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We studied systemic ceftriaxone, and free/local tobramycin and doxycycline in a controlled rat model representing a generic acute exogenous joint infection. We hypothesized that evidence of infection (quantitative colony forming units [CFU], qualitative scanning electron microscopy [SEM], histopathology) (1a) would be reduced with local versus systemic antibiotic, (1b) any antibiotic would be superior to control, (2) there would be a difference among antibiotics, and (3) antibiotic would not be detectable in serum at 4-week euthanasia. Study groups included infected and noninfected (1) control (no treatment), (2) systemic ceftriaxone (daily), (3) local tobramycin, and (4) local doxycycline (10 rats/group; power = 0.8). With IACUC approval, a reliable acute exogenous joint infection was created by slowly injecting 50-μl, 10 4 CFU Staphylococcus aureus, into the distal femoral medullary canal. The antibiotic formulation was introduced locally to the femoral canal and joint space. After 4 weeks, serum, pin, bone, and synovium were obtained. CFU/ml of bone and synovium were quantified using macrotiter method. SEM imaged biofilm on the surface of the pin, histopathology identified tissue response, liquid chromatography/mass spectrometry quantified plasma antibiotic. (1) Groups receiving any antibiotic reported lower CFU/ml in synovium compared with no treatment. (2) In the synovium, free/local tobramycin reduced CFU/ml to a greater extent than free/local doxycycline (p < 0.05). (3) Antibiotic in plasma after the local application was nondetectable in all groups after 4 weeks. SEM revealed no difference in biofilm on pin among all groups., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Meniscal tears are a common orthopedic injury, yet their healing is difficult to assess post-operatively. This impedes clinical decisions as the healing status of the meniscus cannot be accurately determined non-invasively. Thus, the objectives of this study were to explore the utility of a goat model and to use quantitative magnetic resonance imaging (MRI) techniques, histology, and biomechanical testing to assess the healing status of surgically induced meniscal tears. Adiabatic T1ρ, T2, and T2* relaxation times were quantified for both operated and control menisci ex vivo. Histology was used to assign healing status, assess compositional elements, and associate healing status with compositional elements. Biomechanical testing determined the failure load of healing lesions. Adiabatic T1ρ, T2, and T2* were able to quantitatively identify different healing states. Histology showed evidence of diminished proteoglycans and increased vascularity in both healed and non-healed menisci with surgically induced tears. Biomechanical results revealed that increased healing (as assessed histologically and on MRI) was associated with greater failure load. Our findings indicate increased healing is associated with greater meniscal strength and decreased signal differences (relative to contralateral controls) on MRI. This indicates that quantitative MRI may be a viable method to assess meniscal tears post-operatively., (© 2021. The Author(s).)

Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner., (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)

This multi-cohort study delineates developmental trajectories of psychopathic features across childhood and adolescence (ages 7-16) and investigates associations with adult outcomes (ages~23-34). Although most youth demonstrated consistently low levels of psychopathic features, approximately 10%-15% followed a chronically high trajectory. A similar number (~14%) displayed initially high levels that decreased over time, while others (~10%-20%) followed an increasing pattern. Boys in the chronically high trajectory exhibited the most deleterious adult outcomes and some evidence suggested that youth in the decreasing subgroup experienced fewer maladaptive outcomes than those in the increasing and high groups. Findings revealed substantial malleability in the developmental course of psychopathic features and suggest that unique pathways may exert considerable influence on future engagement in antisocial and criminal behaviors.

Bone allograft is used in total joint arthroplasties in order to enhance implant fixation. BMPs are known to stimulate new bone formation within allograft, but also known to accelerate graft resorption. Bisphosphonates are strong inhibitor of bone resorption. The aim of this study was to investigate whether the bisphosphonate zoledronate was able to counteract the accelerated graft resorption without interfering with the BMP induced bone formation. In the present study the two drugs alone and in combination were studied in our canine model of impaction bone grafting. We included 10 dogs in this study. Cancellous allograft bone grafts were soaked in either saline or zoledronate solution (0.005mg/mL) and then vehicle or BMP2 (0.15mg rhBMP2) was added. This produced four treatment groups: A) control, B) BMP2, C) zoledronate and D) BMP2+zoledronate. The allograft treated with A, B, C or D was impacted into a circumferential defect of 2.5mm around HA-coated porous Ti implants. Each dog received all four treatment groups with two implants in the distal part of each femur. The group with allograft soaked in zoledronate (C) showed better biomechanical fixation than all other groups (p<0.05). It had less allograft resorption compared to all other groups (p<0.005) without any statistically significant change in new bone formation. The addition of BMP2 to the allograft did not increase new bone formation significantly, but did accelerate allograft resorption. This was also the case where the allograft was treated with BMP2 and zoledronate in combination (D). This caused a decrease in mechanical implant fixation in both these groups compared to the control group, however only statistically significant for the BMP2 group compared to control. The study shows that topical zoledronate can be a valuable tool for augmenting bone grafts when administered optimally. The use of BMP2 in bone grafting procedures seems associated with a high risk of bone resorption and mechanical weakening., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Adolescents who regularly use marijuana may be at heightened risk of developing subclinical and clinical psychotic symptoms. However, this association could be explained by reverse causation or other factors. To address these limitations, the current study examined whether adolescents who engage in regular marijuana use exhibit a systematic increase in subclinical psychotic symptoms that persists during periods of sustained abstinence., Method: The sample comprised 1,009 boys who were recruited in 1st and 7th grades. Self-reported frequency of marijuana use, subclinical psychotic symptoms, and several time-varying confounds (e.g., other substance use, internalizing/externalizing problems) were recorded annually from age 13 to 18. Fixed-effects (within-individual change) models examined whether adolescents exhibited an increase in their subclinical psychotic symptoms as a function of their recent and/or cumulative history of regular marijuana use and whether these effects were sustained following abstinence. Models controlled for all time-stable factors (default) and several time-varying covariates as potential confounds., Results: For each year adolescent boys engaged in regular marijuana use, their expected level of subsequent subclinical psychotic symptoms rose by 21% and their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. The effect of prior regular marijuana use on subsequent subclinical psychotic symptoms persisted even when adolescents stopped using marijuana for a year. These effects were after controlling for all time-stable and several time-varying confounds. No support was found for reverse causation., Conclusions: These results suggest that regular marijuana use may significantly increase the risk that an adolescent will experience persistent subclinical psychotic symptoms.

Objectives: Examine whether young men who chronically use marijuana are at risk for engaging in drug-related and non-drug-related criminal offending and exhibiting psychopathic personality features in their mid-30s., Methods: Patterns of marijuana use were delineated in a sample of predominately Black and White young men from adolescence to the mid-20s using latent class growth curve analysis. Self-report and official records of criminal offending and psychopathic personality features were assessed in the mid-30s. Analyses controlled for multiple factors indicative of a preexisting antisocial lifestyle and co-occurring use of other substances and tested for moderation by race., Results: Four latent marijuana trajectory groups were identified: chronic high, adolescence-limited, late increasing, and low/nonusers. Relative to low/nonusers, chronic high and late increasing marijuana users exhibited more adult psychopathic features and were more likely to engage in drug-related offending during their mid-30s. Adolescence-limited users were similar to low/nonusers in terms of psychopathic features but were more likely to be arrested for drug-related crimes. No trajectory group differences were found for violence or theft, and the group differences were not moderated by race., Conclusions: Young men who engage in chronic marijuana use from adolescence into their 20s are at increased risk for exhibiting psychopathic features, dealing drugs, and enduring drug-related legal problems in their mid-30s relative to men who remain abstinent or use infrequently.

Background: Given recent changes in marijuana policy in the United States, it is important to understand the long-term effects of marijuana use on adult functioning. We examined whether men who displayed different trajectories of marijuana use from adolescence through emerging adulthood (age ∼15-26) differed in terms of socioeconomic, social, and life satisfaction outcomes in their mid-30s., Methods: Data came from a longitudinal sample of men who were recruited in early adolescence (N=506) and followed into adulthood. Four trajectory groups based on patterns of marijuana use from adolescence into emerging adulthood were compared on adult outcomes (age ∼36) before and after controlling for co-occurring use of other substances and several pre-existing confounding factors in early adolescence. The potential moderating effect of race was also examined., Results: Although there were initially group differences across all domains, once pre-existing confounds and co-occurring other substance use were included in the model, groups only differed in terms of partner and friend marijuana use. Chronic marijuana users reported the highest proportions of both. Frequent and persistent marijuana use was associated with lower socioeconomic status (SES) for Black men only., Conclusions: After statistically accounting for confounding variables, chronic marijuana users were not at a heightened risk for maladjustment in adulthood except for lower SES among Black men. Chronic users were more likely to have friends and partners who also used marijuana. Future studies should take into account pre-existing differences when examining outcomes of marijuana use., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

There is some suggestion that heavy marijuana use during early adolescence (prior to age 17) may cause significant impairments in attention and academic functioning that remain despite sustained periods of abstinence. However, no longitudinal studies have examined whether both male and female adolescents who engage in low (less than once a month) to moderate (at least once a monthly) marijuana use experience increased problems with attention and academic performance, and whether these problems remain following sustained abstinence. The current study used within-individual change models to control for all potential pre-existing and time-stable confounds when examining this potential causal association in two gender-specific longitudinal samples assessed annually from ages 11 to 16 (Pittsburgh Youth Study N = 479; Pittsburgh Girls Study N = 2296). Analyses also controlled for the potential influence of several pertinent time-varying factors (e.g., other substance use, peer delinquency). Prior to controlling for time-varying confounds, analyses indicated that adolescents tended to experience an increase in parent-reported attention and academic problems, relative to their pre-onset levels, during years when they used marijuana. After controlling for several time-varying confounds, only the association between marijuana use and attention problems in the sample of girls remained statistically significant. There was no evidence indicating that adolescents who used marijuana experienced lingering attention and academic problems, relative to their pre-onset levels, after abstaining from use for at least a year. These results suggest that adolescents who engage in low to moderate marijuana use experience an increase in observable attention and academic problems, but these problems appear to be minimal and are eliminated following sustained abstinence.

Some evidence suggests that youth who use marijuana heavily during adolescence may be particularly prone to health problems in later adulthood (e.g., respiratory illnesses, psychotic symptoms). However, relatively few longitudinal studies have prospectively examined the long-term physical and mental health consequences associated with chronic adolescent marijuana use. The present study used data from a longitudinal sample of Black and White young men to determine whether different developmental patterns of marijuana use, assessed annually from early adolescence to the mid-20s, were associated with adverse physical (e.g., asthma, high blood pressure) and mental (e.g., psychosis, anxiety disorders) health outcomes in the mid-30s. Analyses also examined whether chronic marijuana use was more strongly associated with later health problems in Black men relative to White men. Findings from latent class growth curve analysis identified 4 distinct subgroups of marijuana users: early onset chronic users, late increasing users, adolescence-limited users, and low/nonusers. Results indicated that the 4 marijuana use trajectory groups were not significantly different in terms of their physical and mental health problems assessed in the mid-30s. The associations between marijuana group membership and later health problems did not vary significantly by race. Findings are discussed in the context of a larger body of work investigating the potential long-term health consequences of early onset chronic marijuana use, as well as the complications inherent in studying the possible link between marijuana use and health effects., ((c) 2015 APA, all rights reserved).)