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HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Purpose: Oncofertility care at cancer diagnosis remains underimplemented across oncology and fertility care settings, with limited tools to scale up effective implementation strategies. Using implementation science theory, we systematically assessed factors that influence oncofertility care implementation and mapped scalable strategies, particularly electronic health record (EHR)-enabled ones, that fit adult and pediatric oncology care contexts. Methods: Using purposeful sampling, we recruited health care providers and female, reproductive-aged survivors of adolescent and young adult (AYA) cancers (AYA survivors) from a comprehensive cancer center and a freestanding children's hospital to semistructured interviews and focus groups. Using thematic analysis combining inductive codes with deductive codes using the Consolidated Framework for Implementation Research (CFIR), we characterized barriers and facilitators to care and designed responsive strategies. Two coders independently coded each transcript. Results: We recruited 19 oncology and fertility providers and 9 cancer survivors. We identified barriers and facilitators to oncofertility care in the CFIR domains of individual, inner setting, outer setting, and process, allowing us to conceptualize oncofertility care to encompass three core components (screening, referral, and fertility preservation counseling) and map five strategies to these components that fit an adult and a children's context and bridge oncology and fertility practices. The strategies were screening using a best practice advisory, referral order, telehealth fertility counseling, provider audit and feedback, and provider education. All but provider education were EHR tools with embedded efficiencies. Conclusion: An implementation science approach systematically assessed oncofertility care and mapped strategies to provide a theory-based approach and scalable EHR tools to support wider dissemination.

Abstract Background Tinnitus affects 10 to 15% of the population, but its underlying causes are not yet fully understood. Hearing loss has been established as the most important risk factor. Ageing is also known to accompany increased prevalence; however, the risk is normally seen in context with (age-related) hearing loss. Whether ageing per se is a risk factor has not yet been established. We specifically focused on the effect of ageing and the relationship between age, hearing loss, and tinnitus. Methods We used two samples for our analyses. The first, exploratory analyses comprised 2249 Austrian individuals. The second included data from 16,008 people, drawn from a publicly available dataset (NHANES). We used logistic regressions to investigate the effect of age on tinnitus. Results In both samples, ageing per se was found to be a significant predictor of tinnitus. In the more decisive NHANES sample, there was an additional interaction effect between age and hearing loss. Odds ratio analyses show that per unit increase of hearing loss, the odds of reporting tinnitus is higher in older people (1.06 vs 1.03). Conclusions Expanding previous findings of hearing loss as the main risk factor for tinnitus, we established ageing as a risk factor in its own right. Underlying mechanisms remain unclear, and this work calls for urgent research efforts to link biological ageing processes, hearing loss, and tinnitus. We therefore suggest a novel working hypothesis that integrates these aspects from an ageing brain viewpoint.

Abstract Background Fitness has important implications for physical activity behavior and is associated with various health-related outcomes. It can be assessed through a test battery or a self-reported questionnaire. One example is the FFB-Mot (Funktionsfragebogen Motorik; engl. functional fitness questionnaire) which consist of 28 items to assess four components of fitness in adults: cardiorespiratory fitness/ endurance, muscular strength, gross motor coordination, and flexibility. The aims of this manuscript were to (1) provide an English-version of the FFB-Mot questionnaire (developed from the German-version using translation and back-translation) to the international community of researchers in the areas of physical activity, fitness and health in adults, and (2) examine the predictive validity of the FFB-Mot questionnaire in a large sample of community-dwelling adults. Methods We used data from a longitudinal study in Germany with four measurement waves over a period of 18 years, with samples ranging between 310 and 437 participants (1572 adults in total, mean ages 46–58 years). To assess predictive validity, we calculated Pearson correlations between FFB-Mot data collected in 1997 and external health-related criteria (i.e., subjective health status, physician-rated health status, back pain, physical complaints and physical activity in minutes per week) collected in 2002, 2010, and 2015, and separately for males and females. Results We observed correlations between higher FFB-Mot scores with better subjective health status (in 2002: males, r = 0.25; females, r = 0.18; in 2010: males, r = 0.29; females, r = 0.28; in 2015: males, r = 0.40), and higher physical activity (in 2002: males, r = 0.24; females, r = 0.25; in 2010: males, r = 0.30; females, r = 0.38; in 2015: females, r = 0.27). Higher FFB-Mot scores were also correlated with lower back pain (in 2002: males, r = -0.23; females, r = -0.25; in 2010: females, r = -0.22), less physical complaints (in 2002: males, r = -0.36; females, r = -0.24), and better physician-rated health status (in 2002: males, r = -0.41; females, r = -0.29, 2010: males, r = -0.38; females, r = -0.44; in 2015: males, r = -0.47). Conclusions Our results suggest that the FFB-Mot to assess fitness in adults has predictive validity for health-related outcomes as indicated by significant correlations, albeit some effect sizes are small. The FFB-Mot may be used as one-time assessment of self-reported fitness, or for repeated testing to assess change of self-reported fitness over time and in different settings (e.g., public health research).

There is increasing recognition of the crucial need for robust community engagement in health research and clinical trials. Despite this awareness, challenges persist in bridging the gap between researchers and communities. Much of the current discourse focuses on addressing issues such as cultural humility and equitable partnerships. To expand this conversation, we conducted community engagement studios, following the model by Joosten et al. We wanted to gather perspectives on research involvement across New Mexico. This process and resultant findings offer valuable insights into effective community engagement practices and advance clinical and translational science by amplifying community voices and needs.

The recent rise in artificial intelligence systems, such as ChatGPT, poses a fundamental problem for the educational sector. In universities and schools, many forms of assessment, such as coursework, are completed without invigilation. Therefore, students could hand in work as their own which is in fact completed by AI. Since the COVID pandemic, the sector has additionally accelerated its reliance on unsupervised 'take home exams'. If students cheat using AI and this is undetected, the integrity of the way in which students are assessed is threatened. We report a rigorous, blind study in which we injected 100% AI written submissions into the examinations system in five undergraduate modules, across all years of study, for a BSc degree in Psychology at a reputable UK university. We found that 94% of our AI submissions were undetected. The grades awarded to our AI submissions were on average half a grade boundary higher than that achieved by real students. Across modules there was an 83.4% chance that the AI submissions on a module would outperform a random selection of the same number of real student submissions.

Aims: To evaluate a newly developed microscale quantitative suspension test compared to the existing standard suspension test using determination of the bactericidal and yeasticidal activity of glutaral as one step to improve the sustainability of disinfectant testing.Methods: The testing principles of the quantitative suspension test according to VAH method 9 (comparable to EN 13727) was used as a standard suspension test using 8.0 mL product test solution, 1.0 mL organic load and 1.0 mL test suspension. In addition, a micro-scale suspension test was performed in 96-well plates with 160 µL product test solution, 20 µL organic load and 20 µL test suspension. ATCC 6538, ATCC 15442 and ATCC 10231 were test organisms. Glutaral was tested at concentrations of 0.05%, 0.1%, 0.2% and 0.3% with exposure times of 1, 5 and 15 min. Polysorbate 80 (30 g/L), lecithin (9 g/L), L-histidine (1 g/L) and glycine (1/L) were used as validated neutralizers. After serial dilution of the disinfectant-neutralizer-mixture, plates were incubated for 48 h at 36°C (bacteria) or 72 hours at 30°C () and colony forming units (cfu) counted. The lg reduction was calculated as the difference between the results of the water control and the disinfectant at the end of the exposure time. All experiments were done in triplicate under clean conditions. Means of lg reduction were compared with the unpaired test, p

Summary: Adaptive plasticity to the standard chemotherapeutic temozolomide (TMZ) leads to glioblastoma progression. Here, we examine early stages of this process in patient-derived cellular models, exposing the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion. By integration of a reporter, we show its preferential activity in rare, stem-like ALDH1A1+ cells, immediately increasing expression upon TMZ exposure. Naive, genetically unmodified KDM5Bhigh cells phosphorylate AKT (pAKT) and act as slow-cycling persisters under TMZ. Knockdown of KDM5B reverses pAKT levels, simultaneously increasing PTEN expression and TMZ sensitivity. Pharmacological inhibition of PTEN rescues the effect. Interference with KDM5B subsequent to TMZ decreases cellular vitality, and clonal tracing with DNA barcoding demonstrates high individual levels of KDM5B to predict subclonal expansion already before TMZ exposure. Thus, KDM5Bhigh treatment-naive cells preferentially contribute to the dynamics of drug resistance under TMZ. These findings may serve as a cornerstone for future biomarker-assisted clinical trials.

BACKGROUND: Although there is increasing investment to implement evidence-based practices (EBPs) in public systems across the USA, continued or sustained use of EBPs after initial implementation remains a challenge. The low integration of EBPs in routine practice severely limits their public health impact, highlighting the need to understand factors that affect the return on costly investments in EBP implementation. This study aims to (1) characterize trajectories of EBP delivery volume through a reimbursement-driven implementation and (2) examine impacts of system-level policy regulatory activity and state-level mental health services funding on the implementation reimbursement strategy. METHODS: This study involved secondary data analyses. Psychotherapy administrative claims and regulatory site visit data from the Los Angeles County Department of Mental Health and California state mental health expenditures were extracted from 2010 to 2017. Multilevel regression examined EBP claims volume over time with state expenditures and regulatory compliance as predictors. RESULTS: EBP claims volume trajectories demonstrated a rapid initial increase, followed by a period of decrease, and a small increase in the final year. State mental health expenditures increased across time reflecting increased funding availability. State mental health expenditures and system regulatory compliance were inversely related to EBP claims volume. CONCLUSIONS: The impact of reimbursement-driven EBP implementation strategy is sensitive to multiple outer-context determinants. At the system level, commitment to fidelity of implementation regulations resulted in reduced use of the reimbursement strategy. Alternative reimbursement streams not tied to EBPs coupled with an expanded array of reimbursable services also impacted the use of the reimbursement strategy to implement EBPs.

PurposeAlthough patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.Patients and methodsWe conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.ResultsBaseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.ConclusionsB cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

Proponents of ‘Blockchain for Good’–blockchain efforts seeking to enable benefits to humans and the environment–have suggested that the technology can support sustainability. However, while previous research has addressed aspects of the sustainability affordances of Blockchain for Good projects, the constraints that these projects impose have not faced equal consideration. Furthermore, the theoretical concepts of sustainability ‘problems’ and ‘solutions’ implicit in these projects have not been made clear. In this exploratory study, we evaluate the sustainability of 28 Blockchain for Good projects that use cryptocurrencies or tradable tokens with regard to the UN sustainability goals. These projects span a range of goals, such as supply chain tracking, transparent charity, and fairer voting. Despite their admirable goals, we find that current Blockchain for Good projects are unlikely to contribute to a sustainable future due to technical limitations and a conceptual framing that favors the status quo rather than transformative change.

Valid and reliable measures are needed to better understand the relationship between physical activity and crime. This paper provides a comprehensive psychometric evaluation of measures developed in the Safe and Fit Environments (SAFE) Study to assess a crime-PA conceptual framework. In addition to assessing the basic psychometric properties of each measure (e.g., variable distributions [item/scale level], internal consistency reliability), this study formally examined the measurement validity and invariance of measures across four age groups using confirmatory factor analysis. The sample (n = 2173) included 336 Adolescents (aged 12-17), 532 Young adults (aged 18-39), 838 Middle Age Adults, and 467 Older Adults (aged 66+). The psychometric evaluation of (sub)scales showed consistent factorial validity and internal consistency reliability across the majority of the measures and across the four age groups. Specifically, 14 of the 17 measures displayed statistically and practically significant factor loadings and internal consistency values in the overall sample and across the age groups. The pattern of correlations for each (sub)scale with other (sub)scales/indexes largely did not exhibit redundancy across measures. The findings expanded upon the test-retest reliability evaluation reported in Patch et al. (2019), and clarified key aspects of the construct validity of these indicators. The latter bodes well for potential utility of these indicators in future predictive models.