Violence Exposure and Trauma Screener for Youth (VETSY).

BACKGROUND: Youth exposed to violence are at serious risk for physical, emotional, behavioral, and mental distress. Reliable and prompt detection is necessary to mitigate the psychological consequences of youth violence exposure and trauma. OBJECTIVE: To describe the initial creation of the VETSY screener and its construct validity and potential use. METHODS: From 2014 through 2022 we surveyed 20,532 at-risk youth aged 8-18 years from a diverse metropolitan community participating in the Defending Childhood Initiative (DCI). Youth completed a 17-item self-report screener. An Exploratory Factor Analysis (EFA) was used to determine the reliability and variable grouping for this brief screener. Violence exposure, violent behaviors, and trauma symptoms were assessed. Responses were evaluated based on youth demographics. A potential cutoff score meriting further assessment and intervention was established. RESULTS: Sixty-seven percent of youth reported at least one type of violence exposure within the last year, 55 % reported perpetrating at least one type of violent behavior, and 68 % of youth reported at least one trauma symptom. An Exploratory Factor Analysis (EFA) with a geomin (oblique) rotation was applied and yielded a three-factor model with high loadings and acceptable fit for violence exposure, violent behaviors, and trauma symptoms. Additional analyses showed the screener structure was the same across sex, race and age groups. CONCLUSIONS: The use of the brief screener to quickly and reliably assess violence exposure, violent behaviors, and trauma symptoms among youth provides an opportunity for mental health providers to detect and refer at-risk youth for additional assessment and treatment.

Sulfatase 2 (SULF2) Monoclonal Antibody 5D5 Suppresses Human Cholangiocarcinoma Xenograft Growth Through Regulation of a SULF2-Platelet-Derived Growth Factor Receptor Beta-Yes-Associated Protein Signaling Axis.

BACKGROUND AND AIMS: Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis. APPROACH AND RESULTS: In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRß)-Yes-associated protein (YAP) signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody, 5D5, in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRß-YAP signaling and tumor growth in the mouse xenograft model. CONCLUSIONS: These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA.

Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach.

Homologous recombination DNA damage repair (HR-DDR) deficient patients with various solid tumors have been treated with PARP inhibitors. However, the clinical characteristics of patients with melanoma who have HR-DDR gene mutations and the consequences of PARP inhibition are poorly understood. We compared the commercially available next-generation sequencing data from 84 patients with melanomas from our institution with a dataset of 1,986 patients as well as 1,088 patients profiled in cBioportal. In total, 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39%, and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in the datasets from Foundation Medicine (Cambridge, CA) and those from the Cancer Genome Atlas. Treatment of HR-DDR‒mutated patient-derived xenograft models of melanoma with PARP inhibitor produced significant antitumor activity in vivo and was associated with increased apoptotic activity. RNA sequencing analysis of PARP inhibitor-treated tumors indicated alterations in the pathways involving extracellular matrix remodeling, cell adhesion, and cell-cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which is more likely to benefit from checkpoint blockade and may be targeted with PARP inhibitor.

Examination of a New Brief Screener to Measure Trauma Symptoms and Violence Exposure Among Young Children.

The purpose of this study was to create a reliable, quick and easy to administer screening measure of violence exposure and trauma for children from infancy through age 7. In a sample of 6,676 children, caregivers completing a 22-item screener reported nearly one out of five youth had been exposed as witness or victim to at least one kind of violence. For trauma, caregivers reported that their children had trouble going to sleep at least sometimes (15.83%), had cried or had a tantrum to exhaustion (15.61%) and had difficulty concentrating or focusing (15.55%). Analyses showed reliable internal consistency for violence exposure (.74) and trauma (.85) scales. Factor analyses revealed a single trauma factor and two violence exposure factors, witnessing and victimization. These data provide support for a brief screening measure for trauma and violence exposure in children from birth through age seven that can be administered by minimally trained staff in public systems and community-based agencies who can then refer children and families to necessary assessment and treatment services.

Evaluation of Treatment and Other Factors That Lead to Drug Court Success, Substance Use Reduction, and Mental Health Symptomatology Reduction Over Time.

Adults presenting with substance use and mental health disorders in the criminal justice system is well documented. While studies have examined drug courts and medication-assisted treatment (MAT), few have examined social and behavioral health indicators, and even fewer have multiple study periods. This study employed a comprehensive approach to studying the MAT contribution to drug court success; reduce substance use, mental health symptoms, and risky behaviors; and the role that violence or trauma plays in mental health symptomatology. Using three time points, our findings indicated that MAT did not play a significant role in the reduction of substance use, risky behaviors, or mental health symptoms or increasing the odds of successful court graduation. However, there was an overall improvement from intake to termination in reduction of substance use, risky behaviors, and mental health symptomatology. Other factors, including social support, may play a role in drug court graduation. Policy implications are discussed.

Grandchildren's Depressive Symptoms and Perceptions of Family Functioning: Protective and Influencing Factors.

A recent increase in children living with grandparents places more children at increased risk for emotional, psychological, or behavioral problems. This study used the Resiliency Model of Family Stress, Adjustment, and Adaptation to examine how children's living situation, parental monitoring, child's resourcefulness, and perceived support affect depressive symptoms and perceived family functioning. Of participants, 36% ( n = 56) lived with their parents only, 44% ( n = 69) lived with a grandmother as their primary caregiver, and 20% ( n = 31) lived in a multigenerational household. Results indicate parental monitoring and support affected perceptions of family functioning. Subjective support and resourcefulness affected depressive symptoms. No effects were found from living situation and demographic factors. Resourcefulness had the strongest effect on depressive symptoms, with a 3-point decrease in symptoms for each incremental increase in resourcefulness. This study provides insight into factors influencing children's depressive symptoms and perceived family functioning, and provides direction for the development of future interventions.

Using Claims Data to Examine Hospital Readmission Risk in Patients With Schizophrenia and Comorbid Marijuana Use Disorders.

OBJECTIVE: Few epidemiologic studies have examined marijuana use disorder and repeated hospitalizations related to schizophrenia. To address this gap, this study examines time to readmission by indicators for recent marijuana use disorder in the presence of alcohol use disorder (AUD) and other drug use disorder. METHOD: Our sample consisted of 4,349 patients with a primary diagnosis of schizophrenia spectrum disorder (SSD) in 2005 in individually linked California Health Care Cost and Utilization Project (CA HCUP) data. Readmissions were assessed from 2005 to 2011. Predictors for readmission were examined using a stratified, recurrent-event, Cox proportional hazards model. Sensitivity analyses were conducted on patients readmitted in 2010 or 2011. RESULTS: We found that having marijuana use disorder or AUD alone within 90 days of initial hospitalization was associated with longer times until first readmission. A lower risk of readmission for those with recent marijuana use disorder persisted through the fifth readmission (hazard ratio [HR] = 0.92, 95% CI [0.85, 0.99]) but was not significant in the sixth or greater readmission nor in sensitivity analyses. SSD patients with recent other drug use disorder had an increased risk for a second to fifth readmission (HR = 1.13, 95% CI [1.06, 1.20]). Those with recent AUD had an increased risk for a sixth or greater readmission (HR = 1.15, 95% CI [1.07, 1.23]). Both of these results remained significant in the sensitivity analysis. CONCLUSIONS: We found that AUD and other drug use disorder increase readmission risk in patients with SSD after a first hospitalization, whereas marijuana use disorder does not appear to be associated with an increased risk for readmission.

An Electronic Health Record-based Intervention to Promote Hepatitis C Virus Testing Among Adults Born Between 1945 and 1965: A Cluster-randomized Trial.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends one-time hepatitis C virus (HCV) antibody testing for "Birth Cohort" adults born during 1945-1965. OBJECTIVE: To examine the impact of an electronic health record (EHR)-embedded best practice alert (BPA) for HCV testing among Birth Cohort adults. DESIGN: Cluster-randomized trial was conducted from April 29, 2013 to March 29, 2014. SUBJECTS AND SETTING: Ten community and hospital-based primary care practices. Participants were attending physicians and medical residents during 25,620 study-eligible visits. INTERVENTION: Physicians in all practices received a brief introduction to the CDC testing recommendations. At visits for eligible patients at intervention sites, physicians received a BPA through the EHR to order HCV testing or medical assistants were prompted to post a testing order for the physician. Physicians in control sites did not receive the BPA. MAIN OUTCOMES: HCV testing; the incidence of HCV antibody positive tests was a secondary outcome. RESULTS: Testing rates were greater among Birth Cohort patients in intervention sites (20.2% vs. 1.8%, P<0.0001) and the odds of testing were greater in intervention sites after controlling for imbalances of patient and visit characteristics between comparison groups [odds ratio (OR), 9.0; 95% confidence interval, 7.6-10.7). The adjusted OR of identifying HCV antibody positive patients was also greater in intervention sites (OR, 2.1; 95% confidence interval, 1.3-11.2). CONCLUSIONS: An EHR-embedded BPA markedly increased HCV testing among Birth Cohort patients, but the majority of eligible patients did not receive testing indicating a need for more effective methods to promote uptake.

Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck.

Sulfatase 2 (SULF2), an extracellular sulfatase that alters sulfation on heparan sulfate proteoglycans, is involved in the tumorigenesis and progression of several carcinomas. SULF2 expression has not been evaluated in squamous cell carcinoma of the head and neck (HNSCC). Here we report results of IHC of SULF2 expression in HNSCC tissue. SULF2 was detected in 57% of tumors (n = 40) with a significant increase in intensity and number of stained cells compared to adjacent cancer-free tissue (p-value < 0.01), increasing with cancer stage when comparing stages 1 and 2 to stages 3 and 4 (p-value 0.01). SULF2 was not detected in epithelial cells of cancer-free controls, and expression was independent of patient demographics, tumor location and etiological factors, smoking and HPV infection by p16 IHC analysis. Sandwich ELISA was performed on serum of HNSCC patients (n = 28) and controls (n = 35), and although SULF2 was detectable, no change was observed in HNSCC. Saliva, collected by mouthwash, from HNSCC patients (n = 8) and controls (n = 8) was also tested by ELISA in a preliminary investigation and an increase in SULF2 was observed in HNSCC (p-value 0.041). Overall, this study shows that SULF2 is increased in HNSCC independent of tissue location (oral cavity, oropharynx, larynx and hypopharynx), patient demographics and etiology. Although no change in SULF2 was detected in HNSCC serum, its detection in saliva makes it worthy of further investigation as a potential HNSCC biomarker.

Violence Exposure and Early Substance Use in High-Risk Adolescents.

This study examines the relationship between violence exposure and early substance use as mediated by trauma symptoms. The Assessment of Liability and Exposure to Substance Use and Antisocial Behavior Scale was used to assess violence exposure at age 10 and substance use by age 12. Mediation analysis indicated direct relationships between violence exposure and tobacco/illegal drug use and indirect relationships between violence exposure and girls' substance use through trauma symptoms. Practitioners should consider violence exposure as a risk factor for early substance use in high-risk youths and potential gender differences in trauma symptom pathways to early substance use.

Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak.

Even under the most expert care, a properly constructed intestinal anastomosis can fail to heal, resulting in leakage of its contents, peritonitis, and sepsis. The cause of anastomotic leak remains unknown, and its incidence has not changed in decades. We demonstrate that the commensal bacterium Enterococcus faecalis contributes to the pathogenesis of anastomotic leak through its capacity to degrade collagen and to activate tissue matrix metalloproteinase 9 (MMP9) in host intestinal tissues. We demonstrate in rats that leaking anastomotic tissues were colonized by E. faecalis strains that showed an increased collagen-degrading activity and also an increased ability to activate host MMP9, both of which contributed to anastomotic leakage. We demonstrate that the E. faecalis genes gelE and sprE were required for E. faecalis-mediated MMP9 activation. Either elimination of E. faecalis strains through direct topical antibiotics applied to rat intestinal tissues or pharmacological suppression of intestinal MMP9 activation prevented anastomotic leak in rats. In contrast, the standard recommended intravenous antibiotics used in patients undergoing colorectal surgery did not eliminate E. faecalis at anastomotic tissues nor did they prevent leak in our rat model. Finally, we show in humans undergoing colon surgery and treated with the standard recommended intravenous antibiotics that their anastomotic tissues still contained E. faecalis and other bacterial strains with collagen-degrading/MMP9-activating activity. We suggest that intestinal microbes with the capacity to produce collagenases and to activate host metalloproteinase MMP9 may break down collagen in the intestinal tissue contributing to anastomotic leak.

SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis.

BACKGROUND: SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. METHODS: We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. RESULTS: SULF2 was higher in cirrhosis patients (1460 ± 1160 pg/ml, N=34) than in healthy individuals (728 ± 400 pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups. CONCLUSIONS: SULF2 may be a useful serologic biomarker for liver cirrhosis.

The safety of and indications for immediate reconstruction of head and neck melanoma defects: our early experience.

Melanoma excision requires wide margins, leaving large defects. Surgical dogma has taught that definitive reconstruction of melanoma defects be performed after permanent pathology results, with skin grafts favored. However, this results in an open wound and the need for a second operation. The advantages of immediate reconstruction with flaps are single-stage surgery, high patient satisfaction, no period of disfigurement, and cost savings. Our purpose was to evaluate rate of positive margins and local recurrence after immediate reconstruction of head and neck melanoma (HNM) defects with flaps to determine safety of this approach. We prospectively followed all patients with HNM treated at a single center from January 2010 to June 2012 and collected patient and tumor data and reconstruction type. Outcomes assessed were permanent pathology margins and local recurrence rate. Risk factors for positive margins were assessed. Seventy-six patients with HNM were treated with wide excision and immediate flap reconstruction with a mean age of 59 years. Five patients had melanoma in situ and 71 had invasive melanoma. There was a 15.4% ulceration rate. Median thickness for invasive melanoma was 2.2 mm. Mean excision margin was 1.4 cm. Median follow-up was 2 years; 5.3% of patients had positive margins on permanent pathology after reconstruction and 3 were reexcised with negative margins. Local recurrence rate was 2.6% with no recurrence in patients with previous reexcised positive margins. Significant risk factors for positive margins were melanoma in situ excised with 5-mm margins (P=0.012) and desmoplastic melanoma (P<0.02). Immediate flap reconstruction after excision of HNM can be safely performed with low positive margin and local recurrence rates. This should be offered to patients, especially those with primary melanomas with distinct borders and excision margins greater than or equal to 1 cm.

Galactose 6-O-sulfotransferases are not required for the generation of Siglec-F ligands in leukocytes or lung tissue.

Eosinophil accumulation is a characteristic feature of the immune response to parasitic worms and allergens. The cell surface carbohydrate-binding receptor Siglec-F is highly expressed on eosinophils and negatively regulates their accumulation during inflammation. Although endogenous ligands for Siglec-F have yet to be biochemically defined, binding studies using glycan arrays have implicated galactose 6-O-sulfate (Gal6S) as a partial recognition determinant for this receptor. Only two sulfotransferases are known to generate Gal6S, namely keratan sulfate galactose 6-O-sulfotransferase (KSGal6ST) and chondroitin 6-O-sulfotransferase 1 (C6ST-1). Here we use mice deficient in both KSGal6ST and C6ST-1 to determine whether these sulfotransferases are required for the generation of endogenous Siglec-F ligands. First, we characterize ligand expression on leukocyte populations and find that ligands are predominantly expressed on cell types also expressing Siglec-F, namely eosinophils, neutrophils, and alveolar macrophages. We also detect Siglec-F ligand activity in bronchoalveolar lavage fluid fractions containing polymeric secreted mucins, including MUC5B. Consistent with these observations, ligands in the lung increase dramatically during infection with the parasitic nematode, Nippostrongylus brasiliensis, which is known to induce eosinophil accumulation and mucus production. Surprisingly, Gal6S is undetectable in sialylated glycans from eosinophils and BAL fluid analyzed by mass spectrometry. Furthermore, none of the ligands we describe are diminished in mice lacking KSGal6ST and C6ST-1, indicating that neither of the known galactose 6-O-sulfotransferases is required for ligand synthesis. These results establish that ligands for Siglec-F are present on several cell types that are relevant during allergic lung inflammation and argue against the widely held view that Gal6S is critical for glycan recognition by this receptor.

Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome?

BACKGROUND: Previous studies showed conflicting and inconsistent results regarding the effect of anatomic location of the melanoma on sentinel lymph node (SLN) positivity and/or survival. This study was conducted to evaluate and compare the effect of the anatomic locations of primary melanoma on long-term clinical outcomes. METHODS: All consecutive cutaneous melanoma patients (n=2,079) who underwent selective SLN dissection (SLND) from 1993 to 2009 in a single academic tertiary-care medical center were included. SLN positive rate, disease-free survival (DFS), and overall survival (OS) were determined. Kaplan-Meier survival, univariate, and multivariate analyses were performed to determine predictive factors for SLN status, DFS, and OS. RESULTS: Head and neck melanoma (HNM) had the lowest SLN-positive rate at 10.8% (16.8% for extremity and 19.3% for trunk; P=0.002) but had the worst 5-year DFS (P<0.0001) and 5-year OS (P<0.0001) compared with other sites. Tumor thickness (P<0.001), ulceration (P<0.001), HNM location (P=0.001), mitotic rate (P<0.001), and decreasing age (P<0.001) were independent predictive factors for SLN-positivity. HNM with T3 or T4 thickness had significantly lower SLN positive rate compared with other locations (P≤0.05). Also, on multivariate analysis, HNM location versus other anatomic sites was independently predictive of decreased DFS and OS (P<0.001). By Kaplan-Meier analysis, HNM was associated significantly with the worst DFS and OS. CONCLUSIONS: Primary melanoma anatomic location is an independent predictor of SLN status and survival. Although HNM has a decreased SLN-positivity rate, it shows a significantly increased risk of recurrence and death as compared with other sites.

Long-term prognosis and significance of the sentinel lymph node in head and neck melanoma.

OBJECTIVE: To report the long-term significance of sentinel lymph node (SLN) biopsy on prognosis, determine false-negative SLN occurrences, and determine risk factors for death and recurrence in a large series of patients with head and neck melanoma. STUDY DESIGN: Case series with tumor registry review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: A database review was performed of all patients who underwent SLN biopsy for head and neck melanoma from 1994 to 2009. End points assessed were SLN status, recurrence, false-negative SLN results, and survival comparing SLN-positive and SLN-negative patients and different locations. Survival curves and multivariate analyses were performed. RESULTS: SLN biopsy was performed in 365 patients. SLNs were identified in 98.6% of patients with a mean of 3.7 nodes removed from 1.6 nodal basins per patient. Median follow-up was 8 years. The SLN was positive in 40 (11%) patients. SLN-positive patients had significantly thicker melanomas, higher recurrence (P < .0001), and a significant decrease in overall survival compared with SLN-negative patients (P < .002). Scalp melanoma patients had significantly thicker melanomas and an elevated risk of SLN positivity, recurrence, and death compared with other sites. Seventeen of 365 SLN-negative patients developed regional nodal disease for a false-omission rate of 5.2% and a negative predictive value of a negative SLN to be 94.8%. Risks for false negative-SLN occurrences included thick melanomas and scalp melanomas. CONCLUSION: SLN biopsy is accurate in head and neck melanoma and provides significant prognostic data. Scalp melanoma patients present with thicker tumors with an increase in SLN positivity and false-negative SLN occurrences.

Contributing factors to aggressive behaviors in high school students in Turkey.

Violence among young people is an important public health topic as a universal problem. One of the recent issues concerning both the media and parents is the aggressive behavior among the high school students in Istanbul and the worldwide. The aim of this study was to investigate the types and rates of aggressive behavior and the contributing factors to this behavior among high school students. Sample was composed of 805 students of 14-18 ages attending five high schools in Istanbul. The most common aggressive behavior among the students was found to be "beating others," 34.5% (n = 278). Past experiences of violence of high school students (direct exposure to violence/witnessing violence/exposure to/witnessing attack with knife/gun) were determined as the most contributing factor to aggressive behavior. The present study investigated the nature of violent behaviors and associations between violent behaviors and contributing factors among high school students from Turkey.