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We sought to identify concepts that may facilitate National Collegiate Athletic Association efforts to assist member institutions in addressing the mental health needs of student-athletes of colour. A two-step process was followed to generate and refine concepts, guided by Delphi methodology. First, a scoping review was conducted, including original peer-reviewed research articles that quantified or qualitatively described determinant(s) of racial or ethnic differences in athlete mental health or mental healthcare. Next, a multiday virtual meeting was facilitated to review the results of the scoping review, discuss lived experiences and generate potential concepts. Participants included a racially and ethnically diverse group of student-athletes, medical and mental health professionals, athletics administrators, diversity, equity and inclusion experts, health educators and representatives from leading organisations involved in athlete mental health. Through the consensus process, participants identified 42 concepts that member institutions might consider implementing on their campuses. Concepts were largely focused on organisational policies and practices such as staffing diversity and inclusion, expanded options for clinical support (ie, identity-relevant support groups) and within-organisation accountability. Concepts related to specific areas for stakeholder education were also identified. Institutions have the potential to play an important role in supporting the mental well being of student-athletes of colour, and the present concepts can help inform institutional action. While concepts proposed are believed to be broadly relevant across athletics settings, they would need to be further considered and tailored to reflect setting-specific organisational structures, resources and needs.

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 MFGE8expression 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.

Sexual violence in sports is underreported and results in a multitude of adverse physical and mental health consequences. Sports medicine physicians, and other members of the athlete care team, should possess knowledge and skill in the prevention of sexual violence and in the care of individuals who experience sexual violence.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.

Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading to the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR T cell products. In contrast, the clinical experience with CAR T cell therapy for solid tumors and brain tumors has been less encouraging, with only a few patients achieving complete responses. Clinical and preclinical studies have identified multiple “roadblocks,” including (1) a limited array of targetable antigens and heterogeneous antigen expression, (2) limited T cell fitness and survival before reaching tumor sites, (3) an inability of T cells to efficiently traffic to tumor sites and penetrate physical barriers, and (4) an immunosuppressive tumor microenvironment. Herein, we review these challenges and discuss strategies that investigators have taken to improve the effector function of CAR T cells for the adoptive immunotherapy of solid tumors.

The surface of proteins is heterogeneous with sophisticated but precise hydrophobic and hydrophilic patches, which is essential for their diverse biological functions. To emulate such distinct surface patterns on macromolecules, we used rigid spherical synthetic dendrimers (polyphenylene dendrimers) to provide controlled amphiphilic surface patches with molecular precision. We identified an optimal spatial arrangement of these patches on certain dendrimers that enabled their interaction with human adenovirus 5 (Ad5). Patchy dendrimers bound to the surface of Ad5 formed a synthetic polymer corona that greatly altered various host interactions of Ad5 as well as in vivodistribution. The dendrimer corona (1) improved the ability of Ad5-derived gene transfer vectors to transduce cells deficient for the primary Ad5 cell membrane receptor and (2) modulated the binding of Ad5 to blood coagulation factor X, one of the most critical virus–host interactions in the bloodstream. It significantly enhanced the transduction efficiency of Ad5 while also protecting it from neutralization by natural antibodies and the complement system in human whole blood. Ad5 with a synthetic dendrimer corona revealed profoundly altered in vivodistribution, improved transduction of heart, and dampened vector sequestration by liver and spleen. We propose the design of bioactive polymers that bind protein surfaces solely based on their amphiphilic surface patches and protect against a naturally occurring protein corona, which is highly attractive to improve Ad5-based in vivogene therapy applications.

Fibroblasts migrate discontinuously by generating transient leading-edge protrusions and irregular, abrupt retractions of a narrow trailing edge. In contrast, keratinocytes migrate persistently and directionally via a single, stable, broad protrusion paired with a stable trailing-edge. The Rho GTPases Rac1, Cdc42 and RhoA are key regulators of cell protrusions and retractions. However, how these molecules mediate cell-type specific migration modes is still poorly understood. In fibroblasts, all three Rho proteins are active at the leading edge, suggesting short-range coordination of protrusive Rac1 and Cdc42 signals with RhoA retraction signals. Here, we show that Cdc42 was surprisingly active in the trailing-edge of migrating keratinocytes. Elevated Cdc42 activity colocalized with the effectors MRCK and N-WASP suggesting that Cdc42 controls both myosin activation and actin polymerization in the back. Indeed, Cdc42 was required to maintain the highly dynamic contractile acto-myosin retrograde flow at the trailing edge of keratinocytes, and its depletion induced ectopic protrusions in the back, leading to decreased migration directionality. These findings suggest that Cdc42 is required to stabilize the dynamic cytoskeletal polarization in keratinocytes, to enable persistent, directional migration.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a position statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.

Sleep is an important determinant of collegiate athlete health, well-being and performance. However, collegiate athlete social and physical environments are often not conducive to obtaining restorative sleep. Traditionally, sleep has not been a primary focus of collegiate athletic training and is neglected due to competing academic, athletic and social demands. Collegiate athletics departments are well positioned to facilitate better sleep culture for their athletes. Recognising the lack of evidence-based or consensus-based guidelines for sleep management and restorative sleep for collegiate athletes, the National Collegiate Athletic Association hosted a sleep summit in 2017. Members of the Interassociation Task Force on Sleep and Wellness reviewed current data related to collegiate athlete sleep and aimed to develop consensus recommendations on sleep management and restorative sleep using the Delphi method. In this paper, we provide a narrative review of four topics central to collegiate athlete sleep: (1) sleep patterns and disorders among collegiate athletes; (2) sleep and optimal functioning among athletes; (3) screening, tracking and assessment of athlete sleep; and (4) interventions to improve sleep. We also present five consensus recommendations for colleges to improve their athletes’ sleep.

AbstractObjectiveTo determine whether assignment to a multiple-bed room increased the risk of hospital-onset C. difficilediarrhea (HO-CDI).DesignCase-control study.SettingSan Francisco General Hospital and Trauma Center.PopulationAdult general medical and surgical inpatients.MethodsConsecutive cases of HO-CDI were identified between January 1, 2010, and December 31, 2015. To investigate the effect of multiple-bed room exposure both at admission and at the time of symptom onset, 2 sets of controls were selected from the general medical/surgical inpatient population using incidence density sampling. Conditional logistic regression was used to estimate the relationship between room assignment (single bed vs multiple beds) and the development of HO-CDI.ResultsIn total, 187 cases were identified and matched with 512 and 515 controls for the admission and at-diagnosis analyses, respectively. The adjusted rate ratio (RR) associated with the development HO-CDI associated with multiple-bed room exposure during the 7 and 14 days immediately prior to HO-CDI diagnosis were 1.08 (95% confidence interval [CI], 0.93–1.25; P=.31) and 0.96 (95% CI, 0.93–1.18; P=.12), respectively. Furthermore, no significant association was detected in the analysis of the first 7 and 14 days after case admission or among patients with Charlson comorbidity scores ≥4 in either period.ConclusionAssignment of patients to multiple-bed rooms on general medical and surgical wards was not associated with an increased risk in the development of HO-CDI. Future investigation should be performed with larger cohorts in multiple sites to more definitively address the question because this issue could have implications for patient room assignment and hospital design.

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2006.12.038 Byline: Nader Moazami (a), Omid H. Javadi (a), Dean F. Kappel (c), Jessica Wagner (c), Martin D. Jendrisak (b) Author Affiliation: (a) Section of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Mo (b) Section of Transplantation, Department of Surgery, Washington University School of Medicine, St Louis, Mo (c) Mid-America Transplant Services, St Louis, Mo. Article History: Received 31 August 2006; Accepted 12 December 2006

ABSTRACTAnti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitropotencies were identified in an exploration of chemical derivatives. Based on in vitropotency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitroand evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivoin BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

What I Can Do to Make a Difference ... From A to Z Aim to recycle. Balance your needs with nature. Conserve energy. Donate unneeded items. Economize waste. Fill the […]

In neurodegenerative diseases, certain types of neurons perish first, but the mechanisms of this selective neuronal vulnerability remain unclear. A new study now highlights a crucial role for apolipoprotein E in driving neuronal death in both ageing and Alzheimer’s disease.

The Fcγ receptor FcRn transports immunoglobulin G (IgG) so as to avoid lysosomal degradation and to carry it bidirectionally across epithelial barriers to affect mucosal immunity. Here, we identify a calmodulin-binding site within the FcRn cytoplasmic tail that affects FcRn trafficking. Calmodulin binding to the FcRn tail is direct, calcium-dependent, reversible, and specific to residues comprising a putative short amphipathic α-helix immediately adjacent to the membrane. FcRn mutants with single residue substitutions in this motif, or FcRn mutants lacking the cytoplasmic tail completely, exhibit a shorter half-life and attenuated transcytosis. Chemical inhibitors of calmodulin phenocopy the mutant FcRn defect in transcytosis. These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route.

Introduction: Pulse oximeters are reliable, objective, and noninvasive monitors that have broad application in aerospace medicine. New technology enables pulse oximeters to perform well in adverse environments and measure additional parameters. Small, battery-powered devices can be used to monitor oxyhemoglobin saturation while in flight. Theory of Operation: Pulse oximeters use spectrophotometry to measure the ratio of oxyhemoglobin (HbO2) to reduced hemoglobin (Hb) in arterial blood. This value is displayed as oxyhemoglobin saturation (SpO2). A plethysmographic waveform that resembles arterial waveform is also frequently displayed and may indicate relative changes in perfusion and blood volume. Loss and subsequent reappearance of this waveform during occlusion with a cuff has been used to measure systolic blood pressure during helicopter flight. Applications: Accurate determination of oxygen saturation requires a high quality arterial signal and is limited by errors resulting from calibration, motion and vibration, and dyshemoglobinemias. Vasoconstriction may result in decreased pulse amplitude and also impair accurate measurement. Conventional fingertip probes may interfere with the performance of required duties, while helmets and other restrictive clothing can impede the use of sensors on the forehead or ear. Recently introduced devices answer some of these limitations and enable measurement of additional parameters. For example, new probe designs permit more freedom of movement and include a contactless camera and a sensor that fits around a finger like an ordinary ring. This article explains the theory of operation and limitations of pulse oximetry, offers an update on new technology, and discusses applications of this technology in aerospace medicine. [ABSTRACT FROM AUTHOR]

Early experience with deceased donor (DD) organ recovery outside of the hospital setting was found to be safe, efficient and cost effective. A 2-year experience under current practice protocols implemented to further process improvements is now reviewed.

The human MHC class I-related neonatal Fc receptor, hFcRn, mediates bidirectional transport of IgG across mucosal barriers. Here, we find that at steady state hFcRn distributes predominantly to an apical intracellular compartment and almost exclusively to the basolateral cell surface of polarized epithelial cells. It moves only transiently to the apical membrane. Ligand binding does not redistribute the steady state location of the receptor. Removal of the cytoplasmic tail that contains di-leucine and tryptophan-based endocytosis motifs or incubation at low temperature (18 degrees C) redistributes the receptor apically. The rates of endocytosis of the full-length hFcRn from the apical or basolateral membrane domains, however, are equal. Thus, the strong cell surface polarity displayed by hFcRn results from dominant basolateral sorting by motifs in the cytoplasmic tail that nonetheless allows for a cycle of bidirectional transcytosis.

The human MHC class I–related neonatal Fc receptor, hFcRn, mediates bidirectional transport of IgG across mucosal barriers. Here, we find that at steady state hFcRn distributes predominantly to an apical intracellular compartment and almost exclusively to the basolateral cell surface of polarized epithelial cells. It moves only transiently to the apical membrane. Ligand binding does not redistribute the steady state location of the receptor. Removal of the cytoplasmic tail that contains di-leucine and tryptophan-based endocytosis motifs or incubation at low temperature (18°C) redistributes the receptor apically. The rates of endocytosis of the full-length hFcRn from the apical or basolateral membrane domains, however, are equal. Thus, the strong cell surface polarity displayed by hFcRn results from dominant basolateral sorting by motifs in the cytoplasmic tail that nonetheless allows for a cycle of bidirectional transcytosis.

Of the many logistic issues addressed throughout the cadaveric organ donation process, timely access to the operating theater for surgical recovery of organs and tissues can be one of the most problematic. Delay in recovery adds to cost, risks organ viability, and compounds donor family anguish with compromise to donation consent.

Uncontrolled amyloid‐beta (Aβ) fibrillation leads to the deposition of neurotoxic amyloid plaques and is associated with Alzheimer's disease. Inhibiting Aβmonomer fibrillation and dissociation of the formed fibers is regarded as a promising therapeutic strategy. Here, amphiphilic polyphenylene dendrons (APDs) are demonstrated to interrupt Aβassembly 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 Aβaggregates, inhibiting fibrillation and disassemble the already formed Aβfibrils. 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 Aβfibrillation in vivo, which can be beneficial for developing therapeutic strategy for Alzheimer's disease. Amyloid‐beta (Aβ) assembly plays essential roles in Alzheimer's plaque formation. Amphiphilic polyphenylene dendrons (APDs) with their bioconjugation (SA‐D), which inhibit Aβfibrillation, disassemble the already formed fibrils, and significantly reduce the Aβ‐induced cytotoxicity, are presented here. APDs and SA‐D reveal specific neurons uptake and cross the blood–brain barrier in vivo, providing new opportunities as therapeutic candidates for Alzheimer's disease.

Despite evidence that community water fluoridation (CWF) protects oral health, improves health equity, is safe, cost effective, and contributes to social wellbeing, it is unknown which of these benefits should be highlighted to effectively influence support for CWF.

Prabhu: Oncoceutics: Employment. Tarapore:Oncoceutics: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Allen:Oncoceutics: Employment, Equity Ownership. El-Deiry:Oncoceutics: Equity Ownership.

Prabhu: Oncoceutics: Employment. Tarapore:Oncoceutics: Employment, Equity Ownership. El-Deiry:Oncoceutics: Equity Ownership. Stogniew:Oncoceutics Inc.: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Allen:Oncoceutics: Employment, Equity Ownership.

Allen: Oncoceutics, Inc.: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Patents & Royalties.

Allen: Oncoceutics, Inc.: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Patents & Royalties.

Allen: Oncoceutics: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Patents & Royalties.

A response by Keith J. Ruskin to a letter to the editor about his article which demonstrated the importance of pulse oximetry for both aviation medicine and clinical settings, published in the previous issue, is presented.