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To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.

Aims: This study was conducted to determine whether a group of college-age students in New Jersey, USA, had the requisite culinary skills, knowledge, and confidence to take personal control of their meal planning and production. The long-term threat to the public health systems posed by high rates of obesity among young adults in higher education institutions has garnered widespread attention across the world. Studies have shown that assuming personal responsibility over preparing and consuming food can play a key role in addressing the problem of poor nutrient intakes. Methods: Focus groups were conducted with students (N = 24) who fit the eligibility criteria of not having a university meal plan, and living independently at the time of the study (not with family members). The sessions were recorded, transcribed, and then coded into themes. Two trained research assistants tested the results and inter-rater reliability was confirmed. Results: Content analysis revealed three major themes: Health Perceptions, Life influences, and Barriers to Cooking and Eating Healthy. The students’ comments indicated that while they had a basic knowledge of the key principles of eating a balanced diet, it may not have necessarily translated into actual food choices and cooking practices. Several students reported an overreliance on processed and prepared foods, and they consumed few fruits and vegetables. Conclusions: Factors such as lack of culinary knowledge and skill, financial instability, inadequate access to healthy food options, and other time/lifestyle constraints may have played a significant role in limiting their ability to prepare and consume healthy meals. The findings of this study highlight the importance of designing programmes with effective strategies to motivate and encourage college students to improve their food behaviours and practices.

BackgroundImmunotherapies are highly promising and effective strategies for the treatment of cancer; however, continuing challenges persist, including 1) untargeted global immune modulation, resulting in serious side effects; 2) lack of therapeutics capable of in vivo expansion of tumor-specific T cells; 3) inability to visualize in vivo tumor-specific T cell responses; and 4) lack of flexible platforms to rapidly and efficiently explore new therapeutic strategies and immune-escape mechanisms. To address these challenges, we developed a novel class of precision biologics to treat cancer, autoimmune diseases and infectious diseases. We describe a modular platform constructed around an Fc-based covalent pMHC dimer, referred to as synTac (artificial synapse for T cell activation; also termed Immuno-STATs for Selective Targeting and Alteration of T cells), which selectively delivers different cargoes, including costimulatory, coinhibitory or cytokine signals and other modalities to primary T cells of defined specificity. The inherent modularity supports broad applications. Changing the encoded peptide enables targeting of different T cell specificities to address different diseases, while altering the cargo allows for evaluation of different co-modulatory mechanisms or the delivery of mechanistically informative probes.MethodsSortase A-mediated enzymatic coupling supported site-specific and stoichiometric installation of positron emission tomography (PET)-active radiolabels on synTacs to visualize the in vivo localization of antigen-specific T cells. The NSG humanized mouse model allowed for the evaluation of synTacs/Immuno-STATs to drive the in vivo antigen-specific expansion of human CD8 T cells.ResultsUsing radiolabeled synTacs/Immuno-STATs loaded with the appropriate peptides, we employed positron emission tomography to localize human papillomavirus (HPV16)-specific CD8 T cells to implanted HPV16-positive tumors in mice, as well as influenza A virus (IAV)-specific CD8 T cells in the lungs of IAV-infected mice. In vivo administration of HIV- and CMV-specific synTacs/Immuno-STATs to immunodeficient mice intrasplenically engrafted with human donor PBMCs resulted in the marked and selective expansion of HIV-specific and CMV-specific human CD8 T cells populating their spleens, respectively.ConclusionsWe demonstrate the remarkable flexibility of the synTacs/Immuno-STAT platform for addressing a broad range of applications, including the first report of the in vivo imaging of antigen-specific CD8 T cell populations and in vivo antigen-selective expansion of human CD8 T cells. These results suggest that, in addition to broad therapeutic applications, synTac/Immuno-STATs may provide prognostic/diagnostic information. Most notably, these results demonstrate the presence of synTacs/Immuno-STAT biologics in the tumor or infected tissues where they can elicit T cell restimulation and expansion necessary for target killing and enhanced therapeutic efficacy.

It is estimated that approximately 15% of individuals who suffer a concussion experience cognitive impairments that can persist and cause long-term consequences (Post-Concussion Syndrome, 2023). This study builds on previous research on concussion, sustained attention, and inhibitory control to further characterize the mechanisms at work in post-concussion cognitive dysfunction (Moore et al., 2014; Ramage & Robin, 2019; Robin et al., 1999). Sustained attention was measured with a psychomotor vigilance task (Starry Night); inhibitory control was measured with the Flanker and Dimensional Change Card Sort tasks. The current study aims were developed to fill a gap in understanding regarding the potential interactions between disinhibition and disordered attention in young adults with concussion through foundational applications of Kahneman’s limited capacity model of attention and effort (1973), signal detection theory, and Friedman and Miyake’s (2004) proposed frameworks for types of inhibitory control.This study is a retrospective repeated methods design that uses between- and within- groups comparisons to evaluate the effect of group and performance over time on a sustained attention task. The interaction of group and time with performance (measured by accuracy and reaction time) on several tasks of attention and inhibitory control was also examined. Given the small sample size and potential for ceiling effects on the cognitive measures, results were not statistically significant. The reasoning for these results may empower future researchers to develop more sensitive tasks for evaluation of cognitive impairments present in the studied population. The nature of concussion results in relatively mild, but persistently devastating effects that are only identified with tasks that truly challenge cognition. While these tasks are not commonly used in clinical settings, this data points to the value of using tasks of increased complexity for deeper evaluation of a person’s deficits, since these deficits will undoubtedly arise in functional settings.

Differences in sexual development or DSD is used to describe genital atypia or a discrepancy between an individual’s genetic sex and phenotypic appearance. The term intersex is also used by individuals who have genetic, hormonal, or physical sex characteristics that do not fall into the male-female binary. DSDs and intersex traits require multidisciplinary management, typically with endocrinology, psychology, urology and genetic, and ideally operate with both the family and patient at the center of care. It is estimated 1 in 300 infants warrant consideration of a DSD at birth, and 1 in 4,500 with true genital atypia, illustrating this is a large population. Due to societal challenges surrounding discussion of sex and gender identity, it is a struggle for families when diagnoses are identified at birth how to discuss these topics with children. While there is data suggesting disclosure to the patient should occur as early as possible, and information should be given to patients by caregivers, there is little generalized data suggesting how information should be shared. Our study strived to identify ways to improve the disclosure process for patients, to identify strategies and resources to provide to patients and families, and to identify areas of need. Sixteen semi-structured interviews were conducted with members of InterConnect, an online support group for individuals who identify as intersex. We found half of participants received information from healthcare providers not caregivers (50%), after the age of 13 (75%). 25% of participants did not have a formal diagnosis and 25% had a categorical diagnosis. All individuals sought out information regarding their I/DSD and the majority were not provided any educational resources or mental health referrals. One individual expressed positive change regarding their familial relationship while eight individuals (50%) discussed negative changes. Individuals indicating no change to familial relationships learned about their diagnosis as adults, learned information with parents, or had no contact with family. In terms of providing information, participants encouraged using anatomically correct, factual, honest language. Informing the individual in age-appropriate ways, when they begin asking questions, and when they can understand information was also discussed. Participants also brought up the importance of understanding sexual diversity for providers and families. All participants experienced negative healthcare experiences due to lack of knowledge, lack of access to specialized care, and lack of patient-centered care. Overall, this study begins to analyze the disclosure process experienced by individuals who identify as I/DSD and helps to clarify the realities of disclosure. With further research, these findings can be validated and used to better I/DSD care in the future.

[Susan Houghton Debus] has been inspired to be an artist since childhood. With a family background in art, she has really grown to be her own liberated artist. Mainly her focus has been primitive folk art, and she paints her scenes with watercolors, acrylics and oils. Her paintings depict scenes from Vermont, the Midwest and the desert, areas that have always been of interest to her. Influenced by artists such as CharlesWysockiandJane Wooster Scott, she has continued to develop in the style of primitive art.

Patients undergoing evaluation for musculoskeletal concerns are often seen by a physician and physical therapist in the in-person setting in a sequential manner. This process typically delays the onset of nonoperative care, inclusive of physical therapy, and creates the risk of inadequate clinical collaboration between physician and physical therapist. To address these issues, we designed a novel initial patient evaluation to a group visit in which both a specialty-trained musculoskeletal physician and physical therapist simultaneously evaluate a patient together in the digital encounter. The aim of the study is to gain insights from patients on their experience with this innovative digital simultaneous musculoskeletal medical doctor and physical therapist (MD+PT) visit format for the initial evaluation of musculoskeletal concerns. An electronic 7-question survey was sent to 750 patients who completed an MD+PT visit asking them to comment on prior musculoskeletal evaluations and their experience with the MD+PT format. In total, 195 (26%) patients responded to the survey with the frequent body regions of diagnosis being lumbar spine (n=65), knee (n=32), shoulder (n=21), cervical spine (n=20), hip (n=14), and hand (n=11). Most patients had prior musculoskeletal experience with a physician or nurse practitioner (171/195, 87.7%) or physical therapist (148/195, 75.9%) with nearly all such encounters in the in-person setting (161/171,94.2% for physician or nurse practitioner and 144/148, 97.3% for physical therapy). Only 3.1% (6/193) of patients reported seeing both a physician and physical therapist during the same in-person visit. Patients rated the simultaneous MD+PT visit very favorably: this type of digital evaluation saved them time (179/192, 93.2%) and permitted them to promptly start their treatment plan (174/192, 90.6%). Overall, 87.5% (168/192) rated the MD+PT visit as enjoyable, and 92.2% (177/192) responded that it increased their confidence with understanding their medical condition and how to start treating it. Our early experience with the evaluation of patients with musculoskeletal conditions by both a specialty-trained musculoskeletal physician and physical therapist simultaneously in the same digital visit resulted in patients reporting a very positive experience with high satisfaction, engagement, and confidence in understanding their diagnosis and how to start treating it.

Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

Prevention and control of respiratory disease is a major contributor to antibiotic use in swine. A systematic review was conducted to address the question, ‘What is the comparative efficacy of antimicrobials for the prevention of swine respiratory disease?’ Eligible studies were controlled trials published in English evaluating prophylactic antibiotics in swine, where clinical morbidity, mortality, or total antibiotic use was assessed. Four databases and the gray literature were searched for relevant articles. Two reviewers working independently screened titles and abstracts for eligibility followed by full-text articles, and then extracted data and evaluated risk of bias for eligible trials. There were 44 eligible trials from 36 publications. Clinical morbidity was evaluated in eight trials where antibiotics were used in nursery pigs and 10 trials where antibiotics were used in grower pigs. Mortality was measured in 22 trials in nursery pigs and 12 trials in grower pigs. There was heterogeneity in the antibiotic interventions and comparisons published in the literature; thus, there was insufficient evidence to allow quantification of the efficacy, or relative efficacy, of antibiotic interventions. Concerns related to statistical non-independence and quality of reporting were noted in the included trials.