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Abstract We report measurements of the e + e − → B B ¯ $$ B\overline{B} $$ , B B ¯ ∗ $$ B{\overline{B}}^{\ast } $$ , and B ∗ B ¯ ∗ $$ {B}^{\ast }{\overline{B}}^{\ast } $$ cross sections at four energies, 10653, 10701, 10746 and 10805 MeV, using data collected by the Belle II experiment. We reconstruct one B meson in a large number of hadronic final states and use its momentum to identify the production process. In the first 2 – 5 MeV above B ∗ B ¯ ∗ $$ {B}^{\ast }{\overline{B}}^{\ast } $$ threshold, the e + e − → B ∗ B ¯ ∗ $$ {B}^{\ast }{\overline{B}}^{\ast } $$ cross section increases rapidly. This may indicate the presence of a pole close to the threshold.

Abstract We present a study of Ξ c 0 → Ξ 0 π 0 $$ {\Xi}_c^0\to {\Xi}^0{\pi}^0 $$ , Ξ c 0 → Ξ 0 η $$ {\Xi}_c^0\to {\Xi}^0\eta $$ , and Ξ c 0 → Ξ 0 η ′ $$ {\Xi}_c^0\to {\Xi}^0{\eta}^{\prime } $$ decays using the Belle and Belle II data samples, which have integrated luminosities of 980 fb −1 and 426 fb −1, respectively. We measure the following relative branching fractions B Ξ c 0 → Ξ 0 π 0 / B Ξ c 0 → Ξ − π + = 0.48 ± 0.02 stat ± 0.03 syst , B Ξ c 0 → Ξ 0 η / B Ξ c 0 → Ξ − π + = 0.11 ± 0.01 stat ± 0.01 syst , B Ξ c 0 → Ξ 0 η ′ / B Ξ c 0 → Ξ − π + = 0.08 ± 0.02 stat ± 0.01 syst $$ {\displaystyle \begin{array}{c}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.48\pm 0.02\left(\textrm{stat}\right)\pm 0.03\left(\textrm{syst}\right),\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0\eta \right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.11\pm 0.01\left(\textrm{stat}\right)\pm 0.01\left(\textrm{syst}\right),\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\eta}^{\prime}\right)/\mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right)=0.08\pm 0.02\left(\textrm{stat}\right)\pm 0.01\left(\textrm{syst}\right)\end{array}} $$ for the first time, where the uncertainties are statistical (stat) and systematic (syst). By multiplying by the branching fraction of the normalization mode, B Ξ c 0 → Ξ − π + $$ \mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right) $$ , we obtain the following absolute branching fraction results B Ξ c 0 → Ξ 0 π 0 = 6.9 ± 0.3 stat ± 0.5 syst ± 1.3 norm × 10 − 3 , B Ξ c 0 → Ξ 0 η = 1.6 ± 0.2 stat ± 0.2 syst ± 0.3 norm × 10 − 3 , B Ξ c 0 → Ξ 0 η ′ = 1.2 ± 0.3 stat ± 0.1 syst ± 0.2 norm × 10 − 3 , $$ {\displaystyle \begin{array}{c}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)=\left(6.9\pm 0.3\left(\textrm{stat}\right)\pm 0.5\left(\textrm{syst}\right)\pm 1.3\left(\operatorname{norm}\right)\right)\times {10}^{-3},\\ {}\mathcal{B}\left({\Xi}_c^0\to {\Xi}^0\eta \right)=\left(1.6\pm 0.2\left(\textrm{stat}\right)\pm 0.2\left(\textrm{syst}\right)\pm 0.3\left(\operatorname{norm}\right)\right)\times {10}^{-3},\\ {}\mathcal{B}\left({\varXi}_c^0\to {\Xi}^0{\eta}^{\prime}\right)=\left(1.2\pm 0.3\left(\textrm{stat}\right)\pm 0.1\left(\textrm{syst}\right)\pm 0.2\left(\operatorname{norm}\right)\right)\times {10}^{-3},\end{array}} $$ where the third uncertainties are from B Ξ c 0 → Ξ − π + $$ \mathcal{B}\left({\Xi}_c^0\to {\Xi}^{-}{\pi}^{+}\right) $$ . The asymmetry parameter for Ξ c 0 → Ξ 0 π 0 $$ {\Xi}_c^0\to {\Xi}^0{\pi}^0 $$ is measured to be α Ξ c 0 → Ξ 0 π 0 = − 0.90 ± 0.15 stat ± 0.23 syst $$ \alpha \left({\Xi}_c^0\to {\Xi}^0{\pi}^0\right)=-0.90\pm 0.15\left(\textrm{stat}\right)\pm 0.23\left(\textrm{syst}\right) $$ .

Abstract We present the result of a search for the charged-lepton-flavor violating decay τ − → μ − μ + μ − using a 424 fb −1 sample of data recorded by the Belle II experiment at the SuperKEKB e + e − collider. The selection of e + e − → τ + τ − events is based on an inclusive reconstruction of the non-signal tau decay, and on a boosted decision tree to suppress background. We observe one signal candidate, which is compatible with the expectation from background processes. We set a 90% confidence level upper limit of 1.9 × 10 −8 on the branching fraction of the τ − → μ − μ + μ − decay, which is the most stringent bound to date.

Abstract We present measurements of the branching fractions of eight B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ , B − → D (*)0 K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ decay channels. The results are based on data from SuperKEKB electron-positron collisions at the Υ(4S) resonance collected with the Belle II detector, corresponding to an integrated luminosity of 362 fb −1. The event yields are extracted from fits to the distributions of the difference between expected and observed B meson energy, and are efficiency-corrected as a function of m(K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) and m(D (*) K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) in order to avoid dependence on the decay model. These results include the first observation of B ¯ 0 $$ {\overline{B}}^0 $$ → D + K − K S 0 $$ {K}_S^0 $$ , B − → D* 0 K − K S 0 $$ {K}_S^0 $$ , and B ¯ 0 $$ {\overline{B}}^0 $$ → D* + K − K S 0 $$ {K}_S^0 $$ decays and a significant improvement in the precision of the other channels compared to previous measurements. The helicity-angle distributions and the invariant mass distributions of the K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ systems are compatible with quasi-two-body decays via a resonant transition with spin-parity J P = 1− for the K − K S 0 $$ {K}_S^0 $$ systems and J P = 1+ for the K − K* 0 systems. We also present measurements of the branching fractions of four B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ D s − $$ {D}_s^{-} $$ , B − → D (*)0 D s − $$ {D}_s^{-} $$ decay channels with a precision compatible to the current world averages.

Introduction: Childhood specific phobias are among the most common and earliest onset mental disorders with a lifetime prevalence of more than ten percent. Brief intensive cognitive behavioral therapy (CBT) programs such as the One-Session Treatment (OST) are found to be effective in the remission of the specific phobias following treatment, but there is still room for improvement. The goal of the current study is to examine whether the long-term efficacy of OST increases by using a homework program supported by an app specifically designed for children; the Kids Beat Anxiety (KibA) homework program. Methods: Children aged between 7 and 14 years with a specific phobia receive OST preceded by a three-week baseline phase to control for time-effects. Directly following OST, children are randomized to either a four-week homework period supported by an app (OST + app), or standard One-Session Treatment with a four-week homework period that is only supported by therapist instructions (OST-only). Primary outcome variables are diagnosis and severity of the specific phobia. Secondary outcomes include behavioral avoidance, self-reported fear, and functional impairment. Data will be analyzed based on intention-to-treat and per protocol samples using mixed-effects multilevel linear models. Ethics and dissemination: The current study was approved by the METC of the Academic Medical Center, Amsterdam, The Netherlands (number: NL72697.018.20) and the Ethical Committee of the Ruhr University, Bochum, Germany (number: 663). Results of this trial will be published in peer-reviewed journals. Trial registration: The study was pre-registered at the Dutch Trial Register, number: NL 9216.

Abstract Introduction Children in low socioeconomic status (SES) communities are at higher risk of exposure to lead (Pb) and potentially more severe adverse outcomes from Pb exposures. While the factors encompassing SES are complex, low SES households often have less enriching home environments and parent–child interactions. This study investigated the extent to which environmental/behavioral factors (quality of maternal care and richness of the postnatal environment) may modify adverse effects from Pb exposure. Methods Long‐Evans female rats were randomly assigned to Control (no Pb), Early Postnatal (EPN: birth through weaning), or Perinatal (PERI: 14 days pre‐mating through weaning) Pb exposure groups. From postnatal days (PNDs) 2–9, maternal care behaviors were observed, and dams were classified as low or high maternal care based on amounts of licking/grooming and arched back nursing. At weaning, pups were randomly assigned to enriched or non‐enriched environments. At PND 55, animals began trace fear conditioning and associative memory was tested on days 1, 2, and 10 postconditioning. Results Control offspring showed no significant effects of maternal care or enrichment on task performance. Females with EPN‐Pb exposure and males with PERI‐Pb exposure living in the non‐enriched environment and having an LMC mother had significant memory impairments at days 2 and 10 that were not observed in comparably housed animals with HMC mothers. Enriched animals had no deficits, regardless of maternal care status. Conclusion These results show the potential for modulatory influences of maternal care and housing environment on protecting against or reversing at least one aspect of Pb‐induced cognitive/behavioral dysfunction.

Abstract Intensive research has been carried out on two-dimensional materials, in particular molybdenum disulfide, towards high-performance field effect transistors for integrated circuits1. Fabricating transistors with ohmic contacts is a challenging task due to the formation of a high Schottky barrier that severely limits the performance of the transistors for real-world applications. Graphene-based heterostructures can be used in addition to, or as a substitute for unsuitable metals. In this paper, we present lateral heterostructure transistors made of scalable chemical vapor-deposited molybdenum disulfide and chemical vapor-deposited graphene achieving a low contact resistances of about 9 kΩ·µm and high on/off current ratios of 108. Furthermore, we also present a theoretical model calibrated on our experiments showing further potential for scaling transistors and contact areas into the few nanometers range and the possibility of a substantial performance enhancement by means of layer optimizations that would make transistors promising for use in future logic integrated circuits.

Abstract Continuous-flow biocatalysis utilizing immobilized enzymes emerged as a sustainable route for chemical synthesis. However, inadequate biocatalytic efficiency from current flow reactors, caused by non-productive enzyme immobilization or enzyme-carrier mismatches in size, hampers its widespread application. Here, we demonstrate a general-applicable and robust approach for the fabrication of a high-performance enzymatic continuous-flow reactor via integrating well-designed scalable isoporous block copolymer (BCP) membranes as carriers with an oriented and productive immobilization employing material binding peptides (MBP). Densely packed uniform enzyme-matched nanochannels of well-designed BCP membranes endow the desired nanoconfined environments towards a productive immobilized phytase. Tuning nanochannel properties can further regulate the complex reaction process and fortify the catalytic performance. The synergistic design of enzyme-matched carriers and efficient enzyme immobilization empowers an excellent catalytic performance with >1 month operational stability, superior productivity, and a high space-time yield (1.05 × 105 g L−1 d−1) via a single-pass continuous-flow process. The obtained performance makes the designed nano- and isoporous block copolymer membrane reactor highly attractive for industrial applications.

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

Background: Although substantial motion at the acromioclavicular joint (ACJ) occurs during overhead shoulder motion, the influence of ACJ arthritis on postoperative outcomes of patients undergoing reverse total shoulder arthroplasty (rTSA) is unclear. We assessed the influence of ACJ arthritis, defined by degenerative radiographic changes, and its severity on clinical outcomes after primary rTSA. Methods: We conducted a retrospective review of a prospectively collected shoulder arthroplasty database of patients that underwent primary rTSA with a minimum 2-year clinical follow-up. Imaging studies of included patients were evaluated to assess ACJ arthritis classified by radiographic degenerative changes of the ACJ; severity was based upon size and location of osteophytes. Both the Petersson classification and the King classification (a modified Petersson classification addressing superior osteophytes and size of the largest osteophyte) were used to evaluate the severity of degenerative ACJ radiographic changes. Severe ACJ arthritis was characterized by large osteophytes (≥2 mm). Active range of motion (ROM) in abduction, forward elevation, and external and internal rotation as well as clinical outcome scores (American Shoulder and Elbow Surgeons Shoulder, Constant, Shoulder Pain and Disability Index, simple shoulder test, University of California, Los Angeles scores) were assessed both preoperatively and at the latest follow-up; outcomes were compared based on severity of ACJ arthritis. Multivariable linear regression models were used to determine whether increasing severity of ACJ arthritis was associated with poorer outcomes. Results: A total of 341 patients were included with a mean age of 71 ± 8 years and 55% were female. The mean follow-up was 5.1 ± 2.4 years. Preoperatively, there were no differences in outcomes based on the severity of ACJ pathology. Postoperatively, there were no differences in outcomes based upon the severity of ACJ arthritis except for greater preoperative to postoperative improvement in active internal rotation in patients with normal or grade 1 ACJ arthritis vs. grade 2 and 3 (3 ± 2 vs. 1 ± 2 and 1 ± 3, P = .029). Patients with ACJ arthritis and osteophytes ≥2 mm had less favorable Shoulder Pain and Disability Index scores, corresponding to greater pain (−49.3 ± 21.5 vs. −41.3 ± 26.8, P = .015). On multivariable linear regression, increased severity of ACJ arthritis was not independently associated with poorer postoperative ROM or outcome scores. Conclusion: Overall, our results demonstrate that greater ACJ arthritis severity score is not associated with poorer outcome scores and has minimal effect on ROM. However, patients with the largest osteophytes (≥2 mm) did have slightly worse pain postoperatively. Radiographic presence of high-stage ACJ arthritis should not alter the decision to undergo rTSA.

Abstract Background Transgender women (TW) experience significant inequities in healthcare access and health disparities compared to cisgender populations. Access to non-transition related healthcare is understudied among TW. We aimed to assess the association between access to care and gender minority stress and resilience factors among TW living with and without HIV in eastern and southern United States. Methods This study was a cross-sectional analysis of baseline data drawn from a cohort of 1613 adult TW from the LITE Study. The cohort permitted participation through two modes: a site-based, technology-enhanced mode and an exclusively online (remote) mode. Exploratory and confirmatory factor analyses determined measurement models for gender minority stress, resilience, and healthcare access. Structural equation modeling was used to assess the relationships between these constructs. Models were evaluated within the overall sample and separately by mode and HIV status. Results Higher levels of gender minority stress, as measured by anticipated discrimination and non-affirmation were associated with decreased access to healthcare. Among TW living with HIV, higher levels of anticipated discrimination, non-affirmation, and social support were associated with decreased healthcare access. Among TW living without HIV in the site-based mode, resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access. Among TW living without HIV in the online mode, anticipated discrimination was associated with barriers to healthcare access; resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access. Conclusions Gender minority stress was associated with increased barriers to healthcare access among TW in the US, regardless of HIV status. Resilience factors did not mediate this effect. Interventions aiming to increase healthcare access among TW can be aided by efforts to mitigate drivers of gender minority stress and improve patient experiences in healthcare facilities.

Introduction Deprivation is widely known in children and adolescents and means a lack of social, emotional, or sensory stimuli, due to disabilities such as deafness, but also social isolation and reduced parental care. It may cause developmental disorders such as impaired language, motoric and social development. Little is known of the impact of social deprivation in demented patients.Stimulus shielding, which is a widespread option for psychiatric symptoms of dementia such as agitation, vocalization and aggressive behavior may – if frequently used- have similar effects on demented patients. Objectives We report the case of a 71-year-old patient with dementia caused by PSP (Progressive Supranuclear Palsy), who was in inpatient treatment due to continuous undirected vocalizations. She presented with inability to walk, dysarthria, aphasia, and hearing difficulties beside major mnestic impairment. In a prior hospitalization and in her residency, she was frequently isolated from other patients due to loud screaming and vocalizations in terms of stimulus shielding by suspected overstimulation. In order to that, for four months, she developed progressive difficulties to speak, hear, understand, as well as gait disorders. In addition, the vocalizations increased. Methods We rated the symptoms due to deprivation, triggered by lack of mobilization, social experiences, visual, tactile and acoustic stimuli following a vicious circle of anxiety, vocalizations and recurrent isolations. Therefore, a multimodal therapy assessment was implemented, including daily physical therapy, mobilization, basal stimulation, social reintegration and basal conversation training. Results After a few days of high intensity treatment, speech reappeared in form of one- word sentences and proceeded to the ability to have short conversations. Mobility increased, starting from severe gait disorder, including the use of a wheelchair and emerged to the ability of walking up to 50 metres. Additionally, the undirected vocalizations improved and were reduced. In addition, hearing ability improved during the four-week treatment. Conclusions This case highlights the impact of deprivation in demented patients. Especially it shows that these symptoms can be reversible under a high intensity multimodal and multi- professional treatment within a few weeks. Therefore, stimulus shielding, should be carefully evaluated in order to prevent deprivation – and thus deterioration of the symptoms – in demented patients. Disclosure of Interest None Declared

Objective The Digital Healthcare Act introduced the prescription of digital health applications under specific circumstances in 2019 in Germany. They are funded through the social security system. In market access of prescribed digital health applications, Germany is pioneering the market. There remains a gap in understanding the views of medical professionals on the incentives of using these applications. As prescription of digital health applications starts emerging in other European countries, we sought to generate an overview of incentives and barriers that affect the caregivers in their decision of promoting and prescribing them in Germany. Methods A Rapid Review of the Web of Science database for the years 2017–2023 was performed using sensitive search strings. Two reviewers conducted a three-phase selection via title, abstract and full-text independently from each other. The quality of studies was assessed systematically by both reviewers. Both quantitative and qualitative studies with primary data were included, and study quality was assessed using a standardised form. Results Out of 1643 initial results, 12 studies with information from 9302 physicians and psychotherapists were identified. Eight quantitative and four qualitative studies were included in the analysis. Key findings suggest that while between 40% and 60% of caregivers see relevant incentives mainly based on patients’ benefits, 20–40% see relevant barriers. For the physicians’ daily work, there were slightly more barriers than incentives identified in the quantitative synthesis. The qualitative studies revealed no relevant incentives that were not attributed to patients. Conclusion While digital health solutions offer promising avenues for enhancing patient care, their acceptance among healthcare professionals hinges on addressing prevailing concerns. Continuous research and dialogues with the medical community are pivotal to harness the full potential of digital health applications in healthcare.

Abstract While certain inorganic main‐group polymers such as silicones (polysiloxanes) are ubiquitous in our everyday life, poly(iminoborane)s have been elusive for a long time. Incorporation of heterocyclic building blocks into their backbone has recently enabled access to the first derivatives of this inorganic‐polymer class, as this approach effectively prevents undesired side‐reactions to borazines. Information about the microstructure of these cyclolinear macromolecules, however, has been scarce. Herein, we present the synthesis of a series of monodisperse oligomers with up to 7 boron and 8 nitrogen atoms, representing the longest well‐defined molecular [>B=N

This is a comment to an article previously published in The Depositional Record.

We compared three methods for scoring the Balanced Inventory of Desirable Responding (BIDR) to detect faked responses on self-report measures: (1) polytomous, (2) dichotomous emphasizing exaggerating endorsement of socially desirable behaviors, and (3) dichotomous emphasizing exaggerating denial of such behaviors. The results revealed that respondents on average were able to fake good or fake bad and that faking markedly affected score distributions, subscale score intercorrelations, and overall model fits. When using the Impression Management scale, polytomous and dichotomous exaggerated endorsement scoring were best for detecting faking good, whereas polytomous and dichotomous exaggerated denial scoring were best for detecting faking bad. When using the Self-Deceptive Enhancement scale, polytomous and dichotomous exaggerated endorsement scoring again were best for detecting faking good, but dichotomous exaggerated denial scoring was best for detecting faking bad. Percentages of correct classification of honest and faked responses for the most effective methods for any given scale ranged from 85% to 93%, with accuracy on average in detecting faking bad greater than in detecting faking good and greater when using the Impression Management than using the Self-Deceptive Enhancement scale for both types of faking. Overall, these results best support polytomous scoring of the BIDR Impression Management scale as the single most practical and efficient means to detect faking. Cut scores that maximized classification accuracy for all scales and scoring methods are provided for future use in screening for possible faking within situations in which relevant local data are unavailable.

Changes in the structure of bone can occur in space as an adaptive response to microgravity and on Earth due to the adaptive effects to exercise, to the aging of bone cells, or to prolonged disuse. Knowledge of cell-mediated bone remodeling on Earth informs our understanding of bone tissue changes in space and whether these skeletal changes might increase the risk for fractures or premature osteoporosis in astronauts. Comparisons of skeletal health between astronauts and aging humans, however, may be both informative and misleading. Astronauts are screened for a high level of physical fitness and health, are launched with high bone mineral densities, and perform exercise daily in space to combat skeletal atrophy as an adaptive response to reduced weight-bearing function, while the elderly display cellular and tissue pathology as a response to senescence and disuse. Current clinical testing for age-related bone change, applied to astronauts, may not be sufficient for fully understanding risks associated with rare and uniquely induced bone changes. This review aims to (i) highlight cellular analogies between spaceflight-induced and age-related bone loss, which could aid in predicting fractures, (ii) discuss why overreliance on terrestrial clinical approaches may miss potentially irreversible disruptions in trabecular bone microarchitecture induced by spaceflight, and (iii) detail how the cellular effects of the bisphosphonate class of drugs offer a prophylactic countermeasure for suppressing the elevated bone resorption characteristically observed during long-duration spaceflights. Thus the use of the bisphosphonate will help protect the bone from structural changes while in microgravity either along with exercise or alone when exercise is not performed, e.g. after an injury or illness.

Thin-film composite (TFC) membranes containing a metal–polyphenol network (MPN)-based selective layer were fabricated on a porous polyacrylonitrile support. The MPN layer was formed through coordination-based self-assembly between plant-based tannic acid (TA) and an Fe3+ ion. For the first time, we demonstrate that TFC membranes containing TA-Fe3+ selective layers can separate small organic solutes in aqueous media from equimolar mixtures of solutes. The effect of the assembly time on the characteristics and performance of the fabricated selective layer was investigated. An increase in the assembly time led to the formation of selective layers with smaller effective pore sizes. The tannic acid–Fe3+ selective layer exhibited a low rejection towards neutral solutes riboflavin and poly(ethylene glycol) while high rejections were observed for anionic dyes of orange II and naphthol green B. Permeation selectivities in the range of 2–27 were achieved between neutral and charged dyes in both single- and mixed-solute experiments, indicating the significant role of Donnan exclusion and the charge-selective nature of the membranes. The rejection efficiency improved with an increasing assembly time. Overall, this study demonstrates that the assembly time is a vital casting parameter for controlling the permeance, rejection and selectivity of thin-film composite membranes with a tannic acid–Fe3+ selective layer.

ObjectiveThe cytokine profile of human milk may be a key indicator of mammary gland health and has been linked to infant nutrition, growth, and immune system development. The current study examines the extent to which mammary epithelium permeability (MEP) is associated with cytokine profiles during established lactation within a sample of US mothers.MethodsParticipants were drawn from a previous study of human milk cytokines. The present analysis includes 162 participants (98 Black, 64 White) with infants ranging from 1 to 18 months of age. Levels of cytokines were determined previously. Here we measure milk sodium (Na) and potassium (K) levels with ion-selective probes. Two approaches were used to define elevated MEP: Na levels ≥10 mmol/L and Na/K ratios greater than 0.6. Associations between maternal–infant characteristics, elevated MEP, and twelve analytes (IL-6, IL-8, TNFα, IL-1β, FASL, VEGFD, FLT1, bFGF, PLGF, EGF, leptin, adiponectin) were examined using bivariate associations, principal components analysis, and multivariable logistic regression models.ResultsElevated MEP was observed in 12 and 15% of milk samples as defined by Na and Na/K cutoffs, respectively. The odds of experiencing elevated MEP (defined by Na ≥ 10 mmol/L) were higher among Black participants and declined with older infant age. All cytokines, except leptin, were positively correlated with either Na or the Na/K ratio. A pro-inflammatory factor (IL-6, IL-8, TNFα, IL-1β, EGF) and a tissue remodeling factor (FASL, VEGFD, FLT1, bFGF, PLGF, adiponectin) each contributed uniquely to raising the odds of elevated MEP as defined by either Na or the Na/K ratio.ConclusionThis exploratory analysis of MEP and cytokine levels during established lactation indicates that elevated MEP may be more common in US populations than previously appreciated and that individuals identifying as Black may have increased odds of experiencing elevated MEP based on current definitions. Research aimed at understanding the role of MEP in mammary gland health or infant growth and development should be prioritized.

Abstract Introduction Transgender women in the United States experience high HIV incidence and suboptimal Pre‐exposure prophylaxis (PrEP) engagement. We sought to estimate PrEP initiation and discontinuation rates and characterize PrEP discontinuation experiences among a prospective cohort of transgender women. Methods Using a sequential, explanatory, mixed‐methods design, 1312 transgender women at risk for HIV acquisition were enrolled from March 2018 to August 2020 and followed through July 2022 (median follow‐up 24 months; interquartile range 15–36). Cox regression models assessed predictors of initiation and discontinuation. In‐depth interviews were conducted among 18 participants, including life history calendars to explore key events and experiences surrounding discontinuations. Qualitative and quantitative data were integrated to generate typologies of discontinuation, inform meta‐inferences and facilitate the interpretation of findings. Results 21.8% (n = 286) of participants reported taking PrEP at one or more study visits while under observation. We observed 139 PrEP initiations over 2127 person‐years (6.5 initiations/100 person‐years, 95% CI: 5.5–7.7). Predictors of initiation included identifying as Black and PrEP indication. The rate of initiation among those who were PrEP‐indicated was 9.6 initiations/100 person‐years (132/1372 person‐years; 95% CI: 8.1–11.4). We observed 138 PrEP discontinuations over 368 person‐years (37.5 discontinuations/100 person‐years, 95% CI: 31.7–44.3). Predictors of discontinuation included high school education or less and initiating PrEP for the first time while under observation. Four discontinuation typologies emerged: (1) seroconversion following discontinuation; (2) ongoing HIV acquisition risk following discontinuation; (3) reassessment of HIV/STI prevention strategy following discontinuation; and (4) dynamic PrEP use coinciding with changes in HIV acquisition risk. Conclusions PrEP initiation rates were low and discontinuation rates were high. Complex motivations to stop using PrEP did not consistently correspond with HIV acquisition risk reduction. Evidence‐based interventions to increase PrEP persistence among transgender women with ongoing acquisition risk and provide HIV prevention support for those who discontinue PrEP are necessary to reduce HIV incidence in this population.

Abstract Purpose Relating dose-volume histogram (DVH) information to patient outcomes is critical for outcomes research in radiation oncology, but this is statistically challenging. We performed this focused review of DVH toxicity studies to characterize current statistical approaches and determine the need for updated reporting recommendations. Methods and materials We performed a focused MEDLINE search to identify studies published in 5 radiation oncology specialty journals that associated dosimetry with toxicity outcomes in humans receiving radiotherapy between 2015 and 2021. Elements abstracted from each manuscript included the study outcome, organs-at-risk (OARs) considered, DVH parameters analyzed, summary of the analytic approach, use of multivariable statistics, goodness-of-fit reporting, completeness of model reporting, assessment of multicollinearity, adjustment for multiple comparisons, and methods for dichotomizing variables. Each study was also assessed for sufficient reporting to allow for replication of results. Results The MEDLINE search returned 2,300 studies for review and 325 met the inclusion criteria for the analysis. DVH variables were dichotomized using cut points in 154 (47.4%) studies. Logistic regression (55.4% of studies) was the most common statistical method used to relate DVH to toxicity outcomes, followed by Cox regression (20.6%) and linear regression (12.0%). Multivariable statistical tests were performed in 226 (69.5%) studies; of these, the possibility of multicollinearity was addressed in 47.8% and model goodness-of-fit were reported in 32.6%. The threshold for statistical significance was adjusted to account for multiple comparisons in 41 of 196 (17.1%) studies that included multiple statistical comparisons. Twenty-eight (8.6%) studies were classified as missing details necessary to reproduce the study results. Conclusions Current practices of statistical reporting in DVH outcomes suggest that studies may be vulnerable to threats against internal and external validity. Recommendations for reporting are provided herein to guard against such threats and to promote cohesiveness among radiation oncology outcomes researchers.

Abstract Background Morbidity and mortality from Opioid Use Disorder is a health crisis in the United States. During the COVID-19 pandemic, there was a devastating increase of 38.4% in overdose deaths from the 12-month period leading up to June 2019 compared with the 12-month period leading up to May 2020, primarily driven by synthetic opioids. Buprenorphine is an effective medication for opioid use disorder but uptake is slow due in part to lack of provider knowledge, confidence, and negative attitudes/stigma toward patients with OUD. Addressing these barriers in academic training is a promising approach to building workforce able to effectively treat opioid use disorder. Methods Our university developed a training for pre-licensure physicians, physician assistants and psychiatric nurse practitioners that included the DATA Waiver training and a shadowing experience. Expected outcomes included improved knowledge, skills and attitudes about persons with OUD and buprenorphine treatment, plans to provide this treatment post-graduation, for pre-licensure learners to have completed all requirements to prescribe buprenorphine post-graduation, and for the training to be embedded into school’s curricula. Results Results were positive overall including improved knowledge and attitudes toward persons with OUD, better understanding of the benefits of this treatment for patients, increased confidence and motivation to provide this treatment post-graduation. The training is now embedded in each program’s graduation requirements. Conclusion Developing a didactic and experiential training on buprenorphine treatment for opioid use disorder and embedding it into medical, physician assistant, and psychiatric nurse practitioner licensure programs can help prepare future providers to treat opioid use disorder in a range of settings. Key to replicating this program in other university settings is to engage faculty members who actively provide treatment to persons with OUD to ensure shadowing opportunities and serve as role models for learners.

Purpose: Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer. Methods and Materials: Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board–approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review. Results: Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage (P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics (P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics (P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were “per protocol” or met “variation acceptable” ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes. Conclusions: A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace.

Creating an immersive Augmented Reality (AR) experience requires aligning the digital content with the real environment so that the digital content appears and interacts in a similar way to a real object. For that, the virtual object must persist in its position across sessions and be occluded completely or partly, depending on whether a real-world object is in the line of sight. This research makes use of the cutting-edge technology available in the field of AR/MR, the Microsoft HoloLens 2.0, where the in-device Time of Flight (ToF) camera is used to scan the environment to create a Spatial Map. The CityGML LOD1 model enriches the Spatial Map and, in addition, is used as an occlusion mask via a custom rendering pipeline. Spatial Anchors can be tracked using the Simultaneous Localization And Mapping (SLAM) technique, used in conjunction with World Locking Tools to anchor the whole scene to the real-world coordinates. The developed occlusion effect is used in urban planning scenarios to introduce a new area design featuring a car-free environment. The proposed method is evaluated based on performance indicators, including frames per second (FPS) since it is highly correlated to user comfort. The findings of the users’ study demonstrate that the occlusion effect achieves its purpose since most of the participants reported enhancements in the depth perception and overall experience by enabling the occlusion screening.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. Its severity is assessed using scores that rely on visual observation of the affected body surface area, the morphology of the lesions and subjective symptoms, like pruritus or insomnia. Ideally, such scores should be complemented by objective and accurate measurements of disease severity to standardize disease scoring in routine care and clinical trials. Recently, it was shown that raster-scanning optoacoustic mesoscopy (RSOM) can provide detailed three-dimensional images of skin inflammation processes that capture the most relevant features of their pathology. Moreover, precise RSOM biomarkers of inflammation have been identified for psoriasis. However, the objectivity and validity of such biomarkers in repeated measurements have not yet been assessed for AD. Here, we report the results of a study on the repeatability of RSOM inflammation biomarkers in AD to estimate their precision. Optoacoustic imaging analysis revealed morphological inflammation biomarkers with precision well beyond standard clinical severity metrics. Our findings suggest that optoacoustic mesoscopy may be a good choice for quantitative evaluations of AD that are inaccessible by other methods. This could potentially enable the optimization of disease scoring and drug development.

TBX5 is a transcription factor (TF) playing essential role during cardiogenesis. It is well known that TF mutations possibly result in non- or additional binding of the DNA due to conformational changes of the protein. We introduced a Holt-Oram Syndrome (HOS) patient-specific TBX5 mutation c.920_C > A heterozygously in a healthy induced pluripotent stell cell (iPSC) line. This TBX5 mutation results in conformational changes of the protein and displayed ventricular septal defects in the patient itself. Additionally we introduced a FLAG-tag on the TBX5 mutation-carrying allele. The resulting heterozygous TBX5-FLAG iPSC lines are a powerful tool to investigate altered TF activity bonding.

Determining emotions of people during different activities (e.g. surfing the web or walking and driving in urban areas) is of high interest to many industries such as the advertising and marketing industry (Imotions, 2022) or city developers and planners (Zeile et al., 2015). However, as the authors have explained in their previous works (Schneider et al., 2020, Dastageeri et al., 2019, Kohn et al., 2018), it is very difficult to determine emotions using surrogate measurements. This is compounded by the fact that many people have trouble to name their emotions correctly as they are often mixed and hardly ever occur as a single and distinct emotion. In order to improve the attractiveness of cities not just based on general presumptions about how citizens would react to certain changes in the urban environment, but based on physical measurements, previous works have shown approaches to do that (Schneider et al., 2020, Dastageeri et al., 2019). They have developed a first attempt to correlate measured physical parameters such as heart rate and skin conductivity (among others) which are triggered by location and environment to emotional states using machine learning. To correlate locations to emotions is an important aspect for city planners, as a person’s emotion for a location defines the personal relationship to a place which can help to gauge the attractiveness of a place and give indicators about where to improve the city or place.

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.

Abstract Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by enrichment. This was also true for changes in upstream regulators, splicing events and long noncoding RNAs. Non-enriched rats also had memory impairments; enriched rats had no deficits. The results demonstrate that an enriched environment has a profound impact on behavior and the Pb-modified CA1 transcriptome. These findings show the potential for interactions between Pb exposure and the environment to result in significant transcriptional changes in the brain and, to the extent that this may occur in Pb-exposed children, could influence neuropsychological/educational outcomes, underscoring the importance for early intervention and environmental enrichment for Pb-exposed children.

Abstract Background Depression is a serious disorder in childhood and adolescence. Affected children and adolescents show significant impairments in various aspects of life. Studies on the effectiveness or efficacy of psychotherapy in depressed children and adolescents are qualitatively very heterogeneous and reveal small effect sizes. There is thus a need to better tailor psychotherapy approaches to these age groups to improve outcomes like parent-child relationship, symptomatology, or quality of life. To address this gap, we designed a modular, individualized treatment program for children and adolescents based on the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) including caregiver involvement. Method This quasi-experimental pilot feasibility trial is a phase 1 to phase 2 study investigating the feasibility and effectiveness of CBASP@YoungAge by including an intervention group (CBASP@YoungAge) and a treatment-as-usual control group. The treatment of depressive symptoms as well as interpersonal problems with primary caregivers are the main targets of CBASP@YoungAge. Personalization is ensured concerning the treatment course, caregivers’ involvement, and the patient’s age. The primary outcome relates to two areas: the feasibility of the CBASP@YoungAge treatment program in an outpatient context and a change in patients' depressive symptomatology from before to after treatment. We conduct a brief process evaluation after each session in the intervention group to closely monitor the treatment process and examine feasibility from the therapists' and patients' perspectives and mechanisms of symptom change. In addition, we consider interpersonal behavior between children and caregivers, parenting behavior, and monitor the global-health-index in children and parents as secondary outcomes. Pre-, post-, and follow-up data are evaluated. Discussion This is the first study of a modular-based intervention program for children and adolescents with depression and a clear focus on the interpersonal problems between the depressed young patient and her/his caregiver. It will provide important knowledge on the feasibility and effectiveness of the program and potential benefits of including caregivers in psychotherapy. Based on this study’s results, we plan a multicenter, randomized, controlled trial whose long-term aim is to improve the psychotherapeutic care of young patients with depression while preventing persistent courses of depressive disorders. Trial registration German Clinical Trials Register, DRKS (identifier DRKS00023281 ). Registered 17 November 2020–Retrospectively registered

Abstract Exercise could prevent physical and psychological deteriorations, especially during pandemic times of lock-down scenarios and social isolation. But to meet both, the common exercise protocols require optimization based on holistic investigations and with respect to underlying processes. This study aimed to explore individual chronic and acute effects of continuous and interval running exercise on physical and cognitive performance, mood, and affect and underlying neurophysiological factors during a terrestrial simulated space mission. Six volunteers (three females) were isolated for 120 days. Accompanying exercise training consisted of a continuous and interval running protocol in a cross-over design. Incremental stage tests on a treadmill were done frequently to test physical performance. Actigraphy was used to monitor physical activity level. Cognitive performance, mood (MoodMeter®), affect (PANAS), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), vascular-endothelial growth factor (VEGF), and saliva cortisol were investigated prior to, four times during, and after isolation, pre- and post-exercise on two separate days, respectively. As a chronic effect, physical performance increased (and IGF-1 tended) in the course of isolation and training until the end of isolation. Subjective mood and affect state, as well as cognitive performance, basal BDNF and VEGF levels, were well-preserved across the intervention. No acute effects of exercise were detected, besides slower reaction time after exercise in two out of nine cognitive tests, testing sensorimotor speed and memory of complex figures. Consistently higher basal IGF-1 concentrations and faster reaction time in the psychomotor vigilance test were found for the continuous compared to the interval running protocol. The results suggest that 120 days of isolation and confinement can be undergone without cognitive and mental deteriorations. Regular, individual aerobic running training supporting physical fitness is hypothesized to play an important role in this regard. Continuous running exercise seems to trigger higher IGF-1 levels and vigilance compared to interval running. Systematic and prolonged investigations and larger sample size are required to follow up on exercise-protocol specific differences in order to optimize the exercise intervention for long-term psycho-physiological health and well-being.

Background and Aim: Antibiotic-resistant Salmonella is a public health concern. Fluoroquinolones and extended-spectrum beta-lactams are widely used for the treatment of Salmonella infections. This study focused on the detection of plasmid-mediated quinolone resistance (PMQR) and extended-spectrum beta-lactamase (ESBL) genes among multidrug-resistant (MDR) Salmonella enterica isolated from broilers. Materials and Methods: A total of 40 non-typhoidal S. enterica isolates were collected from 28 broiler chicken farms in four Iraqi Governorates. These isolates were examined for their susceptibility to 10 antimicrobial agents by disk-diffusion method followed by polymerase chain reaction assay for the detection of PMQR determinants and ESBLs genes. Results: Salmonella strains revealed high levels of resistance to the following antibiotics: Nalidixic acid 100%, levofloxacin (LEV) 97.5%, amoxicillin-clavulanic acid 95.0%, tetracycline 92.5%, and nitrofurantoin 80.0%. Otherwise, all isolates were susceptible to cefotaxime and ceftriaxone. All isolates were MDR, with 15 different profiles observed. Among 38 amoxicillin/clavulanic acid-resistant Salmonella isolates, 20 (52.6%) had the blaTEM gene, while blaSHV, blaCTX-M, and blaOXA genes were not detected. Only 5 (12.8%) out of 39 LEV-resistant isolates were positive for qnrB, three of which had blaTEM. No qnrC or qnrD, qnrS, aac(6')-Ib-cr, qunA, and oqxAB genes were found in any of the tested isolates. Conclusion: This study demonstrates that broiler chickens may be considered a potential source for spreading MDR non-typhoidal Salmonella and ESBL traits in poultry production. Therefore, it is important to continuously monitor ESBL and PMQR genes to avoid the spread of resistant strains in the food chain and impact public health.

Abstract Objective To assess for differences of intended meaning in the description of reflux‐related symptoms among otolaryngology patients and clinicians. Study Design Cross‐sectional survey‐based study. Setting Five tertiary, academic otolaryngology practices. Methods Between June 2020 and July 2022, a questionnaire consisting of 20 common descriptors of reflux‐related symptoms within four domains (throat‐, chest‐, stomach‐, and sensory‐related symptoms) was completed by patients. Attending otolaryngologists at five academic medical centers then completed the same survey. The primary outcome was to assess differences in patient and clinician perceptions of reflux‐related symptoms. Differences based on geographic location was a secondary outcome. Results A total of 324 patients and 27 otolaryngologists participated. Patients selected a median of six terms compared with 10.5 for otolaryngologists (p

IntroductionDementia is characterized by significant declines in cognitive, physical, social, and behavioral functioning, and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among older underrepresented racial/ethnic minorities in the United States. Our study explored the role of psychiatric and substance use history on the risk of etiology-specific dementias: Alzheimer’s disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data.MethodsWe conducted secondary data analyses based on the National Alzheimer’s Coordinating Center Uniform Data Set (N = 17,592) which is comprised a large, racially, and ethnically diverse cohort of adult research participants in the network of US Alzheimer Disease Research Centers (ADRCs). From 2005 to 2019, participants were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were used to examine the influence of psychiatric and substance use history on the risk of AD and VaD subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health-related factors.ResultsIn addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22–51% and VaD by 22–53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For non-Hispanic White people, history of other psychiatric disorders increased AD risk by 27%, and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present.ConclusionThe findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset of AD and VaD dementia subtypes. Prevention efforts should pay particular attention to non-Hispanic White and African American older adults who have history of other psychiatric disorders.Future research should address diagnostic shortcomings in the measurement of such disorders in ADRCs, especially with regard to diverse racial and ethnic groups.

Background: Sinus CT is the imaging technique of choice for planning endoscopic sinus surgery (ESS). Although MRI has a better soft tissue demonstration, it is not commonly used for ESS due to suboptimal bone demonstration. We hypothesised that adjustment of certain MRI parameters, would allow better demonstration of bones and enable the surgeon to adequately identify surgical landmarks. Methodology: Twenty patients identified as candidates for ESS underwent CT and adjusted MRI exams of the paranasal sinuses (40 in total). rhinologist and a neuroradiologist independently compared and graded 46 bony structures (23 on each side) in each patient's CT and MRI. Overall, 920 anatomical structures were graded by each observer (1840 structures in total). Statistical analysis included overall and per variable grading distribution for each observer, and overall agreement. Results: MRI images were equal, or superior to CT for assessing paranasal anatomy in 66.8% and 86.4% of structures evaluated by the rhinologist and neuroradiologist, respectively. Overall agreement between observers (77%) was moderate. Conclusion: The rhinologist prefers CT demonstration of bony structures, while the neuroradiologist prefers MRI. Still, with the MRI protocol used in this study, according to both, most bony structures are well demonstrated by MRI.

Abstract Background Vaginal bleeding (VB) is common in women with gynecologic (GYN) malignancies. Radiation therapy (RT) is used for the definitive treatment of GYN cancers and palliation of bleeding. The historical dogma is that high dose-per-fraction radiation leads to more rapid bleeding cessation, yet there is scant data supporting this claim. We sought to examine the effect of RT fraction size on VB via retrospective analysis of patients receiving hypofractionated radiation (HFRT) compared to conventionally fractionated radiation (CFRT) for control of bleeding secondary to GYN malignancies. Methods We identified patients receiving external beam RT for continuous VB from GYN malignancy treated in our department from 2012 to 2020. RT was classified as HFRT (> 2.0 Gy/fx) or CFRT (1.8–2.0 Gy/fx). Demographic information, disease characteristics, and treatment details were collected. The primary endpoint was days from RT initiation until bleeding resolution. Characteristics between groups were compared via Fisher’s exact test. Time to bleeding cessation was assessed via Kaplan–Meier and log-rank test. Univariable and multivariable Cox-proportional hazards were used to identify factors associated with bleeding cessation. Results We identified 43 patients meeting inclusion criteria with 26 and 17 patients receiving CFRT and HFRT, respectively. Comparison of baseline characteristics revealed patients receiving HFRT were older (p = 0.001), more likely to be post-menopausal (p = 0.002), and less likely to receive concurrent chemotherapy (p = 0.004). Time to bleeding cessation was significantly shorter for patients receiving HFRT (log-rank p

Although TBX5 plays a major role during human cardiogenesis and initiates and controls limb development, many of its interactions with genomic DNA and the resulting biological consequences are not well known. Existing anti-TBX5-antibodies work very inefficiently in certain applications such as ChIP-Seq analysis. To circumvent this drawback, we introduced a FLAG-tag sequence into the TBX5 locus at the end of exon 9 prior to the stop codon by CRISPR/Cas9. The expressed TBX5-FLAG fusion protein can effectively be precipitated by anti-FLAG antibodies. Therefore, these gene-edited iPSC lines represent powerful cellular in vitro tools to unravel TBX5:DNA interactions in detail.

Abstract Introduction Restrictions during the COVID‐19 pandemic necessitated remote administration of neuropsychological testing. We assessed the test–retest reliability for a telephone‐administered cognitive battery, recommended for use in the National Institute on Aging Alzheimer's Disease Research Center (ADRC). Methods 64 participants in the University of Southern California ADRC clinical core underwent repeat telephone evaluation using the T‐cog Neuropsychological Battery. Reliability was measured by intraclass correlation coefficient (ICC) for continuous variables and weighted Kappa coefficient for categorical variables. Mean scores for Montreal Cognitive Assessment (MoCA) total and Craft Story 21 Immediate and Delayed Recall were compared using paired t tests. Results Mean age was 74.8 (8.3 standard deviation); 73.4% were female. ICCs ranged from 0.52 to 0.84, indicating moderate test–retest reliability except for number span backward, which showed poor reliability. Weighted Kappa for MoCA items ranged from −0.016 to 0.734; however, relatively good observed agreement was seen across all items (70.3% to 98.4%). Although MoCA total scores did not significantly change, Craft Story 21 Immediate and Delayed Recall mean scores increased between first and second administrations (P

Abstract Background The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. Methods We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. Results Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. Discussion These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials’ validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson’s disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (B3GALT2 and B4GALT1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (SPHK1, SPHK2, and SGPL1) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (ST8SIA2 and ST8SIA4) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase NEU4, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.

BackgroundGiven that only 25% of pregnant women elect to receive a COVID-19 vaccine, maternal SARS-CoV-2 infection remains an important route of conferring protective passive immunity to breastfed infants of mothers who are not vaccinated.MethodsWe enrolled 30 lactating participants between December 2020 and March 2021 who had a positive PCR-test and their first COVID-19 symptoms within the previous 21 days. Participants were asked to provide serial bilateral milk samples at 12 timepoints (~ every 3 days) over a period of 35 days. A second set of samples was collected at least four months after the beginning of the first set. Participants also were asked to provide their dried blood spots and infant stool samples. All samples were tested for receptor-binding domain (RBD)-specific immunoglobulin (Ig)A, IgG, and IgM. Milk samples were assessed for neutralizing ability against the spike protein and four SARS-CoV-2 variants: D614G, Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1). Permeability of the breast epithelium was assessed by measuring the sodium to potassium ions (Na:K) in milk. Using flow cytometry, memory CD4 and CD8 T cells (CD45RO+ and CCR7+/-) and mucosal-homing CD4 and CD8 T cells (CD103+) were determined in cells from milk expressed at 35 days and at least 4 months after their first milk donation.ResultsMilk antibodies from SARS-CoV-2 positive participants neutralized the spike complex. Milk from 73, 90, and 53% of participants had binding reactivities to RBD-specific IgA, IgG, and IgM, respectively. In contrast to blood spots, which showed increased levels of IgG, but not IgA or IgM, the COVID-19 response in milk was associated with a robust IgA response. Twenty-seven percent of participants had increased breast-epithelium permeability, as indicated by Na:K ≥ 0.6. The percentage of CD45RO+CCR7- effector-memory T cells in the day ≥120 milk samples was significantly higher than day 35 samples (P< 0.05).ConclusionsAntibodies in milk from participants with recent SARS-CoV-2 infection and those who recovered can neutralize the spike complex. For the first time we show that breastmilk T cells are enriched for mucosal memory T cells, further emphasizing the passive protection against SARS-CoV-2 conferred to infants via breastmilk.

PCB 126 is a pervasive, dioxin-like chemical pollutant which can activate the aryl hydrocarbon receptor (AhR). Despite being banned from the market, PCB 126 can be detected in breast milk to this day. The extent to which interindividual variation impacts the adverse responses to this chemical in the breast tissue remains unclear. This study aimed to investigate the impact of 3 nM PCB 126 on gene expression in a panel of genetically diverse benign human breast epithelial cell (HBEC) cultures and patient derived breast tissues. Six patient derived HBEC cultures were treated with 3 nM PCB 126. RNAseq was used to interrogate the impact of exposure on differential gene expression. Gene expression changes from the top critical pathways were confirmed via qRT-PCR in a larger panel of benign patient derived HBEC cultures, as well as in patient-derived breast tissue explant cultures. RNAseq analysis of HBEC cultures revealed a signature of 144 genes significantly altered by 3 nM PCB 126 treatment. Confirmation of 8 targets using a panel of 12 HBEC cultures and commercially available breast cell lines demonstrated that while the induction of canonical downstream target gene, CYP1A1, was consistent across our primary HBECs, other genes including AREG, S100A8, IL1A, IL1B, MMP7, and CCL28 exhibited significant variability across individuals. The dependence on the activity of the aryl hydrocarbon receptor was confirmed using inhibitors. PCB 126 can induce significant and consistent changes in gene expression associated with xenobiotic metabolism in benign breast epithelial cells. Although the induction of most genes was reliant on the AhR, significant variability was noted between genes and individuals. These data suggest that there is a bifurcation of the pathway following AhR activation that contributes to the variation in interindividual responses.

Epidemiological studies have established obesity as a critical risk factor for postmenopausal breast cancer (post-BC), whereas a reverse association holds prior to menopause. A significant scientific gap exists in understanding the mechanism(s) underpinning this epidemiological phenomenon, particularly the reverse association between obesity and premenopausal breast cancer (pre-BC). This study aimed to understand how folate metabolism and DNA methylation inform the association between obesity and pre-BC. Fifty normal breast tissue samples were collected from premenopausal women who underwent reduction mammoplasty. We modified the Lactobacillus Casei microbiological folate assay and measured folate levels in our breast tissue samples. The DNA methylation of LINE-1, a biomarker of genome-wide methylation, and the expression of a panel of breast cancer-related genes was measured by pyrosequencing and real-time PCR. We found that a high BMI is associated with an increase of folate levels in mammary tissue, with an increase of 2.65 ng/g of folate per every 5-unit increase of BMI (p

Abstract Background Three out of ten children in Germany have immigrant backgrounds and this proportion is expected to further increase in subsequent years. While immigrant youth have been found more vulnerable to developing symptoms of depression and anxiety, the underlying mechanisms of how such disparities unfold during youth development are still understudied. Some previous research has found that immigrant youth are at risk of experiencing a less positive self-concept compared to non-immigrant youth. We investigated whether the self-concept mediates mental health disparities and explored variability in such associations from middle childhood to late adolescence. Methods Overall 1839 children and adolescents aged 6–21 years (M = 14.05 years, SD = 3.03, 49.8% female, n = 782 with immigrant status) participated in a cross-sectional self-report survey in classroom settings using scales from the Beck Youth Inventories II (Beck et al. in Beck Youth Inventories - Second Edition, Psychological Corporation, San Antonio, 2005) to assess self-concept and symptoms of depression and anxiety. Links between immigrant status, age, self-concept and symptom levels of depression as well as anxiety were examined using hierarchical regression and moderated mediation models. Results Immigrant youth reported higher symptom levels of depression and anxiety than their non-immigrant peers but did not differ in their self-concepts. Hypothesized moderated mediation models were not fully supported and self-concept neither mediated the link between immigrant status and depression nor immigrant status and anxiety. However, self-concept was a significant predictor for symptom levels of depression as well as anxiety, with stronger associations in adolescents. Conclusions Our study substantiates previous findings that immigrant youth in Germany have overall increased symptom levels of depression and anxiety compared to non-immigrant youth. Our study however does not support that immigrant youth have a more negative self-concept and that the self-concept mediates such internalizing mental health disparities. Findings match previous evidence that developing a positive attitude towards the self is linked to better mental health. Beyond that, our findings suggest that mental health interventions addressing the self-concept could be especially relevant when targeting adolescents. Further research is needed to deepen the understanding of the mediating processes between migration status and mental health variables.

Abstract Background Spinal stabilisation is recommended for prehospital trauma treatment. In Germany, vacuum mattresses are traditionally used for spinal stabilisation, whereas in anglo-american countries, long spine boards are preferred. While it is recommended that the on-scene time is as short as possible, even less than 10 minutes for unstable patients, spinal stabilisation is a time-consuming procedure. For this reason, the time needed for spinal stabilisation may prevent the on-scene time from being brief. The aim of this simulation study was to compare the time required for spinal stabilisation between a scoop stretcher in conjunction with a vacuum mattress and a long spine board. Methods Medical personnel of different professions were asked to perform spinal immobilizations with both methods. A total of 172 volunteers were immobilized under ideal conditions as well as under realistic conditions. A vacuum mattress was used for 78 spinal stabilisations, and a long spinal board was used for 94. The duration of the procedures were measured by video analysis. Results Under ideal conditions, spinal stabilisation on a vacuum mattress and a spine board required 254.4 s (95 % CI 235.6–273.2 s) and 83.4 s (95 % CI 77.5–89.3 s), respectively (p

Background Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation. Summary Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered as curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies. Key Messages In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.