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The main goal of this paper is to suggest a combination of data analyses -- notably generalized additive models, time-series clustering methodology, visual methods for significance testing and qualitative analyses -- that relate to Complex Dynamic Systems Theory (CDST). To this end, we report on findings from a larger project conducted in a bilingual (pre)primary school in Switzerland, aiming to elucidate the complex ways that L2 English development emerges over time in 45 children who received German/English bilingual instruction over a period of eight years (age 5-12) in combination with emerging extracurricular exposure to English. The results reveal that increased extracurricular activities in English are particularly noticeable during periods of rapid development, but the effects seem temporally limited to the end stages of testing and strongly hinge on the cluster in question (i.e., learners with trajectorial similarities). We relate the findings to the "authenticity gap" between English inside and outside of school, as clusters who perceive a discrepancy between in- and out-of-school encounters with English also show rapid development that is characterized by increased English exposure during extracurricular activities. Methodological implications of adopting non-linear models, which can model complex dynamic relationships in order to better reconcile generalizability, variability, and individuality, are discussed.

This study is the first to explore microdevelopment in sociolinguistic evaluative judgments of standard German and Austro-Bavarian dialect by adult second language learners of German by using dense time serial measurements. Intensive longitudinal data (10 observations per participant) were collected from four learners at approximately weekly intervals over 3 months. We employed generalized additive models with superimposed periods of significant change to identify rapid developmental phases in individual developmental trajectories. By triangulating these models with qualitative introspective and retrodictive interview data, we identified environmental and psychological stimuli for change. Learners evinced increasing and decreasing periods of significant change, independent of length of residence. Dynamic constellations of identity- and agency-related variables alongside more intensive social interaction with target-variety speakers contributed to significant changes. We discuss findings from a complexity perspective and advocate for microlongitudinal studies in variationist second language acquisition to better capture stimuli for change in learners' emerging multivarietal repertoires.

BackgroundThe HIV epidemic disproportionately impacts transgender women in the United States. Cohort studies identify unique risks for affected populations, but use of facility-based methods may bias findings towards individuals living in research catchment areas, more engaged in health services, or, in the case of transgender populations, those who are open about their transgender identity. Digital clinical trials and other online research methods are increasingly common, providing opportunity to reach those not commonly engaged in research. Simultaneously, there is a need to understand potential biases associated with digital research, how these methods perform, and whether they are accepted across populations. ObjectiveThis study aims to assess the feasibility of developing and implementing an online cohort of transgender women to assess risks for HIV acquisition and other health experiences. Further, this study aims to evaluate how an online cohort compares to a site-based, technology-enhanced cohort for epidemiologic research. The overarching goal is to estimate incidence of HIV and other health outcomes among transgender women in eastern and southern United States. MethodsThis substudy is part of a larger multisite prospective cohort (LITE) conducted among transgender women, which also includes a site-based, technology-enhanced cohort in 6 eastern and southern US cities. The online cohort was launched to enroll and follow participants across 72 cities in the same region and with similar demographic characteristics as the site-based cohort. Participants are followed for 24 months. Adult transgender women are recruited via convenience sampling (eg, peer referrals, social media, and dating apps). Participants reporting negative or unknown HIV status are enrolled in a baseline study visit, complete a sociobehavioral survey, and provide oral fluid specimens to test for HIV. Participants not living with HIV (lab-confirmed) at baseline are offered enrollment into the cohort; follow-up assessments occur every 6 months. ResultsEnrollment into the online cohort launched in January 2019. Active recruitment stopped in May 2019, and enrollment officially closed in August 2020. A total of 580 participants enrolled into and are followed in the cohort. A recruitment-enrollment cascade was observed across screening, consent, and completion of study activities. Implementation experiences with HIV test kits highlight the need for heavy staff engagement to support participant engagement, visit completion, and retention, even with automated digital procedures. ConclusionsThis study is responsive to increasing research interest in digital observational and intervention research, particularly for populations who are most affected by the HIV epidemic and for those who may otherwise not participate in person. The progression across stages of the recruitment-enrollment cascade provides useful insight for implementation of cohort studies in the online environment. International Registered Report Identifier (IRRID)DERR1-10.2196/29152

BackgroundThe US National HIV/AIDS Strategy 2020 calls for increasing access to care, improving outcomes of people living with HIV, and targeting biomedical prevention efforts, including access to pre-exposure prophylaxis (PrEP) in communities where HIV is most heavily concentrated. The cities of Baltimore, Maryland (MD); Washington, DC; and Philadelphia, Pennsylvania (PA) are disproportionately burdened by high rates of new cases of HIV infection, with high prevalence among young Black and Latinx men who have sex with men (YBLMSM) and young Black and Latinx transgender women (YBLTW) aged 15-24 years. ObjectiveThis study aims (1) to identify and recruit YBLMSM and YBLTW who are at risk or living with HIV in Baltimore, MD; Philadelphia, PA; and Washington, DC, using respondent-driven sampling (RDS) with targeted seed selection, and (2) to assess the efficacy of a coach-based mobile-enhanced intervention (MEI) compared with standard of care (SOC) to increase successful engagement and retention into HIV, PrEP, and substance use treatment care across the HIV care and prevention continua in 3 Mid-Atlantic cities. This paper describes the protocol and progress as of October 20, 2019. MethodsThis study uses a multiphase mixed methods design. The first phase is a formative, qualitative research with focus group discussions and key informant interviews. The second phase consists of evaluating the ability of RDS with targeted seed selection. The third phase includes 2 embedded randomized controlled trials (RCTs), where participants complete a baseline sociobehavioral survey, rapid HIV testing, and eligible youth enroll in parallel status-dependent RCTs that randomize the participant to 1 of 2 study arms: MEI with coach or SOC. Participants are asked to complete a web-based survey and provide biologic specimens—HIV-1 RNA (viral load) or HIV-1 antibody test and urine drug screen—at baseline and at 3, 6, and 12 months, and an exit interview at 18 months. ResultsA formative qualitative research was conducted in February 2017 and May 2018, and this led to further refinement of recruitment and study methods. Aim 1 recruitment began in September 2017 with subsequent enrollment into the RCTs. Recruitment is ongoing with 520 participants screened and 402 (77.3%) enrolled in aim 1 by October 2020. Of these, 159 are enrolled in the 2 randomized trials: 36 (22.6%) HIV-positive not virally suppressed (aim 2) and 123 (77.4%) high-risk HIV-negative (aim 3). ConclusionsThis study has the potential to significantly impact the medical and substance use services provided to YBLMSM and YBLTW in the United States by providing rigorous scientific evidence outlining approaches and strategies that improve the uptake and engagement of YBLMSM and YBLTW in the HIV treatment and prevention continuum. Trial RegistrationClinicalTrials.gov NCT03194477; https://clinicaltrials.gov/ct2/show/NCT03194477 International Registered Report Identifier (IRRID)DERR1-10.2196/17269

BackgroundBlack and Latina transgender women (TW) experience a disparate burden of HIV and related comorbidities, including poor mental health and cardiovascular disease (CVD) risks. Pervasive multilevel stigma and discrimination operate as psychosocial stressors for TW living with HIV and shape health disparities for this population. Gender-affirming hormone therapy (GAHT) is commonly used by TW to facilitate alignment of the body with gender identity; in the context of stigma, GAHT may both improve mental health and increase CVD risks. ObjectiveThis study aims to quantify the longitudinal relationship between stigma and chronic stress among black and Latina TW living with HIV. Secondary objectives include identifying pathways linking chronic stress to HIV comorbidities and exploring chronic stress as a mediator in the pathway linking stigma and GAHT to CVD comorbidities. MethodsThis US-based mixed methods longitudinal study will enroll a prospective cohort of 200 black and Latina TW living with HIV, collecting quantitative survey data, qualitative interviews, and biomarkers of chronic stress. Interviewer-administered surveys will include validated psychosocial measures of self-reported stigma and discrimination, perceived stress, CVD risk factors, mental health, access to gender-affirming care, coping, and social support. Medical record abstraction will collect data on GAHT use, CD4 count, HIV viral load, antiretroviral therapy, treatment, and comorbid conditions. Clinical measures will include physiological biomarkers as well as salivary and blood-based biomarkers of chronic stress. Survey data will be collected every 6 months (baseline, and 6, 12, 18, and 24 months), and biospecimens will be collected at baseline and at 12 and 24 months. A purposive subsample (stratified by use of GAHT and presence of depressive symptoms) of 20 to 30 TW living with HIV will be invited to participate in in-depth interviews at 6 and 18 months to explore experiences of intersectional stigma, chronic stress, and the role of GAHT in their lives. ResultsThis study was funded by the National Institute on Minority Health and Health Disparities in December 2018. The study community advisory board and scientific advisors provided critical input on study design. Recruitment began in October 2019 (n=29 participants as of submission) and data collection will continue through 2022, with publication of baseline results anticipated summer 2021. ConclusionsThis study will focus on black and Latina TW living with HIV, an understudied health disparities population, advance both stigma and intersectionality research, and move chronic stress physiology research toward a more nuanced understanding of sex and gender. The comprehensive methodology will support the exploration of the role of exogenous estrogen in the pathways between stress and HIV comorbidities, elucidating the role of GAHT in the stress-health relationship. Finally, this study will provide longitudinal evidence of the impact of stigma-related chronic stress on the lives of black and Latina TW living with HIV integrating qualitative and quantitative data with psychosocial, clinical, and biological measures. International Registered Report Identifier (IRRID)DERR1-10.2196/17076

BackgroundPre-exposure prophylaxis (PrEP) is highly effective in the prevention of HIV acquisition, particularly for men who have sex with men (MSM). Questions remain on the benefits of PrEP and implementation strategies for those at occupational risk of HIV acquisition in sex work, as well as on methods to support adherence among young people who initiate PrEP. ObjectiveThe Combination Prevention Effectiveness study for young cisgender MSM and transgender women (TGW) aims to assess the effectiveness and cost-effectiveness of a combination intervention among HIV-uninfected young MSM and TGW engaged in sex work in Thailand. MethodsThis open-label, nonrandomized assessment compares the relative effectiveness of a combination prevention intervention with and without daily oral emtricitabine and tenofovir disoproxil fumarate (Truvada) PrEP with SMS-based adherence support. HIV-uninfected young MSM and TGW aged 18 to 26 years in Bangkok and Pattaya who self-report selling/exchanging sex at least once in the previous 12 months are recruited by convenience sampling and peer referral and are eligible regardless of their intent to initiate PrEP. At baseline, participants complete a standard assessment for PrEP eligibility and may initiate PrEP then or at any time during study participation. All participants complete a survey and HIV testing at baseline and every 3 months. Participants who initiate PrEP complete monthly pill pickups and may opt-in to SMS reminders. All participants are sent brief weekly SMS surveys to assess behavior with additional adherence questions for those who initiated PrEP. Adherence is defined as use of 4 or more pills within the last 7 days. The analytic plan uses a person-time approach to assess HIV incidence, comparing participant time on oral PrEP to participant time off oral PrEP for 12 to 24 months of follow-up, using a propensity score to control for confounders. Enrollment is based on the goal of observing 620 person-years (PY) on PrEP and 620 PY off PrEP. ResultsAs of February 2019, 445 participants (417 MSM and 28 TGW) have contributed approximately 168 PY with 95% (73/77) retention at 12 months. 74.2% (330/445) of enrolled participants initiated PrEP at baseline, contributing to 134 PY of PrEP adherence, 1 PY nonadherence, and 33 PY PrEP nonuse/noninitiation. Some social harms, predominantly related to unintentional participant disclosure of PrEP use and peer stigmatization of PrEP and HIV, have been identified. ConclusionsThe majority of cisgender MSM and TGW who exchange sex and participate in this study are interested in PrEP, report taking sufficient PrEP, and stay on PrEP, though additional efforts are needed to address community misinformation and stigma. This novel multilevel, open-label study design and person-time approach will allow evaluation of the effectiveness and cost-effectiveness of combination prevention intervention in the contexts of both organized sex work and exchanged sex. International Registered Report Identifier (IRRID)RR1-10.2196/15354

This cross-sectional study addresses for the first time the non/linear association between individual learner differences of social, proficiency-related, and socioaffective nature (length of residence [LoR], varietal proficiency, exposure, and socioaffect) and differential outcomes in L2 sociolinguistic repertoires against the backdrop of the Austro-Bavarian naturalistic context. Forty adult migrant L2 German learners participated in a virtual reality experiment involving interactions with dialect-speaking and standard German-speaking interlocutors. The goal was to explore differences in participants' interpersonal varietal behavior, that is, their addressee-relational variable use of standard German, Austro-Bavarian dialect, and mixture varieties. The results of Bayesian multinomial modeling indicated that LoR, dialect exposure, and proficiency, as well as reduced anxiety when speaking dialect, predicted differences in interpersonal varietal behavior. That said, a visual-quantitative analysis revealed critical thresholds concerning when, within these predictors, changes in sociolinguistic behavior manifested, indicating a rapid change in sociolinguistic development at the inter-individual level and ultimately facilitating initial insights as to how advanced one needs to be in order to engage in sociolinguistic variation in the Austro-Bavarian naturalistic context.

As an important source of sub-micrometer particles, atmospheric new particle formation (NPF) has been observed in various environments. However, most studies provide little more than snapshots of the NPF process due to their underlying observations being limited in space and time. To obtain statistically relevant evidence on NPF across various environments, we investigated the characteristics of NPF based on a 5-year dataset of the German Ultrafine Aerosol Network (GUAN). The results were also compared with observations in previous studies, with the aim to depict a relatively complete picture of NPF in central Europe. The highest NPF occurrence frequency was observed in regional background sites, with an average of about 19 %, followed by urban background (15 %), low-mountain-range (7 %), and high Alpine (3 %) sites. The annual mean growth rate between 10 and 25 nm varied from 3.7–4.7 nm h−1, while the formation rate with same size range 10–25 nm from 0.4 to 2.9 cm−3 s−1. The contribution of NPF to ultrafine particles (UFPs) was about 13 %, 21 %, and 7 % for the urban background, regional background, and low mountain range, respectively. The influence of NPF on cloud condensation nuclei (CCN) number concentration and the aerosol extinction coefficient for NPF days was the highest in mountainous areas. These findings underscore the importance of local environments when assessing the potential impact of NPF on regional climate in models, and they also emphasize the usefulness of a long-term aerosol measurement network for understanding the variation in NPF features and their influencing factors over a regional scale.

The present study takes a variationist perspective to explore the varietal repertoires of adult learners of German as a second language (L2), that is, their variable use of standard German, Austro-Bavarian dialect, and mixture varieties. Forty L2 learners completed a virtual reality task involving interactions with dialect-speaking and standard-German-speaking interlocutors. Using Bayesian multilevel modeling, the goal was to explore differential outcomes in the acquisition of sociolinguistic competence by determining whether participants adjusted their varietal behavior to match that of the interlocutor (i.e., varietal convergence). The results show that there were no interindividual addressee-dependent convergence tendencies. A holistic person-centered analysis of individual learners' intraspeaker variation revealed that only select L2 learners adjusted their usage patterns but did not entirely invert their usage of dialect and standard language as a function of the variety of the interlocutor. Introspective qualitative data speak to potential drivers behind the differential development of L2 (multi)varietal repertoires.

This study is the first to investigate subject-level variability in sociolinguistic evaluative judgements by 30 adult L2 German learners and explore whether the observed variability is characterizable as a function of individual differences in proficiency, exposure, and motivation. Because group-level estimates did not paint an accurate picture of the individual, we propose methods capable of integrating population-level estimates with person- and ensemble-centered approaches so as to reconcile generalizability and individuality. Using random effects from Bayesian mixed-effects models, we found that global subject-level variability in evaluative judgements was not predicted by individual differences. By building homogeneous ensembles (i.e., subgroups of individuals with similar evaluative judgements), however, it was possible to assess whether ensembles were characteristic of certain levels of individual differences. This ensemble-centered approach presents an innovative way to address the "group-to-individual generalizability" issue in cross-sectional data and transcend individual variability in order to make tentative generalizations of individual cases to wider populations.

ABSTRACTThis study emphasizes the significance of understanding groundwater flow behavior for effective contaminant transport and heat storage. Aquifers, with their irregular shapes and variable permeability, exhibit anisotropic flow resistances that affect mass and heat transfer, posing challenges for modeling. The dual-porosity model is used as a numerical approach to calculate macroscopic heat transfer without explicitly resolving the structure. By solving equations for mobile and immobile phases and coupling relevant equations for heat conservation, this model was applied to transient numerical experiments simulating heat transfer and storage in a desktop model filled with glass beads. Results indicate alignment with experimental and numerical models resolving porous structures on the microstructure scale. This methodology offers a comprehensive digital toolbox for solving large-scale heat storage problems in aquifers, contributing to digital and sustainability transformations with reasonable computational demands.

Abstract Background Mental health and health-related quality of life (HRQoL) in children and adolescents deteriorated during the COVID-19 pandemic. The aim of this population-based longitudinal study was to explore whether distinct mental health trajectories in youths can be identified over the course of the pandemic. Methods Mental health problems (MHP), psychosomatic symptoms and HRQoL were assessed at five time points between May 2020 and October 2022 in 744 children and adolescents aged 7 to 20 years using established instruments. We used generalized mixture modeling to identify distinct mental health trajectories and fixed-effects regressions to analyse covariates of the identified profiles of change. Results We found five distinct linear latent trajectory classes each for externalising MHP and psychosomatic symptoms and four trajectory classes for internalising MHP. For HRQoL, a single-class solution that indicates a common development process proved to be optimal. The largest groups remained almost stable at a low internalising and externalising symptom level (64 to 74%) and consistently showed moderate psychosomatic symptoms (79%), while 2 to 18% showed improvements across the pandemic. About 10% of the youths had consistently high internalising problems, while externalising problems deteriorated in 18% of youths. Class membership was significantly associated with initial HRQoL, parental and child burden, personal resources, family climate and social support. Conclusions The mental health of most children and adolescents remained resilient throughout the pandemic. However, a sizeable number of youths had consistently poor or deteriorating mental health. Those children and adolescents need special attention in schools and mental health care.

Abstract Optical materials play a key role in enabling modern optoelectronic technologies in a wide variety of domains such as the medical or the energy sector. Among them, nonlinear optical crystals are of primary importance to achieve a broader range of electromagnetic waves in the devices. However, numerous and contradicting requirements significantly limit the discovery of new potential candidates, which, in turn, hinders the technological development. In the present work, the static nonlinear susceptibility and dielectric tensor are computed via density-functional perturbation theory for a set of 579 inorganic semiconductors. The computational methodology is discussed and the provided database is described with respect to both its data distribution and its format. Several comparisons with both experimental and ab initio results from literature allow to confirm the reliability of our data. The aim of this work is to provide a relevant dataset to foster the identification of promising nonlinear optical crystals in order to motivate their subsequent experimental investigation.

The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

BackgroundIn the United States, transgender women are disproportionately impacted by HIV and prioritized in the national strategy to end the epidemic. Individual, interpersonal, and structural vulnerabilities underlie HIV acquisition among transgender women and fuel syndemic conditions, yet no nationwide cohort monitors their HIV and other health outcomes. ObjectiveOur objective is to develop a nationwide cohort to estimate HIV incidence, identify risk factors, and investigate syndemic conditions co-occurring with HIV vulnerability or acquisition among US transgender women. The study is informed by the Syndemics Framework and the Social Ecological Model, positing that stigma-related conditions are synergistically driven by shared multilevel vulnerabilities. MethodsTo address logistical and cost challenges while minimizing technology barriers and research distrust, we aim to establish a novel, hybrid community hub–supported digital cohort (N=3000). The digital cohort is the backbone of the study and is enhanced by hubs strategically located across the United States for increased engagement and in-person support. Study participants are English or Spanish speakers, are aged ≥18 years, identify as transgender women or along the transfeminine spectrum, reside in 1 of the 50 states or Puerto Rico, and do not have HIV (laboratory confirmed). Participants are followed for 24 months, with semiannual assessments. These include a questionnaire and laboratory-based HIV testing using self-collected specimens. Using residential zip codes, person-level data will be merged with contextual geolocated data, including population health measures and economic, housing, and other social and structural factors. Analyses will (1) evaluate the contribution of hub support to the digital cohort using descriptive statistics; (2) estimate and characterize syndemic patterns among transgender women using latent class analysis; (3) examine the role of contextual factors in driving syndemics and HIV prevention over time using multilevel regression models; (4) estimate HIV incidence in transgender women and examine the effect of syndemics and contextual factors on HIV incidence using Poisson regression models; and (5) develop dynamic, compartmental models of multilevel combination HIV prevention interventions among transgender women to simulate their impact on HIV incidence through 2030. ResultsEnrollment launched on March 15, 2023, with data collection phases occurring in spring and fall. As of February 24, 2024, a total of 3084 individuals were screened, and 996 (32.3%) met the inclusion criteria and enrolled into the cohort: 2.3% (23/996) enrolled at a hub, and 53.6% (534/996) enrolled through a community hub–supported strategy. Recruitment through purely digital methods contributed 61.5% (1895/3084) of those screened and 42.7% (425/996) of those enrolled in the cohort. ConclusionsStudy findings will inform the development of evidence-based interventions to reduce HIV acquisition and syndemic conditions among US transgender women and advance efforts to end the US HIV epidemic. Methodological findings will also have critical implications for the design of future innovative approaches to HIV research. International Registered Report Identifier (IRRID)DERR1-10.2196/59846

BackgroundTransgender and nonbinary (TNB) people experience economic and psychosocial inequities that make them more likely to be subject to financial and mental health harms exacerbated by the COVID-19 pandemic. Sustainable, multilevel interventions are needed to address these harms. The onset of the COVID-19 pandemic galvanized many TNB-led organizations to provide emergency financial and peer support for TNB people negatively impacted by the pandemic. However, the efficacy of these interventions has not been evaluated. The Creating Access to Resources and Economic Support (CARES) study seeks to assess the efficacy of feasible, acceptable, and community-derived interventions to reduce economic and psychological harms experienced by transgender people in the wake of the COVID-19 pandemic. ObjectiveThe study aims to (1) compare the efficacy of microgrants with peer mentoring with that of microgrants without peer mentoring in reducing psychological distress, (2) examine mechanisms by which microgrants with or without peer mentoring may impact psychological distress, and (3) explore participants’ intervention experiences and perceived efficacy. MethodsWe will enroll 360 TNB adults into an embedded, mixed methods, 3-arm, and 12-month randomized controlled trial. Participants will be randomized 1:1:1 to arm A (enhanced usual care), which will receive a single microgrant plus monthly financial literacy education, arm B (extended microgrants), which will receive enhanced usual care plus monthly microgrants, or arm C (peer mentoring), which will receive extended microgrants combined with peer mentoring. All intervention arms last for 6 months, and participants complete semiannual, web-based surveys at 0, 6, and 12 months as well as brief process measures at 3 and 6 months. A subset of 36 participants, 12 (33%) per arm, will complete longitudinal in-depth interviews at 3 and 9 months. ResultsFull recruitment began on January 8, 2024, and, as of July 26, 2024, a total of 138 participants have enrolled. Recruitment is expected to be completed no later than March 31, 2025, and the final study visit will take place in March 2026. ConclusionsThis national, web-based study will demonstrate whether an intervention tailored to reduce material hardship and improve peer support among TNB adults will reduce psychological distress. Its equitable, community-academic partnership will ensure the rapid dissemination of study findings. Trial RegistrationClinicalTrials.gov NCT05971160; https://clinicaltrials.gov/study/NCT05971160 International Registered Report Identifier (IRRID)DERR1-10.2196/63656

Background: Neoadjuvant chemotherapy (NACT) is widely used in the treatment of triple-negative and HER2-positive breast cancer (BC), but its use in estrogen receptor (ER) and/or progesterone receptor (PR) positive/HER2-negative BC is questioned because of the low pathologic complete response (pCR) rates. This retrospective study assessed the mRNA-based MammaTyper® assay's capability of predicting pCR with NACT, and ER, PR, Ki67, and HER2 status at immunohistochemical (IHC) through transcriptomics. Methods: Diagnostic biopsies from 76 BC patients treated at the Cremona Hospital between 2012-2018 were analyzed. Relative mRNA expression levels of ERBB2, ESR1, PGR, and MKI67 were measured using the MammaTyper® kit and integrated into a pCR score. Predicting capability of pCR and standard IHC biomarkers could be assessed with ROC curves in 75 and 76 patients, respectively. Results: Overall, 68.0% patients obtained a MammaTyper® high-score and 32.0% a MammaTyper® low-score. Among high-score patients, 62.7% achieved pCR, compared to 16.7% in the low-score group (p = 0.0003). The binary MammaTyper® score showed good prediction of pCR in the overall cohort (area under curve [AUC] = 0.756) and in HR+/HER2-negative cases (AUC = 0.774). In cases with residual disease, the continuous MammaTyper® score correlated moderately with residual tumor size and decrease in tumor size. MammaTyper® showed substantial agreement with IHC for ESR1/ER and ERBB2/HER2, and moderate agreement for PGR/PR and MKI67/Ki67. Conclusion: Overall, MammaTyper® pCR score may serve as a standardized tool for predicting NACT response in HR+/HER2-negative BC, potentially guiding treatment strategies. Additionally, it could provide a more standardized and reproducible assessment of ER, PR, HER2, and Ki67 status.

Abstract Recently, a novel cyclo-heptapeptide composed of alternating d,l-amino acids and a unique thiazolidine heterocycle, called lugdunin, was discovered, which is produced by the nasal and skin commensal Staphylococcus lugdunensis. Lugdunin displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA). Lugdunin specifically inhibits target bacteria by dissipating their membrane potential. However, the precise mode of action of this new class of fibupeptides remains largely elusive. Here, we disclose the mechanism by which lugdunin rapidly destabilizes the bacterial membrane potential using an in vitro approach. The peptide strongly partitions into lipid compositions resembling Gram-positive bacterial membranes but less in those harboring the eukaryotic membrane component cholesterol. Upon insertion, lugdunin forms hydrogen-bonded antiparallel β-sheets by the formation of peptide nanotubes, as demonstrated by ATR-FTIR spectroscopy and molecular dynamics simulations. These hydrophilic nanotubes filled with a water wire facilitate not only the translocation of protons but also of monovalent cations as demonstrated by voltage-clamp experiments on black lipid membranes. Collectively, our results provide evidence that the natural fibupeptide lugdunin acts as a peptidic channel that is spontaneously formed by an intricate stacking mechanism, leading to the dissipation of a bacterial cell’s membrane potential.

Abstract Background Point-of-care ultrasound (POCUS) is a critical diagnostic tool in various medical settings, yet its instruction in medical education is inconsistent. The Rapid Ultrasound for Shock and Hypotension (RUSH) protocol is a comprehensive diagnostic tool, but its complexity poses challenges for teaching and learning. This study evaluates the effectiveness of a single-day training in RUSH for medical students by assessing their performance in clinical scenarios. Methods In this prospective single-center observational proof-of-concept study, 16 medical students from Saarland University Medical Center underwent a single-day training in RUSH, followed by evaluations in clinical settings and on a high-fidelity simulator. Performance was assessed using a standardized scoring tool and time to complete the RUSH exam. Knowledge gain was measured with pre- and post-training written exams, and diagnostic performance was evaluated with an objective structured clinical examination (OSCE). Results Students demonstrated high performance in RUSH exam views across patients (median performance: 85–87%) and improved scanning times, although not statistically significant. They performed better on simulators than on live patients. Written exam scores significantly improved post-training, suggesting a gain in theoretical knowledge. However, more than a third of students could not complete the RUSH exam within five minutes on live patients. Conclusions Single-day RUSH training improved medical students’ theoretical knowledge and simulator performance but translating these skills to clinical settings proved challenging. The findings suggest that while short-term training can be beneficial, it may not suffice for clinical proficiency. This study underscores the need for structured and possibly longitudinal training programs to ensure skill retention and clinical applicability.

Abstract Background Policy protections for transgender adults in the United States are consistently associated with positive health outcomes. However, studies over-represent non-Latinx White transgender people and obscure variation in policies’ intended goals. This study examined racial differences in the relationship between transgender-related policies and transgender women’s self-rated health. Guided by Critical Race Theory, we hypothesized that policies conferring access to resources (e.g., healthcare) would be associated with better self-rated health among all participants while policies signifying equality (e.g., nondiscrimination laws) would be associated with better self-rated health only for White participants. Methods Using cross-sectional data collected between March 2018-December 2020 from 1566 transgender women, we analyzed 7 state-level ‘access policies,’ 5 ‘equality policies,’ and sum indices of each. Participants represented 29 states, and 54.7% were categorized as people of color. We fit a series of multilevel ordinal regression models predicting self-rated health by each policy. Multivariate models were adjusted for relevant covariates at the individual- and state-level. We then tested moderation by race/ethnicity using interaction terms and generated stratified predicted probability plots. Results In bivariate models, 4 access policies, 2 equality policies, and both indices were associated with better self-rated health, but associations did not persist in adjusted models. Results from the multivariable models including interaction terms indicated that policies concerning private insurance coverage of gender-affirming care, private insurance nondiscrimination, credit nondiscrimination, and both indices were statistically significantly associated with better self-rated health for White participants and worse self-rated health for participants of color. Conclusions The policies included in this analysis do not mitigate racism’s effects on access to resources, indicating they may be less impactful for transgender women of color than White transgender women. Future research and policy advocacy efforts promoting transgender women’s health must center racial equity as well as transgender people of color’s priorities.

Background/Aims Hypoxemia is a common side effect of propofol sedation during endoscopy. Applying mild positive airway pressure (PAP) using a nasal mask may offer a simple way to reduce such events and optimize the conditions for diagnostic and therapeutic upper gastrointestinal endoscopies. Methods We compared overweight patients (body mass index >25 kg/m2) with a nasal PAP mask or standard nasal cannula undergoing upper gastrointestinal endoscopies by non-anesthesiologists who provided propofol sedation. Outcome parameters included the frequency and severity of hypoxemic episodes. Results We analyzed 102 procedures in 51 patients with nasal PAP masks and 51 controls. Episodes of hypoxemia (oxygen saturation [SpO2]

Abstract Background Saudi Arabia is implementing a comprehensive health system transformation in health services provision, governance, and financing. Given the high burden of non-communicable diseases (NCD), a key objective of the transformation is to integrate NCD prevention and treatment into primary care. The study objectives were to assess primary care service use for treatment of NCDs, to quantify existing inequities in preventive services utilization, and to identify regional and sociodemographic factors associated with these inequities. Methods Using the 2019 Kingdom of Saudi Arabia World Health Survey, multivariable logistic regression models were conducted to identify predictors of utilization of primary care services for NCD prevention and treatment, unmet need among those with a diagnosis of diabetes, hypertension, or dyslipidemia, and unmet need in breast and cervical cancer screening. Results Among those with an NCD diagnosis, living in a high-income household was associated with a lower probability of having an unmet need compared to those in low-income households. Furthermore, rural residents were less likely to have an unmet need compared to urban residents (OR 0.58, p=0.029). Individuals without a perceived need for healthcare within the last 12 months had three times the probability of unmet need in comparison to those with such a perceived need (p