Infectious and non-infectious precipitants of sarcoidosis.

Sarcoidosis is a chronic inflammatory disease that can affect any organ in the body. Its exact cause remains unknown, but it is believed to result from a combination of genetic and environmental factors. Some potential causes of sarcoidosis include genetics, environmental triggers, immune system dysfunction, the gut microbiome, sex, and race/ethnicity. Genetic mutations are associated with protection against disease progression or an increased susceptibility to more severe disease, while exposure to certain chemicals, bacteria, viruses, or allergens can trigger the formation of immune cell congregations (granulomas) in different organs. Dysfunction of the immune system, including autoimmune reactions, may also contribute. The gut microbiome and factors such as being female or having African American, Scandinavian, Irish, or Puerto Rican heritage are additional contributors to disease outcome. Recent research has suggested that certain drugs, such as anti-Programmed Death-1 (PD-1) and antibiotics such as tuberculosis (TB) drugs, may raise the risk of developing sarcoidosis. Hormone levels, particularly higher levels of estrogen and progesterone in women, have also been linked to an increased likelihood of sarcoidosis. The diagnosis of sarcoidosis involves a comprehensive assessment that includes medical history, physical examination, laboratory tests, and imaging studies. While there is no cure for sarcoidosis, the symptoms can often be effectively managed through various treatment options. Treatment may involve the use of medications, surgical interventions, or lifestyle changes. These disparate factors suggests that sarcoidosis has multiple positive and negative exacerbants on disease severity, some of which can be ameliorated and others which cannot.

GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment.

BACKGROUND: Glioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades of research, the survival rates for GBM remain effectively stagnant. A defining hallmark of GBM is a highly acidic tumor microenvironment, which is thought to activate pro-tumorigenic pathways. This acidification is the result of altered tumor metabolism favoring aerobic glycolysis, a phenomenon known as the Warburg effect. Low extracellular pH confers radioresistant tumors to glial cells. Notably GPR68, an acid sensing GPCR, is upregulated in radioresistant GBM. Usage of Lorazepam, which has off target agonism of GPR68, is linked to worse clinical outcomes for a variety of cancers. However, the role of tumor microenvironment acidification in GPR68 activation has not been assessed in cancer. Here we interrogate the role of GPR68 specifically in GBM cells using a novel highly specific small molecule inhibitor of GPR68 named Ogremorphin (OGM) to induce the iron mediated cell death pathway: ferroptosis. METHOD: OGM was identified in a non-biased zebrafish embryonic development screen and validated with Morpholino and CRISPR based approaches. Next, A GPI-anchored pH reporter, pHluorin2, was stably expressed in U87 glioblastoma cells to probe extracellular acidification. Cell survival assays, via nuclei counting and cell titer glo, were used to demonstrate sensitivity to GPR68 inhibition in twelve immortalized and PDX GBM lines. To determine GPR68 inhibition's mechanism of cell death we use DAVID pathway analysis of RNAseq. Our major indication, ferroptosis, was then confirmed by western blotting and qRT-PCR of reporter genes including TFRC. This finding was further validated by transmission electron microscopy and liperfluo staining to assess lipid peroxidation. Lastly, we use siRNA and CRISPRi to demonstrate the critical role of ATF4 suppression via GPR68 for GBM survival. RESULTS: We used a pHLourin2 probe to demonstrate how glioblastoma cells acidify their microenvironment to activate the commonly over expressed acid sensing GPCR, GPR68. Using our small molecule inhibitor OGM and genetic means, we show that blocking GPR68 signaling results in robust cell death in all thirteen glioblastoma cell lines tested, irrespective of genetic and phenotypic heterogeneity, or resistance to the mainstay GBM chemotherapeutic temozolomide. We use U87 and U138 glioblastoma cell lines to show how selective induction of ferroptosis occurs in an ATF4-dependent manner. Importantly, OGM was not-acutely toxic to zebrafish and its inhibitory effects were found to spare non-malignant neural cells. CONCLUSION: These results indicate GPR68 emerges as a critical sensor for an autocrine pro-tumorigenic signaling cascade triggered by extracellular acidification in glioblastoma cells. In this context, GPR68 suppresses ATF4, inhibition of GPR68 increases expression of ATF4 which leads to ferroptotic cell death. These findings provide a promising therapeutic approach to selectively induce ferroptosis in glioblastoma cells while sparing healthy neural tissue.

Exploring the Complexity of Telehealth Privacy Through a Lens of Adolescent Development.

Many challenges exist related to ensuring adolescent privacy with health care providers (HCPs), and the rapid integration of telehealth visits has created additional complexities in organizing privacy for adolescents. Through interviews with adolescent patients and their parents (n = 34), this qualitative analysis aimed to explore the complicated relationship and balance of adolescent alone time with HCPs, parental presence and support, and organization of privacy in order to consider how privacy during telehealth visits may contribute to adolescents' healthy development. A framework by Blum et al. (2014) proposed four central goals of adolescent development: emotional security, engagement with learning, self-efficacy, and decision-making skills. This conceptual framework was used to outline the ways in which adolescent privacy during telehealth impacts adolescent development. Some adolescents reported that having their parents present during their telehealth visit afforded reassurance and comfort, and many parents explained that they served as a role-model during their adolescent's telehealth visit. However, other adolescents felt higher emotional security when they could establish an independent relationship with their HCP, with many describing how privacy during their telehealth visit enabled them to have more sensitive discussions with their HCP. Adolescents and parents also reported that telehealth allowed increased experiential learning for adolescents, given their proficiency with technology and ability to access their health care visits autonomously. Furthermore, the organization of privacy was complicated by a lack of understanding whose responsibility it was to facilitate alone time between the adolescent and HCP, as well as external factors such as location and quality of technology and the proximity of family members in the home. By ensuring opportunities for private healthcare encounters, both in telehealth and in-person visits, HCPs and parents can help support adolescents in achieving successful and healthy development.

Exploring the Connectivity Paradox: How the Sociophysical Environment of Telehealth Shapes Adolescent Patients' and Parents' Perceptions of the Patient-Clinician Relationship.

Even before the widespread transition to telehealth as a result of COVID-19, there was a considerable amount of research exploring its value and impact. However, telehealth research with adolescent patients is somewhat limited, with most work focusing on access, feasibility, and acceptability but reporting far less frequently on relationship building and rapport. This study examines qualitative interviews with adolescent patients (n = 14) and parents (n = 20) from a larger convergent parallel mixed methods study to explore how they understand telehealth to have altered the sociophysical environment of primary care clinic encounters and whether they perceive these changes to influence adolescents' relationships with clinicians. We show that participants perceived the sociophysical environment of telehealth to be both less institutional (e.g. more relaxed and less rushed) and more instrumental (e.g. more focused on the chief complaint), which shaped interactions with clinicians in ways that were experienced as paradoxically less personal (e.g. lacking social connection) and more person-centered (e.g. more attentive to the individual patient). We discuss theoretical and practical implications of these findings and what they mean for defining person-centered communication for adolescent care.

Adolescent Perceptions of Technology-Based Sexual and Reproductive Health Services: A Systematic Review.

Technology-based services, including telehealth, text messaging, and the internet are increasingly popular methods for adolescents and young adults (AYA) to access sexual and reproductive health (SRH) information and healthcare. This systematic review examined AYA perceptions of privacy and confidentiality of technology-based SRH services. The PubMed, Scopus, and PsycINFO were systematically searched in May 2021 to capture relevant qualitative or quantitative articles from the past 10 years. Included studies had AYA (i.e., mean age, 13-26-years with <10% of the sample outside this range), technology-based services for SRH, and outcomes of perceived privacy or confidentiality. Twenty-eight articles were included (N = 8638 AYA). Most studies utilized the internet and mobile apps to address human immunodeficiency virus infection (HIV), sexually transmitted infections, and general SRH topics. Most AYA reported that these services were private and confidential, with minimal differences across SRH topic addressed. More interactive services had greater concerns (e.g., family or friends seeing notifications). Most AYA considered technology-based SRH to be confidential and private. As technology will likely remain an integrated part of healthcare delivery, improving the privacy and confidentiality of these services can facilitate AYA's independent and autonomous engagement in SRH care, and potentially improve their SRH outcomes.

Improving Food Insecurity Education in Medical School Through Integrative Service Learning.

Introduction: The COVID-19 pandemic has left more than 38% of households food insecure in the United States. Improved education of food security topics in medical school can improve screening for food insecurity and improve health outcomes. The first aim of this study was to address if participation in an experiential integrative service learning program improved medical students' understanding of food insecurity. The second aim was to compare knowledge of food insecurity between the general body of medical students and those who participated in the service learning program. Methods: This was a cohort study at a large medical school in southeast Michigan in 2019-2020. We administered the Food Insecurity for Health Professionals (FISHP) survey to medical student participants; higher scores on the FISHP survey suggest higher knowledge and comfort with food security topics. We administered online Qualtrics surveys to the volunteer group before and after volunteering 12 hours at an urban farm. We also administered a one-time survey to a control group of medical students. We performed univariable and bivariable statistical analyses with StataSE 16. The study was exempted by the institutional IRB. Results: Medical students in the volunteer group (n = 18) and the control group (n = 66) completed online surveys. Participants in the volunteer group had increased knowledge of food security after volunteering in the service learning program (p = .03). There was a statistically significant difference between the mean FISHP scores for the control group and the volunteer group (p = .001). Conclusion: Medical student participation in an experiential integrative service learning program improved knowledge of food security topics and increased comfort discussing food insecurity with patients, compared to students who did not participate. Experiential integrative service learning may improve holistic patient care through physician recognition of food insecurity and other social determinants of health.

Proteomic Changes in the Monolayer and Spheroid Melanoma Cell Models of Acquired Resistance to BRAF and MEK1/2 Inhibitors.

Extracellular signal-regulated kinase-1/2 (ERK1/2) pathway inhibitors are important therapies for treating many cancers. However, acquired resistance to most protein kinase inhibitors limits their ability to provide durable responses. Approximately 50% of malignant melanomas contain activating mutations in BRAF, which promotes cancer cell survival through the direct phosphorylation of the mitogen-activated protein kinase MAPK/ERK 1/2 (MEK1/2) and the activation of ERK1/2. Although the combination treatment with BRAF and MEK1/2 inhibitors is a recommended approach to treat melanoma, the development of drug resistance remains a barrier to achieving long-term patient benefits. Few studies have compared the global proteomic changes in BRAF/MEK1/2 inhibitor-resistant melanoma cells under different growth conditions. The current study uses high-resolution label-free mass spectrometry to compare relative protein changes in BRAF/MEK1/2 inhibitor-resistant A375 melanoma cells grown as monolayers or spheroids. While approximately 66% of proteins identified were common in the monolayer and spheroid cultures, only 6.2 or 3.6% of proteins that significantly increased or decreased, respectively, were common between the drug-resistant monolayer and spheroid cells. Drug-resistant monolayers showed upregulation of ERK-independent signaling pathways, whereas drug-resistant spheroids showed primarily elevated catabolic metabolism to support oxidative phosphorylation. These studies highlight the similarities and differences between monolayer and spheroid cell models in identifying actionable targets to overcome drug resistance.

Adolescent and Parent Perceptions of Telehealth Visits: A Mixed-Methods Study.

PURPOSE: Telehealth presents unique benefits and challenges for adolescents and their parents. This study aimed to explore adolescent and parent perceptions of privacy, confidentiality, and therapeutic alliance during telehealth video visits. METHODS: This was a cross-sectional convergent parallel mixed-methods study. English-speaking parents and 13- to 17-year-old adolescents who completed a video visit at eight academic-affiliated pediatric primary care practices in the Southeastern U.S. were recruited between September 2020 and January 2021. Online surveys were administered and analyzed using descriptive and bivariable analysis. Subsequent semi-structured qualitative interviews were conducted and analyzed using thematic analysis. RESULTS: Forty-eight adolescents and 104 parents completed surveys. Fourteen adolescents and 20 parents were interviewed. Mean ages of adolescents and parents were 15 and 46 years, respectively, and most participants identified as female, non-Hispanic, and white. Seventy-seven percent of adolescents reported very private telehealth visits. Most privacy concerns were related to the location of the visit in the patient's home or family members overhearing. Adolescents reported that alone time with their provider increased comfort in discussing sensitive issues, although only 31% of adolescents reported having time alone with their provider during their telehealth visit. Neither adolescents nor parents reported concerns about confidentiality. Interviews suggested that adolescent autonomy and independence in accessing health care may explain the positive relationship observed between therapeutic alliance and privacy. CONCLUSIONS: Adolescents and parents describe telehealth as convenient, useful, private, and confidential. Providers should strive to maximize privacy and the therapeutic alliance during video visits, including encouraging alone time and supporting adolescent autonomy and independence.