Digital literacy as a new determinant of health: A scoping review.

INTRODUCTION: Harnessing new digital technologies can improve access to health care but can also widen the health divide for those with poor digital literacy. This scoping review aims to assess the current situation of low digital health literacy in terms of its definition, reach, impact on health and interventions for its mitigation. METHODS: A comprehensive literature search strategy was composed by a qualified medical librarian. Literature databases [Medline (Ovid), Embase (Ovid), Scopus, and Google Scholar] were queried using appropriate natural language and controlled vocabulary terms along with hand-searching and citation chaining. We focused on recent and highly cited references published in English. Reviews were excluded. This scoping review was conducted following the methodological framework of Arksey and O'Malley. RESULTS: A total of 268 articles were identified (263 from the initial search and 5 more added from the references of the original papers), 53 of which were finally selected for full text analysis. Digital health literacy is the most frequently used descriptor to refer to the ability to find and use health information with the goal of addressing or solving a health problem using technology. The most utilized tool to assess digital health literacy is the eHealth literacy scale (eHEALS), a self-reported measurement tool that evaluates six core dimensions and is available in various languages. Individuals with higher digital health literacy scores have better self-management and participation in their own medical decisions, mental and psychological state and quality of life. Effective interventions addressing poor digital health literacy included education/training and social support. CONCLUSIONS: Although there is interest in the study and impact of poor digital health literacy, there is still a long way to go to improve measurement tools and find effective interventions to reduce the digital health divide.

APPRAISE-AI Tool for Quantitative Evaluation of AI Studies for Clinical Decision Support.

Importance: Artificial intelligence (AI) has gained considerable attention in health care, yet concerns have been raised around appropriate methods and fairness. Current AI reporting guidelines do not provide a means of quantifying overall quality of AI research, limiting their ability to compare models addressing the same clinical question. Objective: To develop a tool (APPRAISE-AI) to evaluate the methodological and reporting quality of AI prediction models for clinical decision support. Design, Setting, and Participants: This quality improvement study evaluated AI studies in the model development, silent, and clinical trial phases using the APPRAISE-AI tool, a quantitative method for evaluating quality of AI studies across 6 domains: clinical relevance, data quality, methodological conduct, robustness of results, reporting quality, and reproducibility. These domains included 24 items with a maximum overall score of 100 points. Points were assigned to each item, with higher points indicating stronger methodological or reporting quality. The tool was applied to a systematic review on machine learning to estimate sepsis that included articles published until September 13, 2019. Data analysis was performed from September to December 2022. Main Outcomes and Measures: The primary outcomes were interrater and intrarater reliability and the correlation between APPRAISE-AI scores and expert scores, 3-year citation rate, number of Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) low risk-of-bias domains, and overall adherence to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. Results: A total of 28 studies were included. Overall APPRAISE-AI scores ranged from 33 (low quality) to 67 (high quality). Most studies were moderate quality. The 5 lowest scoring items included source of data, sample size calculation, bias assessment, error analysis, and transparency. Overall APPRAISE-AI scores were associated with expert scores (Spearman ρ, 0.82; 95% CI, 0.64-0.91; P < .001), 3-year citation rate (Spearman ρ, 0.69; 95% CI, 0.43-0.85; P < .001), number of QUADAS-2 low risk-of-bias domains (Spearman ρ, 0.56; 95% CI, 0.24-0.77; P = .002), and adherence to the TRIPOD statement (Spearman ρ, 0.87; 95% CI, 0.73-0.94; P < .001). Intraclass correlation coefficient ranges for interrater and intrarater reliability were 0.74 to 1.00 for individual items, 0.81 to 0.99 for individual domains, and 0.91 to 0.98 for overall scores. Conclusions and Relevance: In this quality improvement study, APPRAISE-AI demonstrated strong interrater and intrarater reliability and correlated well with several study quality measures. This tool may provide a quantitative approach for investigators, reviewers, editors, and funding organizations to compare the research quality across AI studies for clinical decision support.

Global healthcare fairness: We should be sharing more, not less, data.

The availability of large, deidentified health datasets has enabled significant innovation in using machine learning (ML) to better understand patients and their diseases. However, questions remain regarding the true privacy of this data, patient control over their data, and how we regulate data sharing in a way that that does not encumber progress or further potentiate biases for underrepresented populations. After reviewing the literature on potential reidentifications of patients in publicly available datasets, we argue that the cost-measured in terms of access to future medical innovations and clinical software-of slowing ML progress is too great to limit sharing data through large publicly available databases for concerns of imperfect data anonymization. This cost is especially great for developing countries where the barriers preventing inclusion in such databases will continue to rise, further excluding these populations and increasing existing biases that favor high-income countries. Preventing artificial intelligence's progress towards precision medicine and sliding back to clinical practice dogma may pose a larger threat than concerns of potential patient reidentification within publicly available datasets. While the risk to patient privacy should be minimized, we believe this risk will never be zero, and society has to determine an acceptable risk threshold below which data sharing can occur-for the benefit of a global medical knowledge system.

Ecocardiografía funcional en la unidad de reanimación como monitor hemodinámico / Functional echocardiography in the intensive care unit as hemodinamyc monitor / Ecocardiografia funcional na unidade de terapia intensiva como monitor hemodinâmico

Resumen: La ecocardiografía es una herramienta que desde hace años se ha introducido en las unidades de reanimación. La ausencia de una formación reglada, la larga curva de aprendizaje y el hecho de que la mayoría de protocolos orientados al estudio de la inestabilidad hemodinámica se basan en un concepto estructural, complican su aplicación rutinaria en un contexto tan complejo. Este artículo pretende dar una visión funcional de la ecocardiografía de manera que, integrándola junto con la clínica y otros sistemas de monitorización, se convierta en una herramienta de monitorización hemodinámica a pie de cama. Mediante el uso de un número limitado de planos explicaremos la valoración de diversas herramientas que nos permiten estimar las variables determinantes de la perfusión (precarga estática y dinámica, función biventricular), que a su vez integradas mediante un mapa mental nos asistirán en la toma de decisiones clínicas.

Abstract: Echocardiography has gained wide acceptance between intensive care physicians during the last fifteen years. The lack of accredited formation, long learning curve and structural orientation of the limited algorithms to study hemodynamic instability hampers its daily use in the intensive care unit. This article aims to explain a functional approach to echocardiography in which it serves as a hemodynamic monitoring tool, useful at the bed site in conjunction with clinical assessment and other monitoring devices. Through a limited number of planes and measurements we will explain how to asses perfusion determinants (static and dynamic preload, biventricular function) and integrate them with a mind map to help everyday decision making in the complex environment of the critical care unit.

Resumo: O ecocardiograma é uma ferramenta que foi introduzida há anos nas unidades de terapia intensiva. A ausência de treinamento formal, a curva de aprendizagem prolongada e o fato de que a maioria dos protocolos orientados ao estudo da instabilidade hemodinâmica são baseados em um conceito estrutural complicam sua aplicação de rotina em um contexto tão complexo. Este artigo tem como objetivo dar uma visão funcional da ecocardiografia de modo que, integrando-a com a clínica e outros sistemas de monitoramento, transforme-se em uma ferramenta de monitoramento hemodinâmico na cabeceira do paciente. Usando um número limitado de imagens e medições explicaremos a valorização de várias ferramentas que nos permitem estimar as variáveis determinantes de perfusão (pré-carga estática e dinâmica, função biventricular), que por sua vez integrados por um mapa mental nos ajudará a tomar decisões clínicas.

Soluble B7-H1: differences in production between dendritic cells and T cells.

Tumor cells aberrantly express several T cell inhibitory molecules including members of the B7-H co-regulatory family. Presumably tumor-expressed B7-H1 and B7-H3 confer resistance to elimination by the immune system. In addition, elevated levels of soluble B7-H1 (sB7-H1) has been identified in the sera of cancer patients, including renal carcinoma patients and is associated with increased cancer related death. Here we report that sB7-H1 is produced and released by activated mature dendritic cells (mDC). Immature DC, macrophages, monocytes, or T cells are refractory to releasing sB7-H1. Exposure of CD4+ and CD8+ T cells to mDC-derived sB7-H1 molecules induced apoptosis. These data suggest that the immunobiology of B7-H1 is perhaps more complex than previously thought. sB7-H1 molecules may represent an unanticipated contributing factor to immune homeostasis. That both immune and tumor cells can be sources of sB7-H1 suggests that optimization of co-regulatory blockade immunotherapy for solid malignancies of necessity will require impact of targeting tumor and immune-derived B7-H1 molecules.

Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma.

PURPOSE: Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether soluble B7-H1 (sB7-H1) levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. EXPERIMENTAL DESIGN: We developed an ELISA for quantification of sB7-H1 in biological fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein microsequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T-cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. RESULTS: sB7-H1 was detected in the cell supernatants of some B7-H1-positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver proapoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (P < 0.001), tumors of advanced stage (P = 0.017) and grade (P = 0.044), and tumors with necrosis (P = 0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (P = 0.010). CONCLUSION: Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome.

TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination.

Agonists of TLR have been explored as vaccine adjuvants for tumor immunotherapy. However, their immunological consequences are not fully understood. Although TLR signaling increases the functional potential of dendritic cells (DCs) for priming T cells, coinduction of potentially negative immunoregulatory capacities may impair effector T cell generation. We examined the expression and function of B7 family costimulatory molecules on DCs after activation with the TLR3 agonist, polyinosinic:polycytidylic acid. We demonstrated that polyinosinic:polycytidylic acid consistently up-regulated both B7-2 and B7-H1 molecules on resident, migratory DCs from spleen and lymph nodes. Depletion or blockade of B7-H1 on activated DCs increased the magnitude of effector CD8 T cell expansion. DC-based or protein-based tumor vaccines, in combination with B7-H1 blockade, induced strong effector CD8 T cell responses, resulting in protective immunity against newly established tumors. Our studies suggest that TLR3 signaling has the potential to up-regulate both positive and negative coregulatory molecules on APCs. Selective blockade of negative regulatory molecules in combination with TLR3 agonist may be an effective strategy for increasing the efficacy of tumor vaccines.

Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma.

PURPOSE: Although the prognostic value of B7-H1 and B7-H4 expression by tumor cells in clear cell renal cell carcinoma (ccRCC) has been established, the role of B7-H3 is unknown. As such, we evaluated the association of B7-H3 expression with clinicopathologic outcomes in patients treated for ccRCC. EXPERIMENTAL DESIGN: Nephrectomy specimens from 743 consecutive patients treated for ccRCC at our institution from 1990 to 1999 were evaluated for B7-H3 expression by immunohistochemical staining. Associations of B7-H3 expression with clinical and pathologic features were evaluated using chi2 and Fisher's exact tests. Associations of B7-H3 expression with death from RCC were evaluated using Cox proportional hazards regression models. RESULTS: B7-H3 expression by tumor cells or tumor vasculature was noted in 17% and 95% of specimens, respectively. The presence of either tumor cell or diffuse tumor vasculature expression of B7-H3 was present in 46% of specimens and was associated with multiple adverse clinical and pathologic features. After multivariable adjustment, the presence of either tumor cell or diffuse tumor vasculature B7-H3 expression was significantly associated with an increased risk of death from RCC (risk ratio, 1.38; 95% confidence interval, 1.03-1.84; P = 0.029). CONCLUSIONS: Both tumor cell and tumor vasculature B7-H3 expression convey important information to predict ccRCC outcomes. Collectively, our past and present studies pertaining to B7-H ligand expression indicate that ccRCC may use redundant mechanisms to compromise host antitumoral immunity. Future studies will focus on the effect of combined B7-H ligand expression in RCC.

Questionable relevance of gamma delta T lymphocytes in renal cell carcinoma.

Adoptive gammadelta T cell immunotherapy has moved briskly into clinical trials prompted by several small studies suggesting abundant accumulation of gammadelta T cells within renal cell carcinoma (RCC). In this study, we re-examined levels of gammadelta T cells within RCC tumors and correlated levels of these cells with pathologic features and outcome associated with this form of cancer. Tissues from 248 consecutive clear cell RCC tumors obtained from 2000 to 2003 were stained and quantified for total CD3+ and gammadelta T cells per mm2. Wilcoxon rank sum and Kruskal-Wallis tests were used to evaluate associations between T cell amounts and prognostic factors (age, gender, tumor size, stage, grade, tumor necrosis). Cox models were used to assess associations with RCC-specific death. Median numbers of total CD3+ and gammadelta T cells were 281/mm2 (interquartile range (IQR): 149-536) and 2.6/mm2 (IQR: 1.3-4.6), respectively. The median percentage of CD3+ T cells that were gammadelta T cells was 1.0% (IQR: 0.4-1.9). This low percentage of intratumoral gammadelta T cells was diluted even further with rising CD3+ T cell infiltration. Percentages of gammadelta T cells were not associated with even one single clinicopathologic feature examined. Median follow-up for this study was 3.1 years (48 patients died of RCC) and Cox analysis failed to demonstrate that gammadelta T cells (hazard ratio=1.02, p=0.25) were predictive of RCC-specific death. gammadelta T cells are rare and not recruited nor expanded within RCC tumors. Percentages of gammadelta T cells fail to correlate with any prognostic features of RCC nor specific death. As such, the role of gammadelta T cells in RCC immunobiology remains questionable.

Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine.

Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.

B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy.

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well.

Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.

PURPOSE: Regulatory T cells (Tregs) have been implicated as inhibitors of antitumoral immunity, and evidence suggests that elimination of Tregs may augment natural and pharmacologic immunity. We tested for the presence of putative Tregs within renal cell carcinoma (RCC) tumors. EXPERIMENTAL DESIGN: We identified 170 patients who underwent radical or partial nephrectomy for clear cell RCC between 2000 and 2002. Specimens were stained with anti-CD4, anti-CD25, and anti-Foxp3 antibodies and examined using confocal microscopy. Associations of CD4(+)CD25(+)Foxp3(-) and CD4(+)CD25(+)Foxp3(+) T cells with death from RCC were evaluated using Cox proportional hazards regression models. RESULTS: At last follow-up, 46 of 170 patients had died; of these, 37 died from RCC at a median of 1.4 years following nephrectomy (range, 0-4.4). Among the 124 remaining patients, median follow-up was 3.7 years (range, 0-5.7). Forty-three (25.3%) tumors harbored CD4(+)CD25(+)Foxp3(+) T cells. The presence of Foxp3(+) T cells was not significantly associated with RCC death univariately. One hundred forty-three (84.1%) tumors harbored CD4(+)CD25(+)Foxp3(-) T cells. The indicator for >or=10% CD4(+)CD25(+)Foxp3(-) T cells was significantly associated with RCC death univariately [risk ratio (RR), 2.60; 95% confidence interval (95% CI), 1.35-4.98; P = 0.004], after adjusting for tumor B7-H1 expression (RR, 2.53; 95% CI, 1.32-4.85; P = 0.005) and lymphocytic infiltration (RR, 2.53; 95% CI, 1.32-4.87; P = 0.005). CONCLUSIONS: Increased presence of CD4(+)CD25(+)Foxp3(+) T cells was not significantly associated with RCC death. In contrast, CD4(+)CD25(+)Foxp3(-) T cells, which may represent a unique set of Tregs or activated helper T cells, was significantly associated with outcome.

PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression.

BACKGROUND: PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder. METHODS: Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment. RESULTS: PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment. CONCLUSIONS: Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.

Costimulation, coinhibition and cancer.

The immune system is an important defense mechanism against cancer and is often dysfunctional in patients with malignancies. The central regulator of the anti-cancer adaptive immune response is the T lymphocyte. T lymphocyte activation requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Particularly important is the provision of a costimulatory signal, the binding of accessory molecules on the antigen presenting cell to receptors on the T lymphocyte. Though costimulatory signals were traditionally envisioned as T lymphocyte-activating events, recent discoveries have highlighted their duality: they can be either stimulatory (costimulation) or inhibitory (coinhibition). In this article we review costimulation and coinhibition as potential targets for cancer therapy. We begin by presenting a general framework for thinking about the immune system in the context of cancer. Our discussion then bridges the various aspects of immune dysfunction seen in cancer with the presence of coinhibitory (ex: PD-1, PD-L1, CTLA-4, BTLA) and costimulatory (ex: CD28, ICOS, 4-1BB, CD40, OX40, CD27) signaling. Lastly, we develop a model of cancer-related immune dysfunction that parallels the concept of immunoediting. Throughout the article we emphasize clinically relevant research often applicable-but not limited-to the example of renal cell carcinoma.

Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival.

BACKGROUND: The impact of mononuclear cell infiltration on renal cell carcinoma (RCC) biology has been controversial, previously reported to be associated with either a favorable or unfavorable prognosis. The objective of the current study was to evaluate associations between mononuclear cell infiltration in routinely prepared paraffin-embedded specimens with survival in patients with clear-cell RCC. METHODS: A total of 306 patients were identified treated with nephrectomy for clear-cell RCC between 1990 and 1994. A single urologic pathologist, blinded to patient outcome, reviewed the specimens and quantified the extent of mononuclear cell infiltration as absent, focal, moderate, or marked. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of mononuclear cell infiltration with death from RCC were assessed using Cox proportional hazards regression models. RESULTS: At last follow-up, 173 of the 306 patients studied had died, including 96 patients who died from RCC. Mononuclear cell infiltration was absent in 165 (54%), focal in 70 (23%), moderate in 53 (17%), and marked in 18 (6%). Univariately, patients with specimens that had mononuclear cell infiltration were over 2 times more likely to die from RCC compared with patients whose specimens exhibited no mononuclear cell infiltration (risk ratio, 2.63; P < .001). After adjusting for the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score, patients with specimens that had mononuclear cell infiltration exhibited a significantly increased likelihood of dying from RCC compared with patients whose specimens had no mononuclear cell infiltration (risk ratio, 1.61; P = .028). CONCLUSIONS: Mononuclear cell infiltration is associated with death from RCC even after multivariate adjustment. Routine documentation of mononuclear cell infiltration is recommended during the pathologic assessment of RCC.