Correction: Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

[This corrects the article DOI: 10.2196/49100.].

Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

BACKGROUND: Timely collection of patient-reported outcomes (PROs) decreases emergency department visits and hospitalizations and increases survival. However, little is known about the outcome predictivity of unpaid informal caregivers' reporting using similar clinical outcome assessments. OBJECTIVE: The aim of this study is to assess whether caregivers and adults with cancer adhered to a planned schedule for electronically collecting patient-reported outcomes (PROs) and if PROs were associated with future clinical events. METHODS: We developed 2 iPhone apps to collect PROs, one for patients with cancer and another for caregivers. We enrolled 52 patient-caregiver dyads from Kaiser Permanente Northern California in a nonrandomized study. Participants used the apps independently for 4 weeks. Specific clinical events were obtained from the patients' electronic health records up to 6 months following the study. We used logistic and quasi-Poisson regression analyses to test associations between PROs and clinical events. RESULTS: Participants completed 97% (251/260) of the planned Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) surveys and 98% (254/260) of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys. PRO-CTCAE surveys completed by caregivers were associated with patients' hospitalizations or emergency department visits, grade 3-4 treatment-related adverse events, dose reductions (P<.05), and hospice referrals (P=.03). PROMIS surveys completed by caregivers were associated with hospice referrals (P=.02). PRO-CTCAE surveys completed by patients were not associated with any clinical events, but their baseline PROMIS surveys were associated with mortality (P=.03), while their antecedent or final PROMIS surveys were associated with all clinical events examined except for total days of treatment breaks. CONCLUSIONS: In this study, caregivers and patients completed PROs using smartphone apps as requested. The association of caregiver PRO-CTCAE surveys with patient clinical events suggests that this is a feasible approach to reducing patient burden in clinical trial data collection and may help provide early information about increasing symptom severity.

What Works Best to Engage Participants in Mobile App Interventions and e-Health: A Scoping Review.

Background: Despite the growing popularity of mobile app interventions, specific engagement components of mobile apps have not been well studied. Methods: The objectives of this scoping review are to determine which components of mobile health intervention apps encouraged or hindered engagement, and examine how studies measured engagement. Results: A PubMed search on March 5, 2020 yielded 239 articles that featured the terms engagement, mobile app/mobile health, and adult. After applying exclusion criteria, only 54 studies were included in the final analysis. Discussion: Common app components associated with increased engagement included: personalized content/feedback, data visualization, reminders/push notifications, educational information/material, logging/self-monitoring functions, and goal-setting features. On the other hand, social media integration, social forums, poor app navigation, and technical difficulties appeared to contribute to lower engagement rates or decreased usage. Notably, the review revealed a great variability in how engagement with mobile health apps is measured due to lack of established processes. Conclusion: There is a critical need for controlled studies to provide guidelines and standards to help facilitate engagement and its measurement in research and clinical trial work using mobile health intervention apps.

Chronic kidney disease, atherosclerotic plaque characteristics on carotid magnetic resonance imaging, and cardiovascular outcomes.

BACKGROUND: It is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events. METHODS: In a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial. (SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR < 60 ml/min/1.73m2) with progression of carotid plaques and the SPRINT cardiovascular endpoint. RESULTS: One hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m2, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events. CONCLUSIONS: Presence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening. TRIAL REGISTRATION: NCT01475747 , registered on November 21, 2011.

Mobile app activity engagement by cancer patients and their caregivers informs remote monitoring.

Mobile phone applications ("apps") are potentially an effective, low-burden method to collect patient-reported outcomes outside the clinical setting. Using such apps consistently and in a timely way is critical for complete and accurate data capture, but no studies of concurrent reporting by cancer patient-caregiver dyads have been published in the peer-reviewed literature. This study assessed app engagement, defined as adherence, timing, and attrition with two smartphone applications, one for adult cancer patients and one for their informal caregivers. This was a single-arm, pilot study in which adult cancer patients undergoing IV chemotherapy or immunotherapy used the DigiBioMarC app, and their caregivers used the TOGETHERCare app, for approximately one month to report weekly on the patients' symptoms and wellbeing. Using app timestamp metadata, we assessed user adherence, overall and by participant characteristics. Fifty patient-caregiver dyads completed the study. Within the one-month study period, both adult cancer patients and their informal caregivers were highly adherent, with app activity completion at 86% for cancer patients and 84% for caregivers. Caregivers completed 86% of symptom reports, while cancer patients completed 89% of symptom reports. Cancer patients and their caregivers completed most activities within 48 h of availability on the app. These results suggest that the DigiBioMarC and TOGETHERCare apps can be used to collect patient- and caregiver-reported outcomes data during intensive treatment. From our research, we conclude that metadata from mobile apps can be used to inform clinical teams about study participants' engagement and wellbeing outside the clinical setting.

A novel smartphone application for the informal caregivers of cancer patients: Usability study.

Informal caregivers are a critical source of support for cancer patients. However, their perspectives are not routinely collected, despite health impacts related to the burden of caregiving. We created the TOGETHERCare smartphone application (app) to collect observer-reported outcomes regarding the cancer patient's health and caregiver's perceptions of their own mental and physical health, and to provide tips and resources for self-care and patient care. We enrolled 54 caregivers between October 2020 and March 2021 from Kaiser Permanente Northern California (KPNC), an integrated healthcare system. Fifty caregivers used the app for approximately 28 days. Usability and acceptability were assessed using questions from the Mobile App Rating Scale (MARS), the System Usability Scale (SUS), the Net Promoter Score (NPS), and semi-structured interviews. The caregivers' mean age was 54.4 years, 38% were female and 36% were non-White. The SUS total mean score was 83.4 (SD = 14.2), for a percentile rank of 90-95 ("excellent"). Median MARS responses to the functionality questions were also high. The NPS score of 30 at the end of the study indicated that most caregivers would recommend the app. Themes from semi-structured interviews were consistent across the study period and indicated that the app was easy to use and helpful. Caregivers indicated a need for feedback from the app, suggested some changes to the wording of questions, the app's visuals, and timing of notifications. This study demonstrated that caregivers are willing to complete frequent surveys about themselves and their patients. The app is unique because it provides a remote method to collect caregivers' observations about the patient that may be useful for clinical care. To our knowledge, TOGETHERCare is the first mobile app developed specifically to capture adult cancer patient symptoms from the informal caregiver's perspective. Future research will examine whether use of this app can help improve patient outcomes.

Usability evaluation of mobile phone technologies for capturing cancer patient-reported outcomes and physical functions.

Background: By eliminating the requirement for participants to make frequent visits to research sites, mobile phone applications ("apps") may help to decentralize clinical trials. Apps may also be an effective mechanism for capturing patient-reported outcomes and other endpoints, helping to optimize patient care during and outside of clinical trials. Objectives: We report on the usability of Digital BioMarkers for Clinical Impact (DigiBioMarC™ (DBM)), a novel smartphone-based app used by cancer patients in conjunction with a wearable device (Apple Watch®). DBM is designed to collect patient-reported outcomes and record physical functions. Methods: In a fully decentralized "bring-your-own-device" smartphone study, we enrolled 54 cancer patient and caregiver dyads from Kaiser Permanente Northern California (KPNC) from October 2020 through March 2021. Patients used the app for at least 28 days, completed weekly questionnaires about their symptoms, physical functions, and mood, and performed timed physical tasks. Usability was determined through a subset of the Mobile App Rating Scale (MARS), the full System Usability Scale (SUS), the Net Promoter Score (NPS), and semi-structured interviews. Results: We obtained usability survey data from 50 of 54 patients. Median responses to the selected MARS questions and the mean SUS scores indicated above average usability. The NPS from the semi-structured interviews at the end of the study was 24, indicating a favorable score. Conclusions: Cancer patients reported above average usability for the DBM app. Qualitative analyses indicated that the app was easy to use and helpful. Future work will emphasize implementing further patient recommendations and evaluating the app's clinical efficacy in multiple settings.

Comparison of low and high dose ionising radiation using topological analysis of gene coexpression networks.

BACKGROUND: The growing use of imaging procedures in medicine has raised concerns about exposure to low-dose ionising radiation (LDIR). While the disastrous effects of high dose ionising radiation (HDIR) is well documented, the detrimental effects of LDIR is not well understood and has been a topic of much debate. Since little is known about the effects of LDIR, various kinds of wet-lab and computational analyses are required to advance knowledge in this domain. In this paper we carry out an "upside-down pyramid" form of systems biology analysis of microarray data. We characterised the global genomic response following 10 cGy (low dose) and 100 cGy (high dose) doses of X-ray ionising radiation at four time points by analysing the topology of gene coexpression networks. This study includes a rich experimental design and state-of-the-art computational systems biology methods of analysis to study the differences in the transcriptional response of skin cells exposed to low and high doses of radiation. RESULTS: Using this method we found important genes that have been linked to immune response, cell survival and apoptosis. Furthermore, we also were able to identify genes such as BRCA1, ABCA1, TNFRSF1B, MLLT11 that have been associated with various types of cancers. We were also able to detect many genes known to be associated with various medical conditions. CONCLUSIONS: Our method of applying network topological differences can aid in identifying the differences among similar (eg: radiation effect) yet very different biological conditions (eg: different dose and time) to generate testable hypotheses. This is the first study where a network level analysis was performed across two different radiation doses at various time points, thereby illustrating changes in the cellular response over time.

Pulse wave velocity and central aortic pressure in systolic blood pressure intervention trial participants.

Arterial stiffness, typically assessed as the aortic pulse wave velocity (PWV), and central blood pressure levels may be indicators of cardiovascular disease (CVD) risk. This ancillary study to the Systolic Blood Pressure Intervention Trial (SPRINT) obtained baseline assessments (at randomization) of PWV and central systolic blood pressure (C-SBP) to: 1) characterize these vascular measurements in the SPRINT cohort, and 2) test the hypotheses that PWV and C-SBP are associated with glucose homeostasis and markers of chronic kidney disease (CKD). The SphygmoCor® CPV device was used to assess carotid-femoral PWV and its pulse wave analysis study protocol was used to obtain C-SBP. Valid results were obtained from 652 participants. Mean (±SD) PWV and C-SBP for the SPRINT cohort were 10.7 ± 2.7 m/s and 132.0 ± 17.9 mm Hg respectively. Linear regression analyses for PWV and C-SBP results adjusted for age, sex, and race/ethnicity in relation to several markers of glucose homeostasis and CKD did not identify any significant associations with the exception of a marginally statistically significant and modest association between PWV and urine albumin-to-creatinine ratio (linear regression estimate ± SE, 0.001 ± 0.0006; P-value 0.046). In a subset of SPRINT participants, PWV was significantly higher than in prior studies of normotensive persons, as expected. For older age groups in the SPRINT cohort (age > 60 years), PWV was compared with a reference population of hypertensive individuals. There were no compelling associations noted between PWV or C-SBP and markers of glucose homeostasis or CKD. CLINICAL TRIAL REGISTRATION: NCT01206062.

Effect of Intensive Versus Standard Blood Pressure Treatment According to Baseline Prediabetes Status: A Post Hoc Analysis of a Randomized Trial.

OBJECTIVE: To determine whether the effects of intensive (<120 mmHg) compared with standard (<140 mmHg) systolic blood pressure (SBP) treatment are different among those with prediabetes versus those with fasting normoglycemia at baseline in the Systolic Blood Pressure Intervention Trial (SPRINT). RESEARCH DESIGN AND METHODS: This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose <100 mg/dL). The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment among those with prediabetes and normoglycemia. RESULTS: Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively (P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia (P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05). CONCLUSIONS: In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia.

Ultrasound detection and characterization of polycystic kidney disease in a mouse model.

We sought to use ultrasonography to quantify renal size and echogenicity in a mouse model of polycystic kidney disease. We imaged 36 wild-type (WT) and juvenile cystic kidney (jck) mice by using a standard ultrasound unit and 10-5 MHz linear transducer. Mice were imaged at 3 (6 WT, 7 jck), 6 (7 WT, 5 jck), and 9 (6 WT, 5 jck) wk of age. Kidney length, width, and height were recorded for volume calculation. Sagittal images of both kidneys were recorded for assessment of intensity. Quantitative values were obtained from areas of similar depth and gain settings. Kidney and liver intensities were determined for calculation of their ratio. Representative histologic kidney sections were stained with hematoxylin and eosin and digitized for calculation of cyst number, mean cyst area, and percentage cystic area. We found that renal volume was greater in jck than WT mice at 3 (P < 0.0001), 6 (P < 0.0001), and 9 (P < 0.0001) wk of age. In addition, kidney intensity and kidney:liver ratio were higher in jck than WT mice at 3 (P < 0.002 for both parameters), 6 (P < 0.04), and 9 wk (P < 0.008). Kidneys with smaller mean cyst size and less percentage cystic space had higher intensity values. We therefore conclude that ultrasound measures of renal volume and intensity can noninvasively identify jck-affected mice as early as 3 wk of age. Cortical intensity is greater in jck versus WT mice and appears affected by percentage cyst area and mean cyst size.

Genomic characterization of a three-dimensional skin model following exposure to ionizing radiation.

This study aimed at characterizing the genomic response to low versus moderate doses of ionizing radiation (LDIR versus MDIR) in a three-dimensional (3D) skin model, which exhibits a closer tissue complexity to human skin than monolayer cell cultures. EpiDermFT skin plugs were exposed to 0, 0.1 and 1 Gy doses of X-rays and harvested at 5 min, 3, 8 and 24 h post-irradiation (post-IR). RNA was interrogated for global gene expression alteration. Our results show that MDIR modulated a larger number of genes over the course of 24 h compared to LDIR. However, immediately and throughout the first 3h post-IR, LDIR modulated a larger number of genes than MDIR, mostly associated with cell-cell signaling and survival promotion. Significant modulation of pathways was detected only at 3 h post-IR in MDIR with induction of genes promoting apoptosis. Collectively, the data show different dynamics in the response to LDIR versus MDIR, especially in cell-cycle distribution. LDIR-exposed tissues showed signs of attempted cell-cycle re-entry as early as 3 h post-IR, but were arrested beyond 8 h at the G1/S checkpoint. At 24 h, cells appeared to accumulate at the G2/M checkpoint. MDIR-exposed tissues did not exhibit a prolonged G1/S arrest but rather a prolonged G2/M arrest, which was sustained at least up to 24 h. By 24 h cells exhibited signs of recovery in both LDIR- and MDIR-exposed tissues. In summary, the most pronounced difference in the initial cellular response to LDIR versus MDIR is the promotion of protection and survival in LDIR versus the promotion of apoptosis in MDIR.

Transcriptional response of ex vivo human skin to ionizing radiation: comparison between low- and high-dose effects.

Although human exposure to low-dose ionizing radiation can occur through a variety of sources, including natural, medical, occupational and accidental, the true risks of low-dose ionizing radiation are still poorly understood in humans. Here, the global transcriptional responses of human skin after ex vivo exposure to low (0.05 Gy) and high (5 Gy) doses of X rays and of time in culture (0 Gy) at 0, 2, 8 and 30 h postirradiation were analyzed and compared. Responses to low and high doses differed quantitatively and qualitatively. Differentially expressed genes fell into three groups: (1) unique genes defined as responsive to either 0.05 or 5 Gy but not both and also responsive to time in culture, (2) specific genes defined as responsive to either 0.05 or 5 Gy but not both and not responsive to time in culture, and (3) dose-independent responsive genes. Major differences observed in ex vivo irradiated skin between transcriptional responses to low or high doses were twofold. First, gene expression modulated by 0.05 Gy was transient, while in response to 5 Gy persistence of modified gene expression was observed for a limited number of genes. Second, neither TP53 nor TGFß target genes were modulated after exposure to an acute low dose, suggesting that the TP53-dependent DNA damage response either was not triggered or was triggered only briefly.

Nek8 mutation causes overexpression of galectin-1, sorcin, and vimentin and accumulation of the major urinary protein in renal cysts of jck mice.

The jck murine model, which results from a double point mutation in the nek8 gene, has been used to study the mechanism of autosomal recessive polycystic kidney disease (ARPKD). The renal proteome of jck mice was characterized by two-dimensional gel electrophoresis combined with mass spectrometry (MALDI-TOF/TOF). Four newly identified proteins were found to accumulate in the kidneys of jck mice with polycystic kidney disease (PKD) compared with their wild-type littermates. The proteins galectin-1, sorcin, and vimentin were found to be induced 9-, 9-, and 25-fold, respectively, in the PKD proteome relative to the wild type. The identity of these proteins was established by peptide mass fingerprinting and de novo MS/MS sequencing of selected peptides. Up-regulation of these three proteins may be due to the nek8 mutation, and their function may be related to the signaling and structural processes in the primary cilium. Additionally a series of protein isoforms observed only in the ARPKD kidney was identified as the major urinary protein (MUP). Peptide sequencing demonstrated that the isoforms MUP1, MUP2, and MUP6 are contained in this series. The MUP series showed a number of male-specific isoforms and a phosphorylation of the entire series with an increasing degree of phosphorylation of the acidic isoforms. In addition, the MUP series was localized to the cyst fluid of PKD mice, and a cellular mislocalization of galectin-1, sorcin, and vimentin in PKD tubular epithelial cells was shown. The abnormal and extremely high accumulation of the MUPs in the ARPKD kidney may be linked to a defect in protein transport and secretion. The discovery of these proteins will provide new information on the molecular and cellular processes associated with the mechanism of ARPKD.

Association between rate of viral genome replication and virulence of Marek's disease herpesvirus strains.

The early pathogenesis of Marek's disease virus (MDV) infection is characterized by a lytic infection followed by the induction of latency. Genetically resistant N2a and susceptible P2a chickens were infected with the less virulent JM-16 or the very virulent plus (vv+) RK-1 MDV strains to examine the relationship between virulence and resistance on virus replication during 1-10 days postinfection (dpi) using real-time quantitative polymerase chain reaction (qPCR) and quantitative reverse transcriptase (qRT)-PCR assays. The numbers of copies of the viral DNA or transcripts amplified by these assays were normalized relative to cellular controls and subjected to three-way ANOVA. Viral DNA but not RNA was present in spleens at 1-3 dpi in decreasing quantities, and at 4 dpi, viral DNA started to increase concomitant with the initiation of viral transcription independently of virus strain and genetic resistance. At 6 dpi, JM-16 became latent in resistant N2a and susceptible P2a chickens with low levels of viral transcripts, but transcriptional activity increased in susceptible P2a chickens at 9 and 10 dpi. In contrast, infection with vv+ RK-1 never went into latency in both chicken lines. Viral transcripts were present from 4 to 10 dpi showing a higher and more persistent viral activity that may lead to severe damage to the lymphoid organs resulting in increased immunosuppression and increased incidence of MD. The use of qPCR and qRT-PCR to determine viral DNA load and transcriptional activity may offer an alternative to the current system of pathotyping to characterize new MDV isolates.