Phase 1 study of MEDI3902, an investigational anti-Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults.

OBJECTIVES: MEDI3902 is a bivalent, bispecific human immunoglobulin G1κ monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and the Psl exopolysaccharide involved in P. aeruginosa colonization and tissue adherence. MEDI3902 is being developed for the prevention of nosocomial P. aeruginosa pneumonia in high-risk patients. METHODS: This phase 1 dose-escalation study (NCT02255760) evaluated the safety, pharmacokinetics, antidrug antibody (ADA) responses and ex vivo anticytotoxicity and opsonophagocytic killing activities of MEDI3902 after a single intravenous infusion in healthy adults aged 18 to 60 years. Fifty-six subjects were randomized in a 3:1 ratio to receive 250, 750, 1500 or 3000 mg of MEDI3902 or placebo and followed for 60 days afterwards. RESULTS: Treatment-emergent adverse events (TEAEs) were mild or moderate in severity; no serious TEAEs were observed. The most common TEAEs were infusion-related reactions. MEDI3902 exhibited approximately linear pharmacokinetics across the 250, 750 and 1500 mg doses and nonlinear pharmacokinetics between the 1500 and 3000 mg doses. One subject in the 3000 mg group tested positive for ADA on day 61 and had a lower MEDI3902 serum concentration from days 43 to 61 than ADA-negative subjects. Serum anticytotoxicity antibody concentrations and opsonophagocytic killing activity were correlated with MEDI3902 serum concentrations across all doses. CONCLUSIONS: Phase 1 study results of MEDI3902 in healthy subjects support further evaluation of its safety and efficacy in subjects at risk for P. aeruginosa pneumonia.

Pseudomonas aeruginosa PcrV and Psl, the Molecular Targets of Bispecific Antibody MEDI3902, Are Conserved Among Diverse Global Clinical Isolates.

Background: Bispecific antibody MEDI3902, targeting the Pseudomonas aeruginosa type 3 secretion system (PcrV) and Psl exopolysaccharide, is currently in phase 2b development for prevention of nosocomial pneumonia in patients undergoing mechanical ventilation. We surveyed a diverse collection of isolates to study MEDI3902 epitope conservation and protective activity. Methods: P. aeruginosa clinical isolates (n = 913) were collected from diverse patients and geographic locations during 2003-2014. We conducted whole-genome sequencing; performed PcrV and Psl expression analyses via immunoblotting and enzyme-linked immunosorbent assay, respectively; performed crystallography to determine the MEDI3902 PcrV epitope, using anti-PcrV Fab and PcrV components (resolved at 2.8 Å); and evaluated MEDI3902 protective activity against select isolates in vitro and in vivo. Results: Intact psl operon and pcrV genes were present in 94% and 99% of isolates, respectively, and 99.9% of isolates contained at least one of the genetic elements. Anti-Psl binding was confirmed in tested isolates harboring a complete Psl operon or lacking nonessential psl genes. We identified 46 PcrV variant sequences, and MEDI3902-PcrV contact residues were preserved. MEDI3902 maintained potent in vivo activity against various strains, including strains expressing only a single target. Conclusions: Psl and PcrV are highly prevalent in global clinical isolates, suggesting MEDI3902 can mediate broad coverage against P. aeruginosa.

Experimentally induced glochidiosis in smallmouth bass (Micropterus dolomieu).

Necropsy was performed on 2 smallmouth bass (Micropterus dolomieu) that died 8 days after experimental gill inoculation with Actinonaias pectorosa glochidia. The salient feature at necropsy was ragged gills containing multiple petechial hemorrhages and numerous white, iridescent dust-like particles easily confirmed as glochidia in squash preparations of the gill filaments. Microscopically, the gills contained multiple rounded glochidia encysted at the tips or along the length of the filaments. Parasitized filaments were thickened, blunted, and often fused. Lamellae were extensively fused and obliterated, with proliferation of the epithelial cells giving the filament a smooth outline. Sometimes glochidia were associated with necrosis and/or hemorrhage. These fish most likely died due to asphyxia associated with the severe branchial lesions caused by the glochidia.

Exploratory study of premenstrual symptoms and serotonin variability.

Premenstrual symptoms can pose significant problems for a large number of women; this small exploratory study was designed to investigate biological markers that may provide etiological clues. Using an algorithm based on daily symptom charting for two months, 15 participants were assigned to one of three study groups: non-symptomatic (n = 9), probable PMS (n = 3) and probable PMDD (n = 3). During two overnight admissions, one prior to and one following the onset of menses, participants had blood drawn to assess the level of available serotonin via one of its metabolites, 5-HIAA. The three groups exhibited potentially significant differences in several biological markers. This study's results are consistent with a hypothesis implicating serotonin in the generation of premenstrual symptomology.

Assessing attachment: convergent validity of the adult attachment interview and the parental bonding instrument.

OBJECTIVE: The aim of this study was to determine whether or not the Parental Bonding Instrument (PBI) can provide information about parent-child attachment that is comparable to information obtained from the Adult Attachment Interview (AAI), a more complex measure of attachment. METHOD: One hundred and thirty emotionally and/or behaviourally disturbed adolescents (73 male, 57 female; ages 13-19 years, x = 15.3 +/- 1.47 years) participating in a study of attachment and suicidality completed the PBI and the AAI. Data from these measures were compared within participants. RESULTS: Maternal care and overprotection on the PBI differed significantly by AAI attachment classification (F3,122 = 2.79, p = 0.012), with autonomous participants showing the most optimal and unresolved participants the least optimal PBI results. Maternal love and maternal involvement/role reversal on the AAI were significant predictors of maternal care and maternal overprotection, respectively, on the PBI (R2 = 0.15; R2 = 0.16). These predictions improved when AAI scales measuring idealisation and involving anger towards the mother were included in the regression analyses (R2 = 0.35; R2 = 0.20). Autonomous participants on AAI showed the highest scale correlations across instruments. CONCLUSIONS: Attachment information obtained from the PBI and the AAI is comparable in participants with optimal attachment histories, but not in participants showing idealisation or anger towards their mothers. Caution is, therefore, advisable when using the PBI to obtain attachment information in clinical samples where suboptimal attachment histories are likely.

The provision of services for rural youth with serious emotional and behavioral problems: Virginia's Comprehensive Services Act.

The problems of the delivery of mental health and social services to rural children and adolescents encapsulate many of the problems in the larger health care system. Consequently, many of the principles underlying the President's Health Security Plan are applicable to the reformation of this more specialized service system. The experience of the Commonwealth of Virginia in implementing the Comprehensive Services Act (CSA) highlights the scope of vision needed to transform an existing service delivery system into a coordinated system of care on a state-wide scale.

Attachment organization and history of suicidal behavior in clinical adolescents.

One hundred thirty-three adolescents in psychiatric treatment participated in a case-comparison study investigating the association of attachment patterns with a history of suicidal behaviors. The comparison group comprised 64 adolescents who had never experienced suicidal ideation or behaviors; the case group included 69 adolescents with histories of suicidal behavior (n = 53) and severe suicidal ideation (n =16). Attachment patterns were assessed using the Adult Attachment Interview. In accordance with definitions provided in the scoring system, 86% of case and 78% of comparison adolescents in psychiatric treatment had experienced attachment-related trauma. Lapses in the monitoring of reasoning or discourse occurred during the attempted discussion of these events in 73% of adolescents in the case group but in only 44% of adolescents in the clinical comparison group (p = .002), suggesting that cognitive disorganization may be an important variable mediating between traumatic experience and suicidal behavior. Female adolescents and older adolescents were significantly more likely than other adolescents to be in the case group. Preoccupied attachment, in interaction with unresolved-disorganized attachment, was associated with the case group, whereas dismissing attachment was associated with the comparison group.

Prevalence of HIV-related risk behaviors and STDs among incarcerated adolescents.

PURPOSE: To determine the HIV-related risk behaviors and STDs in a population of incarcerated adolescents in order to strategically target education and prevention efforts. METHODS: A single point-in-time prevalence study based on an analysis of intake medical records of 1,215 incarcerated youth were analyzed for HIV risk behaviors and STD history. RESULTS: Incarcerated adolescents report high rates of risk behaviors for HIV infection and STDs, with 75% reporting three or more sex partners, 25% never using condoms and 19% having a current diagnosis of at least one STD. Significantly more females than males reported a history of STDs and had higher rates of current diagnoses of chlamydia/non-gonococcal urethritis, trichomonas and gonorrhea. CONCLUSIONS: Ethnic/racial and gender differences were found in risk behaviors for STDs among a sample of incarcerated adolescents.

Assessing organizational effectiveness in higher education drug prevention consortia.

Eighty-three consortia of institutions of higher education, organized under funding from the Fund for the Improvement of Post-Secondary Education (FIPSE) Drug Prevention Programs of the Department of Education, were surveyed to measure organizational effectiveness. Generalized satisfaction with the functioning of the consortia was related to the number of active members, the average miles traveled to meetings, satisfaction with performance of task functions, members' roles, the level of trust among members and the level of creativity and innovation in problem-solving. Satisfaction with goal attainment was significantly related to the presence of at least one "internal" goal for the consortium.

Parentification of the child: a case study of Bowlby's compulsive care-giving attachment pattern.

Compulsive care-giving is a pattern of adult attachment behavior in which the person emphasizes the importance of giving care in relationships rather than receiving it. The developmental antecedent of this pattern derives from role reversal in the parent-child relationship. Since care-giving directed from the child to the parent was so constantly associated by the parent with attachment, the child too inevitably associates it with attachment. It is important to differentiate this care-giving from care-giving initiatives that arise properly later in life in reciprocal relationships and true parental relationships. These adult care-giving behaviors arise from the care-giving system, and are complementary to the attachment system. By contrast, care-giving behaviors directed from a child to a parent arise from the child's attachment system and lead to dysfunctional relationships later in life as the individual loses any ability to express need or ask for care, yet retains a pervasive, unsatisfied neediness and longing for care. For such an individual in adulthood, the attachment and care-giving systems do not balance each other to yield stable reciprocal relationships but rather reinforce patterns of exclusive care-giving and the suppression of care-seeking.