COVID-19 Vaccine Response in People with Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS). METHODS: Four hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. RESULTS: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01-0.06, p < 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01-0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses. INTERPRETATION: Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 20219999:n/a-n/a.

In Vivo Tumorigenesis, Osteolytic Sarcomas, and Tumorigenic Cell Lines from Transgenic Mice Expressing the Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Viral Oncogene.

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia, a disease commonly associated with hypercalcemia and osteolysis. There is no effective treatment for HTLV-1, and the osteolytic mechanisms are not fully understood. Mice expressing the HTLV-1 oncogene Tax, driven by the human granzyme B promoter (Tax+), develop osteolytic tumors. To investigate the progression of the bone-invasive malignancies, wild-type, Tax+, and Tax+/interferon-γ-/- mice were assessed using necropsy, histologic examination, IHC analysis, flow cytometry, and advanced imaging. Tax+ and Tax+/interferon-γ-/- malignancies of the ear, tail, and foot comprised poorly differentiated, round to spindle-shaped cells with prominent neutrophilic infiltrates. Tail tumors originated from muscle, nerve, and/or tendon sheaths, with frequent invasion into adjacent bone. F4/80+ and anti-mouse CD11b (Mac-1)+ histiocytic cells predominated within the tumors. Three Tax+/interferon-γ-/- cell lines were generated for in vivo allografts, in vitro gene expression and bone resorption assays. Two cell lines were of monocyte/macrophage origin, and tumors formed in vivo in all three. Differences in Pthrp, Il6, Il1a, Il1b, and Csf3 expression in vitro were correlated with differences in in vivo plasma calcium levels, tumor growth, metastasis, and neutrophilic inflammation. Tax+ mouse tumors were classified as bone-invasive histiocytic sarcomas. The cell lines are ideal for further examination of the role of HTLV-1 Tax in osteolytic tumor formation and the development of hypercalcemia and tumor-associated inflammation.

Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation.

Recently, we described a family of non-targeting monomethylauristatin E (MMAE) antibody-drug conjugates (ADCs) whose pharmacokinetics could be tuned through incorporation of a short polyethylene glycol (PEG) moiety of up to twelve units into a drug-linker to render the ADC surface more hydrophilic. That work demonstrated that more hydrophilic ADCs were simultaneously more effective and better tolerated in mouse models, suggesting an improvement in therapeutic index via this strategy. Here, we describe the biodistribution and toxicology assessments in Sprague-Dawley rats after intravenous dosing with the aim of elucidating the relationships between these biological outcomes and the underlying physicochemical properties of non-targeted ADCs. Dosing a non-PEGylated ADC exhibited rapid nonspecific cellular uptake, leading to ADC catabolism and rapid release of the cytotoxic payload which reached peak plasma and tissue concentrations within the first day. Introduction of a PEG chain of four, eight, or twelve units resulted in increasingly slower uptake and decreases in peak payload concentrations in all tissues. These ADCs with minimal non-specific uptake also exhibited substantially less hematologic toxicity, with reduced histologic depletion of bone marrow and less dramatic decreases and/or more rapid recovery in peripheral hematologic cell counts (neutrophils, platelets, and reticulocytes). These results support a strong correlation between ADC hydrophobicity, rate of non-specific uptake, peak tissue concentration of released payload, and resulting toxicology parameters. Should these correlations be translatable to the clinic, this would provide a more general and highly tractable strategy for reducing the antigen-independent toxicity of ADCs through drug-linker design to modulate non-specific biodistribution.

Quality of life and burden in caregivers of youth with obsessive-compulsive disorder presenting for intensive treatment.

BACKGROUND: Pediatric obsessive-compulsive disorder (OCD) is associated with deleterious familial effects; caregivers are often enmeshed in the disorder and can experience considerable burden and decreased quality of life (QoL). Consequently, this study examined burden and QoL in caregivers of youth with OCD enrolled in an intensive outpatient or partial hospitalization program. METHOD: The relationships between caregiver QoL and burden and the following variables were investigated: OCD symptom severity, functioning (youth functional impairment, general family functioning), family (family accommodation, parental relationship satisfaction, positive aspects of caregiving), and comorbid psychopathology (caregiver anxiety and depressive symptoms, youth internalizing and externalizing behaviors). Seventy-two child and caregiver dyads completed clinician- and self-rated questionnaires. RESULTS: Components of caregiver QoL correlated with caregiver-rated functional impairment, family accommodation, youth externalizing behaviors, and caregiver psychopathology. Aspects of caregiver burden correlated with child OCD symptom severity, functional impairment related to OCD, as well as caregiver and child comorbid psychopathology. Caregiver depressive symptoms predicted caregiver QoL, and caregiver depressive symptoms and child externalizing symptoms both predicted caregiver burden. Caregiver burden did not mediate the relationship between obsessive-compulsive symptom severity and caregiver QoL. CONCLUSION: Ultimately, elucidating factors associated with increased caregiver burden and poorer QoL is pertinent for identifying at-risk families and developing targeted interventions.

Social Rejection and Alcohol Use in Daily Life.

BACKGROUND: Prior studies have found that social rejection is associated with increases in negative affect, distress, and hostility. Fewer studies, however, have examined the impact of social rejection on alcohol use, and no known studies have tested whether the impact of social rejection by close others differs from social rejection by acquaintances in its association with subsequent drinking. METHODS: Participants completed event-contingent reports of their social interactions and alcohol use for 14 consecutive days on smartphones. Multilevel negative binomial regression models tested whether experiencing more social rejection than usual was associated with increased drinking, and whether this association was stronger when participants were rejected by close others (e.g., friends, spouses, family members) versus strangers or acquaintances. RESULTS: Results showed a significant interaction between social rejection and relationship closeness. On days characterized by rejection by close others, the likelihood of drinking significantly increased. On days characterized by rejection by acquaintances, by contrast, there was no increase in the likelihood of drinking. There was no main effect of rejection on likelihood of drinking. CONCLUSIONS: These results suggest that relationship type is a key factor in whether social rejection translates to potentially harmful behaviors, such as increased alcohol use. This finding is in contrast to many laboratory paradigms of rejection, which emphasize rejection and ostracism by strangers rather than known others. In the more naturalistic setting of measuring social interactions on smartphone in daily life, our findings suggest that only social rejection delivered by close others, and not strangers, led to subsequent drinking.

Gambling Outcome Expectancies and Gambling Behavior Among African-American Adolescents: Gender as a Moderating Variable.

Most high school adolescents have reported past year gambling, and males gamble more frequently and problematically than females. Ethnic minority adolescents appear to be gambling at a higher rate than Caucasian adolescents. There is evidence indicating that adolescent gambling outcome expectancies are correlated with gambling behavior, but limited evidence that this relation differs by gender. In the present study gender was evaluated as a moderator in the relation between gambling outcome expectancies and gambling behaviors in an African-American high school sample. Males gambled more frequently, gambled more problematically and held more positive gambling outcome expectancies than females. Gender was found to moderate the relations between gambling frequency and the expectations of material gain, affect, self-evaluation and parental approval. Gender also moderated the relations between gambling problems and expectations of affect and self-evaluation. These findings should inform future adolescent gambling prevention and intervention programs.

Medical and sociodemographic factors associated with human papillomavirus (HPV) vaccination adherence among female survivors of childhood cancer.

BACKGROUND: Among those 9-26 years of age, vaccination can prevent specific types of genital human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical and other cancers. The objective of this study was to estimate the prevalence of and factors associated with HPV vaccine initiation and completion among females surviving childhood cancer. PROCEDURE: One-hundred fourteen young adults and 230 mothers with daughters surviving childhood cancer completed surveys querying HPV vaccination history along with medical and sociodemographic factors potentially associated with vaccination outcomes. Vaccination rate differences by age necessitated analysis of outcomes by age group: 9-13 years (preadolescents), 14-17 years (adolescents), and 18-26 years (young adults). Multivariable logistic regression was utilized to identify factors associated with HPV vaccination outcomes. RESULTS: Overall, 34.6% (119/344) of survivors initiated and 20.9% (72/344) completed HPV vaccination. Preadolescents were least likely to have initiated vaccination (P < 0.001). Physician recommendation was associated with initiation across age groups (OR = 6.81-11.96, Ps < 0.001-.01), whereas older age at diagnosis (≥12 years of age) was associated with lower vaccination initiation among young adults only (OR = 0.28; 95%CI, 0.10-0.76, P = 0.012). Physician recommendation (OR = 7.54; 95%CI, 1.19-47.69, P = 0.032; adolescent group) and greater treatment intensity (OR = 5.25; 95%CI, 1.00-27.61, P = 0.050; young adult group) were associated with vaccine completion, whereas being non-White was associated with decreased vaccination completion (OR = 0.17; 95%CI, 0.05-0.66, P = 0.010; adolescent group). CONCLUSIONS: A minority of youths surviving childhood cancer have initiated or completed HPV vaccination. Strategies to increase vaccination among survivors are discussed.

Fertility as a priority among at-risk adolescent males newly diagnosed with cancer and their parents.

PURPOSE: Infertility is a frequent consequence of cancer therapy and is often associated with psychological distress. Although adult survivors prioritize fertility and parenthood, this issue remains unexplored among adolescent males. This study examined future fertility as a priority (relative to other life goals) at time of diagnosis for at-risk adolescents and their parents. METHODS: Newly diagnosed adolescent males (n = 96; age = 13.0-21.9 years) at increased risk for infertility secondary to cancer treatment prioritized eight life goals: to have school/work success, children, friends, wealth, health, a nice home, faith, and a romantic relationship. Patients' parents (fathers, n = 30; mothers, n = 61) rank-ordered the same priorities for their children. RESULTS: "Having children" was ranked as a "top 3" life goal among 43.8 % of adolescents, 36.7 % of fathers, and 21.3 % of mothers. Fertility ranked third among adolescents, fourth among fathers, and fifth among mothers. Future health was ranked the top priority across groups, distinct from all other goals (ps < 0.001), and fertility ranked higher than home ownership and wealth for all groups (ps < 0.001). For adolescents, low/moderate fertility risk perception was associated with higher fertility rankings than no/high risk perceptions (p = 0.01). CONCLUSIONS: Good health is the most important life goal among adolescents newly diagnosed with cancer and their parents. In this relatively small sample, adolescents prioritized fertility as a top goal, parents also rated fertility as being more important than home ownership and financial wealth. Health care providers should communicate fertility risk and preservation options at diagnosis and facilitate timely discussion among families, who may differ in prioritization of future fertility.

The Early Psychosis Intervention Center (EPICENTER): development and six-month outcomes of an American first-episode psychosis clinical service.

BACKGROUND: There is growing evidence that specialized clinical services targeted toward individuals early in the course of a psychotic illness may be effective in reducing both the clinical and economic burden associated with these illnesses. Unfortunately, the United States has lagged behind other countries in the delivery of specialized, multi-component care to individuals early in the course of a psychotic illness. A key factor contributing to this lag is the limited available data demonstrating the clinical benefits and cost-effectiveness of early intervention for psychosis among individuals served by the American mental health system. Thus, the goal of this study is to present clinical and cost outcome data with regard to a first-episode psychosis treatment center within the American mental health system: the Early Psychosis Intervention Center (EPICENTER). METHODS: Sixty-eight consecutively enrolled individuals with first-episode psychosis completed assessments of symptomatology, social functioning, educational/vocational functioning, cognitive functioning, substance use, and service utilization upon enrollment in EPICENTER and after 6 months of EPICENTER care. All participants were provided with access to a multi-component treatment package comprised of cognitive behavioral therapy, family psychoeducation, and metacognitive remediation. RESULTS: Over the first 6 months of EPICENTER care, participants experienced improvements in symptomatology, social functioning, educational/vocational functioning, cognitive functioning, and substance abuse. The average cost of care during the first 6 months of EPICENTER participation was lower than the average cost during the 6-months prior to joining EPICENTER. These savings occurred despite the additional costs associated with the receipt of EPICENTER care and were driven primarily by reductions in the utilization of inpatient psychiatric services and contacts with the legal system. CONCLUSIONS: The results of our study suggest that multi-component interventions for first-episode psychosis provided in the US mental health system may be both clinically-beneficial and cost-effective. Although additional research is needed, these findings provide preliminary support for the growing delivery of specialized multi-component interventions for first-episode psychosis within the United States. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01570972; Date of Trial Registration: November 7, 2011.

College student beliefs about wagering: an evaluation of the adolescent gambling expectancies survey.

Expectancy theory posits that decisions to engage in a given behavior are closely tied to expectations of the outcome of that behavior. Gambling outcome expectancies have predicted adolescent gambling and gambling problems. When high school students' outcome expectancies were measured by Wickwire et al. (Psychol Addict Behav 24(1):75-88 2010), the Adolescent Gambling Expectancy Survey (AGES) revealed five categories of expectancies that were each predictive of gambling frequency and pathology. The present study aimed to explore if the AGES could be successfully replicated with college students. When administered to a diverse college student population, factor analyses identified five factors similar to those found in the high school sample. Several factors of the AGES were also found to predict gambling frequency and gambling problems for college students. Gambling frequency and gambling activity preference were also addressed.

Canine prostate cancer cell line (Probasco) produces osteoblastic metastases in vivo.

BACKGROUND: In 2012, over 240,000 men were diagnosed with prostate cancer and over 28,000 died from the disease. Animal models of prostate cancer are vital to understanding its pathogenesis and developing therapeutics. Canine models in particular are useful due to their similarities to late-stage, castration-resistant human disease with osteoblastic bone metastases. This study established and characterized a novel canine prostate cancer cell line that will contribute to the understanding of prostate cancer pathogenesis. METHODS: A novel cell line (Probasco) was derived from a mixed breed dog that had spontaneous prostate cancer. Cell proliferation and motility were analyzed in vitro. Tumor growth in vivo was studied by subcutaneous, intratibial, and intracardiac injection of Probasco cells into nude mice. Tumors were evaluated by bioluminescent imaging, Faxitron radiography, µCT, and histology. RT-PCR and genome-wide DNA copy number profiling were used to characterize the cell line. RESULTS: The Probasco cells grew in vitro (over 75 passages) and were tumorigenic in nude mice. Probasco cells expressed high levels of BMP2, CDH1, MYOF, FOLH1, RUNX2, and SMAD5 modest CXCL12, SLUG, and BMP, and no PTHrP mRNA. Following intracardiac injection, Probasco cells metastasized primarily to the appendicular skeleton, and both intratibial and intracardiac injections produced osteoblastic tumors in bone. Comparative genomic hybridization demonstrated numerous DNA copy number aberrations throughout the genome, including large losses and gains in multiple chromosomes. CONCLUSIONS: The Probasco prostate cancer cell line will be a valuable model to investigate the mechanisms of prostate cancer pathogenesis and osteoblastic bone metastases.

Biochemical characterization of prostate-specific membrane antigen from canine prostate carcinoma cells.

BACKGROUND: Prostate-specific membrane antigen (PSMA) remains an important target for diagnostic and therapeutic application for human prostate cancer. Model cell lines have been recently developed to study canine prostate cancer but their PSMA expression and enzymatic activity have not been elucidated. The present study was focused on determining PSMA expression in these model canine cell lines and the use of fluorescent small-molecule enzyme inhibitors to detect canine PSMA expression by flow cytometry. METHODS: Western blot and RT-PCR were used to determine the transcriptional and translational expression of PSMA on the canine cell lines Leo and Ace-1. An endpoint HPLC-based assay was used to monitor the enzymatic activity of canine PSMA and the potency of enzyme inhibitors. Flow cytometry was used to detect the PSMA expressed on Leo and Ace-1 cells using a fluorescently tagged PSMA enzyme inhibitor. RESULTS: Canine PSMA expression on the Leo cell line was confirmed by Western blot and RT-PCR, the enzyme activity, and flow cytometry. Kinetic parameters Km and Vmax of PSMA enzymatic activity for the synthetic substrate (PABGγG) were determined to be 393 nM and 220 pmol min(-1) mg protein(-1) , respectively. The inhibitor core 1 and fluorescent inhibitor 2 were found to be potent reversible inhibitors (IC50 = 13.2 and 1.6 nM, respectively) of PSMA expressed on the Leo cell line. Fluorescent labeling of Leo cells demonstrated that the fluorescent PSMA inhibitor 2 can be used for the detection of PSMA-positive canine prostate tumor cells. Expression of PSMA on Ace-1 was low and not detectable by flow cytometry. CONCLUSIONS: The results described herein have demonstrated that PSMA is expressed on canine prostate tumor cells and exhibits similar enzymatic characteristics as human PSMA. The findings show that the small molecule enzyme inhibitors currently being studied for use in diagnosis and therapy of human prostate cancer can also be extended to include canine prostate cancer. Importantly, the findings demonstrate that the potential of the inhibitors for use in diagnosis and therapy can be evaluated in an immunocompetent animal model that naturally develops prostate cancer before use in humans.