Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of Krtcap3.

We previously identified Keratinocyte-associated protein 3, Krtcap3, as a novel adiposity gene, but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between Krtcap3, adiposity, and stress, we exposed wild-type (WT) and Krtcap3 knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited metabolic and behavioral responses to chronic stress exposure. Specifically, stress-exposed KO rats gained more weight, consumed more food when socially isolated, and displayed more anxiety-like behaviors relative to control KO rats. Meanwhile, there were minimal differences between control and stressed WT rats. At study conclusion stress-exposed KO rats had increased corticosterone (CORT) relative to control KO rats with no differences between WT rats. In addition, KO rats, independent of prior stress exposure, had an increased CORT response to removal of their cage-mate (psychosocial stress), which was only seen in WT rats when exposed to chronic stress. Finally, we found differences in expression of the glucocorticoid receptor, Nr3c1, in the pituitary and colon between control and stress-exposed KO rats that were not present in WT rats. These data support that Krtcap3 expression affects stress response, potentially via interactions with Nr3c1, with downstream effects on adiposity and behavior. Future work is necessary to more thoroughly understand the role of Krtcap3 in the stress response.

Applying a Social Ecological Model to Medical Legal Partnerships Practice and Research.

The social ecological model (SEM) is a conceptual framework that recognizes individuals function within multiple interactive systems and contextual environments that influence their health. Medical Legal Partnerships (MLPs) address the social determinants of health through partnerships between health providers and civil legal services. This paper explores how the conceptual framework of SEM can be applied to the MLP model, which also uses a multidimensional approach to address an individual's social determinants of health.

Analysis of secondary pharmacology assays received by the US Food and Drug Administration.

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission. A total of 1120 INDs submitted by 480 sponsors between 1999 and October 2020 were included in this study. The overall results were largely consistent with previous internal and external studies, showing that the most tested target in our set was the histamine 1 receptor (tested 938 times), the most hit target was sodium channel site 2 (hit 141 times), and the target with the highest hit percentage was the vesicular monoamine transporter 2 (hit 42.2% of the time). Additionally, this study demonstrated that improvements in the secondary pharmacology submission process, such as changes in formatting and nomenclature, could enhance the utility of these assays for regulatory review, including assisting with identifying the safety liabilities of a drug candidate early in development. This updated data set will allow FDA-industry collaborative working groups to continue developing the best methods for regulatory submission of secondary pharmacology data and evaluate the need for a standard target panel.

Sex at Sea: Undergraduates' Perceptions of Sexual Relationships During Their Semester at Sea Voyage.

Often viewed as right of passage in emerging adulthood on college campuses, most undergraduate students participate in casual sex during their undergraduate career. Sexual exploration typically continues during study abroad programs; however, these programs have previously been associated with an increase in risky sexual behavior due to a lack of familiar social norms and community. The current study examined the casual sexual relationships of 302 undergraduates participating in Semester at Sea, an eleven country, 106-day voyage which incorporates aspects of a traditional college campus combined with the novel experience of studying abroad. The purpose of this research was to explore students' casual sexual relationship perceptions and behaviors in the context of a structured and community-oriented study abroad environment. Over half (52%) of the student population completed a series of open-ended questions regarding their uncommitted sexual activity during the Semester at Sea voyage. Results indicated that 16.9% of students engaged in at least one casual sexual relationship over the course of the trip. Casual sex relationships on-board the Semester at Sea voyage were less prevalent than those on traditional college campuses, but casual sex relationships at sea appeared to focus more on the importance of communication and boundaries during the sexual relationship and concluded on a more positive note. It is likely that these decisions were influenced by the established communal culture on-board the ship, which encouraged students to maintain harmonious social relationships and a high level of awareness of others.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.

Cefiderocol Retains Antibiofilm Activity in Multidrug-Resistant Gram-Negative Pathogens.

Cefiderocol is a siderophore cephalosporin with potent antibacterial activity against a broad range of Gram-negative pathogens, including multidrug-resistant strains. Siderophore antibiotics bind ferric iron and utilize iron transporters to cross the cell membrane. In the biofilm setting, where antibiotic resistance is high but iron scavenging is important, cefiderocol may have advantageous antimicrobial properties. In this study, we compared the antimicrobial activity of cefiderocol to that of seven commonly used antibiotics in well-characterized multidrug-resistant pathogens and then determined their efficacy in the biofilm setting. MIC90 values for cefiderocol were consistently lower than those of other antibiotics (ceftolozane-tazobactam, ceftazidime-avibactam, ceftazidime, piperacillin-tazobactam, imipenem, and tobramycin) in all strains tested. Cefiderocol treatment displayed a reduction in the levels of Pseudomonas aeruginosa biofilm (93%, P < 0.0001) superior to that seen with the other antibiotics (49% to 82%). Cefiderocol was generally as effective as or superior to the other antibiotics, depending on the pathogen-antibiotic combination, in reducing biofilm in other pathogens. There was a trend toward greater biofilm reduction seen with increased antibiotic dose or with increased frequency of antibiotic treatment. We conclude that cefiderocol effectively reduces biofilm and is a potent inhibitor of planktonic growth across a range of Gram-negative medically important pathogens.

Optimizing Breast Pocket Irrigation: The Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) Era.

BACKGROUND: Specific antimicrobial breast pocket irrigations have been proven over the past 20 years to reduce the incidence of capsular contracture by a factor of 10, and the emergence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and its link to bacteria/technique has created renewed interest in different antimicrobial breast pocket preparation agents. Our previous studies have identified that both Betadine-containing and non-Betadine-containing antimicrobial irrigations provide excellent broad-spectrum bacterial coverage. The current science of BIA-ALCL has implicated the Gram-negative microbiome as a key in pathogenesis. OBJECTIVES: The aim of this study was to revisit the antimicrobial effectiveness of clinically utilized Betadine and non-Betadine solutions, along with other antimicrobial agents that have not yet been tested, against multiple organisms, including additional common Gram-negative bacteria associated with chronic breast implant infections/inflammation. METHODS: Current and new antimicrobial breast irrigations were tested via standard techniques for bactericidal activity against multiple Gram-positive and Gram-negative strains. Test results are detailed and clinical recommendations for current antimicrobial irrigations are provided. RESULTS: Betadine-containing irrigations were found to be superior according to the testing performed. CONCLUSIONS: There are quite few misconceptions with regard to antimicrobial breast pocket irrigation. These are discussed and final evidence-based recommendations for practice are given.

AcrAB-TolC Inhibition by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Antibiotic Activity in Vitro and in Vivo.

Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and ß-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for acrA, which was the most effective at reducing antibiotic efflux. This acrA-PPMO enhances the antimicrobial effects of the levofloxacin and azithromycin in a panel of clinical Enterobacteriaceae strains. Additionally, acrA-PPMO enhanced azithromycin in vivo in a K. pneumoniae septicemia model. PPMOs targeting the homologous resistance-nodulation-division (RND)-efflux system in P. aeruginosa, MexAB-OprM, also enhanced potency to several classes of antibiotics in a panel of strains and in a cell culture infection model. These data suggest that PPMOs can be used as an adjuvant in antibiotic therapy to increase the efficacy or extend the spectrum of useful antibiotics against a variety of Gram-negative infections.

Antisense Inhibitors Retain Activity in Pulmonary Models of Burkholderia Infection.

The Burkholderia cepacia complex is a group of Gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers are antisense molecules that inhibit bacterial mRNA translation. Targeting of PPMOs to the gene acpP, which is essential for membrane synthesis, lead to defects in the membrane and ultimately bactericidal activity. Exploration of additional PPMO sequences identified the ATG and Shine-Dalgarno sites as the most efficacious for targeting acpP. The CF lung is a complex microenvironment, but PPMO inhibition was still efficacious in an artificial model of CF sputum. PPMOs had low toxicity in human CF cells at doses that were antibacterial. PPMOs also reduced the bacterial burden in the lungs of immunocompromised CyBB mice, a model of CGD. Finally, the use of multiple PPMOs was efficacious in inhibiting the growth of both Burkholderia and Pseudomonas in an in vitro model of coinfection. Due to the intrinsic resistance of Burkholderia to traditional antibiotics, PPMOs represent a novel and viable approach to the treatment of Burkholderia infections.

MCR-1 Inhibition with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Sensitivity to Polymyxin in Escherichia coli.

In late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur in many Gram-negative pathogens, and the mechanism of MCR-1-mediated resistance was rapidly determined: an ethanolamine is attached to lipid A phosphate groups, rendering the membrane more electropositive and repelling positively charged polymyxins. Acquisition of MCR-1 is clinically significant because polymyxins are frequently last-line antibiotics used to treat extensively resistant organisms, so acquisition of this mechanism might lead to pan-resistant strains. Therefore, the ability to inhibit MCR-1 and restore polymyxin sensitivity would be an important scientific advancement. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense molecules that were designed to target mRNA, preventing translation. Peptide conjugation enhances cellular entry, but they are positively charged, so we tested our lead antibacterial PPMOs by targeting an essential Escherichia coli gene, acpP, and demonstrated that they were still effective in mcr-1-positive E. coli strains. We then designed and synthesized two PPMOs targeted to mcr-1 mRNA. Five clinical mcr-1-positive E. coli strains were resensitized to polymyxins by MCR-1 inhibition, reducing MICs 2- to 16-fold. Finally, therapeutic dosing of BALB/c mice with MCR-1 PPMO combined with colistin in a sepsis model reduced morbidity and bacterial burden in the spleen at 24 h and offered a survival advantage out to 5 days. This is the first example of a way to modulate colistin resistance with an antisense approach and may be a viable strategy to combat this globally emerging antibiotic resistance threat.IMPORTANCE Polymyxin use has been increasing as a last line of defense against Gram-negative pathogens with high-level resistance mechanisms, such as carbapenemases. The recently described MCR-1 is a plasmid-mediated mechanism of resistance to polymyxins. MCR-1 is currently found in Gram-negative organisms already possessing high-level resistance mechanisms, leaving clinicians few or no antibacterial options for infections caused by these strains. This study utilizes antisense molecules that target mRNA, preventing protein translation. Herein we describe antisense molecules that can be directly antibacterial because they target genes essential to bacterial growth or blockade of MCR-1, restoring polymyxin sensitivity. We also demonstrate that MCR-1 antisense molecules restore the efficacies of polymyxins in mouse models of E. coli septicemia. Considering all things together, we demonstrate that antisense molecules may be effective therapeutics either alone when they target an essential gene or combined with antibiotics when they target specific resistance mechanisms, such as those seen with MCR-1.

Planning Adolescent Mental Health Promotion Programming in Saskatoon.

BACKGROUND: We assessed associations between key demographic risk factors and the outcome of depressed mood in Saskatoon, Saskatchewan, to inform the planning and implementation of mental health promotion programming in schools. METHODS: In the 2008/2009 school year, 3958 students from grades 5 through 8 from 76 elementary schools completed questions regarding depressed mood on the Student Health Survey administered by the Saskatoon Health Region. The demographic risk factors for depressed mood considered in this study included age, sex, cultural status, and neighborhood income, as well as the role of school and age cohorts or grades within schools. RESULTS: We found Aboriginal students were significantly more likely to report moderate/severe depressed mood than other students. We also found older female adolescents were significantly more likely to report moderate/severe depressed mood. Neighborhood income explained the largest proportion (40%) of depressed mood differences between schools. CONCLUSIONS: These results can inform the planning and implementation of mental health promotion programming by the health sector in Saskatoon's elementary schools, including an appropriate balance between targeted and population-based interventions that address both the distal and proximal determinants of depressed mood in adolescents.

No longer his and hers, but ours: examining sexual arousal in response to erotic stories designed for both sexes.

Research on sexual arousal and erotica has focused primarily on men and women's responses to erotic films and stories designed for a sex-specific audience. To reduce the confounds of relying on separate materials when evaluating sex differences in arousal, the present study designed suggestive and explicit erotic stories that were rated as being equally appealing to men and women. Participants were 212 undergraduate students who completed self-report measures of sexual self-esteem, sexual desire, and pre- and posttest measures of arousal. As hypothesized, women in the suggestive and explicit conditions reported a significant increase in sexual arousal; however, only men who read the explicit story demonstrated significant elevations in arousal. The creation of "equally appealing" erotic stories has challenged the existing research paradigm and has initiated the investigation of sexual arousal from a set of common materials designed for both sexes. The benefits of creating a series of equally appealing erotic materials extends beyond empirical research and may ultimately facilitate greater openness and communication between heterosexual couples.

Suicidal ideation: the role of economic and aboriginal cultural status after multivariate adjustment.

OBJECTIVE: To determine if Aboriginal (in this paper, First Nations and Métis people) cultural status is independently associated with lifetime suicidal ideation in the Saskatoon Health Region after controlling for other covariates, particularly income status. METHODS: Data collected by Statistics Canada in all 3 cycles of the Canadian Community Health Survey (CCHS) were merged with identical questions asked in February 2007 by the Saskatoon Health Region. The health outcome was lifetime suicidal ideation. The risk indicators included demographics, socioeconomic status, cultural status, behaviours, life stress, health care use, and other health problems. RESULTS: Participants (n = 5948) completed the survey with a response rate of 81.1%. The prevalence of lifetime suicidal ideation was 11.9%. After stratification, it was found that high-income Aboriginal people have similar low levels of suicidal ideation, compared with high-income Caucasian people. The risk-hazard model demonstrated a larger independent effect of income status in explaining the association between Aboriginal cultural status and lifetime suicidal ideation, compared with the independent effect of age. After full multivariate adjustment, Aboriginal cultural status had a substantially reduced association with lifetime suicidal ideation. The odds of lifetime suicidal ideation for Aboriginal people reduced from 3.28 to 1.99 after multivariate adjustment for household income alone. CONCLUSION: The results of this study suggest reductions in lifetime suicidal ideation can be observed in Aboriginal people in Canada by adjusting levels of household income.

The role of economic and cultural status as risk indicators for alcohol and marijuana use among adolescents.

INTRODUCTION: A number of reports suggest that Aboriginal cultural status is a major risk indicator for drug and alcohol use. The primary purpose of the present paper was to determine whether Aboriginal cultural status is independently associated with risk behaviours, such as marijuana use and alcohol abuse, among youth after multivariate adjustment for other factors, such as socioeconomic status. METHODS: Every student between grades 5 and 8 in Saskatoon, Saskatchewan, was asked to complete a questionnaire in February 2007. Logistic regression was used to determine the independent risk indicators associated with alcohol abuse and marijuana use. RESULTS: Four thousand ninety-three youth participated in the school health survey. At the cross-tabulation level, cultural status and neighbourhood income were both strongly associated with alcohol and marijuana use. After multivariate adjustment, the association between Aboriginal cultural status and alcohol abuse was not statistically significant (crude OR=3.52 to adjusted OR=0.80). For marijuana use, the association was significantly reduced (crude OR=9.91 to adjusted OR=2.79). After controlling for all other variables, results showed that low-income youth were 103% more likely to get drunk at least once and were 163% more likely to have tried marijuana at least once. CONCLUSION: To be more successful, future policies directed toward reducing risk behaviours among youth should consider neighbourhood income characteristics.

Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin.

Cells expressing elevated levels of allelic variants of human glutathione S-transferase P1 (GSTP1) and/or efflux transporters, MRP1 or MRP2, were used to evaluate the role of GSTP1-1 in cisplatin resistance. These studies revealed that GSTP1-1 confers low-level resistance (1.4- to 1.7-fold) to cisplatin-induced cytotoxicity in MCF7 cells. However, expression of MRP1 (MCF7 cells) or MRP2 (HepG2 cells) failed to augment or potentiate GSTP1-1-mediated resistance in either cell line. To understand the mechanism by which variants of GSTP1-1 confer resistance to cisplatin, their relative abilities to catalyze conjugation of cisplatin with glutathione were examined. Enzymes encoded by all three alleles tested, GSTP1a (I(104)A(113)), GSTP1b (V(104)A(113)), and GSTP1c (V(104)V(113)), increased the formation rate of the mono-platinum/glutathione derivative of cisplatin with relative catalytic activities of 1.0 (GSTP1a-1a variant) and 1.8 to 1.9 (GSTP1b-1b and GSTP1c-1c variants). Although these data are consistent with the idea that very low level resistance to cisplatin may be conferred by GSTP1-1-mediated cisplatin/glutathione conjugation, two observations indicate that such catalysis plays a minor role in the protection from cisplatin toxicity. First, the rates of GSTP1-1-mediated conjugation are extremely slow (1.7-2.6 h(-1) at 25 degrees C). Second, despite an 80% to 90% increase in catalysis of cisplatin conjugation by GSTP1b-1b or GSTP1c-1c over GSTP1a-1a, we observed no discernable differences in relative resistances conferred by these alternative variants when expressed in MCF7 cells. We conclude that high-level cisplatin resistance attributed to GSTP1-1 in other studies is not likely due to catalysis of cisplatin conjugation but rather must be explained by other mechanisms, which may include GSTP1-mediated modulation of signaling pathways.

A meta-analysis of marijuana and alcohol use by socio-economic status in adolescents aged 10-15 years.

OBJECTIVES: A majority of population-based studies suggest prevalence of drug and alcohol risk behaviour increases during late adolescence to early adulthood. The purpose of this systematic literature review is to clarify if socio-economic status (SES) is a determinant of marijuana and alcohol risk behaviour in adolescents between the ages of 10-15 years. METHODS: We performed a meta-analysis to identify published or unpublished papers between January 1, 1980 and February 9, 2007 that reviewed marijuana and alcohol risk behaviour by SES in adolescents aged 10-15 years. SYNTHESIS: We found nine studies that fulfilled our inclusion criteria and passed the methodological quality review. The prevalence of marijuana and alcohol risk behaviour was 22% higher (RR = 1.22; 95% CI 1.14-1.31) in adolescents with low SES in comparison to adolescents with higher SES. Stratification by country of origin revealed that American and New Zealand studies had statistically significant variability in the reported effects as compared to European and UK studies. DISCUSSION: The evidence suggests that low SES has an inverse association with the prevalence of marijuana and alcohol risk behaviour in adolescents between the ages of 10-15 years. Higher rates of marijuana and alcohol risk behaviour among lower SES adolescents may impact emotional development, limit future educational and occupational achievement, and increase the likelihood for adult marijuana and alcohol addiction. CONCLUSION: Lower SES adolescents have higher rates of marijuana and alcohol risk behaviour than higher SES adolescents.

Risk indicators for depressed mood in youth: Limited association with Aboriginal cultural status.

INTRODUCTION: There have been too few studies on urban Aboriginal youth to permit inferences about depressed mood in this subgroup. The purpose of the present study was to determine whether Aboriginal cultural status is independently associated with moderate or severe depressed mood in youth after controlling for other covariates, including socioeconomic status. METHODS: Every student between grades 5 and 8 in the city of Saskatoon, Saskatchewan, was asked to complete a questionnaire in February of 2007. Depressed mood was measured with a 12-question depression scale derivative of the 20-question Center for Epidemiologic Studies Depression Scale. RESULTS: Four thousand ninety-three youth participated in the school health survey. For Aboriginal youth, the prevalence rate of moderate or severe depressed mood was 21.6% in comparison with 8.9% for Caucasian youth (rate ratio 2.43; 95% CI 1.92 to 3.08). Aboriginal cultural status was not associated with depressed mood after adjustment for other covariates in the final multivariate model (OR 1.132; 95% CI 0.682 to 1.881). Parental educational status and sex were confounders to the association between Aboriginal cultural status and depressed mood. CONCLUSIONS: The recognition that Aboriginal cultural status is not independently associated with moderate or severe depressed mood in youth after full multivariate adjustment allows policy makers to acknowledge that mental health disparity prevention is possible because the determinants of health (ie, education) are modifiable (in comparison with Aboriginal cultural status).

Types of food aversions: animal, vegetable, and texture.

Despite a growing body of research investigating the origins and effects of food aversions, few research instruments have been developed to measure aversions to specific types or categories of food. Undergraduates (N = 209) responded to a series of food aversion questionnaires. The results suggest that people tend to be averse to 2 types of foods (vegetables and meats or fats) and to the texture and taste of certain foods (e.g., oysters). Aversions were slightly more prevalent among women than among men and were correlated with lower educational levels. The authors provide a means of advancing future research on this problem by reliably identifying 3 categories of food aversions. Future researchers should evaluate additional food categories and expand the focus on food aversions beyond the current concern with learned avoidance of specific food items.

Whose life is it, anyway? Supporting clients to live at risk.

This paper introduces readers to the concept of (capable) frail elderly clients choosing to live at risk. Promoting client centred care and independence can be particularly challenging where the client's goals are different than those of the health care team, and there are identified risks to the client's health. Discussion includes the ethical principles of autonomy, non-maleficence, benefecence and paternalism, and other factors that influence the assessment of risk, including the degree of risk, probability of risk, and risk of harm to others. Client Centred Care is introduced as a process model to guide decision-making in cases where clients choose to live at risk.