumbar DRG were significantly greater in females compared with males. Furthermore, exogenous Hsp90 applied to primary Pirt-GCaMP3 nociceptors induced increases in calcium responses. Responses were estrogen-dependent such that greater activity was observed in female or estrogen-primed male nociceptors compared with unprimed male nociceptors. Treatment of mice with the selective eHsp90 inhibitor HS-131 (10 nmol) significantly reversed CFA-induced mechanical pain, thermal heat pain, and hind paw edema. Notably, a higher dose (20 nmol) of HS-131 was required to achieve analgesic and anti-inflammatory effects in females. Here, we provide the first demonstration that inflammation leads to an upregulation of eHsp90 on DRG nociceptors in a sex-dependent manner and that inhibition of eHsp90 reduces nociceptor activity, pain, and inflammation. Thus, eHsp90 represents a novel therapeutic axis for the development of gender-tailored treatments for inflammatory pain.

Private Equity Acquisition And Responsiveness To Service-Line Profitability At Short-Term Acute Care Hospitals.

As private equity firms continue to increase their ownership stake in various health care sectors in the US, questions arise about potential impacts on the organization and delivery of care. Using a difference-in-differences approach, we investigated changes in service-line provision in private equity-acquired hospitals. Relative to nonacquired hospitals, private equity acquisition was associated with a higher probability of adding specific profitable hospital-based services (interventional cardiac catheterization, hemodialysis, and labor and delivery), profitable technologies (robotic surgery and digital mammography), and freestanding or satellite emergency departments. Moreover, private equity acquisition was associated with an increased probability of providing services that were previously categorized as unprofitable but that have more recently become areas of financial opportunity (for example, mental health services). Finally, private equity-acquired hospitals were less likely to add or continue services that have unreliable revenue streams or that may face competition from nonprofit hospitals (for example, outpatient psychiatry), although fewer shifts were noted among unprofitable services. This may reflect a prevailing shift by acute care hospitals toward outpatient settings for appropriate procedures and synergies with existing holdings by private equity firms.

Dual acting oximes designed for therapeutic decontamination of reactive organophosphates via catalytic inactivation and acetylcholinesterase reactivation.

A conventional approach in the therapeutic decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of α-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each composed of an OP-reactive oxime core linked to an amine-terminated scaffold, which varied through an N-alkyl functionalization. This library was screened by enzyme assays performed with human and electric eel subtypes of OP-inactivated AChE, which led to identifying three oxime leads that displayed significant enhancements in reactivation activity comparable to 2-PAM. They were able to reactivate both enzymes inactivated by three OP types including paraoxon, chlorpyrifos and malaoxon, suggesting their broad spectrum of OP susceptibility. All compounds in the library were able to retain catalytic reactivity in paraoxon inactivation by rates increased up to 5 or 8-fold relative to diacetylmonoxime (DAM) under controlled conditions at pH (8.0, 10.5) and temperature (17, 37 °C). Finally, selected lead compounds displayed superb efficacy in paraoxon decontamination on porcine skin in vitro. In summary, we addressed an unmet need in therapeutic OP decontamination by designing and validating a series of congeneric oximes that display dual modes of action.

TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases.

Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κß signalling in turn amplifying a cell's inflammatory response and exacerbating disease. Within the TNF intracellular inflammatory signalling cascade, transforming growth factor-ß-activated kinase 1 (TAK1) has been shown to play a critical role in mediating signal transduction and downstream NF-κß activation. Owing to its role in TNF inflammatory signalling, TAK1 has become a potential therapeutic target for the treatment of inflammatory diseases such as RA. This review highlights the current development of targeting the TNF-TAK1 signalling axis as a novel therapeutic strategy for the treatment of inflammatory diseases.

Shielded α-Nucleophile Nanoreactor for Topical Decontamination of Reactive Organophosphate.

Here, we describe a nanoscale reactor strategy with a topical application in the therapeutic decontamination of reactive organophosphates (OPs) as chemical threat agents. It involves functionalization of poly(amidoamine) dendrimer through a combination of its partial PEG shielding and exhaustive conjugation with an OP-reactive α-nucleophile moiety at its peripheral branches. We prepared a 16-member library composed of two α-nucleophile classes (oxime, hydroxamic acid), each varying in its reactor valency (43-176 reactive units per nanoparticle), and linker framework for α-nucleophile tethering. Their mechanism for OP inactivation occurred via nucleophilic catalysis as verified against P-O and P-S bonded OPs including paraoxon-ethyl (POX), malaoxon, and omethoate by 1H NMR spectroscopy. Screening their reactivity for POX inactivation was performed under pH- and temperature-controlled conditions, which resulted in identifying 13 conjugates, each showing shorter POX half-life up to 2 times as compared to a reference Dekon 139 at pH 10.5, 37 °C. Of these, 10 conjugates were further confirmed for greater efficacy in POX decontamination experiments performed in two skin models, porcine skin and an artificial human microtissue. Finally, a few lead conjugates were selected and demonstrated for their biocompatibility in vitro as evident with lack of skin absorption, no inhibition of acetylcholinesterase (AChE), and no cytotoxicity in human neuroblastoma cells. In summary, this study presents a novel nanoreactor library, its screening methods, and identification of potent lead conjugates with potential for therapeutic OP decontamination.

TAK1 regulates the tumor microenvironment through inflammatory, angiogenetic and apoptotic signaling cascades.

Transforming growth factor beta-activated kinase 1 (TAK1) has been implicated for its role in inflammatory signaling and as an important mediator of cellular apoptosis and necroptosis in various cell types. Our recent discovery of a first-in-class, potent and selective TAK1 inhibitor, takinib, represents a novel pharmacological tool to evaluate TAK1's role in cancer. In this study we evaluated the potential therapeutic capacity of TAK1 inhibition on tumor growth and on tumor microenvironment remodeling. In a screen of 16 cancer cell lines, takinib in combination with tumor necrosis factor (TNF) was found to induce cell death (>20%) in 6 out of 16 cell lines. Furthermore, knocking out of TAK1 in MDA-MB-231 cells dramatically increased their sensitization to TNF-mediated apoptosis. In vivo xenographs of MDA-MB-231 TAK1KO tumors displayed delayed tumor growth and increased overall survival compared to TAK1WT controls. Histological and proteomic analysis of TAK1KO tumors showed altered angiogenic signaling and inflammatory signaling via immune cells. Overall, these findings suggest that the targeting of TAK1 in immune mediated cancers may be a novel therapeutic axis.

Spacer-Mediated Control of Coumarin Uncaging for Photocaged Thymidine.

Despite its importance in the design of photocaged molecules, less attention is focused on linker chemistry than the cage itself. Here, we describe unique uncaging properties displayed by two coumarin-caged thymidine compounds, each conjugated with (2) or without (1) an extended, self-immolative spacer. Photolysis of 1 using long-wavelength UVA (365 nm) or visible (420, 455 nm) light led to the release of free thymidine along with the competitive generation of a thymidine-bearing recombination product. The occurrence of this undesired side reaction, which is previously unreported, was not present with the photolysis of 2, which released thymidine exclusively with higher quantum efficiency. We propose that the spatial separation between the cage and the substrate molecule conferred by the extended linker can play a critical role in circumventing this unproductive reaction. This report reinforces the importance of linker selection in the design of coumarin-caged oligonucleosides and other conjugates.

A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.

Interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, as well as transforming growth factor ß-activated kinase 1 (TAK1), are protein kinases essential for transducing inflammatory signals from interleukin receptors. IRAK family proteins and TAK1 have high sequence identity within the ATP-binding pocket, limiting the development of highly selective IRAK-1/4 or TAK1 inhibitors. Beyond kinase activity, IRAKs and TAK1 act as molecular scaffolds along with other signaling proteins, complicating the interpretation of experiments involving knockin or knockout approaches. In contrast, pharmacological manipulation offers the promise of targeting catalysis-mediated signaling without grossly disrupting the cellular architecture. Recently, we reported the discovery of takinib, a potent and highly selective TAK1 inhibitor that has only marginal activity against IRAK-4. On the basis of the TAK1-takinib complex structure and the structure of IRAK-1/4, here we defined critical contact sites of the takinib scaffold within the nucleotide-binding sites of each respective kinase. Kinase activity testing of takinib analogs against IRAK-4 identified a highly potent IRAK-4 inhibitor (HS-243). In a kinome-wide screen of 468 protein kinases, HS-243 had exquisite selectivity toward both IRAK-1 (IC50 = 24 nm) and IRAK-4 (IC50 = 20 nm), with only minimal TAK1-inhibiting activity (IC50 = 0.5 µm). Using HS-243 and takinib, we evaluated the consequences of cytokine/chemokine responses after selective inhibition of IRAK-1/4 or TAK1 in response to lipopolysaccharide challenge in human rheumatoid arthritis fibroblast-like synoviocytes. Our results indicate that HS-243 specifically inhibits intracellular IRAKs without TAK1 inhibition and that these kinases have distinct, nonredundant signaling roles.

Disparities in Mental Health Care Utilization and Perceived Need Among Asian Americans: 2012-2016.

OBJECTIVE: The objective was to examine mental health treatment access disparities between Asians and whites in the United States as well as the role of perceived and objective need and barriers to treatment in these disparities. METHODS: Data are five annual cross-sections (2012-2016) of responses from Asian Americans and whites to the nationally representative National Survey on Drug Use and Health. Multivariate logistic regression analyses adjusting for sociodemographic factors were conducted to compare past-year treatment access rates between Asians and whites across three need subgroups: those with perceived need for treatment, those with past-year serious psychological distress, and those with a past-year major depressive episode. Barriers to treatment were compared between Asians and whites with perceived need. RESULTS: Asians were less likely than whites to have accessed mental health treatment in the past year in all analyses. Compared with Asians with need determined by structured diagnostic instruments, Asians with perceived need had higher rates of mental health care access, but even among respondents with perceived need, the disparity between whites and Asians remained. Regarding barriers to treatment, only one barrier (not knowing where to go for treatment) was more likely to be reported for Asians than whites. CONCLUSIONS: Differences between Asians and whites in perceived need for mental health treatment do not explain the wide disparities in mental health care access between these two groups. Clinical interventions improving the relevance and fit of mental health care and community-based outreach interventions increasing awareness of available services are needed to improve access to mental health treatment among Asians.

Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.

OBJECTIVES: To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. METHODS: Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 µM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). RESULTS: Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. CONCLUSION: Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

Reactivity and mechanism of α-nucleophile scaffolds as catalytic organophosphate scavengers.

Despite their unique benefits imparted by their structure and reactivity, certain α-nucleophile molecules remain underexplored as chemical inactivators for the topical decontamination of reactive organophosphates (OPs). Here, we present a library of thirty α-nucleophile scaffolds, each designed with either a pyridinium aldoxime (PAM) or hydroxamic acid (HA) α-nucleophile core tethered to a polar or charged scaffold for optimized physicochemical properties and reactivity. These library compounds were screened for their abilities to catalyze the hydrolysis of a model OP, paraoxon (POX), in kinetic assays. These screening experiments led to the identification of multiple lead compounds with the ability to inactivate POX two- to four-times more rapidly than Dekon 139-the active ingredient currently used for skin decontamination of OPs. Our mechanistic studies, performed under variable pH and temperature conditions suggested that the differences in the reactivity and activation energy of these compounds are fundamentally attributable to the core nucleophilicity and pKa. Following their screening and mechanistic studies, select lead compounds were further evaluated and demonstrated greater efficacy than Dekon 139 in the topical decontamination of POX in an ex vivo porcine skin model. In addition to OP reactivity, several compounds in the PAM class displayed a dual mode of activity, as they retained the ability to reactivate POX-inhibited acetylcholine esterase (AChE). In summary, this report describes a rationale for the hydrophilic scaffold design of α-nucleophiles, and it offers advanced insights into their chemical reactivity, mechanism, and practical utility as OP decontaminants.