Immunogenicity of 2 therapeutic mosaic HIV-1 vaccine strategies in individuals with HIV-1 on antiretroviral therapy.

Mosaic HIV-1 vaccines have been shown to elicit robust humoral and cellular immune responses in people living with HIV-1 (PLWH), that had started antiretroviral therapy (ART) during acute infection. We evaluated the safety and immunogenicity of 2 mosaic vaccine regimens in virologically suppressed individuals that had initiated ART during the chronic phase of infection, exemplifying the majority of PLWH. In this double-blind, placebo-controlled phase 1 trial (IPCAVD013/HTX1002) 25 ART-suppressed PLWH were randomized to receive Ad26.Mos4.HIV/MVA-Mosaic (Ad26/MVA) (n = 10) or Ad26.Mos4.HIV/Ad26.Mos4.HIV plus adjuvanted gp140 protein (Ad26/Ad26+gp140) (n = 9) or placebo (n = 6). Primary endpoints included safety and tolerability and secondary endpoints included HIV-specific binding and neutralizing antibody titers and HIV-specific T cell responses. Both vaccine regimens were well tolerated with pain/tenderness at the injection site and fatigue, myalgia/chills and headache as the most commonly reported solicited local and grade 3 systemic adverse events, respectively. In the Ad26/Ad26+gp140 group, Env-specific IFN-γ T cell responses showed a median 12-fold increase while responses to Gag and Pol increased 1.8 and 2.4-fold, respectively. The breadth of T cell responses to individual peptide subpools increased from 11.0 pre-vaccination to 26.0 in the Ad26/Ad26+gp140 group and from 10.0 to 14.5 in the Ad26/MVA group. Ad26/Ad26+gp140 vaccination increased binding antibody titers against vaccine-matched clade C Env 5.5-fold as well as augmented neutralizing antibody titers against Clade C pseudovirus by 7.2-fold. Both vaccine regimens were immunogenic, while the addition of the protein boost resulted in additional T cell and augmented binding and neutralizing antibody titers. These data suggest that the Ad26/Ad26+gp140 regimen should be tested further.

Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis.

BACKGROUND: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail. METHODS: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children's Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with those from 45 healthy, asymptomatic, age-matched vaccinated control subjects. RESULTS: Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic vaccinated control subjects (unpaired t test; P<0.0001). CONCLUSIONS: Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause.

Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine.

Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten-eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.

Increased Ascorbate Content of Glioblastoma Is Associated With a Suppressed Hypoxic Response and Improved Patient Survival.

Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF transcription factors are regulated at the post-translation level via HIF-hydroxylases. These hydroxylases require oxygen and 2-oxoglutarate as substrates, and ferrous iron and ascorbate as cofactors. In this retrospective observational study, we aimed to determine whether ascorbate played a role in the hypoxic response of glioblastoma, and whether this affected patient outcome. We measured the ascorbate content and members of the HIF-pathway of clinical glioblastoma samples, and assessed their association with clinicopathological features and patient survival. In 37 samples (37 patients), median ascorbate content was 7.6 µg ascorbate/100 mg tissue, range 0.8 - 20.4 µg ascorbate/100 mg tissue. In tumours with above median ascorbate content, HIF-pathway activity as a whole was significantly suppressed (p = 0.005), and several members of the pathway showed decreased expression (carbonic anhydrase-9 and glucose transporter-1, both p < 0.01). Patients with either lower tumour HIF-pathway activity or higher tumour ascorbate content survived significantly longer than patients with higher HIF-pathway or lower ascorbate levels (p = 0.011, p = 0.043, respectively). Median survival for the low HIF-pathway score group was 362 days compared to 203 days for the high HIF-pathway score group, and median survival for the above median ascorbate group was 390 days, compared to the below median ascorbate group with 219 days. The apparent survival advantage associated with higher tumour ascorbate was more prominent for the first 8 months following surgery. These associations are promising, suggesting an important role for ascorbate-regulated HIF-pathway activity in glioblastoma that may impact on patient survival.

Limited Association Between Ascorbate Concentrations and Vitamin C Transporters in Renal Cell Carcinoma Cells and Clinical Samples.

BACKGROUND/AIMS: Maintenance of whole-body ascorbate levels and distribution is mediated via sodium-dependent vitamin C transporters (SVCTs). The kidney is one of a few organs that express both SVCT1 and SVCT2. Recent evidence suggests that accumulation of ascorbate may be different in tumour compared to normal tissue, but data on SVCT levels in tumours is sparse. METHODS: The role of the two SVCT isoforms in ascorbate uptake in renal cell carcinoma (RCC) was investigated in vitro and in clinical samples. In three human RCC cell lines, we investigated SVCT protein levels and cellular location in response to ascorbate supplementation and withdrawal. In clinical RCC samples (n=114), SVCT patterns of staining and protein levels were analysed and compared to ascorbate levels. RESULTS: In cell culture, transporter levels and cellular location were not modified by ascorbate availability at any time up to 8h, although basal SVCT2 levels governed maximal ascorbate accumulation. In clinical samples, SVCT1 protein levels in papillary RCC (pRCC) were similar to matched normal renal cortex, but were increased in clear-cell RCC (ccRCC). Native SVCT2 (72 kDa) was significantly decreased in both pRCC and ccRCC tissues compared to cortex (p<0.01), whereas a modified form of SVCT2 (100 kDa) was significantly increased (p<0.001). There was no association between the transporters (SVCT1, native or modified SVCT2) and ascorbate concentrations in either normal or tumour tissues. SVCT1 and SVCT2 displayed diffuse cytoplasmic staining in both pRCC and ccRCC tumour cells, with cortex showing distinct membrane staining for SVCT1. CONCLUSION: We observed a re-distribution of ascorbate transporters in tumour tissue compared to normal cortex and a shift from native to modified SVCT2 in cell culture and clinical samples. Data presented here show that SVCT protein levels do not appear to predict intracellular ascorbate accumulation in RCC.

Care Managers and Role Ambiguity: The Challenges of Supporting the Mental Health Needs of Patients with Chronic Conditions.

As U.S. healthcare organizations transition to value-based healthcare, they are increasingly focusing on supporting patients who have difficulties managing chronic care, including mental health, through the growing role of care managers (CMs). CMs communicate with patients, provide access to resources, and coach them toward healthy behaviors. CMs also coordinate patient-related issues internally with healthcare practitioners and externally with community organizations and insurance providers. While there have been many interaction design studies regarding the work of clinical and non-clinical healthcare providers and how best to design support systems for them, we know little about the work of CMs. In this study, we examine the role of CMs, particularly focusing on their work to support patient mental health, through interviews with 11 CMs who are part of a large Midwestern U.S. health system. Workflow observations were conducted to supplement the interview data. We describe the role of CMs and identify challenges that they face in supporting patient mental health. A key challenge is a high degree of role ambiguity in this professional role. We discuss sociotechnical implications to better support care delivery processes and technologies for the delivery of mental health services by CMs.

Gene and Protein Expression Is Altered by Ascorbate Availability in Murine Macrophages Cultured under Tumour-Like Conditions.

Tumour-associated macrophages (TAMs) are ubiquitously present in tumours and commonly associated with poor prognosis. In immune cells, ascorbate affects epigenetic regulation, differentiation and phenotype via its co-factor activity for the 2-oxoglutarate dependent dioxygenase enzymes. Here, we determined the effect of ascorbate on TAM development in response to tumour microenvironmental cues. Naïve murine bone marrow monocytes were cultured with Lewis Lung Carcinoma conditioned media (LLCM) or macrophage colony-stimulating factor (MCSF) to encourage the development into tumour-associated macrophages. Cells were stimulated with hypoxia (1% O2), with or without ascorbate (500 µM) supplementation. Cells and media were harvested for gene, cell surface marker and protein analyses. LLCM supported bone marrow monocyte growth with >90% of cells staining CD11b+F4/80+, indicative of monocytes/macrophages. LLCM-grown cells showed increased expression of M2-like and TAM genes compared to MCSF-grown cells, which further increased with hypoxia. In LLCM-grown cells, ascorbate supplementation was associated with increased F4/80 cell surface expression, and altered gene expression and protein secretion. Our study shows that ascorbate modifies monocyte phenotype when grown under tumour microenvironmental conditions, but this was not clearly associated with either a pro- or anti-tumour phenotype, and reflects a complex and nuanced response of macrophages to ascorbate. Overall, ascorbate supplementation clearly has molecular consequences for TAMs, but functional and clinical consequences remain unknown.

The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response.

Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.

Communication Hotspots: How Infrastructure Shapes People's Health.

Informed by communication infrastructure theory (CIT) and the social capital approach to health, this study focused on the role played by communication hotspots: physical places in a community (e.g., parks, churches, or restaurants) where health information is shared between network actors. By analyzing survey data that included information about communication infrastructure, frequency of health conversations, as well as the size and diversity of respondents' social networks, this study illustrates how communication hotspots may reduce perceived barriers to healthcare among Latinas in the greater Los Angeles area (N = 780). The results suggest that communication hotspots can influence people's health by facilitating information-sharing activities. In addition, communication hotspots may reduce perceived barriers to healthcare by bringing together diverse network actors. We conclude by considering future health interventions and policy planning to leverage and enhance community members' interactions at communication hotspots.

Low Vitamin C Status in Patients with Cancer Is Associated with Patient and Tumor Characteristics.

Vitamin C (ascorbate) acts as an antioxidant and enzyme cofactor, and plays a vital role in human health. Vitamin C status can be affected by illness, with low levels being associated with disease due to accelerated turnover. However, robust data on the ascorbate status of patients with cancer are sparse. This study aimed to accurately measure ascorbate concentrations in plasma from patients with cancer, and determine associations with patient or tumor characteristics. We recruited 150 fasting patients with cancer (of 199 total recruited) from two cohorts, either prior to cancer surgery or during cancer chemo- or immunotherapy. A significant number of patients with cancer had inadequate plasma ascorbate concentrations. Low plasma status was more prevalent in patients undergoing cancer therapy. Ascorbate status was higher in women than in men, and exercising patients had higher levels than sedentary patients. Our study may prompt increased vigilance of ascorbate status in cancer patients.

Provider perspectives on the integration of patient-reported outcomes in an electronic health record.

OBJECTIVE: Integrating patient-reported outcomes (PROs) into electronic health records (EHRs) can improve patient-provider communication and delivery of care. However, new system implementation in health-care institutions is often accompanied by a change in clinical workflow and organizational culture. This study examines how well an EHR-integrated PRO system fits clinical workflows and individual needs of different provider groups within 2 clinics. MATERIALS AND METHODS: Northwestern Medicine developed and implemented an EHR-integrated PRO system within the orthopedics and oncology departments. We conducted interviews with 11 providers who had interacted with the system. Through thematic analysis, we synthesized themes regarding provider perspectives on clinical workflow, individual needs, and system features. RESULTS: Our findings show that EHR-integrated PROs facilitate targeted conversation with patients and automated triage for psychosocial care. However, physicians, psychosocial providers, and medical assistants faced different challenges in their use of the PRO system. Barriers mainly stemmed from a lack of actionable data, workflow disruption, technical issues, and a lack of incentives. DISCUSSION: This study sheds light on the ecosystem around EHR-integrated PRO systems (such as user needs and organizational factors). We present recommendations to address challenges facing PRO implementation, such as optimizing data collection and auto-referral processes, improving data visualizations, designing effective educational materials, and prioritizing the primary user group. CONCLUSION: PRO integration into routine care can be beneficial but also require effective technology design and workflow configuration to reach full potential use. This study provides insights into how patient-generated health data can be better integrated into clinical practice and care delivery processes.

"I think people are powerful": The Sociality of Individuals Managing Depression.

Millions of Americans struggle with depression, a condition characterized by feelings of sadness and motivation loss. To understand how individuals managing depression conceptualize their self-management activities, we conducted visual elicitations and semi-structured interviews with 30 participants managing depression in a large city in the U.S. Midwest. Many depression support tools are focused on the individual user and do not often incorporate social features. However, our analysis showed the key importance of sociality for self-management of depression. We describe how individuals connect with specific others to achieve expected support and how these interactions are mediated through locations and communication channels. We discuss factors influencing participants' sociality including relationship roles and expectations, mood state and communication channels, location and privacy, and culture and society. We broaden our understanding of sociality in CSCW through discussing diffuse sociality (being proximate to others but not interacting directly) as an important activity to support depression self-management.

Sensi-steps: Using Patient-Generated Data to Prevent Post-stroke Falls.

We present Sensi-steps, an application using patient-generated data (PGD) to prevent falls for geriatric and especially poststroke patients. The Sensi-steps tool incorporates a wearable wrist device, pedometer, pressure and proximity sensors, and tablet. PGD collection occurs through Timed Up and Go (TUG) tests and collection of physiological data, which is integrated into the EHR. Fall risk factor active tracking encourages new ways of shared decision-making between patients, caregivers, and practitioners. PGD will be managed at the primary care nurse or Care Manager level (see 3-tier PGD service proposal), presenting a novel way to incorporate PGD into clinical decision-support systems. We expect our solution to be easier to use routinely by the patient at home than other fall risk tracking solutions. Sensi-steps has the potential to improve patient care, help patients make informed decisions, and help clinicians understand patient-generated, environmental, and lifestyle information to deliver personalized, preventative healthcare.