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ABSTRACTThe increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has sparked global concern due to the dwindling availability of effective antibiotics. To increase our treatment options, researchers have investigated naturally occurring antimicrobial compounds and have identified MC21-A (C58), which has potent antimicrobial activity against MRSA. Recently, we have devised total synthesis schemes for C58 and its chloro-analog, C59. Here, we report that both compounds eradicate 90% of the 39 MRSA isolates tested [MIC90 and minimum bactericidal concentration (MBC90)] at lower or comparable concentrations compared to several standard-of-care (SoC) antimicrobials including daptomycin, vancomycin, and linezolid. Furthermore, a stable, water-soluble sodium salt of C59, C59Na, demonstrates antimicrobial activity comparable to C59. C59, unlike vancomycin, kills stationary-phase MRSA in a dose-dependent manner and completely eradicates MRSA biofilms. In contrast to vancomycin, exposing MRSA to sub-MIC concentrations of C59 does not result in the emergence of spontaneous resistance. Similarly, in a multi-step study, C59 demonstrates a low propensity of resistance acquisition when compared to SoC antimicrobials, such as linezolid and clindamycin. Our findings suggest C58, C59, and C59Na are non-toxic to mammalian cells at concentrations that exert antimicrobial activity; the lethal dose at median cell viability (LD50) is at least fivefold higher than the MBC90 in the two mammalian cell lines tested. A morphological examination of the effects of C59 on a MRSA isolate suggests the inhibition of the cell division process as a mechanism of action. Our results demonstrate the potential of this naturally occurring compound and its analogs as non-toxic next-generation antimicrobials to combat MRSA infectionsIMPORTANCEThe rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) isolates has precipitated a critical need for novel antibiotics. We have developed a one-pot synthesis method for naturally occurring compounds such as MC21-A (C58) and its chloro-analog, C59. Our findings demonstrate that these compounds kill MRSA isolates at lower or comparable concentrations to standard-of-care (SoC) antimicrobials. C59 eradicates MRSA cells in biofilms, which are notoriously difficult to treat with SoC antibiotics. Additionally, the lack of resistance development observed with C59 treatment is a significant advantage when compared to currently available antibiotics. Furthermore, these compounds are non-toxic to mammalian cell lines at effective concentrations. Our findings indicate the potential of these compounds to treat MRSA infections and underscore the importance of exploring natural products for novel antibiotics. Further investigation will be essential to fully realize the therapeutic potential of these next-generation antimicrobials to address the critical issue of antimicrobial resistance.

Abstract Background Reducing the energy cost of running with exoskeletons could improve enjoyment, reduce fatigue, and encourage participation among novice and ageing runners. Previously, tethered ankle exoskeleton emulators with offboard motors were used to greatly reduce the energy cost of running with powered ankle plantarflexion assistance. Through a process known as “human-in-the-loop optimization”, the timing and magnitude of assistance torque was optimized to maximally reduce metabolic cost. However, to achieve the maximum net benefit in energy cost outside of the laboratory environment, it is also necessary to consider the tradeoff between the magnitude of device assistance and the metabolic penalty of carrying a heavier, more powerful exoskeleton. Methods In this study, tethered ankle exoskeleton emulators were used to characterize the effect of peak assistance torque on metabolic cost during running. Three recreational runners participated in human-in-the-loop optimization at four fixed peak assistance torque levels to obtain their energetically optimal assistance timing parameters at each level. Results We found that the relationship between metabolic rate and peak assistance torque was nearly linear but with diminishing returns at higher torque magnitudes, which is well-approximated by an asymptotic exponential function. At the highest assistance torque magnitude of 0.8 Nm/kg, participants’ net metabolic rate was 24.8 ± 2.3% (p = 4e–6) lower than running in the unpowered devices. Optimized timing of peak assistance torque was as late as allowed during stance (80% of stance) and optimized timing of torque removal was at toe-off (100% of stance); similar assistance timing was preferred across participants and torque magnitudes. Conclusions These results allow exoskeleton designers to predict the energy cost savings for candidate devices with different assistance torque capabilities, thus informing the design of portable ankle exoskeletons that maximize net metabolic benefit.

The purpose of the current study was to conduct a thorough review of the literature on the interview-informed synthesized contingency analysis (IISCA) developed by (Hanley et al., Journal of Applied Behavior Analysis 47:16-36, 2014)) and its subsequent treatment outcomes. A total of 39 articles were identified with 235 participants participating in 293 synthesized contingency analyses (SCAs) and 111 treatment evaluations. Results indicated that 95.56% of identified SCAs were reported to be differentiated. Similarly, reductions in problem behavior were seen in all 111 treatment analyses. Results of the current review, including effect size measures (i.e., Tau-U and Hedge's g), indicate that the IISCA and function-based interventions developed from the results of IISCA produce statistically significant results. Limitations and future directions are also discussed.

Abstract:: The Ross Sea embayment is the outlet for one-third of all Antarctic ice flow, receiving input from both East and West Antarctica. Marine-based ice streams, whose stability is susceptible to global sea-level changes, expand and contract across the Ross Sea continental shelf, eroding and deforming the substrate and transporting sediment subglacially. Deposits from the Last Glacial Maximum in the western Ross Sea provide an opportunity to investigate paleo-ice stream processes using sediment cores associated with glacial landforms. This study combines micro-to macro-sedimentological analyses to characterize lithofacies that represent a glacial-interglacial succession. We observe subtle variations in sediment properties within the subglacial unit that suggest till heterogeneity. Physical characteristics that vary both laterally and vertically indicates different sediment response to glacial stress, resulting in non-pervasive deformation within the till. These observations are consistent with the interpretation that a dynamic ice sheet with variable flow regimes existed across the Ross Sea during the Last Glacial Maximum. Further microscopic evidence of dynamic subglacial conditions includes sediment aggregates preserved as discrete grains in the form of soft sediment clasts or till pellets. Till pellet-rich sediment is commonly associated with the transition from a subglacial to proximal glaciomarine environment, although here we demonstrate they are widespread in both facies. Their widespread occurrence downcore and distribution across the continental shelf provides sedimentological evidence of a deformable bed beneath an ice stream during the Last Glacial Maximum. Ultimately, better tools for discriminating between glacial deposits will allow for more detailed reconstructions of ice-sheet history, and thus determine the forcing mechanisms to which the ice is responding.

This qualitative interview study investigated the opinions of 28 high school-attending youth in Massachusetts related to the content of their sexuality education, what they wished they could learn from a sex education class, and whether and how pornography was addressed. Participants felt that the sex education they received was not in-depth and did not provide them with the information they needed. Further, participants indicated that their instructors were not engaging, approachable, or credible sources of sex-related information. There was strong support for including healthy relationships education as part of sex education as well as including multiple subtopics related to pornography (e.g., body image and pornography, compulsive pornography use, misogyny and pornography). Although there was no clear consensus on whether the ideal modality for delivering sex education is in-person or self-delivered, there was enthusiasm for the "gamification" of sex education content.

This qualitative interview study investigated the opinions of 28 high school–attending youth in Massachusetts related to the content of their sexuality education, what they wished they could learn from a sex education class, and whether and how pornography was addressed. Participants felt that the sex education they received was not in-depth and did not provide them with the information they needed. Further, participants indicated that their instructors were not engaging, approachable, or credible sources of sex-related information. There was strong support for including healthy relationships education as part of sex education as well as including multiple subtopics related to pornography (e.g., body image and pornography, compulsive pornography use, misogyny and pornography). Although there was no clear consensus on whether the ideal modality for delivering sex education is in-person or self-delivered, there was enthusiasm for the "gamification" of sex education content. [ABSTRACT FROM AUTHOR]

Objective: With rising rates of complementary and alternative medicine (CAM) use, the exploration of CAM integration into oncology treatments is becoming increasingly prevalent. Antioxidants have been proposed as potentially beneficial to prevent or treat cancer. However, evidence summaries are limited, and the United States Preventive Services Task Force has recently recommended the use of Vitamin C and E supplementation for cancer prevention. Thus, the objective of this systematic review is to evaluate the existing literature on the safety and efficacy of antioxidant supplementation in oncology patients. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using prespecified search terms in PubMed and CINAHL. Two reviewers independently reviewed titles, abstracts, and full-text articles, with a third reviewer resolving conflicts, before the included articles underwent data extraction and quality appraisal. Results: Twenty-four articles met the inclusion criteria. Of the included studies, nine evaluated selenium, eight evaluated Vitamin C, four evaluated Vitamin E, and three of these studies included a combination of two or more of these agents. The most frequently evaluated cancer types included colorectal cancer (n = 4), leukemias (n = 4), breast cancer (n = 3), and genitourinary cancers (n = 3). Most of the studies focused on the antioxidants' therapeutic efficacy (n = 15) or their use in protecting against chemotherapy- or radiation-induced side effects (n = 8), and one study evaluated the role of an antioxidant in protection against cancer. Findings were generally favorable among the studies, and adverse effects of supplementation were limited. Furthermore, the average score for all the included articles on the Mixed Methods Appraisal Tool was 4.2, indicating the high quality of the studies. Conclusions: Antioxidant supplements may provide benefits in reducing incidence or severity of treatment-induced side effects with limited risk for adverse effects. Large, randomized controlled trials are needed to confirm these findings among various cancer diagnoses and stages. Healthcare providers should understand the safety and efficacy of these therapies to address questions that arise in caring for those with cancer. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms (avolition, anhedonia, asociality) are a prevalent symptom in those across the psychosis-spectrum and also occur at subclinical levels in the general population. Recent work has begun to examine how environmental contexts (e.g. locations) influence negative symptoms. However, limited work has evaluated how environments may contribute to negative symptoms among youth at clinical high risk for psychosis (CHR). The current study uses Ecological Momentary Assessment to assess how four environmental contexts (locations, activities, social interactions, social interaction method) impact state fluctuations in negative symptoms in CHR and healthy control (CN) participants. Methods: CHR youth (n = 116) and CN (n = 61) completed 8 daily surveys for 6 days assessing negative symptoms and contexts. Results: Mixed-effects modeling demonstrated that negative symptoms largely varied across contexts in both groups. CHR participants had higher negative symptoms than CN participants in most contexts, but groups had similar symptom reductions during recreational activities and phone call interactions. Among CHR participants, negative symptoms were elevated in several contexts, including studying/working, commuting, eating, running errands, and being at home. Conclusions: Results demonstrate that negative symptoms dynamically change across some contexts in CHR participants. Negative symptoms were more intact in some contexts, while other contexts, notably some used to promote functional recovery, may exacerbate negative symptoms in CHR. Findings suggest that environmental factors should be considered when understanding state fluctuations in negative symptoms among those at CHR participants. [ABSTRACT FROM AUTHOR]

Mechanisms of Th1-like Treg suppression are unknown in cancer. Two studies in Immunity by Ayala et al. and Zagorulya et al. demonstrate that Th1-like Treg cells interact with type 1 dendritic cells in tumors and draining lymph nodes to potently suppress anti-tumor immunity. [ABSTRACT FROM AUTHOR]