Integrated antibody and cellular immunity monitoring are required for assessment of the long term protection that will be essential for effective next generation vaccine development.

The COVID pandemic exposed the critical role T cells play in initial immunity, the establishment and maintenance of long term protection, and of durable responsiveness against novel viral variants. A growing body of evidence indicates that adding measures of cellular immunity will fill an important knowledge gap in vaccine clinical trials, likely leading to improvements in the effectiveness of the next generation vaccines against current and emerging variants. In depth cellular immune monitoring in Phase II trials, particularly for high risk populations such as the elderly or immune compromised, should result in better understanding of the dynamics and requirements for establishing effective long term protection. Such analyses can result in cellular immunity correlates that can then be deployed in Phase III studies using appropriate, scalable technologies. Measures of cellular immunity are less established than antibodies as correlates of clinical immunity, and some misconceptions persist about cellular immune monitoring usefulness, cost, complexity, feasibility, and scalability. We outline the currently available cellular immunity assays, review their readiness for use in clinical trials, their logistical requirements, and the type of information each assay generates. The objective is to provide a reliable source of information that could be leveraged to develop a rational approach for comprehensive immune monitoring during vaccine development.

The need for more holistic immune profiling in next-generation SARS-CoV-2 vaccine trials.

First-generation anit-SARS-CoV-2 vaccines were highly successful. They rapidly met an unforeseen emergency need, saved millions of lives, and simultaneously eased the burden on healthcare systems worldwide. The first-generation vaccines, however, focused too narrowly on antibody-based immunity as the sole marker of vaccine trial success, resulting in large knowledge gaps about waning vaccine protection, lack of vaccine robustness to viral mutation, and lack of efficacy in immunocompromised populations. Detailed reviews of first-generation vaccines, including their mode of action and geographical distribution, have been published elsewhere. Second-generation clinical trials must address these gaps by evaluating a broader range of immune markers, including those representing cell-mediated immunity, to ensure the most protective and long-lasting vaccines are brought to market.

Changes in Continuous, Long-Term Heart Rate Variability and Individualized Physiological Responses to Wellness and Vacation Interventions Using a Wearable Sensor.

There are many approaches to maintaining wellness, including taking a simple vacation to attending highly structured wellness retreats, which typically regulate the attendee's personal time and activities. In a healthy English-speaking cohort of 112 women and men (aged 30-80 years), this study examined the effects of participating in either a 6-days intensive wellness retreat based on Ayurvedic medicine principles or unstructured 6-days vacation at the same wellness center setting. Heart rate variability (HRV) was monitored continuously using a wearable ECG sensor patch for up to 7 days prior to, during, and 1-month following participation in the interventions. Additionally, salivary cortisol levels were assessed for all participants at multiple times during the day. Continual HRV monitoring data in the real-world setting was seen to be associated with demographic [HRVALF: ßAge = 0.98 (95% CI = 0.96-0.98), false discovery rate (FDR) < 0.001] and physiological characteristics [HRVPLF: ß = 0.98 (95% CI = 0.98-1), FDR =0.005] of participants. HRV features were also able to quantify known diurnal variations [HRVLF/HF: ßACT:night vs. early-morning = 2.69 (SE = 1.26), FDR < 0.001] along with notable inter- and intraperson heterogeneity in response to intervention. A statistically significant increase in HRVALF [ß = 1.48 (SE = 1.1), FDR < 0.001] was observed for all participants during the resort visit. Personalized HRV analysis at an individual level showed a distinct individualized response to intervention, further supporting the utility of using continuous real-world tracking of HRV at an individual level to objectively measure responses to potentially stressful or relaxing settings.

Self-Monitoring Utilization Patterns Among Individuals in an Incentivized Program for Healthy Behaviors.

BACKGROUND: The advent of digital technology has enabled individuals to track meaningful biometric data about themselves. This novel capability has spurred nontraditional health care organizations to develop systems that aid users in managing their health. One of the most prolific systems is Walgreens Balance Rewards for healthy choices (BRhc) program, an incentivized, Web-based self-monitoring program. OBJECTIVE: This study was performed to evaluate health data self-tracking characteristics of individuals enrolled in the Walgreens' BRhc program, including the impact of manual versus automatic data entries through a supported device or apps. METHODS: We obtained activity tracking data from a total of 455,341 BRhc users during 2014. Upon identifying users with sufficient follow-up data, we explored temporal trends in user participation. RESULTS: Thirty-four percent of users quit participating after a single entry of an activity. Among users who tracked at least two activities on different dates, the median length of participating was 8 weeks, with an average of 5.8 activities entered per week. Furthermore, users who participated for at least twenty weeks (28.3% of users; 33,078/116,621) consistently entered 8 to 9 activities per week. The majority of users (77%; 243,774/315,744) recorded activities through manual data entry alone. However, individuals who entered activities automatically through supported devices or apps participated roughly four times longer than their manual activity-entering counterparts (average 20 and 5 weeks, respectively; P<.001). CONCLUSIONS: This study provides insights into the utilization patterns of individuals participating in an incentivized, Web-based self-monitoring program. Our results suggest automated health tracking could significantly improve long-term health engagement.

Development of a Weight Loss Mobile App Linked With an Accelerometer for Use in the Clinic: Usability, Acceptability, and Early Testing of its Impact on the Patient-Doctor Relationship.

BACKGROUND: Although complications of obesity are well acknowledged and managed by clinicians, management of obesity itself is often difficult, which leads to its underdiagnosis and undertreatment in hospital settings. However, tools that could improve the management of obesity, including self-monitoring, engagement with a social network, and open channels of communication between the patient and doctor, are limited in a clinic-based setting. OBJECTIVE: The objective of our study was to evaluate the usability and acceptability of a newly developed mobile app linked with an accelerometer and its early effects on patient-doctor relationships. METHODS: From September 2013 to February 2014, we developed a mobile app linked with an accelerometer as a supportive tool for a clinic-based weight loss program. The app used information from electronic health records and delivered tailored educational material. Personal goal setting, as well as monitoring of weight changes and physical activity combined with feedback, are key features of the app. We also incorporated an interactive message board for patients and doctors. During the period of March 2014 to May 2014, we tested our mobile app for 1 month in participants in a hospital clinic setting. We assessed the app's usability and acceptability, as well as the patient-doctor relationship, via questionnaires and analysis of app usage data. RESULTS: We recruited 30 individuals (18 male and 12 female) for the study. The median number of log-ins per day was 1.21, with the most frequently requested item being setting goals, followed by track physical activities and view personal health status. Scales of the depth of the patient-doctor relationship decreased from 27.6 (SD 4.8) to 25.1 (SD 4.5) by a Wilcoxon signed rank test (P=.02). CONCLUSIONS: A mobile phone app linked with an accelerometer for a clinic-based weight loss program is useful and acceptable for weight management but exhibited less favorable early effects on patient-doctor relationships.

Limestone: high-throughput candidate phenotype generation via tensor factorization.

The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in consultation with a medical expert, we confirmed 82% of the top 50 candidates automatically extracted by Limestone are clinically meaningful.

The use of intravenous enoxaparin in elective percutaneous coronary intervention in patients with renal impairment: results from the SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation (STEEPLE) trial.

BACKGROUND: The STEEPLE trial assessed outcomes of patients undergoing elective percutaneous coronary intervention randomized to receive a bolus of intravenous enoxaparin (0.5 or 0.75 mg/kg, n = 2,298) or activated clotting time-adjusted unfractionated heparin (UFH, n = 1,230), stratified according to planned glycoprotein IIb/IIIa inhibitor use. METHODS: In this subanalysis, we assessed outcomes in patients with renal impairment (creatinine clearance < or =60 mL/min, n = 659). RESULTS: Major bleeding occurred more often in patients with renal impairment compared with those without (2.7% vs 1.5%, P = .04). Enoxaparin was associated with less major bleeding than UFH with normal renal function (0.9% for enoxaparin 0.5 mg/kg or 1.0% for enoxaparin 0.75 mg/kg vs 2.6%, respectively; both P = .01 vs UFH), with a trend toward less major bleeding with impaired renal function (2.6% or 1.8% vs 3.8%, P = .18 for enoxaparin 0.5 mg/kg and P = .47 for 0.75 mg/kg vs UFH). Minor bleeding rates were similar irrespective of renal function or anticoagulation regimen. The incidence of death, nonfatal myocardial infarction, or urgent target-vessel revascularization was similar between patients with and without renal impairment (5.7% vs 6.5%, P = .45). In patients with renal impairment, event rates were 6.2% or 5.3% with enoxaparin vs 5.6% with UFH (P = nonsignificant). Target anticoagulation levels were achieved 4 to 5 times more often with enoxaparin compared with UFH in patients with normal and impaired renal function (both P < .0001). CONCLUSIONS: A single bolus of enoxaparin was associated with similar ischemic events and a trend for less major bleeding compared with UFH in patients with renal impairment undergoing percutaneous coronary intervention. Enoxaparin can be administered safely without dose adjustment in these patients.

Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway.

OBJECTIVE: The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation. METHODS AND RESULTS: In this report, we characterize heterogeneity in LPA responses among individuals. Platelets isolated from approximately 20% of healthy donors consistently failed to aggregate in response to LPA. Our studies indicate that, rather than lacking stimulatory pathways, platelets from "nonresponsive" donors respond to LPA by triggering inhibitory pathway(s) to block platelet aggregation. Consistent with this observation, LPA-induced aggregation could be partially restored to "nonresponsive" platelets by pharmacological inhibition of cAMP generation. LPA "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPARgamma. Among 70 patients with stable coronary artery disease (CAD), only 1 (1.4%) was identified as an LPA nonresponder. Moreover, in 33 patients presenting for diagnostic catheterization, CAD was identified as having a bivariate association with platelet LPA responder/nonresponder status. CONCLUSIONS: Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in approximately 20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.