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This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4 hi MHCII lo residential macrophages and an influx of increased pro-inflammatory TIM4 lo MHCII hi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation. Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in rhesus macaques and a mouse model of endometriosis.

Background While allied health plays a central role in healthcare, workforce challenges are straining the sector. Challenges are shaped by population changes, emerging models of care, and educational limitations, and were exacerbated by COVID-19. This study aimed to identify drivers of recruitment and retention for allied health clinicians in an Australian metropolitan setting. Identifying and addressing these factors is essential to the design and implementation of tailored, evidence-informed workforce strategy and policy. Methods This cross-sectional, online survey explored workplace attraction, job seeking behaviours, and workplace perceptions. 29 Likert-scale statements informed by the existing literature examined factors influencing allied health retention. Allied health employees from a single Australian metropolitan health network were invited to participate. Descriptive statistics, logistic regression, and deductive content analysis were undertaken. Results 42.6% ( n  = 593) of those invited participated in the survey, with 45.7% ( n  = 271) of participants having been with the organisation for six or more years. 35% ( n  = 197) of respondents to a question about intention to leave agreed that they aimed to leave their current role within six months. Variables associated with intention to leave were not feeling a sense of satisfaction with their role (odds ratio [OR] 1.51, 95% CI 1.22–1.85), not being recognised and rewarded by the team manager (OR 1.37, 95% CI 1.12–1.67), not working in the preferred clinical area (OR 1.56; 95% CI 1.25–1.95), and feeling burned out by the job (OR 1.44; 95% CI 1.16–1.78). Qualitative findings support the centrality of aspects of the job (job characteristics), the organisational context (rewards offered; climate; organisational support) and person-context interface (peer/group relations; work-life conflict) to attraction, retention, and attrition in roles. Conclusion This study identifies factors affecting recruitment, retention, and attrition of allied health professionals in a metropolitan setting. Findings are impacted by the personal and professional effects of the COVID-19 pandemic response. Results provide a baseline upon which the impact of interventions can be measured, while informing the prioritisation and design of tailored workforce strategies. Further, findings may inform local policy responses to improve the allied health workforce and ensure excellent care for the community.

APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors. Previous studies have proposed that APOBEC3B (A3B) is the major source of mutagenesis in breast cancer (BRCA). We show that APOBEC3A (A3A) is the only APOBEC whose expression correlates with APOBEC-induced mutation load and that A3A expression is responsible for cytidine deamination in multiple BRCA cell lines. Comparative analysis of A3A and A3B expression by qRT-PCR, RSEM-normalized RNA-seq, and unambiguous RNA-seq validated the use of RNA-seq to measure APOBEC expression, which indicates that A3A is the primary correlate with APOBEC-mutation load in primary BRCA tumors. We also demonstrate that A3A has >100-fold more cytidine deamination activity than A3B in the presence of cellular RNA, likely explaining why higher levels of A3B expression contributes less to mutagenesis in BRCA. Our findings identify A3A as a major source of cytidine deaminase activity in breast cancer cells and possibly a prominent contributor to the APOBEC mutation signature.

The research-to-practice gap is a well-known phenomenon. The adoption of evidence into clinical practice needs to consider the complexity of the health care system and a multitude of contextual issues. Research evidence is usually a form of extrinsic motivation for practice change, but works best when it aligns with the intrinsic values of the system and the people in it. Health professionals tend to refer to internal, local policies, information sources and procedures more than external academic research evidence. This protocol paper describes a mixed-methods study with a quasi-experimental design that seeks to investigate how involvement in research might impact the uptake or implementation of recommendations arising from that research. Research evidence for the effectiveness and cost-effectiveness of mobilisation alarms for falls prevention will be disseminated at 36 hospital wards in Victoria, Australia. Eighteen of these wards will be sites where this research evidence was generated; another 18 wards will not have been involved in evidence generation. The uptake of research evidence will be measured across three time points using quantitative and qualitative data. Trial registration : This study has been registered with the Australian New Zealand Clinical Trials Registry: ACTRN12621000823875p .

UV exposure induces a mutation signature of C > T substitutions at dipyrimidines in skin cancers. We recently identified additional UV-induced AC > TT and A > T substitutions that could respectively cause BRAF V600K and V600E oncogenic mutations. The mutagenic bypass mechanism past these atypical lesions, however, is unknown. Here, we whole genome sequenced UV-irradiated yeast and used reversion reporters to delineate the roles of replicative and translesion DNA polymerases in mutagenic bypass of UV-lesions. Our data indicates that yeast DNA polymerase eta (pol η) has varied impact on UV-induced mutations: protecting against C > T substitutions, promoting T > C and AC > TT substitutions, and not impacting A > T substitutions. Surprisingly, deletion rad30 Δ increased novel UV-induced C > A substitutions at CA dinucleotides. In contrast, DNA polymerases zeta (pol ζ) and epsilon (pol ε) participated in AC > TT and A > T mutations. These results uncover lesion-specific accurate and mutagenic bypass of UV lesions, which likely contribute to key driver mutations in melanoma. Vandenberg et al. identify differing roles of yeast DNA polymerases during accurate and mutagenic synthesis past common and rare ultraviolet light photoproducts. Similar mechanisms may contribute to driver mutations causing skin cancer in humans.

Vitamin A is required for male fertility and normal spermatogenesis. Retinoic acid (RA), an active metabolite of vitamin A, is necessary for spermatogonial maturation and proper entry of germ cells into meiotic prophase in the postnatal testes. The expression of Stra8, which is essential for successful meiosis in both male and female gonads and normal spermatogenesis, is directly related to the availability of RA. This study examined the developmental expression pattern of Stra8 transcript in both male and female gonads, provided specific cellular localization of STRA8 protein in the postnatal and adult testis, and investigated RA actions in adult germ cells in a vitamin A-sufficient condition. The peak of Stra8 mRNA expression coincided with the onset of meiosis in postnatal testes. STRA8 protein was detected in gonocytes as early as 5 days postpartum. The expression of STRA8 protein in the neonatal testes was not uniform among spermatogonia, perhaps heralding the asynchronous beginning of spermatogenesis. In adult testes, the highest level of Stra8 mRNA and protein was found in seminiferous epithelial stages VI-VIII. STRA8 protein was localized to some type A and B spermatogonia, preleptotene spermatocytes, and early leptotene spermatocytes. In the vitamin A-sufficient adult testes, RA but not retinol acetate stimulated Stra8 mRNA expression. STRA8 protein expression in adult spermatogonia was induced by RA stimulation, suggesting its role in spermatogonial differentiation. Retinoic acid also increased the number of preleptotene spermatocytes exhibiting 5-bromo-2-deoxyuridine incorporation, indicating a more synchronized premeiotic DNA replication.

Background: One form of domestic and family violence (DFV) is financial abuse, which involves a person manipulating another person’s access to finances, assets, and financial decision-making. The aim of this study was to understand the perceived role of Australian financial institutions, government bodies and other key stakeholders in the prevention, early identification and resolution of financial abuse in small businesses. Methods: A single workshop was conducted in Melbourne, Australia, in November 2024. Representatives from five stakeholder groups were invited to participate: (i) Australian regulated financial institutions; (ii) Australian unregulated commercial lenders; (iii) government bodies; (iv) small business professional services organisations and their peak bodies; and (v) industry and representative bodies. Results: Four main themes were generated relating to the prevention, early identification and resolution of financial abuse in small businesses: (1) shining a light on financial abuse; (2) detecting and revealing red flags; (3) business lending practices create vulnerability; and (4) building a collective response. Conclusion: Whilst institutions demonstrate inherent potential for addressing family violence and financial abuse within small business contexts, realising this capacity requires substantial investment in education, contextual literacy development, collective responses and structural and legislative reform.

Disinvestment is the removal or reduction of previously provided practices or services, and has typically been undertaken where a practice or service has been clearly shown to be ineffective, inefficient and/or harmful. However, practices and services that have uncertain evidence of effectiveness, efficiency and safety can also be considered as candidates for disinvestment. Disinvestment from these practices and services is risky as they may yet prove to be beneficial if further evidence becomes available. A novel research approach has previously been described for this situation, allowing disinvestment to take place while simultaneously generating evidence previously missing from consideration. In this paper, we describe how this approach can be expanded to situations where three or more conditions are of relevance, and describe the protocol for a trial examining the reduction and elimination of use of mobilisation alarms on hospital wards to prevent patient falls. Our approach utilises a 3-group, concurrent, non-inferiority, stepped wedge, randomised design with an embedded parallel, cluster randomised design. Eighteen hospital wards with high rates of alarm use (≥3%) will be paired within their health service and randomly allocated to a calendar month when they will transition to a “Reduced” (<3%) or “Eliminated” (0%) mobilisation alarm condition. Dynamic randomisation will be used to determine which ward in each pair will be allocated to either the reduced or eliminated condition to promote equivalence between wards for the embedded parallel, cluster randomised component of the design. A project governance committee will set non-inferiority margins. The primary outcome will be rates of falls. Secondary clinical, process, safety, and economic outcomes will be collected and a concurrent economic evaluation undertaken.

In responding to Murakami and Siegel’s “Becoming Bermuda grass,” one is led to reflect on one’s own practice in what becomes an example of reflexivity. Following the authors’ lead of incorporating Deleuze and Guattari’s rhizomatic theory and the art form of decalcomania to reflect on practice, discoveries are made regarding the practice of a middle school science teacher. These reflective discoveries can be used to inform teaching practice in a manner that supports the development of identities of participation.

Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries consistent with mutations resulting from 3meC. Ectopic expression of a human AlkB homolog in Shu-deficient yeast rescues MMS-induced growth defects and increased mutagenesis. Thus, our work identifies a novel homologous recombination-based mechanism mediated by the Shu complex for coping with alkylation adducts.