Microscale strain concentrations in tissue-engineered osteochondral implants are dictated by local compositional thresholds and architecture.

Tissue-engineered osteochondral implants manufactured from condensed mesenchymal stem cell bodies have shown promise for treating focal cartilage defects. Notably, such manufacturing techniques have shown to successfully recapture the bulk mechanical properties of native cartilage. However, the relationships among the architectural features, local composition, and micromechanical environment within tissue-engineered cartilage from cell-based aggregates remain unclear. Understanding such relationships is crucial for identifying critical parameters that can predict in vivo performance. Therefore, this study investigated the relationship among architectural features, composition, and micromechanical behavior of tissue-engineered osteochondral implants. We utilized fast-confocal microscopy combined with a strain mapping technique to analyze the micromechanical behavior under quasi-static loading, as well as Fourier Transform Infrared Spectroscopy to analyze the local compositions. More specifically, we investigated the architectural features and compositional distributions generated from tissue maturation, along with macro- and micro-level strain distributions. Our results showed that under compression, cell-based aggregates underwent deformation followed by body movement, generating high local strain around the boundaries, where local aggrecan concentration was low and local collagen concentration was high. By analyzing the micromechanics and composition at the single aggregate length scale, we identified a strong threshold relationship between local strain and compositions. Namely at the aggrecan concentration below 0.015 arbitrary unit (A.U.) and the collagen concentration above 0.15 A.U., the constructs experienced greater than threefold increase in compressive strain. Overall, this study suggests that local compositional features are the primary driver of the local mechanical environment in tissue-engineered cartilage constructs, providing insight into potential quality control parameters for manufacturing tissue-engineered constructs.

Long-term mediation of a sexual risk-reduction intervention for South African adolescents.

OBJECTIVE: Black adolescents in South Africa are disproportionately affected by HIV. A cluster-randomized controlled experiment examining the effects of a sexual risk-reduction intervention successfully reduced self-reported intercourse and unprotected intercourse. Based on long-term follow-up assessments, the present research examines theoretical constructs that could potentially mediate the intervention effects and how time and gender, respectively, moderated the mediation. METHOD: The behavioral outcome was measured by asking whether participants had had any vaginal sex in the past 3 months. Mediation and moderated mediation were tested based on the 3-, 6-, 12-, 42-, and 54-month postintervention outcomes. RESULTS: Three variables through which the sexual risk-reduction intervention had a significant mediated effect on the behavioral outcome were identified: abstinence career opportunities outcome expectancy (α × ß product = -0.086, 95% asymmetric confidence interval [ACI] [-0.126, -0.047]), expected parental approval of sexual intercourse (α × ß product = -0.061, [-0.102, -0.025]), and self-efficacy to avoid sexual-risk situations (α × ß product = -0.022, [-0.049, -0.001]). The moderated mediation analysis showed that gender moderated the intervention's effects on abstinence prevention outcome expectancy (B = -0.186, SEB = 0.079, p = .019), expected parental approval of sexual intercourse (B = 0.143, SEB = 0.058, p = .013), and self-efficacy to avoid sexual-risk situations (B = -0.293, SEB = 0.112, p = .009). The moderated mediation analysis also revealed that time moderated the effects of the intervention on abstinence career opportunities outcome expectancy (B = -0.293, SEB = 0.106, p = .006), self-efficacy to avoid sexual-risk situations (B = 0.335, SEB = 0.060, p < .001), and cultural myths regarding HIV transmission (B = 0.138, SEB = 0.042, p = .001); and the association between four theoretical constructs and the behavioral outcome: abstinence career opportunities outcome expectancy (B = -0.267, SEB = 0.104, p = .001), self-efficacy to refuse sex (B = -0.132, SEB = 0.043, p = .002), self-efficacy to avoid sexual-risk situations (B = -0.093, SEB = 0.055, p = .009), and HIV risk-reduction knowledge (B = -0.286, SEB = 0.134, p = .003). CONCLUSIONS: The present study identifies theoretical constructs that mediated the intervention effects on the sexual behavior among South African adolescents for an extended period of time. The findings also reveal gender differences in psychological mechanisms initiated by a sexual risk-reduction intervention and the long-term temporal dynamics of the intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prospective Predictors of Blood Pressure Among African American Men Living with HIV.

Little is known about the predictors of blood pressure (BP) among African American men living with HIV. We examined whether age and body mass index (BMI) are associated with higher blood pressure (BP) and whether being married and muscular endurance are associated with lower BP among African American men living with HIV. Second, we examined whether being married moderated the effects of the other predictors on BP. Finally, we examined whether BMI mediated the relationship between muscular endurance and BP. This article is a prospective secondary analysis of data from a randomized controlled trial of a health-promotion intervention for African American men living with HIV. We measured the participants' BP pre-intervention and three, six, and 12 months post-intervention. Generalized estimating equations linear regression analyses examined whether marital status, age, BMI, and muscular endurance predicted BP post-intervention, adjusting for pre-intervention BP and the intervention. Older age, higher BMI, and lower muscular endurance predicted higher BP post-intervention, adjusting for the intervention and baseline BP. Although marital status did not predict post-intervention BP, it moderated the negative effect of higher BMI. The positive relation of BMI to BP was weaker among married men than unmarried men. Muscular endurance had an indirect impact on BP mediated through BMI. Public health efforts targeting older African American men with HIV should focus on increasing muscular endurance in this population to lower BMI as a strategy to reduce cardiovascular disease risk in this population.

Physical Activity Intervention Effects on Waist-to-Hip Ratio in African American Men Living With HIV.

People living with HIV on antiretroviral therapy have an increased risk of developing metabolic disturbances and central adiposity. Adequate engagement in physical activity (PA) could reduce the risk of chronic diseases associated with central adiposity. We conducted a secondary analysis of data from a randomized controlled trial of a PA intervention with 302 African American men aged 40 or older (53.9±7.2 years) living with HIV to assess whether the intervention reduced the waist-to-hip ratio (WHR). Generalized estimating equation analyses tested whether the PA intervention reduced WHR compared with the control group and whether age moderated its effect, adjusting for follow-up assessment time (3, 6, and 12 months postintervention) and baseline WHR and age. The analysis revealed that the intervention's effect on WHR was not significant (B = -0.008, p = .097). However, a significant interaction between age and the intervention (B = 0.001, p = .046) indicated that the intervention's effect in reducing WHR waned with increasing age. For instance, when dividing participants into three age subgroups, the intervention reduced WHR for men ages 40 to 50 (B = -0.020, p = .013) and ages 50 and 60 (B = -0.007, p = .315) but increased it among those older than 60 (B = 0.013, p = .252). The intervention's effects on WHR differed by participants' age, suggesting that different PA strategies may be needed based on age to improve the metabolic profile and reduce chronic disease risk in African American men living with HIV.

Beliefs and willingness towards participating in genetic testing for depression in low-income and racial/ethnic minority mothers at-risk.

PURPOSE: To identify mothers' salient normative, behavioral and control beliefs and willingness towards participating in genetic salivary testing for depression. DESIGN: A qualitative, descriptive design was employed. 41 multi-ethnic mothers completed surveys that underwent directed content analysis according to The Theory of Planned Behavior. Percentages and frequency counts were used to categorize responses and calculate willingness. FINDINGS: Salient beliefs included: Behavioral: Finding a cure/treatment for depression (29.3 %), Normative: Family would approve (46.3 %), and Church associates would disapprove (19.5 %). CONTROL: Lacking information/explanations (34.1 %) as barriers, convenient locations (24.4 %) as facilitators. Most mothers indicated a willingness to participate (90.2 %). CONCLUSIONS: Interventions should target families, emphasize benefits, explain purposes and procedures, and use community based participatory methods.

Discovery of Insulin Receptor Partial Agonists MK-5160 and MK-1092 as Novel Basal Insulins with Potential to Improve Therapeutic Index.

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.

Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists.

Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.

Predicting intentions to meet fruit & vegetable recommendations among black emerging adult women.

ObjectiveTo examine Black emerging adult women's (ages 18-29) intention to meet the recommended daily intake of fruits and vegetables using the Theory of Planned Behavior (TPB). Participants: Black emerging adult women (BEAW; N = 100). Methods: A cross-sectional survey design. Results: Hierarchical regression analyses revealed that in Model 1, attitudes (p<.0001) and subjective norms (p<.05) were significant predictors of intentions to meet the recommended daily intake of fruits and vegetables. In Model 2, attitudes (p=.0001) and perceived behavioral control (p<.0001) were revealed to be significant predictors of intentions. The change in R squared from Model 1 (R2=.304) and Model 2 (R2=.559), was 0.255 (F = 40.08, p<.0001) with the addition of perceived behavioral control to the second model. Conclusion: The TPB may be a suitable framework to assess factors associated with fruit and vegetable intentions among BEAW. Interventions designed to increase fruit and vegetable intake in BEAW should prioritize modifying perceived behavioral control.

The Effects of a Community-Based, Multicomponent, Depression Prevention Intervention in Mothers At-Risk.

The purpose of this study was to develop a 12-week multicomponent, depression prevention pilot intervention and evaluate its feasibility and preliminary effects on improving levels and correlates of depressive symptoms, including anger, self-esteem perceived stress, social support, and racism. A quasi-experimental, mixed-methods design and a community-based participatory research (CBPR) approach was employed. University faculty, students and community residents collaborated at a low-income housing complex in a low-resourced, urban community. Fifteen low-income, ethnic minority mothers ages 23-46 years completed the intervention and evaluation surveys. Eight mothers participated in a focus group. The intervention included social group-dance, health education, and socialization. t-Tests, sign-tests, and thematic analysis was employed. Mothers identified barriers and facilitators of program engagement. Depressive symptoms were significantly reduced (t(14) = 2.41, p = .030). Self-esteem (t(14) = 2.28, p = .039) and social support levels (M = 4.5, p = .035) were significantly increased. This multicomponent intervention is feasible. Preliminary efficacy evidence was mixed.

Effects of a Health Promotion Intervention on Physical Activity in African American Men Living with HIV: Randomized Controlled Trial.

HIV and its treatment with antiretroviral therapy increase the risk of noncommunicable diseases (NCDs) tied to physical inactivity. Older African American men are also at high risk for NCDs. We tested the efficacy of a theory-based intervention to increase adherence to federal aerobic and muscle-strengthening physical activity (PA) guidelines among African American men aged 40 years and older living with HIV. We randomized African American men aged 40 years and older living with HIV to a three-session social cognitive theory-informed health promotion intervention targeting PA or a one-session health awareness control condition. The primary outcome was PA guideline adherence assessed (self-reported) preintervention, immediate postintervention, and 3, 6, and 12 months postintervention. Secondary outcomes were the number of days on which participants reported moderate-intensity aerobic PA, vigorous-intensity aerobic PA, and muscle-strengthening PA in the past 7 days. Of 302 participants, 255 completed the 12-month postintervention measures. Generalized estimated equation logistic regression indicated that the health promotion intervention participants had higher odds of meeting PA guidelines than health awareness control participants, adjusting for baseline adherence (p = 0.011). Health promotion intervention participants also reported more muscle-strengthening PA (p = 0.001), vigorous-intensity aerobic PA (p = 0.049), and moderate-intensity aerobic PA (p = 0.010) than control participants. The rise in self-reported adherence to PA guidelines and improvements in muscle-strengthening and aerobic PA considered separately suggest that a relatively brief behavioral intervention can increase PA among African American men aged 40 years and older living with HIV and potentially curb their risk of NCDs that PA can prevent.

Predictors of Colorectal Cancer Screening Among African American Men Living with HIV.

African American men living with HIV are at high risk of colorectal cancer (CRC). Screening to detect CRC is associated with a reduced risk of CRC mortality. However, little is known about CRC screening predictors in this population. This study examined the relation of self-efficacy, a potential mediator of screening that interventions could target, to CRC screening. It also investigated several variables that might identify subpopulations of African American men non-adherent to CRC screening recommendations. We report a secondary analysis on baseline data from a randomized controlled trial of a health promotion intervention for African American men living with HIV. Before their intervention, they completed measures of CRC screening, self-efficacy, marital status, age, education, and adherence to physical activity guidelines and were assessed for obesity. A total of 270 African American men aged 45 to 88 (Mean = 55.07; SD = 6.46) living with HIV participated. About 30% reported CRC screening in the past six months. Multiple logistic regression revealed greater CRC screening self-efficacy and meeting physical activity guidelines were associated with receiving CRC screening. Obese men and men reporting higher education were less likely to report screening. Age and marital status were unrelated to screening. The results of this study suggest CRC screening rates may be low among African American men living with HIV, and interventions targeting self-efficacy may improve their screening uptake. Moreover, public-health efforts to increase screening should prioritize interventions with subpopulations of African American men living with HIV who are physically inactive and obese.

Reasoned Action Approach Correlates of Fruit and Vegetable Diet Among African American Men Living With HIV: A Cross-Sectional Study.

Epidemiological evidence of the protective role of fruits and vegetables for a host of chronic health conditions is well-documented. However, there is a dearth of studies examining predictors of fruit and vegetable intake among African American men living with HIV. We report secondary analyses-multiple regression and logistic regression models fitted to examine the strength of the relationships between the reasoned action approach constructs; namely, attitudes, subjective norms, descriptive norms, self-efficacy and intention to consume fruits and vegetables, and self-reported adherence to 5-A-DAY guidelines. We used baseline data from a randomized controlled trial of a physical activity intervention trial with 302 African American men aged 40 years or older (M = 53.9; SD = 7.2) living with HIV. Attitudes, subjective norms, descriptive norms, and self-efficacy were positively associated with intention to meet 5-A-DAY guidelines. More positive attitudes toward 5-A-DAY guidelines were associated with higher odds of meeting 5-A-DAY guidelines. More positive attitudes and self-efficacy were also positively associated with meeting the guidelines for intake of vegetable servings and fruit-and-vegetable servings combined. To increase fruit and vegetable intake among African American men living with HIV, interventions should be tailored to address the perceived benefits of consumption.

Reasoned Action Approach Correlates of Physical Activity Among African American Men Living With HIV: A Cross-Sectional Study.

ABSTRACT: Physical activity (PA) is associated with a reduced incidence of chronic diseases. However, little is known about the predictors of PA among African American men living with HIV. We report secondary analyses examining the strength of the relationships between the reasoned action approach constructs, attitude, subjective norm, descriptive norm, and self-efficacy and intention to exercise and self-reported adherence to Department of Health and Human Services PA guidelines using baseline data from a trial of a PA intervention with 302 African American men, between 40 and 88 years of age (M = 53.9; SD = 7.2) living with HIV. Multiple regression revealed that attitude, subjective norm, and self-efficacy were positively associated with intention. Logistic regression revealed higher odds of meeting PA guidelines as self-efficacy increased. Self-efficacy and descriptive norm predicted meeting the aerobic guideline. Self-efficacy predicted meeting the muscle-strengthening guideline. Interventions targeting reasoned action approach variables may contribute to efforts to improve PA among African American men living with HIV.

Eliciting Willingness and Beliefs towards Participation in Genetic Psychiatric Testing in Black/African American Mothers at Risk for Depression.

Black/African American women are at high risk for depression, yet are underrepresented in psychiatric genetic research for depression prevention and treatment. Little is known about the factors that influence participation in genetic testing for Black/African American women at risk. The purpose of this study was to elicit the beliefs that underlie participation in genetic testing for depression in Black/African American mothers, a subgroup at high risk. Willingness to participate in genetic testing procedures was also determined. A qualitative, descriptive design was employed. Exactly 19 mothers aged 21-42 completed open-ended questionnaires. Directed content and descriptive analyses of the text were conducted based on the Theory of Planned Behavior. Salient beliefs included: behavioral advantages-diagnosing/detecting depression (31.6%), finding cure/treatment (21.1%); disadvantages-not finding follow-up treatment/help (21.1%); salient referents, who approves-family members (47.4%), agencies/organizations (26.3%); who disapproves-church associates (21.1%). Control beliefs included: barriers-unpleasant/difficult testing procedures (42.1%), limited knowledge about the purpose of testing (26.3%); facilitator-a convenient location (21.1%). Most mothers (89.5%) indicated willingness to participate in testing. Interventions can target families, address barriers, emphasize future benefits, and use convenient locations and community-based participatory research methods. Policies can address social determinants of participation to increase inclusion of these mothers in psychiatric genetic research.

Design and synthesis of novel proline based factor XIa selective inhibitors as leads for potential new anticoagulants.

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.

The Use of Closing Questions in Qualitative Research: Results of a Web-Based Survey.

BACKGROUND: Scarce and differing reasons for including closing questions in qualitative research exist, but how data generated from these questions are used remains uncertain. OBJECTIVES: The purpose of the study was to understand if and how researchers use closing questions in qualitative research, specifically the research questions were: (a) "Why do qualitative researchers include or exclude closing questions during interviews?" and (b) "How do qualitative researchers use data from closing questions?" METHODS: A qualitative descriptive design using a single, asynchronous, web-based, investigator-designed survey containing 14 items was used to collect data. Convenience and snowball sampling were used to recruit participants. Data were analyzed using descriptive statistics and qualitative content analysis. Codes were developed from the qualitative data. Subcategories were derived from similar codes, and these subcategories were further scrutinized and were used to create broad categories. RESULTS: The number of respondents per question ranged from 76 to 99; most identified nursing and sociology as their academic disciplines, lived in the United States, and were involved in qualitative research for 1-10 years. Data, the interview, the interviewee, and the interviewer were broad categories to emerge as reasons for including closing questions. Only one respondent reported a reason for excluding closing questions. The uses of closing question data were described in four broad categories: analysis, data, the interview guide, and inquiry. DISCUSSION: Researchers frequently included closing questions in qualitative studies. The reasons for including these questions and how data are used vary, and support limited previously published literature. One unique reason, adding "new breath" to the interview, emerged. Study findings can aid qualitative researchers in deciding whether to include closing questions.

Site-Selective Synthesis of Insulin Azides and Bioconjugates.

A synthetic method to access novel azido-insulin analogs directly from recombinant human insulin (RHI) was developed via diazo-transfer chemistry using imidazole-1-sulfonyl azide. Systematic optimization of reaction conditions led to site-selective azidation of amino acids B1-phenylalanine and B29-lysine present in RHI. Subsequently, the azido-insulin analogs were used in azide-alkyne [3 + 2] cycloaddition reactions to synthesize a diverse array of triazole-based RHI bioconjugates that were found to be potent human insulin receptor binders. The utility of this method was further demonstrated by the concise and controlled synthesis of a heterotrisubstituted insulin conjugate.

Exploring Expressions of Depression in Black Single Mothers.

PROBLEM: This study investigates the experience of depression from the perspective of Black single mothers, an understudied diverse-sub-group who consistently report high levels of depressive symptoms that go undetected and untreated. PARTICIPANTS: The sample consisted of 210 Black single mothers aged 18-45 who reside in urban communities. METHODS: A descriptive, cross-sectional design was used to categorize the responses of Black single mothers to an open-ended question that asks about feelings of depression according to the four domains of the Centers for Epidemiologic Studies Depression Scale. Percentages and frequencies were used to describe the results of the analysis. FINDINGS: The 303 usable responses were most consistent with the depressed affect domain (N = 172), followed by somatic activity (N = 108), interpersonal symptoms (N = 21), and lack of positive affect (N = 2). The most prevalent raw responses included sadness (N = 59), forms of anger (N = 48), depressed (N = 24), cry (N = 23), do not want to be around people (N = 21), lonely (N = 17), tired (N = 16), and stressed (N = 12). CONCLUSIONS/IMPLICATIONS: Consider culture and individualized assessments to explore feelings of anger and sadness when screening for depressive symptoms in specific sub-groups of Black single mothers. Consider the use of appropriate screening tools.

Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts.

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.