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Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. ispartof: Nature vol:612 issue:7938 pages:123-131 ispartof: location:England status: published

Urban Black men who have sex with men (MSM) bear a disproportionate burden of HIV and syphilis in the U.S. Experiences of enacted sexual minority stigma and psychological distress among these men may be associated with HIV/STI sexual and drug risk behaviors. The objective was to determine the associations between enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. In an urban prospective cohort study, survey measures assessed past 3-month exposure to enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. Multivariable logistic regression models were utilized for hypothesis testing. The Black MSM (N = 140) reported the following: 22.1% experiences of enacted sexual minority stigma, 39% high levels of psychological distress, 48.6% 1 sex partner, 8.6% transactional sex, and 6% injection drug use (IDU). In models adjusted for age and education, enacted sexual minority stigma significantly increased the odds of reporting 1 sex partner, transactional sex, and IDU. Adjusting additionally for homelessness, the association between enacted sexual minority stigma and transactional sex remained significant. Adding psychological distress to this model showed a significant association between psychological distress and transactional sex, while the association was no longer significant for transactional sex. These findings highlight some of the complex psycho-social relationships that may be associated with sexual and drug risk behaviors among Black MSM placing them at increased risk for HIV and syphilis.Hombres urbanos de raza Negra que tienen sexo con hombres (HSH) sobrellevan una carga desproporcionada de VIH y sífilis en los EE.UU. Experiencias de estigma efectivo de minoría sexual y angustia psicológica entre estos hombres pudiese ser asociado con conductas sexuales de riesgo VIH/ITS y drogas. El objetivo era determinar las asociaciones entre un estigma efectivo de minoría sexual, angustia psicológica, y comportamientos sexuales y de riesgo de drogas. En un estudio de cohortes prospectivo urbano, las medidas de la encuesta evaluada en los últimos tres meses de exposición al estigma efectivo, angustia psicológica, y sus conductas sexuales y comportamientos riesgoso de drogas. Modelos de regresión logística multivariante se utilizaron para la prueba de hipótesis. Los HSH de raza negra (N = 140) reportaron lo siguiente: 22.1% experiencias de estigma efectivo, 39% niveles altos de angustia psicológica, 48.6% y 1 pareja sexual, 8.6% sexo transaccional, y 6% uso de drogas inyectables (UDI). En modelos ajustados a edad y educación, un estigma efectivo de minoría sexual aumentó de manera significante las probabilidades de reportar y 1 pareja sexual, sexo transaccional, y UDI. Ajustando adicionalmente para personas sin vivienda, la asociación entre estigma efectivo de minoría sexual y sexo transaccional permaneció significante. La adición de angustia psicológica al modelo mostró una asociación significativa entre angustia psicológica y sexo transaccional, mientras que la asociación ya no era significativa para el sexo transaccional. Estos resultados destacan algunas de las complejas relaciones psicosociales que pudiesen estar asociadas con conductas sexuales y de riesgo de drogas entre HSH de raza negra, poniéndolos a mayor riesgo de contraer VIH y sífilis.

Supplementary Figures 11-18

Chimeric antigen receptor (CAR) T-cell therapy has had limited success in early-phase clinical studies for solid tumors. Lack of efficacy is most likely multifactorial, including a limited array of targetable antigens. We reasoned that targeting the cancer-specific extra domain B (EDB) splice variant of fibronectin might overcome this limitation because it is abundantly secreted by cancer cells and adheres to their cell surface. In vitro, EDB-CAR T cells recognized and killed EDB-positive tumor cells. In vivo, 1 × 106 EDB-CAR T cells had potent antitumor activity in both subcutaneous and systemic tumor xenograft models, resulting in a significant survival advantage in comparison with control mice. EDB-CAR T cells also targeted the tumor vasculature, as judged by IHC and imaging, and their antivascular activity was dependent on the secretion of EDB by tumor cells. Thus, targeting tumor-specific splice variants such as EDB with CAR T cells is feasible and has the potential to improve the efficacy of CAR T-cell therapy.

TMA Clinical Data

RNAseq

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.Significance:This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.See related commentary by Sherman, p. 230.This article is highlighted in the In This Issue feature, p. 211

Microarray

Amino Acid- Mass Spec

TMA IHC Scores

18 supplementary figures and corresponding legends

Lists all key resources and reagents

Sup Tables 5-7- Amino Acid Biochrom

Supplementary Figure Legends

Zusammenfassung Ziel der Studie Fetale Alkoholspektrum-Störungen sind nicht nur häufig, sie sind aufgrund des hohen Risikos für psychiatrische Komorbiditäten auch im Erwachsenenalter klinisch relevant. Die diagnostische Abklärung im Erwachsenenalter ist die Voraussetzung für eine zielgerichtete Behandlung und bedarfsgerechte Unterstützung. Methodik In einer Metropolenregion wurde zwischen Mai 2015 und Juli 2020 bei 80 Personen der Verdacht auf eine FASD diagnostisch abgeklärt. Die Ergebnisse dieser interdisziplinären Diagnostik wurden systematisch ausgewertet und die klinischen Charakteristika der Personen mit bzw. ohne FASD analysiert. Ergebnisse Bei ca. 70% der Inanspruchnahmepopulation wurde eine Diagnose aus dem FAS-Spektrum gestellt. Personen mit FASD zeigten häufiger eine Lernbehinderung (50 vs. 33%) oder Intelligenzminderung (40 vs. 10%), während keine Gruppenunterschiede für Alter und Geschlecht bestanden. Psychiatrische Komorbiditäten, insbesondere Depressionen (39%) und Abhängigkeitserkrankungen (31%), waren in beiden Gruppen häufig. Schlussfolgerung Im Rahmen einer multiprofessionellen standardisierten Diagnostik ist die FASD Abklärung auch im Erwachsenenalter möglich und nötig. Die Entwicklung standardisierter und spezifischer Diagnosekriterien für Erwachsene ist sinnvoll.

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People with adisorder of intellectual development (German draft of the ICD-11, which came into force on 1January 2022) suffer more frequently from mental illnesses. According to the international treatment guidelines multimodal approaches should include not only psychopharmacological treatment, but also disorder-specific psychotherapeutic methods. These psychotherapeutic interventions have to be adapted to the communicative and cognitive abilities (performance diagnostics with IQ tests) as well as the emotional developmental stage (developmental diagnostics, e.g., with the scale of emotional development, short version, SED-S2; [1]). To ensure this, the rules of simple language should be observed and when appropriate relatives or caregivers should be involved in the therapeutic process. The effectiveness of cognitive behavioral therapy has received most scientific attention, especially for affective disorders. Posttraumatic stress disorders can be validly treated with eye movement desensitization and reprocessing (EMDR). There is also good evidence for exposure therapy with reinforcement in the treatment of anxiety disorders. © 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature., Menschen mit einer Störung der Intelligenzentwicklung (deutsche Entwurfsfassung der ICD-11, in Kraft getreten am 01.01.2022) leiden überdurchschnittlich häufig an psychischen Erkrankungen. Die leitliniengerechte, multimodale Behandlung beinhaltet neben psychopharmakologischen auch störungsspezifische psychotherapeutische Methoden, die auf die kommunikativen und kognitiven Fähigkeiten (Leistungsdiagnostik mit IQ-Tests) sowie den emotionalen Entwicklungsstand (Entwicklungsdiagnostik z. B. mit der Skala der emotionalen Entwicklung SEED-2) der Person angepasst werden sollten [1]. Dabei sind die Regeln der leichten Sprache zu beachten und ggf. Angehörige bzw. Bezugspersonen in die Therapieumsetzung einzubeziehen. Am besten untersucht ist die Wirksamkeit der kognitiven Verhaltenstherapie, insbesondere für affektive Störungen. Posttraumatische Belastungsstörungen sind valide mit EMDR („eye movement desensitization and reprocessing“) behandelbar. Eine gute Evidenz gibt es für die Expositionstherapie mit Verstärkung in der Behandlung von Angsterkrankungen.

Syphilis among men who have sex with men (MSM) has increased greatly in the past twenty years in the U.S. Geographically explicit ecological momentary assessment (GEMA), in which behaviors are geotagged and contextualized in time and space, may contribute to a greater understanding of transmission risk. The objective was to determine the acceptability and feasibility of GEMA for assessing HIV and syphilis transmission risk behaviors among a sample of MSM. Participants responded to a brief survey five times a day for two weeks. Feasibility was measured by participant recruitment, enrollment, prompts received and answered, geotagged prompts, and technical interference with data collection. Acceptability was measured by ratings of enjoyment and willingness for future participation. Summaries of five behavioral measures from the brief survey were calculated. Among the 83 participants contacted, 67.5% (56) expressed interest, 98% (55) were scheduled, and 81.8% (45) were enrolled. Participants answered 78.3% (2,277) of prompts received and 87.7% (1,998) of answered prompts were geotagged. Overall, 70.5% (31) enjoyed participating and 91.1% (41) were willing to participate in the future. Among prompts answered, missingness was low for five behavioral measures (range 0.2% (4) to 0.7% (16)). Feasibility and acceptability were high and missingness was low on behavioral measures in this MSM study population. Most participants reported that they would participate again. Future work should focus on whether GEMA improves our understanding of syphilis and HIV transmission risk.

Athletes are vulnerable to sexual violence. Perpetrators of sexual violence may be a trusted coach, a member of the health care team, or a peer. The consequences of sexual violence are wide ranging, resulting in immediate and long-term physical and mental health outcomes that require recognition and comprehensive, multidisciplinary care. Sports medicine providers need to have specific knowledge and skill to care for athletes who experience sexual violence. Several sports organizations (e.g., International Olympic Committee, United States Olympic and Paralympic Committee, the National Collegiate Athletic Association, and the National Athletic Trainers' Association) have developed policies and procedures to prevent sexual violence and help sports medicine specialists provide care and services for athletes affected by sexual violence. Nevertheless, there remains a need for clinical guidelines, screening tools, and education, as well as clinical best practices to address sexual violence in sports medicine.

BACKGROUND Gay, bisexual, and other sexual minority men have expressed the acceptability of patient portals as tools for supporting HIV prevention behaviors, including facilitating disclosure of HIV and other sexually transmitted infection (STI/HIV) laboratory test results to sex partners. However, these studies, in which Black or African American sexual minority men were undersampled, failed to determine the relationship of reported history of discussing HIV results with sex partners and anticipated willingness to disclose web-based STI/HIV test results using a patient portal. OBJECTIVE Among a sample of predominantly Black sexual minority men, this study aimed to (1) determine preferences for patient portal use for HIV prevention and (2) test the associations between reported history of discussing HIV results and anticipated willingness to disclose web-based STI/HIV test results with most recent main and nonmain partners using patient portals. METHODS Data come from audio-computer self-assisted interview survey data collected during the 3-month visit of a longitudinal cohort study. Univariate analysis assessed patient portal preferences by measuring the valuation rankings of several portal features. Multiple Poisson regression models with robust error variance determined the associations between history of discussing HIV results and willingness to disclose those results using web-based portals by partner type, and to examine criterion validity of the enhancing dyadic communication (EDC) scale to anticipated willingness. RESULTS Of the 245 participants, 71% (n=174) were Black and 22% (n=53) were White. Most participants indicated a willingness to share web-based STI/HIV test results with their most recent main partner. Slightly fewer, nonetheless a majority, indicated a willingness to share web-based test results with their most recent nonmain partner. All but 2 patient portal features were valued as high or moderately high priority by >80% of participants. Specifically, tools to help manage HIV (n=183, 75%) and information about pre- and postexposure prophylaxis (both 71%, n=173 and n=175, respectively) were the top-valuated features to include in patient portals for HIV prevention. Discussing HIV test results was significantly associated with increased prevalence of willingness to disclose web-based test results with main (adjusted prevalence ratio [aPR] 1.46, 95% CI 1.21-1.75) and nonmain partners (aPR 1.54, 95% CI 1.23-1.93). CONCLUSIONS Our findings indicate what features Black sexual minority men envision may be included in the patient portal’s design to optimize HIV prevention, further supporting the criterion validity of the EDC scale. Efforts should be made to support Black sexual minority men’s willingness to disclose STI/HIV testing history and status with partners overall as it is associated significantly with a willingness to disclose testing results digitally via patient portals. Future studies should consider discussion behaviors regarding past HIV test results with partners when tailoring interventions that leverage patient portals in disclosure events. CLINICALTRIAL

Chimeric antigen receptor (CAR) T-cell therapy has had limited success in early-phase clinical studies for solid tumors. Lack of efficacy is most likely multifactorial, including a limited array of targetable antigens. We reasoned that targeting the cancer-specific extra domain B (EDB) splice variant of fibronectin might overcome this limitation because it is abundantly secreted by cancer cells and adheres to their cell surface. In vitro, EDB-CAR T cells recognized and killed EDB-positive tumor cells. In vivo, 1 × 106 EDB-CAR T cells had potent antitumor activity in both subcutaneous and systemic tumor xenograft models, resulting in a significant survival advantage in comparison with control mice. EDB-CAR T cells also targeted the tumor vasculature, as judged by IHC and imaging, and their antivascular activity was dependent on the secretion of EDB by tumor cells. Thus, targeting tumor-specific splice variants such as EDB with CAR T cells is feasible and has the potential to improve the efficacy of CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy offers promise to improve outcomes for pediatric patients with recurrent/refractory osteosarcoma (OS), a ‘poor-prognosis’ cancer. However, early-phase clinical studies have shown limited activity despite potent antitumor activity in preclinical xenograft models, highlighting the need to develop better preclinical models. B7-H3 has emerged as a promising immunotherapeutic target for pediatric solid tumors including OS, and we and other investigators are actively exploring B7-H3-CAR T cell therapies in early-phase clinical studies. Our goal was to develop a murine immunocompetent OS model (F331) for the realistic pre-clinical evaluation of B7-H3-CAR T cells and to explore additional genetic modifications to improve their effector function. We generated murine B7-H3-CAR T cells expressing a 2nd generation B7-H3-CD28.ζ CAR by retroviral transduction. In vitro, B7-H3-CAR T cells recognized B7-H3-positive F331 cells as judged by IFNγ production and cytolytic activity in contrast to B7-H3-negative tumor cells; Control (ctrl) CAR T-cells recognizing an irrelevant antigen (SP6) did not recognize or kill B7-H3-positive tumor cells confirming specificity. Since lung is the primary OS metastasis site, we focused on the intravenous (i.v.) disseminated lung F331 OS metastasis model. In this model, a single i.v. infusion of 5x106 CD8+ B7-H3-CAR T cells demonstrated significant antitumor activity compared to CD8+ ctrl CAR T cells, resulting in a significant survival advantage (median: 70 vs 38 days respectively). Unfortunately, tumors invariably recurred. We found limited B7-H3-CAR T cell expansion and persistence, even though recurring tumors still expressed B7-H3, excluding tumor antigen escape mechanism. We therefore embarked on a comprehensive screen to knock out (KO) known negative regulators of T-cell function, starting with Regnase-1 (Reg-1). Reg-1 is known to have RNase activity and to regulate activation of immune cells. KO of Reg-1 in CD8+ B7-H3-CAR T cells improved their expansion post-infusion in spleen and lungs as judged by flow cytometric analysis without systemic toxicities based on mice body weight assessment. This resulted in a significant improvement in overall survival in comparison to control KO B7-H3-CAR T cells at a cell dose (1x106) at which ctrl-KO CD8+ B7-H3-CAR T cells were ineffective. Reg1-KO ctrl CAR T cells had no therapeutic benefit, excluding nonspecific effects. In summary, we have established an immune-competent OS model to evaluate the effector function of B7-H3-CAR T cells and have demonstrated the advantage given by 2nd genetic modifications to enhance their antitumor activity. We are currently using this model to define mechanisms of immune resistance with the goal of further enhancing OS-redirected CAR T-cell therapy. Citation Format: Adeleye O. Adeshakin, Peipei Zhou, Jean-Yves Métais, Phuong Nguyen, Scott Perry, Heather Sheppard, Xiang Sun, Trevor Cunningham, Hao Shi, Jessica Wagner, Jason T. Yustein, Christopher DeRenzo, Giedre Krenciute, Hongbo Chi, Stephen Gottschalk. B7-H3-CAR T-cell therapy in immune-competent osteosarcoma models: Regnase-1 KO overcomes limited CAR T-cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1778.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. Significance: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function. See related commentary by Sherman, p. 230. This article is highlighted in the In This Issue feature, p. 211

This article outlines the development of a three-credit digital archives course designed for undergraduates. In it, students study basic archival and digital archives terminology and learn about how these concepts can help them understand current events. This course strives not only to help students develop critical thinking skills by engaging with primary source content; it also helps familiarize students with archives, archivists, and the importance of archival work. In addition, the course relies heavily on active learning techniques, which allow students to participate in decision-making activities in archival work, giving them an appreciation for the labor involved. The course therefore fulfills an outreach function: It shows students why archives are relevant to their lives and to the world around them. The article places this course in the context of archival education for undergraduates and non-professionals, highlighting the benefits this approach offers for students and for the professional archival field.

Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic surface groups and one reactive ethynyl group at the core is reported. The amphiphilic surface groups serve as biorecognition units that bind to the surface of adenovirus 5 (Ad5), which is a common vector in gene therapy. The Ad5/dendron complexes showed high gene transduction efficiencies in coxsackie‐adenovirus receptor (CAR)‐negative cells. Moreover, the dendrons offer incorporation of new functions at the dendron core by in situ post‐modifications, even when bound to the Ad5 surface. Surfaces coated with these dendrons were analyzed for their blood‐protein binding capacity, which is essential to predict their performance in the blood stream. A new platform for introducing bioactive groups to the Ad5 surface without chemically modifying the virus particles is provided., Amphiphilic polyphenylene dendrons were prepared and bound to gene vector adenovirus 5 (Ad5) through polar and nonpolar surface groups that control its cellular uptake. The new dendron layer at the Ad5 surface provides reactive groups that are accessible for post‐modifications at the virus surface.

Fetal alcohol spectrum disorders (FASD) are quite common and, due to the risk of psychiatric comorbidities, highly relevant until adulthood. Diagnostic clarification in adulthood is a prerequisite for targeted treatment and needs-based support. In a German metropolitan region, 80 people with suspicion of FASD were assessed from May 2015 to July 2020. The results of this interdisciplinary diagnostic assessment were systematically evaluated and the clinical characteristics of the persons with or without FASD were analysed.Approximately 70% of the population accessing relevant health care was diagnosed with an entity from the FAS spectrum. People with FASD were more likely to have learning disabilities (50 vs. 33%) or intellectual disabilities (40 vs. 10%), while there were no group differences for age and gender. Psychiatric comorbidities, particularly depression (39%) and addiction disorders (31%), were common in both groups.As part of a multi-professional standardized diagnosis, FASD clarification is also possible and necessary in adulthood. The diagnostic criteria for FASD should be further evaluated and specified for adults. Fetale Alkoholspektrum-Störungen sind nicht nur häufig, sie sind aufgrund des hohen Risikos für psychiatrische Komorbiditäten auch im Erwachsenenalter klinisch relevant. Die diagnostische Abklärung im Erwachsenenalter ist die Voraussetzung für eine zielgerichtete Behandlung und bedarfsgerechte Unterstützung. In einer Metropolenregion wurde zwischen Mai 2015 und Juli 2020 bei 80 Personen der Verdacht auf eine FASD diagnostisch abgeklärt. Die Ergebnisse dieser interdisziplinären Diagnostik wurden systematisch ausgewertet und die klinischen Charakteristika der Personen mit bzw. ohne FASD analysiert. Bei ca. 70% der Inanspruchnahmepopulation wurde eine Diagnose aus dem FAS-Spektrum gestellt. Personen mit FASD zeigten häufiger eine Lernbehinderung (50 vs. 33%) oder Intelligenzminderung (40 vs. 10%), während keine Gruppenunterschiede für Alter und Geschlecht bestanden. Psychiatrische Komorbiditäten, insbesondere Depressionen (39%) und Abhängigkeitserkrankungen (31%), waren in beiden Gruppen häufig. Im Rahmen einer multiprofessionellen standardisierten Diagnostik ist die FASD Abklärung auch im Erwachsenenalter möglich und nötig. Die Entwicklung standardisierter und spezifischer Diagnosekriterien für Erwachsene ist sinnvoll.

This study sought to determine whether completion of the National Collegiate Athletic Association’s “Supporting Student-Athlete Mental Wellness” online module for coaches increased mental health literacy, reduced stigma, and increased intentions to: 1) communicate proactively with team members about the importance of mental health care seeking, and 2) respond appropriately to support an athlete believed to be struggling with a mental health issue. College head coaches completed pre-test surveys (n = 969) and immediate post-test surveys (n = 347, completion rate = 36%). Module completion was associated with increased mental health literacy, decreased stigma about help seeking and increased intentions to engage in culture setting communication. These findings suggest that the online module is a good start for coach education about mental health; however, additional modifications may be warranted to the extent coach referral to sports medicine staff or provision of emotional support to student-athletes struggling with mental health concerns are considered desired behaviors.

Los nematodos fitoparásitos son una de las principales causas de pérdidas económicas en la agricultura a nivel mundial. En los cultivos de Musa paradisiaca, los nematodos más abundantes y de mayor impacto son Radopholus similis, y Meloidogyne spp.

Uncontrolled amyloid-beta (Aβ) fibrillation leads to the deposition of neurotoxic amyloid plaques and is associated with Alzheimer's disease. Inhibiting Aβ monomer fibrillation and dissociation of the formed fibers is regarded as a promising therapeutic strategy. Here, amphiphilic polyphenylene dendrons (APDs) are demonstrated to interrupt Aβ assembly and reduce Aβ-cell interactions. Containing alternating negatively charged sulfonic acid and hydrophobic n-propyl peripheral groups, APDs bind to the secondary structure of the Aβ aggregates, inhibiting fibrillation and disassemble the already formed Aβ fibrils. APDs reveal vesicular cellular uptake in endosomes as well as cell compatibility for endothelial and neuronal cells, and significantly reduce Aβ-induced neuron cytotoxicity in vitro. Moreover, they are transported into the brain and successfully cross the blood-brain barrier after systemic application in mice, indicating their high potential to inhibit Aβ fibrillation in vivo, which can be beneficial for developing therapeutic strategy for Alzheimer's disease.

Background The impact of coronavirus disease 2019 (COVID-19) mitigation measures on sexually transmitted infection (STI) transmission and racial disparities remains unknown. Our objectives were to compare sex and drug risk behaviors, access to sexual health services, and STI positivity overall and by race during the COVID-19 pandemic compared with pre-pandemic among urban sexual minority men (MSM). Methods Sexually active MSM aged 18–45 years were administered a behavioral survey and STI testing every 3-months. Participants who completed at least 1 during-pandemic (April 2020–December 2020) and 1 pre-pandemic study visit (before 13 March 2020) that occurred less than 6 months apart were included. Regression models were used to compare during- and pre-pandemic visit outcomes. Results Overall, among 231 MSM, reports of more than 3 sex partners declined(pandemic-1: adjusted prevalence ratio 0.68; 95% confidence interval: .54–.86; pandemic-2: 0.65, .51–.84; pandemic-3: 0.57, .43–.75), substance use decreased (pandemic-1: 0.75, .61–.75; pandemic-2: 0.62, .50–.78; pandemic-3: 0.61, .47–.80), and human immunodeficiency virus/preexposure prophylaxis care engagement (pandemic-1: 1.20, 1.07–1.34; pandemic-2: 1.24, 1.11–1.39; pandemic-3: 1.30, 1.16–1.47) increased. STI testing decreased (pandemic-1: 0.68, .57–.81; pandemic-2: 0.78, .67–.92), then rebounded (pandemic-3: 1.01, .87–1.18). Nei­ther Chlamydia (pandemic-2: 1.62, .75–3.46; pandemic-3: 1.13, .24–1.27) nor gonorrhea (pandemic-2: 0.87, .46 1.62; pandemic-3: 0.56, .24–1.27) positivity significantly changed during vs pre-pandemic. Trends were mostly similar among Black vs. non-Black MSM. Conclusions We observed sustained decreases in STI risk behaviors but minimal change in STI positivity during compared with pre-pandemic. Our findings underscore the need for novel STI prevention strategies that can be delivered without in-person interactions.

We determined whether racial disparities in HIV infection among gay and bisexual men (MSM) may be partially explained by racial differences in the HIV transmission potential (i.e. mixing of people living with HIV and people not living with HIV or of unknown HIV serostatus) and density (i.e. sex partner concurrency) of sexual networks. Data included a behavioral survey, testing for HIV, and an egocentric sexual network survey. Mixed effects logistic regressions were used for hypothesis testing. Black (vs. non-Black) MSM were more likely to not know their partner's HIV serostatus (21.8% vs. 9.6%). Similar proportions reported sex partner concurrency (67.1% vs. 68.0%). In adjusted analyses, among Black MSM, sex partner concurrency significantly increased the odds of an HIV transmission potential partnership (TPP), and this association was not significant among non-Black indexes. The association between an HIV TPP and sex partner concurrency may help explain persistent racial disparities in HIV prevalence.Determinamos si las disparidades raciales en infecciones del VIH entre hombres homosexuales y bisexuales (hombres que tienen sexo con hombres) puede ser parcialmente explicado por diferencias raciales en el potencial de transmisión del VIH (es decir, mezcla de personas viviendo con VIH y personas que no viven con VIH o cuyo estado serológico del VIH es desconocido) y densidad (es decir, concurrencia de pareja sexual) de redes sexuales. Los datos incluyeron una encuesta de comportamiento, pruebas para el VIH y una encuesta de redes sexuales egocéntrica. Regresiones logísticas de efectos mixtos fueron usados para la prueba de hipótesis. HSH negros (vs. HSH no-negros) eran más propensos a no saber el estado serológico del VIH de su pareja (21.8% vs. 9.6%). Proporciones similares reportaron concurrencia de pareja sexual (67.1% vs. 68.0%). En análisis ajustados, entre HSH negros, la concurrencia de pareja sexual aumentó significativamente las probabilidades de una asociación potencial de transmisión del VIH (TPP por sus siglas en inglés), y esta asociación no fue significativa entre índices de no-negros. La asociación entre una TPP VIH y concurrencia de pareja sexual puede ayudar a explicar disparidades raciales persistentes en la prevalencia del VIH.

The outcome for metastatic pediatric osteosarcoma (OS) remains poor. Thus, there is an urgent need to develop novel therapies, and immunotherapy with CAR T cells has the potential to meet this challenge. However, there is a lack of preclinical models that mimic salient features of human disease including reliable development of metastatic disease post orthotopic OS cell injection. To overcome this roadblock, and also enable real-time imaging of metastatic disease, we took advantage of LM7 OS cells expressing firefly luciferase (LM7.ffLuc). LM7.ffLuc were implanted in a collagen mesh into the tibia of mice, and mice reliably developed orthotopic tumors and lung metastases as judged by bioluminescence imaging and histopathological analysis. Intratibial implantation also enabled surgical removal by lower leg amputation and monitoring for metastases development post-surgery. We then used this model to evaluate the antitumor activity of CAR T cells targeting B7-H3, an antigen that is expressed in a broad range of solid tumors including OS. B7-H3-CAR T cells had potent antitumor activity in a dose-dependent manner and inhibited the development of pulmonary metastases resulting in a significant survival advantage. In contrast T cells expressing an inactive B7-H3-CAR had no antitumor activity. Using unmodified LM7 cells also enabled us to demonstrate that B7-H3-CAR T cells traffic to orthotopic tumor sites. Hence, we have developed an orthotopic, spontaneously metastasizing OS model. This model may improve our ability not only to predict the safety and efficacy of current and next generation CAR T cell therapies but also other treatment modalities for metastatic OS.