Adolescent Depression Symptom Trajectories Detected Via Universal Screening in Pediatric Primary Care.

Unique trajectories of adolescent depression symptoms have been identified, yet less is known about whether such patterns translate to real-world clinical settings. Because annual adolescent depression screening is becoming more prevalent in primary care, we examined whether longitudinal patterns of depression symptoms documented in the developmental psychopathology literature can also be detected via routine screening in primary care and explored how membership in the identified trajectories varied based on concurrent suicide risk and sociodemographic factors. A total of 1,359 adolescents aged 12-16 years old at the first timepoint were included in the current analyses. These adolescents completed three depression screeners during their well-visits in a large pediatric primary care network between November 15, 2017 and February 1, 2020. Retrospective electronic health record data were extracted, including sociodemographic variables and depression screening results. Dynamic functional time series clustering results indicated the optimal number of clusters was five. The five depression symptom trajectories were: (1) A-Shaped (i.e., relatively low depression symptoms at Time 1, a substantial increase in symptoms at Time 2, and a return to low symptoms at Time 3), (2) Increasing, (3) Low-Stable, (4) High-Decreasing, and (5) Low-Decreasing. Cluster differences in suicide risk largely mapped onto depression symptom levels at each assessment. We found cluster differences based on practice location, insurance type, and adolescent race. The symptom trajectories observed in this study resemble those found in the developmental psychopathology literature, though some key differences were noted. Findings can inform future research and symptom monitoring in primary care.

Emerging Risk of Adolescent Depression and Suicide Detected Through Pediatric Primary Care Screening.

OBJECTIVE: The goal of the current study was to document patterns of stability and change in adolescent depression and suicide risk detected via universal depression screening in pediatric primary care and to determine who may go on to experience emerging risk. METHODS: Retrospective electronic health record information (sociodemographic data and depression screening results for 2 timepoints) was extracted for adolescents aged 12-17 who attended well-visits between November 15, 2017, and February 1, 2020, in a large pediatric primary care network. A total of 27,335 adolescents with 2 completed depression screeners were included in the current study. RESULTS: While most adolescents remained at low risk for depression and suicide across the 2 timepoints, others experienced emerging risk (i.e., low risk at time 1 but elevated risk at time 2), decreasing risk (i.e., high risk at time 1 but low risk at time 2) or stable high risk for depression or suicide. Odds of experiencing emerging depression and suicide risk were higher among adolescents who were female (compared to males), Black (compared to White), and had Medicaid insurance (compared to private insurance). Odds of experiencing emerging depression risk were also higher among older adolescents (compared to younger adolescents) as well as adolescents who identified as Hispanic/Latino (compared to non-Hispanic/Latino). CONCLUSIONS: Findings can inform symptom monitoring and opportunities for prevention in primary care.

Screening Adolescents for Sensitive Health Topics in Primary Care: A Scoping Review.

We sought to aggregate common barriers and facilitators to screening adolescents for sensitive health topics (e.g., depression, chlamydia) in primary care, as well as those that are unique to a given health topic. We conducted a literature search of three databases (PsycInfo, MEDLINE, and CINAHL) and reference lists of included articles. Studies focused on barriers and facilitators to screening adolescents (ages 12-17 years) for sensitive health topics in primary care that are recommended by national guidelines. Articles were peer-reviewed, presented empirical data, and were published in English in 2006-2021. We coded barriers and facilitators using the Consolidated Framework for Implementation Research, a well-established framework within implementation science. In total, 39 studies met inclusion criteria and spanned several health topics: depression, suicide, substance use, HIV, and chlamydia. We found common barriers and facilitators to screening across health topics, with most relating to characteristics of the primary care clinics (e.g., time constraints). Other factors relevant to screening implementation ranged from confidentiality concerns to clinician knowledge. Barriers and facilitators specific to certain health topics, such as the availability of on-site laboratories for HIV screening, were also noted. Findings can guide refinements to screening implementation.

Adolescent depression screening in primary care: Who is screened and who is at risk?

BACKGROUND: Limited research has simultaneously focused on sociodemographic differences in who receives recommended adolescent depression screening in primary care and who endorses elevated depression and suicide risk on these screeners. We describe screening and risk rates in a large pediatric primary care network in the United States after the network expanded its universal depression screening guideline to cover all well-visits (i.e., annual medical checkups) for adolescents ages 12 and older. METHODS: Between November 15, 2017 and February 1, 2020, there were 122,682 well-visits for adolescents ages 12-17 (82,531 unique patients). The Patient Health Questionnaire - Modified for Teens (PHQ-9-M) was administered to screen for depression. RESULTS: A total of 99,961 PHQ-9-Ms were administered (screening rate=81.48%). The likelihood of screening was higher among adolescents who were female, 12-14 years of age at their first well-visit during the study, White, Hispanic/Latino, or publicly-insured (i.e., Medicaid-insured). Additionally, 5.92% of adolescents scored in the threshold range for depression symptoms and 7.19% endorsed suicidality. Heightened depression and suicide risk were observed among adolescents who were female, 15-17 years of age at their first well-visit during the study, Black, Hispanic/Latino, attending urban primary care practices, or Medicaid-insured. Odds of endorsing suicidality were also higher among teens who identified as other races. LIMITATIONS: Limitations related to data available in the electronic health record and reliance on data from a single hospital system are noted. CONCLUSIONS: Findings highlight misalignments in screening and risk status that are important to address to ensure more equitable screening implementation and health outcomes.

COVID-19 and Adolescent Depression and Suicide Risk Screening Outcomes.

BACKGROUND: Mental health concerns increased during the coronavirus disease 2019 pandemic, but previous studies have not examined depression screening in pediatric primary care. We aimed to describe changes in screening, depressive symptoms, and suicide risk among adolescents during the coronavirus disease 2019 pandemic. METHODS: In a repeat cross-sectional analysis of electronic health record data from a large pediatric primary care network, we compared the percentage of primary care visits where adolescents aged 12 to 21 were screened for depression, screened positive for depressive symptoms, or screened positive for suicide risk between June and December 2019 (prepandemic) and June and December 2020 (pandemic). Changes were examined overall, by month, and by sex, race and ethnicity, insurance type, and income. Modified Poisson regression was used to calculate prevalence ratios (PRs) for the prepandemic to pandemic changes. RESULTS: Depression screening at primary care visits declined from 77.6% to 75.8% during the pandemic period (PR: 0.98, 95% confidence interval [CI]: 0.90-1.06). The percentage of adolescents screening positive for depressive symptoms increased from 5.0% to 6.2% (PR: 1.24, 95% CI: 1.15-1.34), with greater increases among female, non-Hispanic Black, and non-Hispanic white adolescents. Positive suicide risk screens increased from 6.1% to 7.1% (PR: 1.16, 95% CI: 1.08-1.26), with a 34% relative increase in reporting recent suicidal thoughts among female adolescents (PR: 1.34, 95% CI: 1.18-1.52). CONCLUSIONS: Results suggest that depression and suicide concerns have increased during the pandemic, especially among female adolescents. Results underscore the importance of consistent depression and suicidality screening.

A functionally significant polymorphism in ID3 is associated with human coronary pathology.

AIMS: We previously identified association between the ID3 SNP rs11574 and carotid intima-media thickness in the Diabetes Heart Study, a predominantly White diabetic population. The nonsynonymous SNP rs11574 results in an amino acid substitution in the C-terminal region of ID3, attenuating the dominant negative function of ID3 as an inhibitor of basic HLH factor E12-mediated transcription. In the current investigation, we characterize the association between the functionally significant polymorphism in ID3, rs11574, with human coronary pathology. METHODS AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal study of subclinical cardiovascular disease, including non-Hispanic White (n = 2,588), African American (n = 2,560) and Hispanic (n = 2,130) participants with data on coronary artery calcium (CAC). The Coronary Assessment in Virginia cohort (CAVA) included 71 patients aged 30-80 years, undergoing a medically necessary cardiac catheterization and intravascular ultrasound (IVUS) at the University of Virginia. ID3 SNP rs11574 risk allele was associated with the presence of CAC in MESA Whites (P = 0.017). In addition, the risk allele was associated with greater atheroma burden and stenosis in the CAVA cohort (P = 0.003, P = 0.04 respectively). The risk allele remained predictive of atheroma burden in multivariate analysis (Model 1: covariates age, gender, and LDL, regression coefficient = 9.578, SE = 3.657, p = 0.0110; Model 2: covariates Model 1, presence of hypertension, presence of diabetes, regression coefficient = 8.389, SE = 4.788, p = 0.0163). CONCLUSIONS: We present additional cohorts that demonstrate association of ID3 SNP rs11574 directly with human coronary artery pathology as measured by CAC and IVUS: one a multiethnic, relatively healthy population with low levels of diabetes and the second a predominantly White population with a higher incidence of T2DM referred for cardiac catheterization.

Intrathecally synthesized IgG in multiple sclerosis cerebrospinal fluid recognizes identical epitopes over time.

Intrathecal antibody production manifest as oligoclonal bands (OCBs) is a hallmark of multiple sclerosis (MS). Once present, OCBs can be detected in CSF throughout the lifetime of MS patients. To determine the specificity of the OCBs, we applied CSF IgG obtained from 2 consecutive lumbar punctures of 5 MS patients to screen phage-displayed random peptide libraries, and selected identical and related peptides that reacted with the paired CSF IgGs from each patient. Highly sensitive phage-mediated immuno-PCR revealed that the phage peptides bound specifically to IgG in MS CSF collected over time. IEF immunoblots also showed that these peptides were recognized by OCBs in MS CSF. We further demonstrated that the peptides represented linear epitopes, indicating that they represent natural epitopes of corresponding protein antigens. A database search combined with alanine scan mutagenesis of peptides that bound to CSF IgG from 3 MS patients revealed that they are derived from proteins including serine/threonine-protein kinase, protein ZIP2 and MHC class II. Identification of epitopes that are recognized by IgG in MS CSF over time provides a critical tool to investigate the specificity of OCBs, which may determine the cause of disease, leading to strategies for diagnostic and therapeutic intervention.

Blocking angiotensin II Type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with an annual mortality rate close to its annual incidence. We recently demonstrated that angiotensin II (AngII) type 1 receptor (AT1R) might be involved in PDA angiogenesis. This study evaluated the antiproliferative and proapoptotic effects of an AT1R blocker, losartan, in PDA cells with different p53 mutation status. METHODS: Cell cycle was analyzed by flow cytometric analysis of DNA content; apoptosis by annexin V-fluorescein isothiocyanate (V-FITC) and terminal deoxytransferase (TdT)-mediated dUTP nick-end labeling staining; messenger RNA and protein by real-time polymerase chain reaction and Western blotting; caspase-3 activity by colorimetric assay; and promoter activity by luciferase assay. RESULTS: Losartan dose-dependently decreased cell survival and increased their preG1 accumulation. It also increased p53, p21, p27, and Bax and reduced Bcl-2 and Bcl-xl expression. In wtp53 cells, losartan increased p53 transcription and activated caspase-3 in both cell lines. However, its proapoptotic effects in mtp53 cells were mainly caspase-3-dependent. CONCLUSION: Our data describe the involvement of AT1R in PDA cell apoptotic machinery and provide the first evidences that losartan stimulates the proapoptotic signaling pathways regardless of the p53 mutation status. As loss of p53 function is frequently observed in PDA patients, our data suggest AT1R blockade as a novel therapeutic strategy to control PDA growth.

Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1.

BACKGROUND & AIMS: The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with nonalcoholic steatohepatitis. METHODS: The aim of the present study was to determine whether metformin also prevents steatosis and liver damage in mouse models of acute and chronic alcohol exposure. RESULTS: Acute ethanol exposure caused a >20-fold increase in hepatic lipids, peaking 12 hours after administration. Metformin treatment significantly blunted the ethanol effect by >60%. Although metformin is a known inducer of AMP kinase (AMPK) activity, the hepatoprotective property of metformin did not correlate with activation of AMPK or of AMPK-dependent pathways. Instead, the protective effects of metformin correlated with complete prevention of the upregulation of plasminogen activator inhibitor (PAI)-1 caused by ethanol. Indeed, a similar protective effect against acute alcohol-induced lipid accumulation was observed in PAI-1-/- mice. Hepatic fat accumulation caused by chronic enteral ethanol feeding was also prevented by metformin or by knocking out PAI-1. Under these conditions, necroinflammatory changes caused by ethanol were also significantly attenuated. CONCLUSIONS: Taken together, these findings suggest a novel mechanism of action for metformin and identify a new role of PAI-1 in hepatic injury caused by ethanol.

Critical role of plasminogen activator inhibitor-1 in cholestatic liver injury and fibrosis.

Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein known to correlate with hepatic fibrosis. However, whether or not PAI-1 plays a causal role in this disease process had not been directly tested. Therefore, wild-type or PAI-1 knockout (PAI-1(-/-)) mice underwent bile duct ligation. Mice were sacrificed either 3 or 14 days after surgery for assessment of early (i.e., inflammation) and late (i.e., fibrosis) changes caused by bile duct ligation. Liver injury was determined by histopathology and plasma enzymes. Accumulation of extracellular matrix was evaluated by Sirius red staining and by measuring hydroxyproline content. Hepatic expression of PAI-1 was increased approximately 9-fold by bile duct ligation in wild-type mice. Furthermore, early liver injury and inflammation due to bile duct ligation was significantly blunted in PAI-1(-/-) mice in comparison with wild-type mice. Although PAI-1(-/-) mice were significantly protected against the accumulation of extracellular matrix caused by bile duct ligation, increases in expression of indices of stellate cell activation and collagen synthesis caused by bile duct ligation were not attenuated. Protection did, however, correlate with an elevation in hepatic activities of plasminogen activator and matrix metalloprotease activities. In contrast, the increase in tissue inhibitor of metalloproteases-1 protein, a major inhibitor of matrix metalloproteases, caused by bile duct ligation was not altered in PAI-1(-/-) mice compared with the wild-type strain. The increase in hepatic activity of urokinase-type plasminogen activator was also accompanied by more activation of the hepatocyte growth factor receptor c-Met. Taken together, these data suggest that PAI-1 plays a causal role in mediating fibrosis during cholestasis.