Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans.

BACKGROUND: Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD's analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD's effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). METHODS: We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). DISCUSSION: Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD's analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. TRIAL REGISTRATION: This protocol is registered at clinicaltrials.gov under study number NCT06213233.

'I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID.

AIMS AND OBJECTIVES: In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. BACKGROUND: As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. DESIGN: We employed an interpretive description study design. METHODS: We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. RESULTS: We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. CONCLUSION: Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. RELEVANCE TO CLINICAL PRACTICE: Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. NO PATIENT OR PUBLIC CONTRIBUTION: While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes.

There are over 220 identified genotypes of Human papillomavirus (HPV), and the HPV genome encodes 3 major oncogenes, E5, E6, and E7. Conservation and divergence in protein sequence and function between low-risk versus high-risk oncogenic HPV genotypes has not been fully characterized. Here, we used modern computational and structural folding algorithms to perform a comparative analysis of HPV E5, E6, and E7 between multiple low risk and high risk genotypes. We first identified significantly greater sequence divergence in E5 between low- and high-risk genotypes compared to E6 and E7. Next, we used AlphaFold to model the structure of papillomavirus proteins and complexes with high confidence, including some with no established consensus structure. We observed that HPV E5, but not E6 or E7, had a dramatically different 3D structure between low-risk and high-risk genotypes. To our knowledge, this is the first comparative analysis of HPV proteins using Alphafold artificial intelligence (AI) system. The marked differences in E5 sequence and structure in high-risk HPVs may contribute in important and underappreciated ways to the development of HPV-associated cancers.

Farnesol remodels the peritoneal cavity immune environment influencing Candida albicans pathogenesis during intra-abdominal infection.

Candida albicans is a lifelong member of the mycobiome causing mucosal candidiasis and life-threatening, systemic, and intra-abdominal disease in immunocompromised and transplant patients. Despite the clinical importance of intra-abdominal candidiasis with mortality rates between 40% and 70%, the contribution of fungal virulence factors and host immune responses to disease has not been extensively studied. Secretion of the quorum-sensing molecule, farnesol, acts as a virulence factor for C. albicans during systemic infection, while inducing local, protective innate immune responses in oral models of infection. Previously, we reported that farnesol recruits macrophages to the peritoneal cavity in mice, suggesting a role for farnesol in innate immune responses. Here, we expand on our initial findings, showing that farnesol profoundly alters the peritoneal cavity microenvironment promoting innate inflammation. Intra-peritoneal injection of farnesol stimulates rapid local death of resident peritoneal cells followed by recruitment of neutrophils and inflammatory macrophages into the peritoneal cavity and peritoneal mesothelium associated with an early increase in chemokines followed by proinflammatory cytokines. These rapid inflammatory responses to farnesol significantly increase morbidity and mortality of mice with intra-abdominal candidiasis associated with increased formation of peritoneal adhesions, despite similar rates of fungal clearance from the peritoneal cavity and retro-peritoneal organs. C. albicans ddp3Δ/ddp3Δ knockout and reconstituted strains recapitulate these findings. This indicates that farnesol may be detrimental to the host during intra-abdominal infections. Importantly, our results highlight a need to understand how C. albicans virulence factors modulate the host immune response within the peritoneum, an exceedingly common site of Candida infection.

Seafood-Associated Outbreak of ctx-Negative Vibrio mimicus Causing Cholera-Like Illness, Florida, USA.

Vibrio mimicus caused a seafood-associated outbreak in Florida, USA, in which 4 of 6 case-patients were hospitalized; 1 required intensive care for severe diarrhea. Strains were ctx-negative but carried genes for other virulence determinants (hemolysin, proteases, and types I-IV and VI secretion systems). Cholera toxin-negative bacterial strains can cause cholera-like disease.

Are vertebrates constrained to two sets of paired appendages? The morphology, development, and evolution of pre-pelvic claspers in the Holocephali.

Holocephalans exhibit auxiliary appendages called pre-pelvic claspers (PPCs) that are located anterior to the pelvic fins, while pelvic claspers are pelvic fin modifications located posteriorly as modified metapterygia. Articulation points of the PPCs have not previously been imaged or evaluated in a comparative context, therefore, they may represent modified pelvic fin structures if they articulate with the propterygium. Alternatively, they could represent the only example of an independent third set of paired appendages in an extant taxon, if they articulate independently from any pelvic fin basal cartilages, challenging the current paradigm that extant jawed vertebrates are constrained to two sets of paired appendages. Two extinct groups, including Placoderms and Acanthodians, exhibit variation in the number of paired appendages, suggesting this may be a plesiomorphic trait. We evaluated PPC developmental growth rates, morphology, and articulation points in spotted ratfish (Hydrolagus Colliei, Holocephali). We also compared variation in PPC morphology among representatives of the three extant holocephalan families. Both, the pre-pelvic and pelvic claspers exhibit a dramatic surge in growth at sexual maturity, and then level off, suggesting synchronous development via shared hormonal regulation. While mature females are larger than males, pelvic fin growth and development is faster in males, suggesting a selective advantage to larger fins with faster development. Finally, microcomputed tomography scans revealed that PPCs are not modified propterygia, nor do they articulate with the propterygium. They articulate with the anterior pre-pelvic process on the anterior puboischiadic bar (or pelvic girdle), suggesting that while they are associated with the pelvic girdle, they may indeed represent a third, independent set of paired appendages in extant holocephalans.

Targeting macrophage Syk enhances responses to immune checkpoint blockade and radiotherapy in high-risk neuroblastoma.

Background: Neuroblastoma (NB) is considered an immunologically cold tumor and is usually less responsive to immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) are highly infiltrated in NB tumors and promote immune escape and resistance to ICB. Hence therapeutic strategies targeting immunosuppressive TAMs can improve responses to ICB in NB. We recently discovered that spleen tyrosine kinase (Syk) reprograms TAMs toward an immunostimulatory phenotype and enhances T-cell responses in the lung adenocarcinoma model. Here we investigated if Syk is an immune-oncology target in NB and tested whether a novel immunotherapeutic approach utilizing Syk inhibitor together with radiation and ICB could provide a durable anti-tumor immune response in an MYCN amplified murine model of NB. Methods: Myeloid Syk KO mice and syngeneic MYCN-amplified cell lines were used to elucidate the effect of myeloid Syk on the NB tumor microenvironment (TME). In addition, the effect of Syk inhibitor, R788, on anti-tumor immunity alone or in combination with anti-PDL1 mAb and radiation was also determined in murine NB models. The underlying mechanism of action of this novel therapeutic combination was also investigated. Results: Herein, we report that Syk is a marker of NB-associated macrophages and plays a crucial role in promoting immunosuppression in the NB TME. We found that the blockade of Syk in NB-bearing mice markedly impairs tumor growth. This effect is facilitated by macrophages that become immunogenic in the absence of Syk, skewing the suppressive TME towards immunostimulation and activating anti-tumor immune responses. Moreover, combining FDA-approved Syk inhibitor, R788 (fostamatinib) along with anti-PDL1 mAb provides a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in mice bearing small tumors (50 mm3) but not larger tumors (250 mm3). However, combining radiation to R788 and anti-PDL1 mAb prolongs the survival of mice bearing large NB9464 tumors. Conclusion: Collectively, our findings demonstrate the central role of macrophage Syk in NB progression and demonstrate that Syk blockade can "reeducate" TAMs towards immunostimulatory phenotype, leading to enhanced T cell responses. These findings further support the clinical evaluation of fostamatinib alone or with radiation and ICB, as a novel therapeutic intervention in neuroblastoma.

Abdominal Ecchymosis: Emergency, or Urgen-C?

Scurvy is a multisystem disease caused by vitamin C deficiency, historically associated with lethargy, gingivitis, ecchymosis, edema, and death if left untreated. Contemporary socioeconomic risk factors for scurvy include smoking, alcohol abuse, fad diets, mental health conditions, social isolation, and economic marginalization. Food insecurity is also a risk factor. This report describes a case of a man in his 70s who presented with unexplained dyspnea, abdominal pain, and abdominal ecchymosis. His plasma vitamin C level was undetectable, and he improved with vitamin C supplementation. This case highlights the significance of awareness of these risk factors and emphasizes the need for a comprehensive social and dietary history to enable the timely treatment of this rare but potentially fatal disease.

Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway.

The role that human papillomavirus (HPV) oncogenes play in suppressing responses to immunotherapy in cancer deserves further investigation. In particular, the effects of HPV E5 remain poorly understood relative to E6 and E7. Here, we demonstrate that HPV E5 is a negative regulator of anti-viral interferon (IFN) response pathways, antigen processing, and antigen presentation. Using head and neck cancer as a model, we identify that E5 decreases expression and function of the immunoproteasome and that the immunoproteasome, but not the constitutive proteasome, is associated with improved overall survival in patients. Moreover, immunopeptidome analysis reveals that HPV E5 restricts the repertoire of antigens presented on the cell surface, likely contributing to immune escape. Mechanistically, we discover a direct interaction between E5 and stimulator of interferon genes (STING), which suppresses downstream IFN signaling. Taken together, these findings identify a powerful molecular mechanism by which HPV E5 limits immune detection and mediates resistance to immunotherapy.

Social determinants of depression in systemic lupus erythematosus: A systematic scoping review.

Social determinants of health (SDOH) influence inequities in systemic lupus erythematosus (SLE). While these inequities contribute to overall disease experience, there is little consensus guiding our understanding of the psychological implications of SDOH in SLE. Given the paucity of evidence in this area, the aim of this scoping review was to systematically assess the volume and features of available research literature on associations of SDOH with depression in SLE over the past 20 years, from 1 January 2000 to 16 November 2021. We developed a search strategy for PubMed and EMBASE that included keywords for depression and lupus. After screening 2188 articles, we identified 22 original articles that met our inclusion criteria. At least one SDOH was associated with depression in two of the six studies with unadjusted estimates and 13 of the 16 studies with adjusted estimates. Results provide consistent but sparse evidence that SDOH are associated with depression in SLE. Additionally, depression epidemiology in SLE may differ from the general population such that depression risk is more similar across genders and racial/ethnic groups. More work is needed to identify the SDOH that have the greatest impact on depression and mental health among SLE patients, as well as how and when to intervene.

Opportunities to Improve Long COVID Care: Implications from Semi-structured Interviews with Black Patients.

BACKGROUND: Long coronavirus disease (COVID) is an emerging condition that could considerably burden healthcare systems. Prior qualitative studies characterize the experience of having long COVID, which is valuable for informing care strategies. However, evidence comes from predominantly White samples. This is a concern because underrepresentation of Black patients in research and intervention development contribute to racial inequities. OBJECTIVE: To facilitate racial equity in long COVID care, the purpose of this qualitative study was to inform the development of care strategies that are responsive to the experiences and perspectives of Black patients with long COVID in the United States of America. METHODS: Using convenience sampling, we conducted race-concordant, semi-structured, and open-ended interviews with Black adults (80% female, mean age = 39) who had long COVID. We transcribed and anonymized the recorded interviews. We analyzed the transcripts using inductive, thematic analysis. Theme development focused on who can help or hinder strategies for reducing health inequities, what should be done to change care policies or treatment strategies, and when are the critical timepoints for intervention. RESULTS: We developed four main themes. Participants reported challenges before and after COVID testing. Many participants contacted primary care physicians as a first step for long COVID treatment. However, not all respondents had positive experiences and at times felt dismissed. Without a qualifying diagnosis, participants could not obtain disability benefits, which negatively influenced their employment and increased financial hardship. CONCLUSIONS: There are possible targets for improving long COVID care, from COVID testing through to long-term treatment plans. There is a need to increase long COVID awareness among physicians. Diagnosis and a standardized treatment plan could help patients avoid unnecessary healthcare utilization and obtain comprehensive support.

Healthy Debate: Major Depression among Older Immigrants and the United States 2016 Election.

This study investigated whether anti-immigrant sentiment leading up to the 2016 election increased risk of major depression among older U.S. immigrants. Drawing data from the Health and Retirement Study, we tested whether there was a disproportionate increase in major depression among U.S. immigrants than non-immigrants from 2014 to 2016 using a Difference in Difference approach. Older immigrants had a higher relative change in major depression from 2014 to 2016 than non-immigrants (RRR 1.35; 95% CI 1.06, 1.73). This relationship was driven by associations among those who are White (RRR 2.07; 95% CI 1.26, 3.41) or Hispanic (RRR 1.55; 95% CI 0.99, 2.40). Anti-immigrant sentiment leading up to the 2016 election was associated with an increase in major depression among older U.S. immigrants. Findings may help identify high-risk groups in future election years and inform treatment strategies for major depression that consider the influence of sociopolitical factors.

Heart failure with reduced ejection fraction due topolycythemia vera.

Polycythemia vera is a rare hematological disorder that can cause heart failure with reduced ejection fraction from chronic micro-vascular ischemia. Appropriately recognizing the underlying cause of cardiomyopathy is essential to decrease morbidity and mortality. Patients can present with elevated troponin level and have patent epicardial coronary arteries on coronary angiogram, hence presenting a diagnostic challenge for health care professionals. Furthermore, the presentation can mimic myocarditis. Herein, we report a case of a 61-year-old female who presented with heart failure due to microvascular thrombotic complication associated with polycythemia vera. Laboratory investigation and coronary angiogram were inconclusive. A high degree of clinical suspicion and utilizing non-invasive techniques, such as cardiac imaging, can describe myocardial pathology and aid with the diagnosis.

Recurrent deep venous thromboses in a patient with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder affecting just over one in a million people. Due to its rarity, understanding of its pathophysiology and the spectrum of its clinical associations are limited. Improved case identification and creation of patient registries have begun to reveal sporadic reports of deep venous thromboses associated with AOSD. Herein, we report the first case of recurrent deep venous thrombosis in a patient with AOSD despite treatment with therapeutic dose anticoagulant medication. This case points for a judicious approach to the selection of an anticoagulation strategy for deep venous thromboses in the setting of active AOSD. This case is of contemporary interest in its clinical similarity with COVID-19 symptoms and pathophysiology for which a careful diagnostic approach with a broad differential should be considered given the limitations of SARS-CoV-2 testing and the risk associated with treatment in the event of misdiagnosis.

Prognostic value of coronary computed tomography angiography in patients with prior percutaneous coronary intervention.

OBJECTIVE: We sought to determine the prognostic value of coronary computed tomography angiography (CCTA) in patients with a history of percutaneous coronary intervention (PCI). BACKGROUND: Although the prognostic value of CCTA has been well studied, its incremental value in patients with previous PCI has not been robustly investigated. METHODS: Consecutive patients with previous PCI were prospectively enrolled and CCTA images were evaluated for coronary artery disease (CAD) severity. Patients were followed for major adverse cardiovascular events (MACE) which was a composite of cardiac death and non-fatal myocardial infarction. All-cause death was assessed as a secondary endpoint. RESULTS: A total of 501 patients were analyzed with a mean follow-up time of 59.5 ± 32.0 months and 52 patients (10.4%) experienced MACE. Multivariable Cox regression analysis showed that CAD severity was a predictor of MACE with 0, 1, 2, and 3 vessel disease having annual rates of 1.3%, 2.2%, 2.2%, and 5.3%, respectively. All-cause death was similar in all categories of CAD. CONCLUSIONS: In patients with previous PCI, CAD severity as measured with CCTA has independent and incremental prognostic value.

Examining associations of food insecurity with major depression among older adults in the wake of the Great Recession.

As a psychosocial stressor, the degree to which food insecurity impacts major depression may be dependent on macro-level context, which can be examined in the wake of the Great Recession. The objective of this study was to determine (1) whether food insecurity transition status (i.e. initially food insecure, becoming food insecure, and remaining food insecure vs. not food insecure) was associated with major depression in older adults and; (2) whether this association was moderated by macro-level context. Data came from the United States Health and Retirement Study, 2008-2016. Multivariable logistic regression across all years revealed that major depression was associated with any exposure to food insecurity, however; this association was moderated by time period. Remaining food insecure was associated with major depression during all time periods. In contrast, becoming food insecure was associated with major depression in the years during and immediately following the Recession, but not in later time periods. Findings suggest that associations of food insecurity with major depression among older adults are moderated by macro-level context, consistent with theories of social comparison and relative disadvantage. Food insecurity may represent an important risk factor for major depression and mental health disparities across socioeconomic strata in old age. Thus, policies that increase access to food assistance programs or improve the quality of local food environments may buffer against the impact of food insecurity on depression and associated complications among older adults.

Nivolumab Immunotherapy in Malignant Mesothelioma: A Case Report Highlighting a New Opportunity for Exceptional Outcomes.

BACKGROUND Malignant pleural mesothelioma (MPM) is a highly lethal cancer with a median survival of ~12 months even with aggressive intervention. Frontline therapy relies on systemic cisplatin and pemetrexed chemotherapy and has a response rate of ~35-41%; currently, there are no US Food and Drug Administration approved second-line therapies for MPM. Herein, we present a patient with MPM who experienced rapid disease progression after standard therapy but who had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. CASE REPORT A 68-year-old male with a history of work-related asbestos exposure was diagnosed with MPM. He was treated with primary resection followed by systemic chemotherapy with cisplatin and pemetrexed. When chemotherapy failed, he was switched to immunotherapy with nivolumab and achieved an exceptional response. CONCLUSIONS We report the first case of a patient with MPM who experienced rapid disease progression after standard therapy but had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. As outcomes with traditional chemotherapy regimens remain disappointing, there is a substantial need for new approaches to MPM; our case highlights a new therapeutic opportunity even in the face of aggressive disease. Indeed, a new era of investigation utilizing immunotherapy for mesothelioma is beginning, with much anticipation.