Overview of CD70 as a Potential Therapeutic Target for Osteosarcoma.

Osteosarcoma is a primary malignant bone tumor. Effective chemotherapy regimens for refractory disease are scarce, accounting for no improvement in survival. Immune-based cell therapies have emerged as novel alternatives. However, advancements with these therapies have been seen mostly when immune cells are armed to target specific tumor Ags. Recent studies identified cluster of differentiation 70 (CD70) as a promising target to osteosarcoma particularly because CD70 is highly expressed in osteosarcoma lung metastases (Pahl et al. 2015. Cancer Cell Int. 15: 31), and its overexpression by tumors has been correlated with immune evasion and tumor proliferation (Yang et al. 2007. Blood 110: 2537-2544). However, the limited knowledge of the overall CD70 expression within normal tissues and the potential for off-target effect pose several challenges (Flieswasser et al. 2022. J. Exp. Clin. Cancer Res. 41: 12). Nonetheless, CD70-based clinical trials are currently ongoing and are preliminarily showing promising results for patients with osteosarcoma. The present review sheds light on the recent literature on CD70 as it relates to osteosarcoma and highlights the benefits and challenges of targeting this pathway.

Dissociation protocols used for sarcoma tissues bias the transcriptome observed in single-cell and single-nucleus RNA sequencing.

BACKGROUND: Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Classification of bulk tumors by their individual cellular constituents has also created new opportunities to generate single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous promise of this technology, recent evidence studying epithelial tissues and diverse carcinomas suggests the methods used for tissue processing, cell disaggregation, and preservation can significantly bias gene expression and alter the observed cell types. To determine whether sarcomas - tumors of mesenchymal origin - are subject to the same technical artifacts, we profiled patient-derived tumor explants (PDXs) propagated from three aggressive subtypes: osteosarcoma (OS), Ewing sarcoma (ES), desmoplastic small round cell tumor (DSRCT). Given the rarity of these sarcoma subtypes, we explored whether single-nuclei RNA-seq from more widely available archival frozen specimens could accurately be identified by gene expression signatures linked to tissue phenotype or pathognomonic fusion proteins. RESULTS: We systematically assessed dissociation methods across different sarcoma subtypes. We compared gene expression from single-cell and single-nucleus RNA-sequencing of 125,831 whole-cells and nuclei from ES, DSRCT, and OS PDXs. We detected warm dissociation artifacts in single-cell samples and gene length bias in single-nucleus samples. Classic sarcoma gene signatures were observed regardless of the dissociation method. In addition, we showed that dissociation method biases could be computationally corrected. CONCLUSIONS: We highlighted transcriptional biases, including warm dissociation and gene-length biases, introduced by the dissociation method for various sarcoma subtypes. This work is the first to characterize how the dissociation methods used for sc/snRNA-seq may affect the interpretation of the molecular features in sarcoma PDXs.

Prevalence of sleep-related problems and risks in a community-dwelling older adult population: a cross-sectional survey-based study.

BACKGROUND: Despite evidence of adverse health consequences of inadequate restorative sleep for older adults, assessment of sleep quantity, quality, and use of sleep aids is not routinely done. We aimed to characterize sleep problems, sleep risks, and advice received about sleep in a community-dwelling older adult population, overall and in subgroups with health conditions and functional difficulties. METHODS: This cross-sectional study used weighted self-report data for 5074 Kaiser Permanente Northern California members aged 65-79y who responded to a 2017 or 2020 Member Health Survey. We estimated usual amount of sleep (< 6, 6 to < 7, ≥7 hours) and prevalence of sleep problems (frequent insomnia, frequent daytime fatigue, poor quality sleep, and potential sleep apnea (OSA) symptoms (frequent very loud snoring, apnea episodes)) for older adults overall, by self-rated health, and in subgroups reporting hypertension, diabetes, heart disease, frequent problems with balance/walking, and frequent memory problems. We also estimated percentages who regularly used sleep aids and had discussed sleep adequacy with a healthcare professional in the past year. RESULTS: Approximately 30% of older adults usually got less than the recommended ≥7 hours sleep per day, and 9% experienced frequent daytime fatigue, 13% frequent insomnia, 18% frequent insomnia/poor quality sleep, and 8% potential OSA symptoms. Prevalence of frequent insomnia was higher among women than men (16% vs. 11%). Higher percentages of those in fair/poor health and those with frequent balance/walking and memory problems reported sleeping < 6 hours per day and having all four types of sleep problems. Nearly 20% of all older adults (22% of women vs. 17% of men) and 45% of those with frequent insomnia (no sex difference) reported regular sleep aid use. Only 10% of older adults reported discussing sleep with a healthcare professional whereas > 20% reported discussing diet and exercise. CONCLUSIONS: Large percentages of older adults experience sleep problems or get less sleep than recommended for optimal sleep health. Older patients should routinely be assessed on multiple components of sleep health (sleep hygiene, quantity, quality, problems, and sleep aid use) and educated about sleep hygiene and the importance of getting adequate restorative sleep for their overall health and wellbeing.

Prevalence of prediabetes and diabetes vary by ethnicity among U.S. Asian adults at healthy weight, overweight, and obesity ranges: an electronic health record study.

BACKGROUND: Asian adults develop Type 2 diabetes at a lower body mass index (BMI) compared to other racial/ethnic groups. We examined the variation in prevalence of prediabetes and diabetes among Asian ethnic groups within weight strata by comparing middle-aged Chinese, Filipino, South Asian, and White adults receiving care in the same integrated healthcare delivery system. METHODS: Our retrospective cross-sectional U.S. study examined data from 283,110 (non-Hispanic) White, 33,263 Chinese, 38,766 Filipino, and 17,959 South Asian adults aged 45-64 years who were members of a Northern California health plan in 2016 and had measured height and weight. Prediabetes and diabetes were classified based on laboratory data, clinical diagnoses, or diabetes pharmacotherapy. Age-standardized prevalence of prediabetes and diabetes were compared by race/ethnicity within healthy weight, overweight, and obesity categories, using standard BMI thresholds for White adults (18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) and lower BMI thresholds for Asian adults (18.5 to < 23, 23 to < 27.5, ≥ 27.5 kg/m2). Prevalence ratios (PRs) were used to compare the prevalence of diabetes and prediabetes for Asian groups to White adults in each weight category, adjusted for age and BMI. RESULTS: Across all weight categories, diabetes prevalence was higher for Asian than White adults, and among Asian groups it was highest for Filipino and South Asian adults. Compared to White, PRs for South Asian men/women at healthy BMI were 1.8/2.8 for prediabetes and 5.9/8.0 for diabetes, respectively. The PRs for Filipino men/women at healthy BMI were 1.8/2.6 for prediabetes and 5.0/7.5 for diabetes, respectively. For Chinese men/women at healthy BMI, the PRs for prediabetes (2.1/2.9) were similar to Filipino and South Asian, but the PRs for diabetes were lower (2.1/3.4). CONCLUSION: Chinese, Filipino, and South Asian adults have higher prevalence of prediabetes and diabetes than White adults in all weight categories, despite using lower BMI thresholds for weight classification in Asian groups. Within Asian ethnic groups, Filipino and South Asian adults had considerably higher diabetes prevalence than Chinese adults. Our data emphasize the disproportionate metabolic risk among middle-aged Asian adults and underscore the need for diabetes screening among high-risk Asian groups at healthy BMI levels.

Prospective evaluation of social risks, physical function, and cognitive function in prediction of non-elective rehospitalization and post-discharge mortality.

BACKGROUND: Increasing evidence suggests that social factors and problems with physical and cognitive function may contribute to patients' rehospitalization risk. Understanding a patient's readmission risk may help healthcare providers develop tailored treatment and post-discharge care plans to reduce readmission and mortality. This study aimed to evaluate whether including patient-reported data on social factors; cognitive status; and physical function improves on a predictive model based on electronic health record (EHR) data alone. METHODS: We conducted a prospective study of 1,547 hospitalized adult patients in 3 Kaiser Permanente Northern California hospitals. The main outcomes were non-elective rehospitalization or death within 30 days post-discharge. Exposures included patient-reported social factors and cognitive and physical function (obtained in a pre-discharge interview) and EHR-derived data for comorbidity burden, acute physiology, care directives, prior utilization, and hospital length of stay. We performed bivariate comparisons using Chi-square, t-tests, and Wilcoxon rank-sum tests and assessed correlations between continuous variables using Spearman's rho statistic. For all models, the results reported were obtained after fivefold cross validation. RESULTS: The 1,547 adult patients interviewed were younger (age, p = 0.03) and sicker (COPS2, p < 0.0001) than the rest of the hospitalized population. Of the 6 patient-reported social factors measured, 3 (not living with a spouse/partner, transportation difficulties, health or disability-related limitations in daily activities) were significantly associated (p < 0.05) with the main outcomes, while 3 (living situation concerns, problems with food availability, financial problems) were not. Patient-reported cognitive (p = 0.027) and physical function (p = 0.01) were significantly lower in patients with the main outcomes. None of the patient-reported variables, singly or in combination, improved predictive performance of a model that included acute physiology and longitudinal comorbidity burden (area under the receiver operator characteristic curve was 0.716 for both the EHR model and maximal performance of a random forest model including all predictors). CONCLUSIONS: In this insured population, incorporating patient-reported social factors and measures of cognitive and physical function did not improve performance of an EHR-based model predicting 30-day non-elective rehospitalization or mortality. While incorporating patient-reported social and functional status data did not improve ability to predict these outcomes, such data may still be important for improving patient outcomes.

Bempegaldesleukin (BEMPEG; NKTR-214) efficacy as a single agent and in combination with checkpoint-inhibitor therapy in mouse models of osteosarcoma.

Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) immune checkpoint inhibitors. Treatment with the T-cell growth factor interleukin-2 (IL-2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, alone and in combination with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2-WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti-CTLA-4 and anti-PD-1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T-regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG-based regimens in human osteosarcoma.

Racial/ethnic, gender, and age group differences in cardiometabolic risks among adults in a Northern California health plan: a cross-sectional study.

BACKGROUND: In the U.S., the prevalence of diabetes and hypertension are higher among African American/Black (Black), Latinx, and Filipino adults than non-Hispanic White (White) and Chinese adults. We compared the racial/ethnic-specific prevalence of several modifiable cardiometabolic risks in an insured adult population to identify behaviors that may drive racial/ethnic differences in cardiometabolic health. METHODS: This cross-sectional study used data for middle-aged (35-64) and older (65-79) Kaiser Permanente Northern California (KPNC) adult health plan members. Smoking status and BMI were derived from electronic health record data. Weighted pooled self-reported data from the 2014/2015 and 2017 KPNC Member Health Survey cycles were used to estimate daily number of servings of fruits/vegetables, general sodium avoidance, sugar-sweetened beverage (SSB) consumption frequency, alcohol use within daily recommended limit, weekly exercise frequency, and number of hours of sleep daily. Age-standardized estimates of all cardiometabolic risks were produced for middle-aged and older-aged women and men in the five racial/ethnic groups. Analyses focused on racial/ethnic differences within age-gender groups and gender and age group differences within racial/ethnic groups. RESULTS: In both age groups, Black, Latinx, and Filipino adults were more likely than White and Chinese adults to have overweight and obesity and were less likely to engage in health promoting dietary (fruit/vegetable and SSB consumption, sodium avoidance (women only)) and sleep behaviors. Middle-aged Black and Filipino men were more likely than White men to be current smokers. Less racial/ethnic variation was seen in exercise frequency. Significant gender differences were observed for dietary behaviors overall and within racial/ethnic groups, especially among middle-aged adults; however, these gender differences were smaller for sleep and exercise. Age differences within gender and racial/ethnic groups were less consistent. Racial/ethnic and gender differences in these behaviors were also seen in the subsample of adults with diabetes and/or hypertension and in the subsample of adults who reported they were trying to engage in health promoting behaviors. CONCLUSIONS: Black, Latinx, and Filipino adults were more likely than White and Chinese adults to report dietary and sleep behaviors associated with development and worsening of cardiometabolic conditions, with men exhibiting poorer dietary behaviors than women.

Understanding differences within ethnic group designation: comparing risk factors and health indicators between Iranian and Arab Americans in Northern California.

BACKGROUND: The Middle Eastern and North African (MENA) ethnic group is a diverse group composed of two primary subsets in the United States: Iranian and Arab Americans. We aimed to compare health risk factors, chronic health conditions, and mental health conditions of Iranian and Arab American adults in Northern California. METHODS: We used cross-sectional electronic health record (EHR) data from a 2016 Northern California health plan study cohort to compare adults classified as Iranian or Arab American based on ethnicity, language, or surname. We produced age-standardized prevalence estimates of obesity, smoking, hyperlipidemia, prediabetes, diabetes, hypertension, depression, and anxiety for Iranian and Arab American men and women by age group (35-44, 45-64, and 65-84) and overall (35-84). We used generalized linear models to calculate prevalence ratios (PR) to compare Iranian and Arab American adults ages 35-84 on all health indicators. RESULTS: Compared to Arab Americans, Iranian Americans had a lower prevalence of obesity (PR: 0.77, 95% confidence interval, CI: 0.73, 0.82), current smoking (PR: 0.80, 95% CI: 0.73, 0.89), and ever smoking (PR: 0.95, 95% CI: 0.91, 0.99), but a higher prevalence of hyperlipidemia (PR: 1.09, 95% CI: 1.06, 1.12), prediabetes (PR: 1.12, 95% CI: 1.09, 1.16), depression (PR; 1.41, 95% CI: 1.30, 1.52), and anxiety (PR: 1.52, 95% CI: 1.42, 1.63). Similar patterns were observed for men and women. CONCLUSION: This work supports the need to collect granular data on race and ethnicity within the MENA ethnic group to improve identification in clinical care settings and population health reporting to better address the physical and mental health needs of different MENA subgroups.

Autophagy in Osteosarcoma.

Osteosarcoma (OS) remains a difficult disease to treat. The standard chemotherapy regimen has not improved survival for the past three decades. Resistance to chemotherapy remains a challenge and constitutes a major concern to clinical investigators. Autophagy has been recognized as a survival mechanism implicated in resistance to chemotherapy. We previously demonstrated chemotherapy to induce autophagy in OS. However, whether induction of autophagy will lead to survival or death has been the focus of many laboratories. Autophagy is a very context-dependent process, and no specific biomarker has been identified to define whether the process will lead to survival or death. In the present chapter, we present some of the mechanisms involved in the process of autophagy and summarize some of the most recent work related to autophagy in OS and the challenges encountered with the use of old and new autophagy inhibitors.

Aerosolized Chemotherapy for Osteosarcoma.

Inhalation therapy remains a suitable approach to treat lung diseases including cancer. This approach has been used to deliver various therapies including chemotherapy. The rationale for using the inhalation route vs. the systemic route has been the fewer side effects encountered when drugs are administered via inhalation. Furthermore, this approach overcomes one of the major limitations of systemic chemotherapy that results from inability of the drug to reach high concentrations in the lungs. Local delivery overcomes this limitation and spares exposure of vital organs to the drug, resulting in a more effective delivery system.Pulmonary metastasis of osteosarcoma (OS) remains a major cause of death and is very difficult to treat. Using various OS mouse models, we demonstrated that aerosol chemotherapy causes regression of pulmonary metastases and improves survival of mice with OS. In these studies, we used gemcitabine, a nucleoside analog that is effective against various solid tumors. An initial phase I study done in Europe in patients with primary lung cancer demonstrated aerosol gemcitabine therapy to be feasible and safe. In this chapter, we describe different chemotherapeutic agents delivered by inhalation to treat lung diseases with an emphasis on an ongoing study of aerosolized gemcitabine for patients with solid tumors and lung metastases developed at the MD Anderson Cancer Center that uses a convenient approach to track patient lung health with the ultimate goal of implementing this therapy at home.

The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma.

The prognosis for metastatic osteosarcoma (OS) is poor and has not changed in several decades. Therapeutic paradigms that target and exploit novel molecular pathways are desperately needed. Recent preclinical data suggests that modulation of the Fas/FasL pathway may offer benefit in the treatment of refractory osteosarcoma. Fas and FasL are complimentary receptor-ligand proteins. Fas is expressed in multiple tissues, whereas FasL is restricted to privilege organs, such as the lung. Fas expression has been shown to inversely correlate with the metastatic potential of OS cells; tumor cells which express high levels of Fas have decreased metastatic potential and the ones that reach the lung undergo cell death upon interaction with constitutive FasL in the lung. Agents such as gemcitabine and the HDAC inhibitor, entinostat/Syndax 275, have been shown to upregulate Fas expression on OS cells, potentially leading to decreased OS pulmonary metastasis and improved outcome. Clinical trials are in development to evaluate this combination as a potential treatment option for patients with refractory OS.

Sexual Orientation Disparities in Physical Activity: Results From Insured Adults in California.

BACKGROUND: The majority of adults in the United States fail to meet the Centers for Disease Control and Prevention (CDC) physical activity (PA) guideline recommendations for health promotion. Despite evidence of disparities by sexual orientation in adverse health outcomes related to PA, little is known about whether PA patterns and the likelihood of meeting these guidelines differ between heterosexual and sexual minority (SM) men and women. METHODS: In 2018, we pooled unweighted respondent data from Kaiser Permanente Northern California Member Health Surveys conducted in 2008, 2011, and 2014/15 (N=42,534) to compare PA patterns among heterosexual and SM men and women. RESULTS: In total, 38.8% of heterosexual men, 43.4% of SM men, 32.9% of heterosexual women, and 40.0% of SM women meet the CDC PA guidelines, yet there was no statistically significant difference in the adjusted odds of meeting these guidelines. Compared with heterosexual women, SM women engage in PA more frequently [odds ratio=0.81; 95% confidence interval (CI), 0.74-0.89], for more minutes per week on average (12.71; 95% CI, 4.85-20.57), and at higher levels of intensity (relative risk ratio=1.26; 95% CI, 1.02-1.56). Compared with heterosexual men, SM men engage in PA more frequently (OR=0.85; 95% CI, 0.74-0.98), for fewer minutes per week on average (-12.89; 95% CI, -25.84 to 0.06), and at lower levels of intensity (relative risk ratio=0.83; 95% CI, 0.67-0.99). CONCLUSIONS: We find that SMs get more frequent PA than their heterosexual peers, which suggests that the higher prevalence of obesity and other PA-related adverse health outcomes among SMs may be due to factors other than PA patterns.

Correction to: Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI.

There was a typo in author Andrew Wahba's name in the initial online publication. The original article has been corrected.

Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI.

PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.

Aggregation of Asian-American subgroups masks meaningful differences in health and health risks among Asian ethnicities: an electronic health record based cohort study.

BACKGROUND: Few large cohort studies have examined the prevalence of diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), obesity, and smoking among middle-aged and older adults in the major Asian-American ethnic groups and Native Hawaiian/Pacific Islanders (PIs). The aim of this study was to evaluate how prevalence of these conditions and risk factors differs across Asian-American and PI ethnic groups and compares with an aggregated All Asian-American racial group. METHODS: This study used a cohort of 1.4 million adults aged 45 to 84 who were Kaiser Permanente Northern California health plan members during 2016. The cohort included approximately 274,910 Asian-Americans (Chinese, Filipino, Japanese, Korean, Southeast Asian, South Asian, other), 8450 PIs, 795,080 non-Hispanic whites, 107,200 blacks, and 210,050 Latinos. We used electronic health record data to produce age-standardized prevalence estimates of DM, HTN, CAD, obesity (using standard and Asian thresholds), and smoking for men and women in all racial/ethnic subgroups and compared these subgroups to an aggregated All Asian-American racial group and to whites, blacks, and Latinos. RESULTS: We found large differences in health burden across Asian-American ethnic subgroups. For both sexes, there were 16 and > 22 percentage point differences between the lowest and highest prevalence of DM and HTN, respectively. Obesity prevalence among Asian subgroups (based on an Asian BMI ≥ 27.5 kg/m2 threshold) ranged from 14 to 39% among women and 21 to 45% among men. Prevalence of smoking ranged from 1 to 4% among women and 5 to 14% among men. Across all conditions and risk factors, prevalence estimates for Asian-American and PI ethnic groups significantly differed from those for the All Asian-American group. In general, Filipinos and PIs had greater health burden than All Asians, with prevalence estimates approaching those of blacks. CONCLUSIONS: In a population of middle-aged and older adult Northern California health plan members, we found substantive differences in prevalence of chronic cardiovascular conditions, obesity, and smoking across Asian-American ethnic groups and between Asian-American ethnic groups and an aggregated All Asian racial group. Our study confirms that reporting statistics for an aggregated Asian-American racial group masks meaningful differences in Asian-American ethnic group health.

High-Velocity Nasal Insufflation in the Treatment of Respiratory Failure: A Randomized Clinical Trial.

STUDY OBJECTIVE: We compare high-velocity nasal insufflation, a form of high-flow nasal cannula, with noninvasive positive-pressure ventilation in the treatment of undifferentiated respiratory failure with respect to therapy failure, as indicated by requirement for endotracheal intubation or cross over to the alternative therapy. METHODS: This was a multicenter, randomized trial of adults presenting to the emergency department (ED) with respiratory failure requiring noninvasive positive-pressure ventilation. Patients were randomly assigned to high-velocity nasal insufflation (initial flow 35 L/min; temperature 35°C (95°F) to 37°C (98.6°F); FiO2 1.0) or noninvasive positive-pressure ventilation using an oronasal mask (inspiratory positive airway pressure 10 cm H2O; expiratory positive airway pressure 5 cm H2O). The primary outcome was therapy failure at 72 hours after enrollment. A subjective outcome of crossover was allowed as a risk mitigation to support deferment of informed consent. Noninferiority margins were set at 15 and 20 percentage points, respectively. RESULTS: A total of 204 patients were enrolled and included in the analysis, randomized to high-velocity nasal insufflation (104) and noninvasive positive-pressure ventilation (100). The intubation rate (high-velocity nasal insufflation=7%; noninvasive positive-pressure ventilation=13%; risk difference=-6%; 95% confidence interval -14% to 2%) and any failure of the assigned arm (high-velocity nasal insufflation=26%; noninvasive positive-pressure ventilation=17%; risk difference 9%; confidence interval -2% to 20%) at 72 hours met noninferiority. The effect on PCO2 over time was similar in the entire study population and in patients with baseline hypercapnia. Vital signs and blood gas analyses improved similarly over time. The primary limitation was the technical inability to blind the clinical team. CONCLUSION: High-velocity nasal insufflation is noninferior to noninvasive positive-pressure ventilation for the treatment of undifferentiated respiratory failure in adult patients presenting to the ED.

Older adults' readiness to engage with eHealth patient education and self-care resources: a cross-sectional survey.

BACKGROUND: This study examined access to digital technologies, skills and experience, and preferences for using web-based and other digital technologies to obtain health information and advice among older adults in a large health plan. A primary aim was to assess the extent to which digital divides by race/ethnicity and age group might affect the ability of a large percentage of seniors, and especially those in vulnerable groups, to engage with online health information and advice modalities (eHIA) and mobile health (mHealth) monitoring tools. METHODS: A mailed survey was conducted with age-sex stratified random samples of English-speaking non-Hispanic white, African-American/black (black), Hispanic/Latino (Latino), Filipino-American (Filipino), and Chinese-American (Chinese) Kaiser Permanente Northern California members who were aged 65-79 years. Respondent data were weighted to the study population for the cross-sectional analyses. RESULTS: Older seniors and black, Latino, and Filipino seniors have less access to digital tools, less experience performing a variety of online tasks, and are less likely to believe that they would be capable of going online for health information and advice compared to younger and white Non-Hispanic seniors. Consequently, they are also less likely to be interested in using eHIA modalities. CONCLUSIONS: The same subgroups of seniors that have previously been shown to have higher prevalence of chronic conditions and greater difficulties with healthcare access are also less likely to adopt use of eHIA and mHealth monitoring technologies. At the patient population level, this digital divide is important to take into account when planning health information and chronic disease management programs. At the individual patient level, to provide good patient-centered care, it is important for providers to assess rather than assume digital access, eHealth skills, and preferences prior to recommending use of web-based resources and mHealth tools.

Understanding functional and social risk characteristics of frail older adults: a cross-sectional survey study.

BACKGROUND: Frailty is a condition of increasing importance, given the aging adult population. With an anticipated shortage of geriatricians, primary care physicians will increasingly need to manage care for frail adults with complex functional risks and social-economic circumstances. METHODS: We used cross-sectional data from 4551 adults ages 65-90 who responded to the 2014/2015 cycle of the Kaiser Permanente Northern California Member Health Survey (MHS), a self-administered survey that covers multiple health and social characteristics, to create a deficits accumulation model frailty index, classify respondents as frail or non-frail, and then compare prevalence of functional health issues including Activities of Daily Living (ADL)/Instrumental Activities of Daily Living (IADL) and social determinants of health (SDOHs) by frailty status. RESULTS: The overall prevalence of frailty was 14.3%, higher for women than men, increased with age, and more common among those with low levels of education and income. Frail older adults were more likely than non-frail to have ≥ 3 chronic diseases (55.9% vs. 10.1%), obesity (32.7% vs. 22.8%), insomnia (36.4% vs. 8.8%), oral health problems (25.1% vs. 4.7%), balance or walking problems (54.2% vs. 4.9%), ≥ 1 fall (56.1% vs. 19.7%), to use ≥ 1 medication known to increase fall risk (56.7% vs. 26.0%), and to need help with ≥2 ADLs (15.8% vs. 0.8%) and ≥ 2 IADLs (38.4% vs. 0.8%). They were more likely to feel financial strain (26.9% vs. 12.6%) and to use less medication than prescribed (7.4% vs. 3.6%), less medical care than needed (8.3% vs 3.7%), and eat less produce (9.5% vs. 3.2%) due to cost. Nearly 20% of frail adults were unpaid caregivers for an adult with frailty, serious illness or disability. CONCLUSIONS: This study examined the prevalence of frailty and identified modifiable and non-modifiable risk factors of health. The frail older adult population is heterogeneous and requires a patient-centered assessment of their circumstances by healthcare providers and caregivers to improve their quality of life, avoid adverse health events, and slow physical and mental decline. The characteristics identified in this study can be proactively used for the assessment of patient health, quality of life, and frailty prevention.

Racial-Ethnic Differences in Fall Prevalence among Older Women: A Cross-Sectional Survey Study.

BACKGROUND: Falls are the leading cause of hip fracture in older women, with important public health implications. Fall risk increases with age and other clinical factors, and varies by race/ethnicity. International studies suggest that fall risk is lower in Asians, although data are limited in U.S. POPULATIONS: This study examines racial/ethnic differences in fall prevalence among older U.S. women within a large integrated healthcare delivery system. METHODS: This cross-sectional study used data from 6277 women ages 65-90 who responded to the 2008 or 2011 Kaiser Permanente Northern California Member Health Survey (KPNC-MHS). The KPNC-MHS is a mailed questionnaire sent to a random sample of adult members stratified by age, gender, and geographic location, representing a population estimate of >200,000 women age ≥65 years. Age, race/ethnicity, self-reported health status, presence of diabetes, arthritis or prior stroke, mobility limitations and number of falls in the past year were obtained from the KPNC-MHS. The independent association of race/ethnicity and recent falls was examined, adjusting for known risk factors. RESULTS: The weighted sample was 76.7% non-Hispanic white, 6.2% Hispanic, 6.8% black and 10.3% Asian. Over 20% reported having fallen during the past year (28.5% non-Hispanic white, 27.8% Hispanic, 23.4% black and 20.1% Asian). Older age was associated with greater fall risk, as was having diabetes (OR 1.24, CI 1.03-1.48), prior stroke (OR 1.51, CI 1.09-2.07), arthritis (OR 1.61, CI 1.39-1.85) and mobility limitations (OR 2.82, CI 2.34-3.39), adjusted for age. Compared to whites, Asian (OR 0.64, CI 0.50-0.81) and black (OR 0.73, CI 0.55-0.95) women were much less likely to have ≥1 fall in the past year, adjusting for age, comorbidities, mobility limitation and poor health status. Asians were also less likely to have ≥2 falls (OR 0.62, CI 0.43-0.88). CONCLUSIONS: Among older women, the risk of having a recent fall was substantially lower for black and Asian women when compared to white women. This may contribute to their lower rates of hip fracture. Future studies should examine cultural and behavioral factors that contribute to these observed racial/ethnic differences in fall risk among U.S. women.

Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy.

Interleukin-2 (IL-2) is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. Systemic delivery of IL-2 has shown clinical benefit in renal cell carcinoma and melanoma patients. However, its use has been limited by the numerous toxicities encountered with the systemic delivery. Intravenous IL-2 causes the well-known "capillary leak syndrome," or the leakage of fluid from the circulatory system to the interstitial space resulting in hypotension (low blood pressure), edema, and dyspnea that can lead to circulatory shock and eventually cardiopulmonary collapse and multiple organ failure. Due to the toxicities associated with systemic IL-2, an aerosolized delivery approach has been developed, which enables localized delivery and a higher local immune cell activation. Since proteins are absorbed via pulmonary lymphatics, after aerosol deposition in the lung, aerosol delivery provides a means to more specifically target IL-2 to the local immune system in the lungs with less systemic effects. Its benefits have extended to diseases other than cancer. Delivery of IL-2 via aerosol or as nebulized IL-2 liposomes has been previously shown to have less toxicity and higher efficacy against sarcoma lung metastases. Dogs with cancer provided a highly relevant means to determine biodistribution of aerosolized IL-2 and IL-2 liposomes. However, efficacy of single-agent IL-2 is limited. As in general, for most immune-therapies, its effect is more beneficial in the face of minimal residual disease. To overcome this limitation, combination therapies using aerosol IL-2 with adoptive transfer of T cells or NK cells have emerged.Using a human osteosarcoma (OS) mouse model, we have demonstrated the efficacy of single-agent aerosol IL-2 and combination therapy aerosol IL-2 and NK cells or aerosol IL-2 and interleukin 11 receptor alpha-directed chimeric antigen receptor-T cells (IL-11 receptor α CAR-T cells) against OS pulmonary metastases. Combination therapy resulted in a better therapeutic effect. A Phase-I trial of aerosol IL-2 was done in Europe and proved to be safe. Others and our preclinical studies provided the basis for the development of a Phase-I aerosol IL-2 trial in our institution to include younger patients with lung metastases. OS, our disease of interest, has a peak incidence in the adolescent and young adult years. Our goal is to complete this trial in the next 2 years.In this chapter, we summarize the different effects of IL-2 and cover the advantages of the aerosol delivery route for diseases of the lung with an emphasis on some of our most recent work using combination therapy aerosol IL-2 and NK cells for the treatment of OS lung metastases.