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Objectives: It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but the infectious period starts on average 2 days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: • The algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) • The algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.Trial Design: The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. The study will start with an initial learning phase (maximum of 3 months), followed by period 1 (3 months) and period 2 (3 months). Subjects entering the study at the end of the recruitment period may directly start with period 1 and will not be part of the learning phase. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in either period 1 or period 2 and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either sequence 1 (experimental condition first) or sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.Participants: The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6500 normal-risk individuals and 3500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal and self-sampling serology and PCR kits. More information on the study can be found in www.covid-red.eu . During recruitment, subjects will be invited to visit the COVID-RED web portal. After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria: Inclusion criteria: • Resident of the Netherlands • At least 18 years old • Informed consent provided (electronic) • Willing to adhere to the study procedures described in the protocol • Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, the study team should be notified) • Be able to read, understand and write Dutch Exclusion criteria: • Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) • Current suspected (e.g. waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) • Participating in any other COVID-19 clinical drug, vaccine or medical device trial (self-reported) • Electronic implanted device (such as a pacemaker; self-reported) • Pregnant at the time of informed consent (self-reported) • Suffering from cholinergic urticaria (per the Ava bracelet's user manual; self-reported) • Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronize it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 h, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess the intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo). Note that both algorithms will also instruct to seek testing when any SARS-CoV-2 symptoms are reported in line with those defined by the Dutch national institute for public health and the environment 'Rijksinstituut voor Volksgezondheid en Milieu' (RIVM) guidelines.Main Outcomes: The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with the self-reported Daily Symptom Diary data and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional twenty secondary and exploratory objectives which address, among others, infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2-infected participants and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (between month 0 and 3.5 months after the start of subject recruitment), at the end of the learning phase (month 3; note that this sampling moment is skipped if a subject entered the study at the end of the recruitment period), period 1 (month 6) and period 2 (month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the learning phase is positive, or if the subject entered the study at the end of the recruitment period, and samples collected at the end of period 1 will only be analysed if the sample collected at the end of period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called COVID-positive mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using the data collected in period 2 (months 6 through 9). Within this period, serology tests (before and after period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.Randomization: All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in approximately equal numbers of high-risk and normal-risk individuals between the sequences.Blinding (masking): In this study, subjects will be blinded to the study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on the data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.Numbers To Be Randomized (sample Size): A total of 20,000 subjects will be recruited and randomized 1:1 to either sequence 1 (experimental condition followed by control condition) or sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6500 normal-risk and 3500 high-risk individuals per sequence.Trial Status: Protocol version: 3.0, dated May 3, 2021. Start of recruitment: February 19, 2021. End of recruitment: June 3, 2021. End of follow-up (estimated): November 2021 TRIAL REGISTRATION: The Netherlands Trial Register on the 18th of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. [ABSTRACT FROM AUTHOR]

Background: The vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake. Methods: A total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), =60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov's wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived. Results: Three age groups: 60-69, 70-79 and = 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (µmol/L) 12, 15 and 16 (p < 0.001), MMA (nmol/L) 207, 221 and 244 (p < 0.001). Hcy and MMA (both p < 0.001), but not holoTC (p = 0.12) and vitamin B12 (p = 0.44) were found to be affected by kidney function. In a linear regression model Fedosov's wellness score was independently associated with kidney function (p < 0.001) but not with age. Total serum folate and red blood cell (RBC) folate drift apart with increasing age: whereas the former decreases (p = 0.01) RBC folate remains in the same bandwidth across all age groups (p = 0.12) A common reference interval combining age and gender strata can be obtained for vitamin B12 and holoTC, whereas a more differentiated approach seems warranted for serum folate and RBC folate. Conclusion: Whereas the vitamin B12 and holoTC levels remain steady after 60 years of age, we observed a significant increment in MMA levels accompanied by increments in Hcy; this is better explained by age-related reduced kidney function than by vitamin B12 insufficiency. Total serum folate levels but not RBC folate levels decreased with progressing age. [ABSTRACT FROM AUTHOR]

Background: Vitamin D and the components of humoral immunity play important roles in human health. Older people have lower 25-hydroxyvitamin D (25(OH)D) serum levels than younger adults. We aimed to determine the levels of 25(OH)D serum concentrations in healthy senior citizens and to study their relationship to the levels of components of humoral immunity. Methods: A total of 1,470 healthy Swiss men and women, 60 years or older, were recruited for this study. A total of 179 subjects dropped out of the study because of elevated serum concentrations of C-reactive protein. Fasting blood sera were analyzed for 25(OH)D with the high-performance liquid chromatography (HPLC) and for parathyroid hormone (PTH), immunoglobulins and complement C4 and C3 concentrations with immunoassays. The percentage of participants in each of the four 25(OH)D deficiency groups - severely deficient (<10 ng/ml), deficient (10 to 20), insufficient (21 to 29 ng/ml) and normal (>=30 ng/ml) - were statistically compared. The relationship of the major components of the humoral system and age with 25(OH)D levels was also assessed. Results: About 66% of the subjects had insufficient levels of 25(OH)D. Normal levels of 25(OH)D were found in 26.1% of the subjects of which 21% were males and 30.5% were females (total study population). Severely deficient levels of 25(OH)D were found in 7.98% of the total study population. Low levels of 25(OH)D were positively associated with IgG2 (P = 0.01) and with C4 (P = 0.02), yet were inversely related to levels of IgG1 and IgA (P < 0.05) and C3 (P = 0.01). Serum levels of total IgA, IgG, IgG2 and IgG4 peaked together with 25(OH)D during late summer. Conclusions: Approximately two-thirds of the healthy, older Swiss population presented with Vitamin D insufficiency. The incremental shift in IgA and C3 levels might not necessarily reflect a deranged humoral immune defense; however, given the high prevalence of vitamin D deficiency, the importance of this condition in humoral immunity will be worth looking at more closely. This study supports the role of vitamin D in the competent immune system. [ABSTRACT FROM AUTHOR]