Glioblastoma vulnerability to neddylation inhibition is dependent on PTEN status, and dysregulation of the cell cycle and DNA replication.

Background: Neddylation (NAE) inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report the cytotoxic vulnerability to NAE inhibitors in a subset of glioblastoma (GBM) preclinical models and identify genetic alterations and biological processes underlying differential response. Methods: GBM DNA sequencing and transcriptomic data were queried for genes associated with response to NAE inhibition; candidates were validated by molecular techniques. Multi-omics and functional assays revealed processes implicated in NAE inhibition response. Results: Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and DNA repair pathways as significant differentiators between sensitive and resistant models. Vulnerability to MLN4924, a NAE inhibitor, is associated with elevated S-phase populations, DNA re-replication, and DNA damage. In a panel of GBM models, loss of WT PTEN is associated with resistance to different NAE inhibitors. A NAE inhibition response gene set could segregate the GBM cell lines that are most resistant to MLN4924. Conclusions: Loss of WT PTEN is associated with non-sensitivity to 3 different compounds that inhibit NAE in GBM. A NAE inhibition response gene set largely consisting of DNA replication genes could segregate GBM cell lines most resistant to NAEi and may be the basis for future development of NAE inhibition signatures of vulnerability and clinical trial enrollment within a precision medicine paradigm.

Incidence and Medical Hospitalization Rates of Patients With Pediatric Eating Disorders.

Objective Eating disorders typically onset in preadolescence and adolescence and cause negative mental and physical health sequelae over the life span. This study examined the incidence and medical hospitalization rates of pediatric eating disorders in an integrated health system in the United States. Methods This retrospective cohort study examined 4883 Kaiser Permanente Northern California members 8-18 years of age with an eating disorder diagnosis from January 2015 to June 2019. Medical hospitalizations include admissions at any of the 13 Kaiser Permanente Northern California hospitals with a primary or secondary eating disorder diagnosis. Results Incidence rates ranged between 177 and 205 per 100,000 adolescents per year. More than half the adolescents were non-White: 10.8% Asian, 4.3% Black, 26.7% Hispanic/Latinx, 8.4% multiracial, 0.3% Native American/Alaskan Native, and 0.5% Native Hawaiian/Pacific Islander. Thirteen percent had a body mass index (BMI) below the 5th percentile, 61.8% had a BMI between the 5th and the 84th percentiles, 19.7% had a BMI above the 85th percentile, and 5.6% had an unknown BMI. During the 12-month follow-up period, 5.4% of adolescents had medical hospitalizations. Conclusions This study adds to the evidence that eating disorders affect children/adolescents across all weight/BMI ranges and racial/ethnic backgrounds. Future studies call for exploration on treatment strategies that tailor to the diverse populations.

Young Adult Substance Use and Healthcare Use Associated With Screening, Brief Intervention and Referral to Treatment in Pediatric Primary Care.

PURPOSE: Screening, brief intervention, and referral to treatment (SBIRT) may impact future comorbidity and healthcare utilization among adolescents screening positive for substance use or mood problems. METHODS: In a randomized trial sample, we compared an SBIRT group to usual care for substance use, mental health, medical diagnoses, and healthcare utilization over 7 years postscreening. RESULTS: In logistic regression models adjusting for patient characteristics, the SBIRT group had lower odds of any substance (Odds Ratio[OR] = 0.80, 95% Confidence Interval [CI] = 0.66-.98), alcohol (OR = 0.69, 95% CI = 0.51-0.94), any drug (OR = 0.73, 95% CI = 0.54-0.98), marijuana (OR = 0.70, 95% CI = 0.50-0.98), and tobacco (OR = 0.83, 95% CI = 0.69-1.00) diagnoses, and lower odds of any inpatient hospitalizations (OR = 0.59, 95% CI = 0.41-0.85) compared with usual care. Negative binomial models examining number of visits among adolescents with at least one visit of that type found that those in the SBIRT group had fewer primary care (incidence rate ratio[iRR] = 0.90, p < .05) and psychiatry (iRR = 0.64, p < .01) and more addiction medicine (iRR = 1.52, p < .01) visits over 7 years compared with usual care. In posthoc analyses, we found that among Hispanic patients, those in the SBIRT group had lower odds of any substance, any drug and marijuana use disorder diagnoses compared with usual care, and among Black/African American patients, those in the SBIRT group had lower odds of alcohol use disorder diagnoses compared with usual care. DISCUSSION: Beneficial effects of adolescent SBIRT on substance use and healthcare utilization may persist into young adulthood.

PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.

BACKGROUND: Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response. METHODS: GBM sequencing data were queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response. RESULTS: Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic. CONCLUSIONS: We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.

Screening for Gender Identity in Adolescent Well Visits: Is It Feasible and Acceptable?

PURPOSE: This study aimed to pilot systematic gender identity screening during adolescent well checks and examine perceptions of feasibility and acceptability of screening from adolescents, parents/guardians, and clinicians. METHODS: Adolescents aged 12-18 years with a well visit between July 1, 2018, and June 30, 2019 (n = 134,114; 817 pilot and 133,297 usual care) in Kaiser Permanente Northern California (KPNC) pediatric primary care clinics. "What is your gender?" was added to the previsit questionnaire in pilot clinics; all other KPNC clinics provided usual care. Additional anonymous surveys were administered to adolescents and parents/guardians in the pilot clinics and to all KPNC pediatric clinicians. Multivariable logistic regression examined associations between clinics and patients reporting as transgender and gender diverse (TGD). Descriptive statistics summarized patient, parent/guardian, and clinician perceptions of gender identity screening. RESULTS: Adjusting for age and race/ethnicity, adolescents had higher odds of reporting as TGD in pilot clinics than in usual care (odds ratio = 6.91, 95% confidence interval = 3.76-12.74). Two thirds of adolescents, 75.5% of parents/guardians, and 92.5% of clinicians felt it was important to screen for gender identity in primary care. Less than 2% of adolescents found the question confusing, offensive, or uncomfortable, and 2.8% of parents/guardians felt it was offensive. In addition, 36.4% of clinicians and 3.6% of parents/guardians were concerned it would affect visit workflow/time. CONCLUSIONS: Most adolescents, parents/guardians, and pediatric clinicians viewed systematic gender identity screening as both feasible and acceptable. Standardized gender identity screening during adolescent well checks could facilitate and increase identification of TGD adolescents and the delivery of gender-affirming care for adolescents and families in need.

Three-Year Outcomes After Brief Treatment of Substance Use and Mood Symptoms.

BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT) for adolescents exhibiting co-occurring substance use and mental health problems may improve outcomes and have long-lasting effects. This study examined the relationship between access to SBIRT and substance use, depression and medical diagnoses, and health services use at 1 and 3 years postscreening for such adolescents. METHODS: The study draws from a cluster-randomized trial comparing SBIRT to usual care (UC) for adolescents endorsing past-year substance use and recent mood symptoms during visits to a general pediatrics clinic between November 1, 2011, and October 31, 2013, in a large, integrated health system (N = 1851); this sample examined the subset of adolescents endorsing both problems (n = 289). Outcomes included depression, substance use and medical diagnoses, and emergency department and outpatient visits 1 and 3 years later. RESULTS: The SBIRT group had lower odds of depression diagnoses at 1 (odds ratio [OR] = 0.31; confidence interval [CI] = 0.11-0.87) and 3 years (OR = 0.51; CI = 0.28-0.94) compared with the UC group. At 3 years, the SBIRT group had lower odds of a substance use diagnosis (OR = 0.46; CI = 0.23-0.92), and fewer emergency department visits (rate ratio = 0.65; CI = 0.44-0.97) than UC group. CONCLUSIONS: The findings suggest that SBIRT may prevent health complications and avert costly services use among adolescents with both mental health and substance use problems. As SBIRT is implemented widely in pediatric primary care, training pediatricians to discuss substance use and mental health problems can translate to positive outcomes for these vulnerable adolescents.

Health Care Use Over 3 Years After Adolescent SBIRT.

BACKGROUND: Most studies on adolescent screening, brief intervention, and referral to treatment (SBIRT) have examined substance use outcomes. However, it may also impact service use and comorbidity-an understudied topic. We address this gap by examining effects of SBIRT on health care use and comorbidities. METHODS: In a randomized trial sample, we assessed 3 SBIRT care modalities: (1) pediatrician-delivered, (2) behavioral clinician-delivered, and (3) usual. Medical comorbidity and health care use were compared between a brief-intervention group with access to SBIRT for behavioral health (combined pediatrician and behavioral clinician arms) and a group without (usual care) over 1 and 3 years. RESULTS: Among a sample of eligible adolescents (n = 1871), the SBIRT group had fewer psychiatry visits at 1 year (incidence rate ratio [iRR] = 0.76; P = .05) and 3 years (iRR = 0.65; P < .05). Total outpatient visits did not differ in year 1. The SBIRT group was less likely to have mental health diagnoses (odds ratio [OR] = 0.69; 95% confidence interval [CI] = 0.48-1.01) or chronic conditions (OR = 0.66; 95% CI = 0.45-0.98) at 1 year compared with those in usual care. At 3 years, the SBIRT group had fewer total outpatient visits (iRR = 0.85; P < .05) and was less likely to have substance use diagnoses (OR = 0.64; 95% CI = 0.45-0.91) and more likely to have substance use treatment visits (iRR = 2.04; P < .01). CONCLUSIONS: Providing SBIRT in pediatric primary care may improve health care use and health, mental health, and substance use outcomes. We recommend further exploring the effects of SBIRT on these outcomes.

Pediatric mandibular metastasis: A rare finding of neuroblastoma.

We present a case of metastatic neuroblastoma to the mandible in an 11-month-old patient presenting with worsening right-sided proptosis and scalp swelling after a fall 2 weeks prior. Initial evaluation with computed tomography of the head demonstrated soft tissue masses centered at the right sphenoid and right mandible. These masses proved to be metastatic lesions from an intra-abdominal neuroblastoma. Review of the literature revealed 20 cases of neuroblastoma metastasis to the mandible over the past 70 years. To our knowledge, our patient is the youngest reported case with asymptomatic mandibular metastasis related to neuroblastoma and the first to be characterized with magnetic resonance imaging.

Underdiagnosis of Influenza Virus Infection in Hospitalized Older Adults.

OBJECTIVES: To describe factors associated with provider-ordered influenza testing in hospitalized older adults. DESIGN: Information on participant demographics, symptoms, and provider-ordered influenza testing were collected by questionnaire and chart review. We conducted prospective laboratory-based surveillance using reverse-transcriptase polymerase chain reaction (RT-PCR), the criterion standard for diagnosis of influenza, to determine how participant characteristics and provider-ordered testing affected accurate influenza diagnosis. SETTING: One academic and three community hospitals in Davidson County, Tennessee. PARTICIPANTS: Adults aged 18 and older with acute respiratory illness or nonlocalizing fever (N=1,422). MEASUREMENTS: We compared characteristics of participants with and without provider-ordered testing for influenza using the Wilcoxon test and Pearson chi-square test. Multivariable logistic regression models were used to identify factors predictive of provider-ordered influenza testing. RESULTS: Twenty-eight percent (399/1,422) of participants had provider-ordered influenza testing. Participants who were tested were younger than those not tested (58 ± 18 vs 66 ± 15, p<.001) and more likely to have influenza-like illness (ILI) (71% vs 49%, p<.001). ILI decreased with increasing age (aged 18-49, 63%; aged 50-64, 60%; aged ≥65, 48%). ILI and younger age were independent predictors of provider-ordered testing. Of the 136 participants with influenza confirmed using RT-PCR, ILI was the only significant predictor of provider-ordered testing (adjusted odds ratio=3.43, 95% confidence interval=1.22-9.70). CONCLUSION: Adults aged 65 and older hospitalized with fever or respiratory symptoms during influenza season are less likely to undergo a provider-ordered influenza test than younger adults. Some, but not all, of this disparity is due to a lower likelihood of ILI. Further strategies are needed to increase clinician awareness and testing in this vulnerable group.

Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells.

The survival of patients diagnosed with glioblastoma (GBM), the most deadly form of brain cancer, is compromised by the proclivity for local invasion into the surrounding normal brain, which prevents complete surgical resection and contributes to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. To discover small molecule inhibitors that disrupt the TWEAK-Fn14 signaling axis, we utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-κB-driven firefly luciferase reporter protein. Focusing on the LOPAC1280 library of 1280 pharmacologically active compounds, we identified aurintricarboxylic acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-κB dependent signaling, but not TNFα-TNFR-NF-κB driven signaling. We demonstrated that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both the chemotherapeutic agent temozolomide (TMZ) and radiation-induced cell death. In summary, this work reports a repurposed use of a small molecule inhibitor that targets the TWEAK-Fn14 signaling axis, which could potentially be developed as a new therapeutic agent for treatment of GBM patients.

A Case of Disulfiram-Induced Psychosis in a Previously Asymptomatic Patient Maintained on Mixed Amphetamine Salts: A Review of the Literature and Possible Pathophysiological Explanations.

Although perhaps better known as an irreversible aldehyde dehydrogenase inhibitor causing increased acetaldehyde levels after concomitant intake of ethanol, disulfiram or one of its metabolites (diethyldithiocarbamate) also inhibit dopamine ß-hydroxylase, an enzyme that converts dopamine to norepinephrine. This mechanism has been advanced as a possible explanation for the development of psychosis, during disulfiram treatment, either in monotherapy or in combination therapy, when interaction-emergent psychosis could be causal. We present a young woman who was taking mixed amphetamine salts for treatment of attention-deficit/hyperactivity disorder and developed a short-lived psychosis after introduction of disulfiram. The psychotic symptoms resolved after discontinuation of both medications, without the use of antipsychotic drugs. We proceed with a review of the literature of disulfiram-induced psychosis and discuss pathophysiological theories that possibly were involved in our patient's phenomenology.

Opiate Injection-associated Infective Endocarditis in the Southeastern United States.

BACKGROUND: Opiate pain reliever (OPR) misuse by injection is increasing in the United States. Infective endocarditis (IE), a devastating complication of injection OPR use, has been understudied. METHODS: We conducted a retrospective chart review of IE cases at an academic tertiary care hospital in North Carolina. Hospital admissions from 2009-2014 were screened for cases of definite IE. Subjects reporting injection drug use (IDU) were classified as IDU-IE, and compared to those without reported IDU, classified as No IDU-IE. Rates of IDU-IE and No IDU-IE, patient demographics, microbiologic data and outcomes were compared between the groups. RESULTS: A total of 127 incident admissions for IE were identified, 48 (37.8%) were classified as IDU-IE and 79 (62.2%) as No IDU-IE. IDU-IE cases increased from 14% of hospitalizations for IE in 2009 to 56% in 2014; reporting of OPR injection increased in 2012 and continued through the study period. IDU-IE subjects were younger (32.6 ± 11.7 versus 54.4 ± 13.1, P < 0.0001), more likely to be single (n = 33 [68.8%] versus n = 23 [29.1%], P < 0.0001) and to reside in rural communities (n = 36 [75.0%] versus n = 25 [31.6%], P < 0.0001) than No IDU-IE subjects. Hospital length of stay (26 days versus 12 days, P < 0.0001) and intensive care unit length of stay (2 days versus 1 day, P = 0.04) were longer for IDU-IE patients and hospital mortality did not differ (10.4% IDU-IE versus 8.9% No IDU-IE, P = 0.77). CONCLUSIONS: IDU-IE rates increased over time, and OPR injection use in rural communities appears to be a major contributor. Interventions to reduce IDU-IE and OPR misuse are needed to halt this growing epidemic in at-risk rural communities.

Severe pulmonary arterial hypertensive rats are tolerant to mild exercise.

A frequently used end point of clinical outcomes in patients with pulmonary arterial hypertension (PAH) is the 6-minute walk distance. Furthermore, some data suggest that mild to moderate exercise as an intervention in stable PAH is beneficial. Some of these questions have been recapitulated in the monocrotaline and hypoxia animal models of pulmonary hypertension. However, mild exercise and walk distance as end points have not been rigorously examined in the severe progressive Sugen 5416/hypoxia/normoxia (Su/Hx/Nx) animal model of PAH at each stage of worsening disease. Our hypothesis was that animals that were preselected as runners would have increased walk times and improved right ventricle/left ventricle plus septum (RV/LV+S) ratios, echocardiography, and histology compared with nonexercised Su/Hx/Nx animals. We examined four groups of rats: Su/Hx/Nx sedentary, Su/Hx/Nx exercised, control sedentary, and control exercised. Echocardiography was performed at 5, 8, and 13 weeks to assess right ventricular inner diameter in diastole and left ventricular eccentricity index. We found no difference between exercised and sedentary Su/Hx/Nx rats, and both were worsened compared with controls. Rats were euthanized at 13 weeks, and we found that neither RV/LV+S nor the occurrence of occlusive lesions were influenced by exercise. Most interesting, however, was that despite progressive PAH development, exercised Su/Hx/Nx rats showed no decrease in time or distance for treadmill exercise. In all, our data suggest that, despite severe PAH development, Su/Hx/Nx rats retain the same treadmill exercise capacity as control animals.

Administration of a selective ß2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease.

Currently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-ß (Aß) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The ß2 adrenergic receptors (ß2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent ß-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective ß2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Aß levels and Aß plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of ß2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between ß2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of ß blockers on AD.

Parental acceptability of contraceptive methods offered to their teen during a confidential health care visit.

PURPOSE: To examine parental acceptability of contraceptive methods offered confidentially to their adolescent daughter. METHODS: A random sample of 261 parents/guardians with a daughter aged 12-17 years completed a telephone survey examining the relationship between parental acceptability of seven contraceptive methods and adolescents' likelihood to have sex, parenting beliefs, parents' sexual health as teens, sexually transmitted infection knowledge, and demographic factors. RESULTS: Acceptability was highest for oral contraceptive pills (59%) and lowest for intrauterine device (18%). Parental acceptance of teens' autonomy was significantly associated with increased acceptability of all methods. Parental knowledge of sexually transmitted infections was poor, and 51% found it acceptable for clinicians to provide their sexually active teen with condoms. CONCLUSIONS: Parents were more accepting of oral contraceptive pills and condoms compared with intrauterine devices and implants. Parental recognition of their teen's autonomy was associated with greater parental acceptability of clinicians providing their adolescent with contraceptives (regardless of the specific type of method being offered).

Adolescent contraception: review and guidance for pediatric clinicians.

The objectives of this article are to review current contraceptive methods available to adolescents and to provide information, guidance, and encouragement to pediatric clinicians to enable them to engage in informed up-to-date interactions with their sexually active adolescent patients. Pregnancy prevention is a complex and dynamic process, and young people benefit from having a reliable authoritative source for information, counseling, and support. Clinicians who provide services for adolescents have a responsibility to develop their skills and knowledge base so that they can serve as that source. This review begins with a discussion about adolescent sexuality and pregnancy in the context of the adolescent developmental stages. We discuss approaches to introduce the topic of contraception during the clinic visit and contraceptive counseling techniques to assist with the discussion around this topic. In addition, information is included regarding confidential services, support of parental involvement, and the importance of male involvement in contraception. The specific contraceptive methods are reviewed in detail with the adolescent patient in mind. For each method, we discuss the mechanism of action, efficacy, contraindications, benefits and risks from the medical perspective, advantages and disadvantages from the patient's perspective, side effects, patient adherence, patient counseling, and any medication interactions. Furthermore, we have included a section that focuses on the contraceptive management for the adolescent patient with a disability and/or chronic illness. The article concludes with an approach to frequently asked or difficult questions. This section largely summarizes subsections on specific contraceptive methods and can be used as a quick reference on particularly challenging topics. Finally, a list of useful contraceptive management resources is provided for both clinicians and patients.