Parents\u27 and students\u27 perceptions of college alcohol risk: the role of parental risk perception in intentions to communicate about alcohol

Introduction: The current study aims to examine discrepancies in parents\u27 and college students\u27 perceptions of alcohol risk and the role of perceived risk in predicting parents\u27 intentions to discuss alcohol with their child. Methods: In total, 246 college student–parent dyads (56.1% female students, 77.2% mothers) were recruited from a mid-size university. Participants completed measures of absolute likelihood, comparative likelihood, and severity of alcohol consequences. Results: In comparison to students, parents perceived the risks of alcohol poisoning (p \u3c .001), academic impairment (p \u3c .05), and problems with others (p \u3c .05) to be more likely. In addition, parents rated the majority of alcohol consequences (e.g., passing out, regrettable sexual situation, throwing up) as more severe than students (all ps \u3c .001). However, parents tended to be more optimistic than their child about the comparative likelihood of alcohol consequences. After controlling for demographics and past alcohol communication, greater absolute likelihood (β = .20, p = .016) and less confidence in knowledge of student behavior (β = .20, p = .013) predicted greater intentions to discuss alcohol. Conclusions: Providing parents of college students with information about college drinking norms and the likelihood of alcohol consequences may help prompt alcohol-related communication

Multicenter Validation of the Vasoactive-Ventilation-Renal Score as a Predictor of Prolonged Mechanical Ventilation After Neonatal Cardiac Surgery

Objectives: We sought to validate the Vasoactive-Ventilation-Renal score, a novel disease severity index, as a predictor of outcome in a multicenter cohort of neonates who underwent cardiac surgery. Design: Retrospective chart review. Setting: Seven tertiary-care referral centers. Patients: Neonates defined as age less than or equal to 30 days at the time of cardiac surgery. Interventions: Ventilation index, Vasoactive-Inotrope Score, serum lactate, and Vasoactive-Ventilation-Renal score were recorded for three postoperative time points: ICU admission, 6 hours, and 12 hours. Peak values, defined as the highest of the three measurements, were also noted. Vasoactive-Ventilation-Renal was calculated as follows: ventilation index + Vasoactive-Inotrope Score + Δ creatinine (change in creatinine from baseline × 10). Primary outcome was prolonged duration of mechanical ventilation, defined as greater than 96 hours. Receiver operative characteristic curves were generated, and abilities of variables to correctly classify prolonged duration of mechanical ventilation were compared using area under the curve values. Multivariable logistic regression modeling was also performed. Measurements and Main Results: We reviewed 275 neonates. Median age at surgery was 7 days (25th–75th percentile, 5–12 d), 86 (31%) had single ventricle anatomy, and 183 (67%) were classified as Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Category 4 or 5. Prolonged duration of mechanical ventilation occurred in 89 patients (32%). At each postoperative time point, the area under the curve for prolonged duration of mechanical ventilation was significantly greater for the Vasoactive-Ventilation-Renal score as compared to the ventilation index, Vasoactive-Inotrope Score, and serum lactate, with an area under the curve for peak Vasoactive-Ventilation-Renal score of 0.82 (95% CI, 0.77–0.88). On multivariable analysis, peak Vasoactive-Ventilation-Renal score was independently associated with prolonged duration of mechanical ventilation, odds ratio (per 1 unit increase): 1.08 (95% CI, 1.04–1.12). Conclusions: In this multicenter cohort of neonates who underwent cardiac surgery, the Vasoactive-Ventilation-Renal score was a reliable predictor of postoperative outcome and outperformed more traditional measures of disease complexity and severity

Sleep Quality and Alcohol Risk in College Students: Examining the Moderating Effects of Drinking Motives

Objective Sleep problems and alcohol misuse are common issues experienced by college students that can have detrimental effects on overall health. Previous work indicates a strong relationship between poor sleep quality and alcohol risk in this population. This study explored the moderating effect of drinking motives in the relationship between global sleep quality and experience of alcohol-related negative consequences. Participants College students (N = 1,878) who reported past-month drinking. Methods Participants completed online surveys assessing sleep and alcohol-related behaviors. Results Poorer sleep quality and higher drinking motives (coping, conformity, and enhancement) predicted greater alcohol-related consequences, controlling for drinking. Further, coping motives moderated the relationship between sleep quality and consequences such that participants reporting poor sleep and high coping motives experienced heightened levels of consequences. Conclusions These findings advance the understanding of the relationship between sleep problems and alcohol-related risk and provide implications for targeted campus-based health promotion interventions

The Efficacy of a Standalone Protective Behavioral Strategies Intervention for Students Accessing Mental Health Services

Objective Students with poor mental health are at increased risk for problematic alcohol use. These students also tend to underutilize alcohol-related protective behavioral strategies (PBS). Cross-sectional studies indicate that PBS use may be particularly useful for students with mental health challenges; however, it is unclear whether training these students to use PBS is an effective approach for reducing alcohol use and consequences. The current study evaluated the efficacy of a standalone PBS skills training and personalized feedback (PBS-STPF) intervention among students accessing mental health services. Method Participants (N = 251) were randomly assigned to either an individual facilitator-led PBS-STPF intervention or a health-related control condition. Participants completed online follow-up surveys 1- and 6-months post-intervention which included measures of alcohol use, negative consequences and a composite measure of PBS use. Results Relative to control participants, students in the PBS-STPF condition reported significantly greater PBS use, but no differences in alcohol use or consequences. Participants in both conditions reported decreases in drinking outcomes over time. Tests of mediation indicated that the intervention indirectly led to reduction in drinking outcomes at 6 months through increased PBS use. Conclusions Although the intervention resulted in changes in PBS use that were maintained for up to 6 months post-intervention, the effects of the intervention on drinking and consequences were limited. A brief standalone PBS training may need augmentation in order to promote effective use of PBS for substantial decreases in alcohol consequences

Extubation Failure after Neonatal Cardiac Surgery: A Multicenter Analysis

Objectives To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. Study design We conducted a prospective observational study of neonates ≤30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. Results We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). Conclusions In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication

Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development

Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting

The Genetic Structure of Leishmania infantum Populations in Brazil and Its Possible Association with the Transmission Cycle of Visceral Leishmaniasis

Leishmania infantum is the etiologic agent of visceral leishmaniasis (VL) in the Americas, Mediterranean basin and West and Central Asia. Although the geographic structure of L. infantum populations from the Old World have been described, few studies have addressed the population structure of this parasite in the Neotropical region. We employed 14 microsatellites to analyze the population structure of the L. infantum strains isolated from humans and dogs from most of the Brazilian states endemic for VL and from Paraguay. The results indicate a low genetic diversity, high inbreeding estimates and a depletion of heterozygotes, which together indicate a predominantly clonal breeding system, but signs of sexual events are also present. Three populations were identified from the clustering analysis, and they were well supported by F statistics inferences and partially corroborated by distance-based. POP1 (111 strains) was observed in all but one endemic area. POP2 (31 strains) is also well-dispersed, but it was the predominant population in Mato Grosso (MT). POP3 (31 strains) was less dispersed, and it was observed primarily in Mato Grosso do Sul (MS). Strains originated from an outbreak of canine VL in Southern Brazil were grouped in POP1 with those from Paraguay, which corroborates the hypothesis of dispersal from Northeastern Argentina and Paraguay. The distribution of VL in MS seems to follow the west-east construction of the Bolivia-Brazil pipeline from Corumbá municipality. This may have resulted in a strong association of POP3 and Lutzomyia cruzi, which is the main VL vector in Corumbá, and a dispersion of this population in this region that was shaped by human interference. This vector also occurs in MT and may influence the structure of POP2. This paper presents significant advances in the understanding of the population structure of L. infantum in Brazil and its association with eco-epidemiological aspects of VL

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis : First-in-human trial of ChAd63-KH

BACKGROUND: Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. METHODS: We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. FINDINGS: ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. CONCLUSION: The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. TRIAL REGISTRATION: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359)