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Abstract Antivenom is currently the first-choice treatment for snakebite envenoming. However, only a low proportion of antivenom immunoglobulins are specific to venom toxins, resulting in poor dose efficacy and potency. We sought to investigate whether linear venom epitopes displayed on virus like particles can stimulate an antibody response capable of recognising venom toxins from diverse medically important species. Bioinformatically-designed epitopes, corresponding to predicted conserved regions of group I phospholipase A2 and three finger toxins, were engineered for display on the surface of hepatitis B core antigen virus like particles and used to immunise female CD1 mice over a 14 weeks. Antibody responses to all venom epitope virus like particles were detectable by ELISA by the end of the immunisation period, although total antibody and epitope specific antibody titres were variable against the different epitope immunogens. Immunoblots using pooled sera demonstrated recognition of various venom components in a diverse panel of six elapid venoms, representing three continents and four genera. Insufficient antibody yields precluded a thorough assessment of the neutralising ability of the generated antibodies, however we were able to test polyclonal anti-PLA2 IgG from three animals against the PLA 2 activity of Naja nigricollis venom, all of which showed no neutralising ability. This study demonstrates proof-of-principle that virus like particles engineered to display conserved toxin linear epitopes can elicit specific antibody responses in mice which are able to recognise a geographically broad range of elapid venoms.

The ascendancy of a federal Australian Labor Party (ALP) government is usually a good omen for the arts. Numerous ALP prime ministers have introduced ambitious schemes: in the 1970s, for [...]

Over the last several years, there has been an increased awareness regarding consensual sexual relationships (CSRs) between professors and students. Specifically, there has been a growing movement for academic institutions to develop policies addressing, discouraging, and/or prohibiting these relationships due to the potential for sexual harassment cases. Even though the appropriateness of such relationships has been widely debated among the university community, a limited amount of empirical work has examined this issue with the majority focusing on attitudinal studies. The current exploratory study consists of a content analysis of 278 faculty and student responses to the question, "If there is a difference between consensual sexual relationships and sexual harassment, what is it?" Responses indicate that there are several overlapping themes for both faculty and students in how they view these differences, with a large number of responses specifically indicating themes such as "CSR is consensual" while "sexual harassment is one sided." There are also some unique perspectives given by faculty regarding the complexities and acceptability of CSRs, who are generally more specific and nuanced in their answers. Considering the complexities of this issue, it is the recommendation of the current study that much more research fully exploring the attitudes of faculty and students is needed to develop a well-rounded and comprehensive policy.

Do quasi-experimental (QE) studies conducted with baseline covariates that are typically available in the longitudinal administrative state databases yield unbiased effect estimates? This paper conducts a within-study comparison (WSC) study that compares experimental impacts of early college high school (ECHS) attendance with QE impacts drawn from the state and locales. We find that (1) QE models for outcomes with natural (matching) pretests replicated the randomized benchmarks quite well; (2) the replication bias is not sensitive to type of propensity score model or method; and (3) imposing locational restrictions (i.e., local matching) on the comparison students--specifically choosing them from among non-treatment students who came from the same feeder middle schools as the treatment students--does not decrease the QE bias; on the contrary, it performed worse than the models that did not impose this restriction for most outcomes. The first two findings are generally consistent with other education WSCs while the third one is not, suggesting that in cases where selection may be driven by individual-level factors, such as this one, local matching may yield biased treatment effect estimates by greatly reducing the pool of potential comparison units and distorting balance on unobservable confounders while prioritizing balance on observable factors.

Abstract A key issue distinguishing prominent evolutionary models of human life history is whether prolonged childhood evolved to facilitate learning in a skill- and strength-intensive foraging niche requiring high levels of cooperation. Considering the diversity of environments humans inhabit, children’s activities should also reflect local social and ecological opportunities and constraints. To better understand our species’ developmental plasticity, the present paper compiled a time allocation dataset for children and adolescents from twelve hunter-gatherer and mixed-subsistence forager societies (n = 690; 3–18 years; 52% girls). We investigated how environmental factors, local ecological risk, and men and women’s relative energetic contributions were associated with cross-cultural variation in child and adolescent time allocation to childcare, food production, domestic work, and play. Annual precipitation, annual mean temperature, and net primary productivity were not strongly associated with child and adolescent activity budgets. Increased risk of encounters with dangerous animals and dehydration negatively predicted time allocation to childcare and domestic work, but not food production. Gender differences in child and adolescent activity budgets were stronger in societies where men made greater direct contributions to food production than women. We interpret these findings as suggesting that children and their caregivers adjust their activities to facilitate the early acquisition of knowledge which helps children safely cooperate with adults in a range of social and ecological environments. These findings compel us to consider how childhood may have also evolved to facilitate flexible participation in productive activities in early life.

Harnessing photocatalysts to facilitate the visible-light-driven breakdown of water molecules is esteemed as a highly auspicious and ecologically sustainable approach for hydrogen production. This study aimed to improve the hydrogen production performance of single ZnO photocatalysts by preparing efficient Bi2Te3/ZnO and Bi2Se3/ZnO composite photocatalysts by microwave method. During the synthesis process, both Bi2Te3 and Bi2Se3 were fully fused and reacted with ZnO to form heterojunctions using magnetic stirring and microwave heating. The experimental results indicate a significant enhancement in the hydrogen production activity of the BT-Z and BS-Z composite photocatalysts. When the Bi2Te3 content is 5%, with a microwave temperature maintained at 135 °C and a microwave time of 90 min, the hydrogen production rate reaches 664.286 μmol∙h−1∙g−1 within 4 hr. On the other hand, when the Bi2Se3 content is 5%, with a microwave temperature maintained at 135 °C and a microwave time of 90 min, the hydrogen production rate reaches 515.306 μmol∙h−1∙g−1 within 4 hr. [ABSTRACT FROM AUTHOR]

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these nonmanufacturers find it difficult to obtain regulatory approval in the U.S. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs. This limits the broad clinical adoption of these drugs and patient access. In this paper, we explore the regulatory landscape for repurposing of small molecule generic drugs within the U.S. We describe case studies of repurposed drugs that have been successfully incorporated into clinical treatment guidelines for cancer without regulatory approval. To encourage greater adoption of generic drugs in clinical practice-that is, to encourage the repurposing of these drugs-we examine existing Food and Drug Administration (FDA) pathways for approval of new uses or indications for generic drugs. We show how non-manufacturers, who are generally more active in generic drug repurposing than manufacturers, could utilize existing regulatory authorities and pathways, and we describe the challenges they face. We propose an extension of the existing 505(b)(2) new drug application (NDA) approval pathway, called a "labeling-only" 505(b)(2) NDA, that would enable non-manufacturers to seek approval of new indications for well-established small molecule drugs when multiple generic products are already available. It would not require new chemistry, manufacturing, and controls (CMC) data or introducing new drug products into the marketplace. This pathway would unlock innovation broadly and enable patients to benefit from the enormous potential of low-cost generic drugs. [ABSTRACT FROM AUTHOR]

Additive manufacturing, commonly known as 3D printing, has significantly advanced component production across multiple industry sectors. Despite its numerous benefits, including reduced lead times and the ability to produce complex geometries, a few obstacles still prevent widespread adoption. Current research efforts have predominantly focused on in situ monitoring and investigating the mechanical properties of 3D-printed materials, with limited attention given to the sources of skewness in the fabricated products. To address this gap, our study aims to explore the factors contributing to skewness in 3D-printed objects. Specifically, we examine the influence of the belt and carriage wheel conditions within the 3D printer on the shape of the fabricated products, resulting from potential distortions in the orientation of the print head carriage during the printing process. A comprehensive analysis was employed, utilizing One-Way ANOVA, Tukey’s test, the Fisher Least Significant Difference Method, and the Friedman Rank Test, to establish statistically significant evidence supporting the notion that the mechanical components, namely the belt and wheel, have a substantial impact on the orientation of the print head, consequently leading to skewness in the final 3D-printed products.

**Background**: The Multidimensional Body-Self Relations Questionnaire (MBSRQ) is a widely used instrument to assess body image. This study aimed to assess MBSRQ Australian norms and test the hypotheses that these would be different to United States norms and to women with breast hypertrophy. Secondary aims were to understand socio-demographic determinants of scores and the change in body image satisfaction associated with breast reduction surgery. **Methods**: Australians ≥18 years were recruited according to the 2016 Census age and sex distribution. Participants completed MBSRQ-Appearance Scales (MBSRQ-AS) and provided socio-demographic information. A comparison was made to previously published US normative scores, to scores of women who had prospectively completed the MBSRQ before and after breast reduction surgery and to women with untreated breast hypertrophy. **Results**: Data for 1016 normative, 209 surgical and 161 breast hypertrophy control participants were analysed. MBSRQ-AS scores for Appearance evaluation and Body areas satisfaction were significantly lower for women than for men. Body mass index (BMI) was a significant predictor across all five scales, with a higher BMI associated with lower scores for appearance and satisfaction. Age and marital status were significant predictors for Body areas satisfaction and Overweight preoccupation. Differences between Australian MBSRQ-AS scale scores and US general population values were significant, with Australian values lower for both sexes. Women with breast hypertrophy had lower scores than population norms but this corrected with breast reduction surgery, with women having scores equivalent to the general population at 12 months post-surgery. **Conclusion**: The Australian population is a distinct population in terms of body image, as measured by the MBSRQ-AS. This normative dataset provides a useful reference for future health-related research in Australian cohorts. Women with breast hypertrophy have a body image that is lower than that of the normal population and this improves with surgery.

ObjectivesChronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults.MethodsThree hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress.ResultsBaseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults.ConclusionsOur data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

We present cosmological results from a combined analysis of galaxy clustering and weak gravitational lensing, using 1321 deg2 of griz imaging data from the first year of the Dark Energy Survey (DES Y1). We combine three two-point functions: (i) the cosmic shear correlation function of 26 million source galaxies in four redshift bins, (ii) the galaxy angular autocorrelation function of 650,000 luminous red galaxies in five redshift bins, and (iii) the galaxy-shear cross-correlation of luminous red galaxy positions and source galaxy shears. To demonstrate the robustness of these results, we use independent pairs of galaxy shape, photometric-redshift estimation and validation, and likelihood analysis pipelines. To prevent confirmation bias, the bulk of the analysis was carried out while "blind" to the true results; we describe an extensive suite of systematics checks performed and passed during this blinded phase. The data are modeled in flat ΛCDM and wCDM cosmologies, marginalizing over 20 nuisance parameters, varying 6 (for ΛCDM) or 7 (for wCDM) cosmological parameters including the neutrino mass density and including the 457×457 element analytic covariance matrix. We find consistent cosmological results from these three two-point functions and from their combination obtain S8≡σ8(Ωm/0.3)0.5=0.773-0.020+0.026 and Ωm=0.267-0.017+0.030 for ΛCDM; for wCDM, we find S8=0.782-0.024+0.036, Ωm=0.284-0.030+0.033, and w=-0.82-0.20+0.21 at 68% C.L. The precision of these DES Y1 constraints rivals that from the Planck cosmic microwave background measurements, allowing a comparison of structure in the very early and late Universe on equal terms. Although the DES Y1 best-fit values for S8 and Ωm are lower than the central values from Planck for both ΛCDM and wCDM, the Bayes factor indicates that the DES Y1 and Planck data sets are consistent with each other in the context of ΛCDM. Combining DES Y1 with Planck, baryonic acoustic oscillation measurements from SDSS, 6dF, and BOSS and type Ia supernovae from the Joint Lightcurve Analysis data set, we derive very tight constraints on cosmological parameters: S8=0.802±0.012 and Ωm=0.298±0.007 in ΛCDM and w=-1.00-0.04+0.05 in wCDM. Upcoming Dark Energy Survey analyses will provide more stringent tests of the ΛCDM model and extensions such as a time-varying equation of state of dark energy or modified gravity.

Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T-score changes from baseline over the 2-year study and contrast these results with the long-term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab-treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T-score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo-to-denosumab: 0.38 and 0.17), with the 2-year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p