Reducing Particulate Matter-associated Cardiovascular Health Effects for Seniors
Phase: NA
Conditions: Cardiometabolic Health
Sponsor: University of Michigan

Reducing particulate matter-associated cardiovascular 
health effects for seniors. (RAPIDS2-Ypsi) 
 
NCT04103346 
 
Date of IRB Approval of Full Protocol: March 10, 2021 

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Title: Reducing particulate matter-associated cardiovascular health effects for seniors.  
(RAPIDS2-Ypsi) 
 
SPECIFIC AIMS  
Fine particulate matter (<2.5 μm, PM2.5) air pollution is the fifth leading risk factor for mortality worldwide1-3. Over 
88 thousand deaths per year are attributable to PM2.5 in the US alone1, with the largest portion from cardiovascular 
(CV) causes (myocardial infarctions, strokes, heart failure)1,3. While several mechanisms are likely responsible1,4, we 
have identified PM2.5-induced elevations in blood pressure (BP) as a key pathway4-8. Beyond triggering acute CV 
events, the BP increase itself (2-10 mm Hg) is clinically relevant, promoting hospitalizations for high BP and chronic 
hypertension4-9. Unfortunately, more than 90% of the global population is exposed to PM2.5 levels above World 
Health Organization Air Quality Guidelines (<10 μg/m3)2,3. Despite improvements across the US, PM2.5 remains 
above 10 μg/m3 in numerous hot-spots (e.g., near roadways)10-12. Moreover, studies show that even PM2.5 levels 
<10 μg/m3 pose CV health risks13-20. Indeed, no safe lower threshold of exposure exists13. It is thus critical to develop 
feasible and effective personal strategies to protect “vulnerable” (urban/near-roadway) and “susceptible” (elderly) 
populations at risk to the harmful effects of PM2.5.  
Emerging trials have shown that portable indoor air filtration units (AFUs) with high-efficiency particulate arrestance 
filters can reduce PM2.5 exposures by 30-50% and improve CV health endpoints (e.g., BP, vascular function)21-29. 
However, most positive studies focused on highly-polluted regions (Asia)22,23, representing only a proof-of-principle 
for Americans who typically face PM2.5 levels 5-10 times lower. Thus, we performed one of the few trials in a 
location typical of US environments, Reducing Air Pollution in Detroit Study (RAPIDS), among older adults living in 
low-income senior housing in Detroit30. Three-day use of two AFUs (bedroom and main living space) reduced 
personal-level PM2.5 exposures by 42% (15.7 to 9.1 μg/m3). This translated into a reduction in systolic BP (primary 
endpoint) by 3.2 mm Hg (95%CI -6.1, 0.2), a trend toward lower diastolic BP (-1.5 mm Hg; 95%CI 3.3, 0.2) and 
improved secondary outcomes (e.g., aortic hemodynamics). The exposure reduction was greatest during nighttime 
(10PM-8AM), accounting for 62% of the total decrease in 24-hr PM2.5 exposure31. This suggests that an AFU in the 
bedroom is a key determinant of the success of the intervention.  
Our results confirm that even low PM2.5 levels pose significant risks to CV health and that AFUs represent a 
promising preventative strategy. However, several important questions remain. Almost all prior trials (including 
RAPIDS) have been of brief duration (2-3 days). No study has addressed whether exposure reductions and health 
improvements can be sustained over more clinically relevant periods of intervention (i.e., several weeks) which are 
required to plausibly yield decreases in actual CV events. In addition, the efficacy of a novel practical approach (i.e., 
less expensive and more feasible in real-world settings) of using a single AFU only in the bedroom to focus on 
reducing nocturnal PM2.5 exposure is unknown. Finally, the mechanisms by which PM2.5 increases BP remain 
incompletely understood32. As a logical extension of our prior grant (R01NR014484), we propose in this renewal 
project (RAPIDS-2) to build upon our findings by addressing two pragmatic issues fundamentally requiring resolution 
before this field can progress from a clinical standpoint (Aims 1 & 2) and by elucidating a novel mechanism 
potentially explaining PM2.5-induced cardiometabolic abnormalities (Aim 3).  
Aim 1: Determine if long-term AFU usage provides sustained reductions in PM2.5 exposure and persistent 
improvements in cardiometabolic outcomes. We propose a randomized double-blind 2-way crossover study (AFUs 
bedroom- vs. sham filtration) in 50 adults living in a low-income senior residence impacted by roadway pollutants. 
We posit that compared to sham, AFU use long-term (4-week) periods will (1a) lower resting morning BP (primary 
outcome), (1b) reduce indoor PM2.5 and 24-hr personal PM2.5 exposures, and (1c) improve secondary health 
outcomes: 24-hr and nocturnal BP, 24-hr and nocturnal aortic hemodynamics (BP, augmentation index), and insulin 
sensitivity.  
Aim 2: Determine if nocturnal PM2.5 exposure reduction alone improves cardiometabolic outcomes. We posit that 
compared to sham, bedroom-only AFU use will (2a) lower resting morning BP. We further posit that (2c) 24-hr 
personal PM2.5 exposure and (2d) secondary health outcomes will improve – particularly nocturnal BP (a powerful 

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predictor of CV events)33-35.  
Aim 3: Demonstrate the key role of adrenal activation as a novel mechanism explaining PM2.5-induced 
cardiometabolic effects. Recent data suggest PM2.5 provokes hypothalamic-pituitary-adrenal axis (HPAA) 
activation32. We posit (3a) AFU will reduce adrenal activation (comprehensive assessment by blood steroidomic 
profiling) after 4 weeks. Steroids with glucocorticoid and mineralocorticoid activity will be shown (3b) to be 
mediators of PM2.5-induced BP changes & insulin resistance.  
PM2.5 is a leading risk factor for mortality. Our proposal, which will help validate the benefits of novel strategies to 
employ AFUs in an elderly vulnerable population living in a non-traditional setting, is directly responsive to the 
Program Announcement (PA-18-142), and is of global public health importance. Positive results would form a key 
part of the evidence base required to promote more wide-scale AFU use. In the long term, given the low cost and 
burden, AFU use could be up-scaled to help protect diverse populations across the world. 
 
RESEARCH STRATEGY  
SIGNIFICANCE  
PM2.5 is a major contributor to the global epidemic of cardiometabolic diseases.  
Fine particulate matter (< 2.5 μm, PM2.5) air pollution is largely derived from fossil fuel combustion processes1-9. 
More than 90% of the world’s population faces levels above World Health Organization Air Quality Guidelines (AQG) 
(>10 μg/m3). PM2.5 is the fifth leading global risk factor for mortality, principally due to cardiovascular (CV) events1-
4. While air quality in the US has improved, numerous hot spots remain (e.g., near roadways)10-12 such that 20% of 
Americans are exposed to PM2.5 levels above 10 μg/m3. Moreover, mounting studies show that PM2.5-induced CV 
events still occur even when levels are below AQG13-19. In two large studies of Medicare patients18,19, exposures to 
low PM2.5 levels over both the short and long term increased mortality. Individuals at greatest risk were from 
“vulnerable” (i.e., more highly-exposed) populations, such as those living in urban or near-roadway settings, as well 
as “susceptible” (i.e., those biologically predisposed to the adverse effects of exposure) adults, such as the elderly 
and minorities. Thus, we designed our prior study, Reducing Air Pollution in Detroit Study (RAPIDS), and this renewal 
to focus on protecting a vulnerable and susceptible population.  
A key mechanism underlying CV events (myocardial infarctions, strokes, heart failure) due to exposure is PM2.5-
induced blood pressure (BP) elevations4-9. In over 20 publications by our group36-56 (and in studies across the 
world)5-8 PM2.5 has proven to increase BP4,5. In a series of panel studies we have shown that exposures to ambient 
levels of PM2.5 over acute and subacute periods (1-7 days) both in lightly- (Michigan) and heavily-polluted (China) 
locations prompt clinically significant elevations in BP (2-10 mm Hg)35-41 and insulin resistance39,40. In 
epidemiological studies we and others have shown that beyond contributing to the triggering of acute CV events, the 
pro-hypertensive/diabetic responses translate into health threats of clinical importance in their own right. PM2.5 
exposure promotes acute (hospitalizations for high BP)48,49 and chronic (development of overt hypertension and 
diabetes)50-54 adverse cardiometabolic health effects4. Several mechanisms have been elucidated including 
autonomic imbalance, reduced arterial compliance, inflammation, vasoconstriction, and vascular dysfunction4. Given 
the large body of evidence4-8, both the American Heart Association (AHA)1 and European Society of Cardiology (ESC)9 
have deemed PM2.5 a risk factor for CV disease.  
Adverse cardiometabolic effects of PM2.5 may be reduced by portable indoor air filtration units (AFUs).  
National regulations have lowered PM2.5 levels over the past few decades leading to improvements in life 
expectancy in the US21. However, millions of susceptible adults remain at risk and exposed to PM2.5 levels above 
AQG2,3,12. Moreover, ambient concentrations <10 μg/m3 still pose significant health risks13-19, and additional efforts 
are urgently needed to help protect the American public to prevent the more than 88 thousand deaths per year in 
the US attributable to PM2.51-3. In a recent review of strategies21, we concluded that the most viable method is to 
specifically target “at-risk” adults for reductions in personal exposure. Americans spend 90% of their time indoors, 
with almost 70% in their own residence57. This makes relatively inexpensive (~$70) indoor AFUs a practical approach 
that fits the US population21. AFUs have proven to reduce PM2.5 exposures by 30-50% and mitigate adverse CV 

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responses (lowered BP, improved insulin sensitivity)21-29. However, notable limitations exist in prior trials. Many were 
conducted in heavily-polluted areas22,23. Almost all were brief (2-9 days) and enrolled healthy people. None evaluated 
personal-level PM2.5 exposure. This makes our recent AFU trial (RAPIDS) unique30. We evaluated: 1) an at-risk 
population (low-income elderly adults), 2) living in a typical US urban environment (Detroit), as well as 3) personal 
PM2.5 exposures. While our positive results showing a significant reduction in personal-level PM2.5 exposures and 
resting systolic BP levels by 3.2 mm Hg were encouraging, we recognize that an AFU intervention lasting 3 days still 
only represents a proof-of-principle.  
Longer-term AFU studies over more clinically relevant periods of intervention are needed.  
Several remaining scientific gaps must be addressed before authoritative medical bodies (e.g., AHA, ESC) have a 
compelling evidence base necessary to promulgate formal recommendations for use of AFUs20. Foremost is if AFUs 
can provide sustained reductions in PM2.5 exposures and persistent improvements in health outcomes over 
durations lasting longer than a few days as in most prior trials21. This question is critical because for AFU use to 
plausibly yield a reduction in actual CV events (e.g., myocardial infarctions), the health benefits will need to be 
maintained over clinically relevant periods (e.g., weeks). Possible changes in patient activities (e.g., compliance, time 
outdoors), filtration effectiveness (e.g., open windows, lower filtration efficiency) and biological factors (e.g., 
diminution of physiologic responsivity) could in theory attenuate the benefits over longer periods. The precise 
duration of intervention sufficient to provide convincing evidence that the benefits of AFUs persist over periods that 
can translate into clinical benefits is not known. We believe 4 weeks is a feasible duration that still allows for a 
crossover design yet also represents a major advancement compared to prior acute studies. If positive, we can next 
justify larger and longer-term follow-up trials.  
A practical “bed-room only” AFU strategy more adoptable to real-life scenarios needs to be evaluated.  
Most prior studies (including RAPIDS) evaluated the effect of AFUs in ≥2 rooms21. While it is logical to lower PM2.5 as 
much as possible throughout the indoor environment, many factors (e.g., multiple household rooms, variability in 
room sizes, indoor PM2.5 sources, outdoor PM2.5 penetration, and time spent in each room) may make this strategy 
untenable in most real-world settings. These factors could obviate the widespread applicability of this strategy if 
numerous AFUs are required, particularly for lower income populations. Importantly, we observed in RAPIDS that 
62% of the total exposure reduction over the 24-hr period was achieved during nighttime alone31. This is most 
obviously explained by the fact that individuals remain indoors near a bedroom AFU while sleeping. As such, we posit 
that a novel, economical and more practical approach that employs a single AFU strategically located in the bedroom 
may lower overall 24-hr PM2.5 exposure by a sufficient degree to yield significant health benefits similar to those 
achieved using a multi-room intervention. Moreover, reducing nighttime exposure has a sound physiological basis for 
why it should prove to be highly protective and beneficial for CV health. It is logical to posit that this strategy should 
yield a robust decrease in nocturnal BP, which ranks among the most powerful determinants of CV outcomes and is a 
superior predictor of morbidity/mortality than clinical and daytime BP33-35,58-62. Thus, even if the bedroom-alone AFU 
strategy fails to lower daytime resting BP (primary outcome), a reduction in nocturnal BP alone would still be of 
major clinical relevance. One prior study showed that ambient PM exposure can raise nocturnal BP63; however, no 
study has evaluated the ability of AFUs to prevent nocturnal (or 24-hour long) elevations in BP (as measured by 
ambulatory BP monitoring). Other leading researchers have endorsed this hypothesis that placing an AFU in the 
bedroom is likely a key determinant of the success of the overall intervention58.  
The mechanisms whereby PM2.5 causes cardiometabolic abnormalities require further elucidation.  
We have shown that a 2-hour exposure to high levels of concentrated PM2.5 (150 μg/m3) acutely raises BP by 
triggering autonomic imbalance44. However, the mechanisms by which far lower ambient levels of PM2.5 (5-25 
μg/m3) cause BP elevations are less clear. In our and others’ panel studies it has been consistently observed that 
subacute changes in ambient PM2.5 levels (1-5 days) cause somewhat delayed (e.g., 1-3 days later) pro-hypertensive 
responses that persist for several days following exposure4. These responses do not match what would be expected 
if they were prompted solely by hyper-acute (seconds-to-minutes) reactions mediated by autonomic pathways. 
Other potential causes for BP elevations include PM2.5-induced endothelial dysfunction and impaired arterial 
compliance4,5. However, our research suggests that changes in these outcomes represent parallel (not causal) 

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responses, as they sometimes (but not always) occur during overlapping (but not identical) periods and are thus not 
necessary responses for the genesis of BP elevations4.  
A recent study in Shanghai corroborated that AFU use for 9 days in healthy students reduces BP23. There were 
concomitant improvements in metabolomic profiles with lower circulating levels of cortisol, cortisone, epinephrine, 
adrenocorticotropic hormone (ACTH), insulin and glucose. These changes correlated with reductions in PM2.5 
exposures. In an accompanying editorial, we interpreted these results to signify that PM2.5 triggers adverse 
cardiometabolic responses via hypothalamic-pituitary-adrenal-axis (HPAA) activation (Fig. 1)32. It is an established 
physiological principle that adrenal steroids with glucocorticoid and mineralocorticoid activities can increase BP and 
impair insulin resistance. However, they typically trigger these adverse responses in a slower (hours-to-days) but 
more persistent manner32. We outlined several pathways explaining how this may occur as supported by our prior 
experiments: a systemic “stress response,” inhaled pollutants stimulating pulmonary afferents that trigger reflex 
hypothalamic activation, and inflammatory mediators (e.g., cytokines) released by pulmonary cells that spill over into 
the circulation and penetrate through CNS-permeable areas to instigate hypothalamic inflammation31. The slower 
onset and more persistent changes in BP and insulin resistance (as would be expected if mediated by HPAA 
activation) matches our prior panel study findings and the decreases in BP observed (peaking 2-3 days after PM2.5 
reductions from AFU use) in RAPIDS. The totality of evidence thus supports that a slower but more persistent 
pathway (i.e., HPAA activation) likely underlies ambient PM2.5-induced cardiometabolic changes32. While intriguing, 
the recent Shanghai findings are limited by the fact that they were derived from a post hoc analysis in people 
exposed to very high PM2.5 levels. A pre-specified, hypothesis-driven trial at more globally relevant PM2.5 
concentrations (as we herein propose) using comprehensive HPAA profiling would more conclusively help to 
establish the mechanistic role of subacute (by late-evening salivary cortisol and blood steroidomic profile) and 
chronic (by hair cortisol) HPAA activation as a causal mediator of PM2.5-induced cardiometabolic abnormalities. 
Beyond elucidating key physiological principles that further scientific knowledge, a better understanding of the 
mechanisms may help in the effort to devise further preventive strategies (beyond AFUs) and target specific 
pathways to reduce the harmful effects of PM2.5.  
 
INNOVATION  
We have a productive track record studying the cardiometabolic effects of air pollutants36-56, and will leverage our 
unique collaborative team, experience, and resources established during the initial project (R01NR014484) and build 
upon our novel findings. This trial is innovative for several reasons. (1) This will be the first study of elderly adults 
living in a non-traditional setting (a low-income senior facility) in a typical US urban location (metropolitan Detroit) 
that will evaluate the efficacy and CV benefits of AFU use to reduce personal PM2.5 exposures over a more clinically 
relevant, longer-term intervention period. (2) We recognize the importance of demonstrating that AFUs can improve 
a primary outcome (resting BP) known to be adversely impacted by PM2.5 which is also a surrogate endpoint 
unquestionably linked to serious health ramifications1,4,9. However, we will also evaluate several novel secondary 
endpoints not previously studied in an AFU trial. This will be the first study to employ the gold-standard 24-hr 
ambulatory BP technique. This novel device allows for the measurement of 24-hr and nocturnal brachial BPs, as well 
as 24-hr aortic hemodynamics (BP levels, augmentation index [AIx]). Aortic BP often differs from brachial BP in the 
elderly64. Along with 24-hr and nocturnal brachial BP, aortic BP and AIx (arterial compliance) are independent 
predictors of CV risk64-71. (3) This will be the first study to test a novel intervention (bedroom-only AFU use) which 
may prove equally effective compared to a multi-room strategy. (4) Finally, we will comprehensively evaluate the 
mediating role of subacute and chronic HPAA activation – producing glucocorticoids, mineralocorticoids, and 
potentiating steroids – as a novel mechanism explaining the cardiometabolic effects of PM2.532. We expect our 
findings will play a key role in validating the clinical benefits of practical inexpensive strategies using AFUs that at-
risk individuals living in vulnerable communities across the US can readily adopt to further reduce the CV risks of 
PM2.5.  
 
APPROACH  

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PROGRESS REPORT (July 2014 – present)  
We successfully completed the RAPIDS clinical trial protocol on schedule (R01 NR014484)21. As with all clinical trials, 
we had to await full completion prior to analysis, which has limited the number of papers for submission at this time. 
We have nonetheless been highly productive. Our main results (Specific Aim 1) are in press in a top-tier medical 
journal30 (“Publication List” #1). We also published a review on strategies to reduce PM2.5 exposures21 (“Publication 
List” #2). Our third manuscript, accepted for publication, characterizes numerous details of personal PM2.5 exposure 
reduction by AFUs31 (“Publication List” #3). Two further manuscripts are currently in preparation. Major findings of 
these manuscripts are briefly discussed in below.  
The specific aims for the original RAPIDS study were: (1) to determine whether filter-based interventions are capable 
of reducing PM2.5 exposures and thereby improve clinically-relevant intermediate CV health endpoints in a senior-
citizen facility; (2) to identify which measurement of PM2.5 – outdoor, indoor or personal – is most closely associated 
with the CV health outcomes under three different filtration scenarios in a senior-citizen residential facility; and (3) 
To determine whether filter-based intervention reduce exposures to specific outdoor sources of PM2.5 and thereby 
improve the CV health endpoints in a senior-citizen residential facility.  
Main results: We enrolled 40 nonsmoking elderly adults living a senior facility in midtown Detroit into a randomized 
double-blind crossover study with daily CV health outcomes and PM2.5 exposure measurements. There were no 
activity restrictions (e.g., window closure requirements) during the study. Participants were exposed to three blinded 
3-day-long scenarios separated by one-week washout periods: unfiltered ambient air  

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Figure 2: AFUs lowered evening-night personal PM2.5 exposures by the greatest extent. 
During night alone (10pm-8am), 62% of the total 24-hr exposure reduction occurred31.  
 
Figure 1: Multiple pathways of HPAA activation due to PM2.5 exposure 

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(sham), low-efficiency (LE) “HEPA-type”, and high-efficiency (HE) “true-HEPA” filtered air using AFUs (one in the 
bedroom and one in the main living space). The primary outcome was average resting brachial systolic BP (BpTRU: 
unattended automated mean of 5 repeats) measured the morning of all 3 days of each intervention. Secondary 
outcomes included aortic hemodynamics and pulse wave velocity (SphygomoCor) and heart rate variability. PM2.5 
exposures were measured by gravimetric analyses of filters collected over each of the 3-day interventions in each 
participant’s living room and by personal-level monitoring (pDR-1500).  
Participants were 67 ± 8 years old (38% female). Three-day personal PM2.5 exposures were reduced by AFUs from 
15.7 μg/m3 (sham) to 10.9 (LE) and 7.4 (HE) μg/m3 (p<0.05). Indoor levels in the living room were also reduced from 
17.5 (sham) to 8.4 (LE) and 7.0 (HE) μg/m3; however, they differed from personal levels, confirming the importance 
of 24-hour personal exposure monitoring to accurately characterize the success of “true” exposure reduction by in-
home AFUs, as we herein propose (Fig. 2; “Publication List” #2). Personal exposure reduction was most effective at 
night (10PM-8AM). Compared to sham, any air filtration (both LE and HE) for 3 days decreased 3-day average 
brachial systolic BP (SBP) and diastolic BP (DBP) by 3.2 mmHg (95% CI: -6.1, -0.2) and 1.5 mmHg (CI: -3.3, 0.2), 
respectively (Fig. 3; “Publication List” #1). Though quantitatively similar, BP reductions measured on each of the 3 
individual lag days during active filtration were of borderline significance. This demonstrates the key importance of 
repeating BP measurements over ≥3 days to accurately assess the benefits of AFUs (as we herein propose). It also 
suggests that longer periods of AFU use will likely provide persistent and more stable improvements in BP. The 
findings also support the use of the gold-standard 24-hr BP64-69 (as we herein propose) to provide a more sensitive 
Figure 4: AFU use and reductions in central aortic AP (augmentation pressure) and PP 
(pulse pressure)30. 
 
 

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evaluation of BP responses. Several secondary outcomes (aortic BP) also showed trends towards improvements 
during AFU use (Fig. 4). This supports that our intended use of the more sensitive technique evaluating aortic BP over 
a 24-hr period is likely to be successful and warranted.  
For Aim 3, we have completed detailed chemical analyses of outdoor PM2.5 samples, and we are now finalizing 
receptor modeling results (via Positive Matrix Factorization). Our preliminary data show contributions from outdoor 
sources including local traffic, iron-steel industry, refinery, incinerators and regional transport.  
No changes in heart rate variability or pulse wave velocity were seen in RAPIDS, suggesting that the BP reduction was 
not due to improved autonomic activity or arterial stiffness and further supporting our aim to assess HPAA activation 
as the mechanism. Finally, in post hoc analyses the 19 obese (body mass index, BMI ≥30 kg/m3) participants were 
found to have a significantly greater reduction in systolic BP from any AFU use (- 6.9 mm Hg). Given the high 
prevalence of obesity in the US (>40% in RAPIDS), these suggestive findings support our pre-specified plan to 
evaluate BMI as an effect modifier of the BP reductions in this follow-up study. Altogether, our results from RAPIDS 
support the rationale and hypotheses of this renewal proposal.  
3.3.2. STUDY DESIGN AND EXECUTION  
We will use well-validated methods with which we have extensive experience through our initial RAPIDS  
project30 (R01 NR014484) and in prior studies36-56 to characterize PM2.5 exposures and health responses. The 
rationale and design/methods of our proposed renewal trial (RAPIDS-2), primary outcome (systolic BP), study power 
and AFU intervention are well-justified by our initial project findings.30 We have also intentionally designed the trial 
to minimize risk and burden to the elderly participants. The protocol will be conducted entirely within a senior living 
facility and will evaluate clinically informative yet minimally-invasive endpoints (Fig. 5). Our design using a 
randomized double-blind cross-over trial and our method for obtaining our primary outcome (the average systolic BP 
measured 4 days in a row by unattended automated 5 repeated measurements) are intended to address NIH’s Rigor 
and Reproducibility guidelines. The trial is principally designed and powered to validate the real-world clinical 
cardiometabolic benefits of AFUs (Aims 1 and 2). While we will explore a novel mechanistic underpinning (Aim 3), we 
recognize that invasive procedures (that might provide more detailed biological understandings) are not feasible in 
this setting and could jeopardize the success of Aims 1 and 2. Thus, we designed Aim 3 to be informative but also as 
unobtrusive as possible. While our secondary outcomes have never been evaluated in an AFU trial (including 
steroidomic profiling), we have extensive experience with each endpoint and thus will have no difficulties in adapting 
them into the study protocol.  
Trial Overview  
We propose a randomized double-blind placebo-controlled (sham filtration) crossover trial comparing the 
effectiveness of bedroom-only AFU use to reduce personal PM2.5 exposures and improve cardiometabolic health 
(Fig. 5). The health benefits (primary outcome: resting BP) of both active AFU strategies will be evaluated over acute 
(4-day) and long-term (4-week) periods in 50 nonsmoking elderly adults living in a senior facility impacted by near-
roadway pollutants. The rationale for assessing the 4-day period is to corroborate the findings from RAPIDS but in a 
different, yet highly relevant  (near-roadway), environment common in the US. The rationale for the 4-week 
intervention is to demonstrate for the first time that AFUs can lower exposures and improve CV endpoints over a 
longer-term, more clinically relevant period. The rationale for the bedroom-only AFU intervention is to show that this 
novel (more practical, less expensive) approach is also an effective strategy., a participant may undergo the following 
ordering: Block 1, bedroom AFU; Block 2, bedroom- sham filtration .  
Study Participants: We will enroll n=50 participants.  
Inclusion criteria: 1) Nonsmoker, 2) ≥60 years old, 3) residing in Carpenter Place Apartments. 4) SBP>115 mm Hg 
These criteria were selected as they focus on the adverse health effects of PM2.5 on an urban/near-roadway 
(“vulnerable”) and elderly (“susceptible”) population. They are also highly responsive to the Program Announcement: 
Environmental Exposures and Health: Exploration of Non-traditional Setting (PA-18-142).  

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Exclusion criteria: 1) Active cigarette smoker 2) daily secondhand smoke exposure (self-report), 3) any CV event 
(myocardial infarction, stroke, heart failure, revascularization) in the past 3 months, 4) unstable CV condition or risk 
factor (uncontrolled diabetes, class 3-4 angina or heart failure) or any medical condition that would place the 
participant at risk from participation or jeopardize study integrity (per investigators), 5) expected overnight travel 
outside their apartment during the 14-week study period, 6) unable to provide informed consent, 7) lung disease 
requiring oxygen, 8) renal dialysis, 9) cancer receiving active treatment or chemotherapy, 10) severe uncontrolled 
high BP ≥160/100 mm Hg or SBP<115 mm Hg.11) CV medication change in the prior month. If participants are on 
medications for high BP, diabetes, or a CV condition, they will need to have stable therapy during the prior month 
with no planned changes during the study period.  
Hypertension or other stable cardiometabolic risk factors or diseases are not exclusions to this trial given their 
prevalence in the elderly. They also enhance the sensitivity to the health impacts of air pollution and are thus 
important to include in the trial to assure the real-world applicability of the findings. Finally, these factors (e.g., 
hypertension status, basal BP, diabetes) did not modify (mitigate or augment) the BP reduction provided by AFUs in 
RAPIDS. We will collect complete health and medication information during screening visits and will plan subgroup 
and effect modification analyses by these and other key clinical characteristics.  
Study location: The study will be conducted within Carpenter Place Apartments, a nonsmoking facility for low-
income seniors ≥60 years of age. The complex houses over 150 residents and is located at 3400 Carpenter Road, 
Ypsilanti, MI 48197. We selected this site because it is important to corroborate the effectiveness of an AFU 
intervention at a different location from that of our initial RAPIDS trial30. The facility is ideal for this renewal project 
(RAPIDS-2) trial because it houses low-income elderly adults (a population known to be susceptible to the health 
effects of PM2.5)1,18,19 and it is located within 150 meters of a 4-lane US highway (US-23; ~78,000 vehicles per day72). 
Each residence consists of a one-bedroom apartment (576 sqft). Given this relatively small living space, the 
apartments are ideal to test the effectiveness of AFUs (positioned in the main room and/or bedroom). We have 
obtained approval from the management of Carpenter Place to conduct RAPIDS-2 in this facility and have observed 
enthusiasm from the residents regarding participation.  
Pollutant levels: Preliminary data during Winter/Spring of 2018 demonstrate that this complex is impacted by near-
roadway air pollutants. Average outdoor PM2.5 levels were 16.6 ± 10.7 μg/m3. This is above AQGs and levels seen in 
RAPIDS in Detroit (15.7 μg/m3) where we have already shown the benefits of lowering exposure to PM2.5 using 
AFUs30. Traffic pollutant levels, including black carbon (1.3 ± 0.5 μg/m3) and ultrafine particles (10,545 ± 2,317 
particles/cc), were also relatively high.  
Recruitment: Potential participants will be recruited directly from Carpenter Place Apartments. Investigators will post 
fliers in public areas and investigators will hold “town-hall” style meetings to help disseminate study information. 
Investigators will note each resident’s status as interested, not interested, or undecided in an attempt to recruit all 
necessary subjects from this limited pool, and to assure residents are disturbed as little as possible. Fliers may be slid 
under each apartment door to reach subjects and flier information may be included in the resident newsletter. 
 
Screening Visit: Interested individuals will contact investigators and undergo screening (fasting >8 hours) in a private 
room at Carpenter Place. Information will be collected on all key demographic factors (age, race, sex), 
cardiometabolic risk factors (diagnosed hypertension, diabetes, hyperlipidemia), prior smoking history (pack years, 
when quit), and CV disease history (e.g., prior MI, stroke) as well as all medications and doses. BP and finger blood 
glucose (glucometer) will be measured. Urine dipstick will be performed to corroborate non-smoker status (i.e., no 
tobacco during past 10 days by NicAlert <100 ng/mL). Inclusion and exclusion criteria will be reviewed and the study 
will be discussed in detail with each individual. Individuals who wish to participate and who satisfy all study entry 
criteria will sign a written informed consent document and be enrolled into the trial on a rolling basis. Height and 
weight will then be measured for calculation of BMI.  
Study Execution: A private room in Carpenter Place will be allocated for all visits. Only one participant will be 
permitted in this room at any given time to protect privacy. The temperature will be maintained between 70-75 ◦F 
for all visits to limit any immediate impact on BP. The entire trial will be conducted within the apartment complex. 

Page 10 of 24 
This assures minimal risks and burden to the participants and reduces the potential impact of outdoor exposures 
(noise, temperature) immediately prior to study outcomes. Once enrolled, participants will be randomized into the 
first study block. The study consists of a 10-week, crossover trial (Fig. 5).  
Activity restrictions: Participants will be provided with an activity log-sheet to record periods of: exercise, over-night 
stays outside their residence (if any), time periods of open outdoor apartment windows, or other concerns. We will 
ask participants to sleep overnight in their bedroom at Carpenter Place during all nights of the study and to notify 
investigators (and note in their activity log) if they must spend a night offsite. If unexpected overnight travel occurs, 
this will not prohibit continued participation unless they spend a total of more than 4 days during any single study 
block offsite. In this case the participant will discontinue the study, and their data will be excluded from analysis due 
to this pre-defined protocol deviation. There are no limitations on air conditioning, heating, or indoor sources of 
pollution (e.g., cooking). All activities will be allowed except no exercise during periods of 24-hour BP and personal 
PM2.5 monitoring. We will place no restrictions on opening outside apartment windows to keep the trial as real-
world as possible. In RAPIDS we did not require any restriction in this regard and nevertheless we achieved the 
reported significant reduction in indoor/personal PM2.5 exposures and improved BP levels. Participants will be 
instructed to record in their logs any periods that windows were opened to facilitate determining its impact on AFU 
efficacy for reducing PM2.5 exposure and BP reductions in sensitivity analyses (although there were no such adverse 
impacts found in RAPIDS).  
Visit logistics: All study visits will commence at the same time for each participant between 8AM-10AM, after fasting 
for >8 hours (prior to breakfast, any caffeine) and before any medications. All BP measurements will be obtained 
prior to antihypertensive medications to obtain a “trough” level, per standard clinical trial practices70. After visits, 
participants will continue daily routines (and take any medications) without restrictions.  
Block 1:  
Week 1/day 1: An investigator will place one AFU in the bedroom of each participant’s apartment. Each AFU will be 
set to either “active mode” (i.e., a HEPA filter inside) or “sham mode” (i.e., no HEPA filter inside) in randomized 
double-blind fashion. We have documented that both modes exhibit similar noise and identical appearance. This will 
be accomplished by having a different (unblinded) investigator set the AFU modes offsite beforehand – so that 
neither the on-site investigator nor the participants will be aware of the settings during all study blocks. This offsite 
unblinded investigator will be the only team member aware of the randomization order. For the placebo 
intervention: both AFUs will be set to “sham mode”. The AFUs will remain running in the same mode for the entire 4-
week study block.  
 
Week 1/days 2-4: Participants will be asked to sleep every night in their own apartment and measure their blood 
pressure using a home BP device we provide just prior to going to bed and upon waking up. At the end of the visit on 
day 4, participants will have heart rate variability determined with a holter monitor for 6 minutes and blood pressure 
measured using the BPTru device. Subjects will be fitted with 2 portable devices: an ambulatory BP monitor and a 
personal PM2.5 monitor. At all times during the 24-hour period, they will wear the PM monitor or have it near them 
(e.g., on bedside stand while sleeping). We have demonstrated that these devices can be worn together for 24 hours 
without excessive burden38,40. During this period, participants will be instructed not to exercise.  
 
Week 1/day 5: Upon arrival the personal monitoring devices will be collected.  
 
Weeks 2-3: Participants will undertake their usual activities (except for overnight travel restrictions).  
 
Week 4: Study visit days 2-5 will be repeated as during week 1.  

Page 11 of 24 
Visit day 5 is completed and prior to eating or taking medications, participants will have blood drawn in the 
study room by an investigator. An investigator will then remove the AFUs from participants’ apartments.  
Washout period: Participants will undergo a 1 or 2-week washout period without restrictions on activities (including 
overnight travel). No AFUs will be in participant’s apartments during this time. We have shown in RAPIDS that a 1-
week washout period is adequate, with no evidence for a carryover effect from the previous intervention on 
endpoints (BP, PM2.5 exposures). There was no statistically significant effect (interaction, confounding) from the 
order of the intervention on the results30. PM2.5 exposures and BP returned to baseline after one week.  
Block 2 (crossover phase): Participants will undergo the same protocol as during Block 1, the only difference being 
that on week 1/visit day 1 of both blocks, the AFUs will be set to different modes (active vs. sham) from prior 
blocks(in randomized order).  
Retention plan: Based on our experience with RAPIDS, we do not anticipate retention problems. During weeks 2 and 
3, investigators will contact each participant at least twice per week (phone, email, or in-person) to assure continued 
participation and compliant usage of AFUs, and to address any study problems.  
Timeline: In RAPIDS, only 1/41 participants dropped out after enrollment. However, given the longer duration of this 
protocol, we intend to be realistically conservative in our estimates for RAPIDS-2. We will allow for a 10% dropout 
rate and thus plan to enroll 55 people to meet our goal of n=50 participants completing the entire study.  
 
Aim 1: Determine if long-term AFU usage provides sustained reductions in PM2.5 exposure and persistent 
improvements in cardiometabolic outcomes.  
Aim 2: Determine if nocturnal PM2.5 exposure reduction improves cardiometabolic outcomes.  
Aim 3: Demonstrate the key role of adrenal activation as a novel mechanistic pathway explaining PM2.5-induced 
cardiometabolic effects.  
 
Experimental Procedures and Protocols  
AFU intervention: We have carefully designed this study to accommodate the needs and limitations of the volunteer 
subjects and minimize changes and burdens on their lifestyle by incorporating noninvasive daily home BP testing 
while also assuring detection of outcome-exposure associations based on our previous studies. As described above in 
the Progress Report section, despite the fact that the RAPIDS protocol did not restrict subjects’ activities (e.g., 
window opening), we were able to reduce personal PM2.5 exposure and observe improved CV health outcomes. 
Thus, we will maintain the same protocol and study real-world exposure to the extent possible. Apartment central air 
conditioning and heating can be used without limitations. Participants will record in activity logs any period in which 
windows are opened. We will employ the same commercially available AFU brand (Holmes) proven in RAPIDS to 
effectively reduce indoor and personal PM2.5 exposures and lower BP among participants30. For the “gold standard” 
comparison (2-room AFU use), we will follow the same deployment protocol successfully used in RAPIDS30 and 
supported by EPA guidance and expert scientific opinions73-76. At 8AM Monday (week 1, visit day 1) of each study 
block, a blinded onsite investigator will place AFUs in each participant’s residence. One AFU each will be placed in 
both the bedroom and main living room. Each AFU will be set to the randomized mode (“active” or “sham”) per the 
description in prior sections in a randomized double-blind fashion by a different offsite investigator beforehand so 
that neither the onsite investigator nor the participant will be aware of the settings (the HEPA filter is not visible from 
the outside). In both rooms the AFU will be a Holmes HAP8650B-NU-1, designed for spaces up to 310 square feet. 
Under the “active” mode, the AFU will be fitted with a new “true HEPA” filter (Holmes HAPF600TCS), validated to 
remove 99.97% of particles at 0.3 μm in size73. Ultrafine (10-100 nm) particles (e.g., from traffic) and larger particles 
(e.g., coarse PM) are typically filtered even more effectively by HEPA filters73-76. Under the “sham” mode, a HEPA 
filter will not be installed in the AFU and there will be no significant removal of PM2.5. Each AFU will be fitted with a 
cumulative power consumption meter (Kill-A-Watt EZ) to verify continuous operation at the correct fan speed setting 
for the entire intervention period. The low noise level of the AFUs will be indistinguishable between active and sham 

Page 12 of 24 
modes. In RAPIDS, no 
participant complained 
or required the AFU to 
be stopped due to 
noise30. The AFUs will 
run in the same blinded 
mode continuously for 
the entire 4-week 
block. During the 
washout periods, the 
offsite investigator will 
remove or install the HEPA filters in the AFUs prior to starting the next block. The HEPA filters are rated to be 
effective for the entire 8 weeks of active usage and will not need to be replaced.  
Protocols for cardiometabolic health endpoints  
Home BP: This BP measurement will be the primary outcome (Table 1). The rationale is that high BP is a well-
established predictor of CV risk68-71, the leading risk factor for global mortality3, increases due to short-term PM2.5 
exposure5-8,36-56, and was shown by our RAPIDS study30 to be reduced by AFUs. Unattended automated BP more 
accurately reflects 24-hour BP, is less impacted by variability and the white coat effect and is superior to the standard 
technique as a predictor of hypertensive complications71. The repeat-measured morning BP average using the BpTRU 
device was the primary outcome in RAPIDS30, thus it is important to use this same method in this renewal project. 
Methods: Guidelines for BP measurement will be meticulously followed (e.g., no caffeine, exercise >1 hr prior)70. The 
BpTRU device will be located in a quiet room where participants will have seated BP measured71. The proper cuff 
size will be fitted on their upper right arm and participants will rest seated with their feet uncrossed on floor and 
their arm supported at midsternal level for 5 minutes. A first BP will be determined to assure proper monitor 
function. Afterward, personnel will leave the room and the BpTRU will measure 5 automated unattended BP readings 
(1-min intervals) with the participant alone. The average of these 5 unattended BP levels and heart rates will be 
recorded as the endpoint for each visit. The primary outcome is average systolic BP (determined as above) obtained 
over 4 consecutive (Tue-Fri) mornings (Fig. 5). The 4-day average (not 3-day as in RAPIDS) will be used because the 
results showed that the BP reduction tended to become more consistent with increasing time of filtration. This will 
improve the stability of BP levels and increase the power for detecting changes in the primary outcome30. The 4-day 
average of unattended fully-automated 5-repeated BPs is a rigorous and repeatable outcome. BP will be 
determined fasting in the morning before participants leave the residence and prior to other factors potentially 
altering BP (e.g., noise, traffic, activity, outdoor temperature). This is a uniquely powerful method to capture an 
effect of any intervention (i.e., AFU) on lowering BP compared to using conventional clinic-based methods as done 
in other trials21-29. This explains our unparalleled capability to detect a BP-lowering effect of AFU use (i.e., even a 
small - yet clinically significant - decrease in systolic BP by ~3 mm Hg as in RAPIDS)30.  
24-hour BP and aortic hemodynamics: We have extensive experience with and will use the SphygmoCor XCEL PWA 
system which non-invasively measures upper arm BP and central aortic hemodynamics over a 24- hour period. These 
endpoints will all be considered secondary study outcomes. The rationale is that aortic BP levels differ from arm 
levels depending on a variety of factors (e.g., height, age, heart rate, arterial stiffness). They are validated superior 
predictors of CV target organ damage and future CV events64-67. Aortic BP levels also change in response to 
interventions (e.g., medications) and possibly to PM2.5 exposures discordant from those detected by traditional arm 
BP measurement. Hence, measuring aortic hemodynamic responses to AFU intervention will provide novel insight 
into the totality of hemodynamic responses induced by PM2.5 exposures. The device calculates aortic BPs (systolic, 
pulse pressure) and hemodynamics: augmentation pressure and index (AIx@75), a metric of arterial pressure wave 
reflection from the periphery back to the aorta and left ventricular load adjusted for a heart rate at 75 beats/min), 
and coronary perfusion index (CPI)64-67. These parameters are calculated by pulse wave analyses (PWA) of arterial 
waveforms recorded from a specialized upper arm cuff of an Oscar-2 (SunTech Medical) 24-hour ambulatory BP 
monitor by a mathematical generalized transfer function. PWA has been used in hundreds of studies64-67. The device 
will be used to determine brachial BP and aortic hemodynamics every 30 minutes over a full 24-hour period. The 
Table 1: List of Study Endpoints 
Health Endpoints 
Endpoint designation 
Unattended automated systolic BP 
4-day average (Tues-Fri) in weeks 1 and 4 
Primary study outcome (Aims 1a, 2a/2b) 
Study is a priori powered for this endpoint 
24-hour BP levels & aortic hemodynamics 
Secondary endpoints (Aims 1c & 2d) 
Insulin sensitivity (HOMA-IR) 
Secondary endpoint (Aims 1c & 2d) 
Adrenal steroid panel (blood) 
Secondary mechanistic endpoints (Aims 3a/3b) 
Exposure Endpoints 
 
24-hr personal PM2.5 (filter-gravimetric mass) 
Primary exposure outcome (Aims 1b, 2c) 
Daily indoor PM2.5 
Primary exposure outcome (Aims 1b) 
Black carbon, hourly personal PM2.5 levels 
Secondary exposure endpoints 

Page 13 of 24 
rationale is that 24-hour BP levels are the “gold standard” endpoint most predictive of CV risk60,68,69. They can change 
discordantly (e.g., white coat or masked high BP) from resting seated values60. Finally, nocturnal BP is important to 
characterize. In RAPIDS, AFU use reduced nighttime PM2.5 exposures by the greatest extent because an AFU was 
situated in each participant’s bedroom (Fig. 2). Given the robust prognostic value of nocturnal BP63, we will also 
explicitly determine the impact of AFU use on reducing PM2.5-mediated nocturnal BP elevations. Methods: We will 
follow guidelines for 24-hour BP monitoring69 and all manuals for the SphygmoCor XCEL 
(http://atcormedical.com/healthcare-professionals/). The appropriate size cuff will be fitted on the right upper arm 
of participants. This cuff is connected to the BP monitor (Oscar-2) worn on a strap. The monitor will record BP every 
30 minutes for a 24-hr period. Subjects will be instructed to have their right arm resting by the side of their body 
during each BP measurement. Instructions for troubleshooting (e.g., loose cuff) will be provided69. Participants will 
record the times they went to bed and awoke to identify nocturnal periods. The data from the Oscar-2 monitor will 
be analyzed by the SphygmoCor system. Outcomes: 24-hr, daytime and nighttime averages of brachial 
systolic/diastolic BP, pulse pressure, and heart rates; and aortic hemodynamics (systolic BP, pulse pressure, 
augmentation pressure, AIx@75, and CPI).  
Protocols for exposure monitoring  
Indoor exposure monitoring: An indoor PM2.5 sampler will be positioned in the main room at the furthest point away 
from the AFU with samples being collected onto Teflon filter media using Teflon-coated aluminum cyclone sample 
inlets at a nominal flow rate of 16.7 L/min. This sampler will use pump systems of a type  
designed and used for previous studies30. These pump systems use acoustically-insulated wood cases designed for 
operation in home environments, minimizing pump noise. Filter samples will be collected from exposure periods 
starting at 8 AM on visit day 1 until 8 AM on visit day 5 during weeks 1 and 4 of each study block. For the entire 
duration of each block (including weeks 2-3), an indoor PM2.5 air pollution sensor (PurpleAir sensor; PA-II-SD) will be 
used to measure continuous PM2.5 concentrations. The PurpleAir is a low-cost, light-scattering-based PM sensor and 
is currently in widespread use77. In order to ensure that the sensor performance is equivalent to the gravimetric 
federal reference method, a correction factor will be calculated by comparing sensor data against gravimetric filter 
measurements from the indoor sampler described above. The filter samples will also allow for particle 
characterization/source apportionment. In addition, an aethalometer (MicroAeth AE 51, Aethlabs) – used to 
continuously measure black carbon concentrations, provide data logging and a continuous readout – will be located 
near the PurpleAir sensor. Rationale: To determine indoor integrated 4-day, as well as daily, indoor PM2.5 and black 
carbon (traffic particles) during the period of health outcomes.  
Personal exposure monitoring: During each 24-hr period of personal monitoring, participants will wear (on a belt or 
strap) a small (2 lbs) battery-powered personal particulate monitor (Thermo Scientific pDR-1500). This scientifically-
validated device provides time-stamped continuous data storage of both ambient temperature and PM2.5 
exposures. While time frames as brief as 5 minutes can be analyzed by the continuous data collection, we plan to 
evaluate 60-min exposure widows as in our prior study (Fig. 2). Rationale: We employed this device in RAPIDS and 
demonstrated the importance of characterizing time-resolved reductions in personal PM2.5 exposures, which 
differed from indoor PM2.5 levels due to variations in daily activity. The personal particulate monitors will be 
provided to the participants after visit 4 is completed and will be worn as much as possible for the ensuing 24 hours 
both indoors and outdoors. While sleeping, monitors will be placed on a nearby nightstand. Participants may also 
remove the monitor during the daytime for certain activities (e.g., showering); however, they will be instructed to 
keep it within close proximity. The monitor has adequate battery power to provide 24 hours of continuous 
monitoring. The pDR-1500 also collects sampled particles onto 37-mm Teflon filters for gravimetric and chemical 
analyses of PM2.5. Continuous PM2.5 data will be validated by comparing results to 24-hr integrated mass values 
obtained by “gold-standard” gravimetric measurements of filters. Using continuous exposure windows in addition to 
24-hr filter-based measurements will allow for a shorter time frame resolution of intra-day exposures and for 
characterizing hourly exposure reductions achieved by the AFU (Fig. 2).  
Activity log: During each 24-hour period of personal monitoring, participants will be asked to keep a log of specific 
activities: sleep/awake time, outdoor windows open, time outdoors, and time in traffic. They will also keep a log 
during the entire study to record: open window times, exercise, nights spent outside their residence.  

P a g e 1 4  of 2 4  
Filt er a n alysis : S a m pl e h a n dli n g, pr oc essi n g, a n d a n alysis will t a k e pl ac e i n a Cl ass 1 0 0 ultr acl e a n r o o m at t h e 
Mic hi g a n St at e U niv ersity Ex p os ur e Sci e nc e L a b or at ory. Gr avi m etric d et er mi n ati o ns of P M 2. 5 m ass will b e m a d e 
usi n g a micr o b al a nc e ( X P 6 U D 5, M ettl er T ol e d o) i n a t e m p/ h u mi dity -c o ntr oll e d r o o m as d escri b e d els e w h er e 3 0, 3 1.  
Pr ot oc ols f or bl o o d o utc o m es  
Bl o o d dr a ws c oll ecti o n: O n w e ek 4/visit d ay 5 ( Bl oc ks 1 -3) aft er B P m e as ur e m e nt, a n ex p eri e nc e d i nv esti g at or will 
dr a w f asti n g bl o o d fr o m t h e p artici p a nt’s a nt ec u bit al f oss a usi n g cl e a n u ni v ers al pr ec a uti o ns. W e will dr a w 1 0 ml of 
bl o o d e ac h ti m e, w hic h will als o all o w f or st or e d  ali q u ots f or p ost h oc st u di es. W e will o bt ai n bl o o d f or st er oi d o mics 
pr ofili n g at t h e d esi g n at e d ti m e p oi nts fr o m as m a ny p artici p a nts as p ossi bl e. Missi n g a ny bl o o d c oll ecti o n m a y 
w e a k e n o ur fi n al p o w er t o m e et ai m 3; h o w e v er, it will n ot i m p act eli gi bilit y f or p artici p a nts t o r e m ai n i n t h e st u dy as 
it will n ot a dv ers el y aff ect t h e m ai n st u dy o bj ecti v es ( Ai ms 1 a n d 2).  
C o m pr e h e nsiv e st er oi d o mic pr ofili n g: T h e H P A A is hi g hl y r es p o nsi v e t o str ess ors s uc h as air p oll uti o n, as w e h er ei n 
hy p ot h esiz e. T h e r ati o n al e f or f oc usi n g o n H P A A acti v ati o n as a c e ntr al m ec h a nis m of P M 2. 5-i n d uc e d 
c ar di o m et a b olic eff ects h as b e e n a d dr ess e d ( Fi g. 1) 3 2. W e will m e as ur e A C T H l e v els ( a m etric of c e ntr al n erv o us 
s yst e m hy p ot h al a mic/ pit uit ar y acti v ati o n) by t h e M D R C cli nic al l a b or at or y. Dr. Ric h ar d A uc h us h as p erf or m e d 
ext e nsiv e w or k t o d e v el o p c o m pr e h e nsiv e st er oi d pr ofili n g usi n g li q ui d c hr o m at o gr a p hy -t a n d e m m ass s p ectr o m etry 
(L C-M S/ M S)
7 8 -8 7. B y si m ult a n e o usl y m e as uri n g m ulti pl e st er oi ds acr oss s e v er al a dr e n al p at h w ays, w e c a n i d e ntif y 
p att er ns a n d bi o m ar k ers f or str ess -r es p o ns es, i ncl u di n g al d ost er o n e8 7, st er oi d s ulf at es a n d 1 1-oxy a n dr o g e ns as 
bi o m ark ers of ac ut e a n d c hr o nic H P A A activ ati o n. A m o n g t h e a dv a nt a g es of L C -M S/ M S is t h e c a p acit y t o i nt err o g at e 
m ulti pl e a dr e n al st er oi ds, i ncl u di n g mi n er al oc ortic oi ds, c ortis ol, a n d 1 1 -ox y g e n at e d st er oi ds ( glyc er r h eti nic aci d-li k e 
f act ors)8 6 t h at i n hi bit 1 1 β-hy dr oxyst er oi d d e hy dr o g e n as es a n d t h us p ot e nti at e t h e hy p ert e nsi v e eff ect of c ortis ol. 
O ur u ni q u e L C -M S/ M S m et h o d all o ws us t o u nc ov er t h e f ull ext e nt of a dr e n al p at h w a y activ ati o n c o ntri b uti n g t o 
hy p ert e nsi o n vi a m ulti pl e m ec h a nis ms wit h u n pr ec e d e nt e d bi oc h e mic al s e nsitivit y a n d s p ecificit y fr o m a  s m all bl o o d 
s a m pl e ( < 0. 2 5 mL of s er u m) a n d m e as ur es u p t o 3 5 st er oi ds ( T a bl e 2). I n t his p a n el ar e m ulti pl e p ar e nt st er oi ds, 
hy bri d st er oi ds a n d st er oi d pr ec urs ors t h at p oss ess gl uc oc ortic oi d a n d mi n er al oc ortic oi d acti vit y. Sy nt h esis a n d 
r el e as e of all or s o m e of t h es e st er oi ds c a n i ncr e as e d u e t o str ess r es p o ns es ( m ulti pl e p ot e nti al p at h w a ys elicit e d by 
P M 2. 5 ex p os ur e) 3 2 a n d pl a y a k e y m ec h a nistic r ol e i n pr o m oti n g b ot h pr o -hy p ert e nsi v e r es p o ns es a n d m et a b olic 
i ns uli n r esist a nc e3 2. M et h o ds: Ali q u ot e d s er u m s a m pl es will b e st or e d i n a -8 0° C fr e ez er f or a n n u al b atc h e d a n al ys es. 
F or st er oi d a n al ysis, s er u m s a m pl es ( 0. 1 mL) ar e mix e d wit h i nt er n al st a n d ar ds a n d c oll ect e d vi a s u p p ort e d -li q ui d 
extr acti o n, r es olv e d by 2 -di m e nsi o n al c hr o m at o gr a p hy ( A gil e nt 1 2 6 0 a n d 1 2 9 0 bi n ar y p u m p syst e ms), a n d m e as ur e d 
usi n g m ulti pl e r e acti o n m o nit ori n g wit h a n A gil e nt 6 4 9 5 tri pl e q u a dr u p ol e L C -M S/ M S o p er ati n g i n p ositi v e 
el ectr os pr ay i o niz ati o n m o d e as d escri b e d 7 9 -8 4. T h e D elt a-5/ 5 α -P a n el is a n al yz e d as oxi m e d eriv ativ es, a n d st er oi d 
s ulf at es ar e a n al yz e d i n n e g ati v e i o n m o d e 7 9, 8 3. C ortis ol i n s aliv a a n d h air is extr act e d wit h m et h a n ol a n d m e as ur e d as 
a b o v e 8 5. T h us, w e will p erf or m a c o m pr e h e nsi v e ass ess m e nt of H P A A acti vit y, a n d t h e b e n efits of A F U us a g e, 
acr oss s e v er al bi ol o gic all y i m p ort a nt ti m esc al es. T his i ncl u d es a disr u pti o n i n di ur n al r h yt h m w hic h al o n e c a n c a us e 
a d v ers e eff ects ( 1 1 P M s ali v a c ortis ol), as w ell as s u b ac ut e H P A A (s er u m A C T H a n d st er oi d o mics p a n el) a n d c hr o nic 
H P A A acti v ati o n ( h air c ortis ol) i n d uc e d b y P M 2. 5.   
T a bl e 2. St er oi d p a n els usi n g L C -M S/ M S  
D elt a -4/ Estr o g e ns P a n el 
( 0. 1 mL)  
D elt a -4/ Estr o g e ns P a n el 
( 0. 1 mL)  
D elt a -5/ 5 - P a n el ( 0. 1 mL)  St er oi d S ulf at e P a n el ( 0. 0 1 
mL)  
C ortis ol Pr ec urs ors  
•  
Pr o g est er o n e  
•  
1 1 O H -Pr o g est er o n e  
•  
1 6 O H -Pr o g est er o n e  
•  
1 7 O H -Pr o g est er o n e  
•  
1 1 -D e ox yc ortis ol  
•  
2 1 -D e ox yc ortis ol  
C ortis ol, C ortis o n e, & 
Hy bri d St er oi ds  
•  
C ortis ol *  
•  
C ortis o n e *  
•  
1 8 O H -C ortis ol *  
•  
1 8 -ox o -C ortis ol *  
A n dr o g e ns & Pr ec urs ors  
•  
A n dr ost e n di o n e  
•  
Pr e g n e n ol o n e  
•  
1 7 O H -Pr e g n e n ol o n e  
•  
D e hy dr o e pi a n dr ost er o
n e  
•  
All o pr e g n a n ol o n e  
•  
5 -Pr e g n a n e - 3, 1 7-
di ol -2 0 -o n e  
•  
A n dr ost er o n e  
•  
Di hy dr ot est ost er o n e  
•  Pr e g n e n ol o n e S ulf at e  
•  1 7 O H -Pr e g n e n ol o n e 
S ulf at e  
•  D e hy dr o e pi a n dr ost er
o n e S ulf at e  
•  5- A n dr ost e n e di ol 
S ulf at e  
•  A n dr ost er o n e S ulf at e  

Page 15 of 24 
Mineralocorticoids/ 
Precursors  
• 
11-
Deoxycorticosterone*  
• 
Corticosterone*  
• 
18OH-Corticosterone*  
• 
Aldosterone*  
• 
Estrogens  
• 
Estrone  
• 
Estradiol  
• 
Testosterone  
• 
11OH-
Androstenedione  
• 
11Keto-
Androstenedione  
• 
11OH-Testosterone  
• 
11Keto-Testosterone  
• Etiocholanolone 
Sulfate  
 
Bio-banked blood: We will store 0.5-ml aliquots of serum and plasma at the end of each study block. We have access 
to a -80°C freezer with alarms and backup power in our research room at the University of Michigan Cardiovascular 
Medicine outpatient clinical facility at Domino’s Farms Lobby A. This will allow for post hoc analyses of many possible 
biomarkers after study completion depending upon the nature of our results.  
Study Pitfalls and Remediation Plans  
We do not anticipate difficulties successfully completing this trial or utilizing the methods proposed as they have all 
been performed in our laboratories and many have been conducted in our previous clinical trials (e.g., RAPIDS). It will 
be critical to maintain robust recruitment and retention of subjects. We plan to further reinforce mutually beneficial 
relationships that have already been established with residents and facility staff and address concerns about the 
study on an ongoing basis (e.g., townhall meetings). We will adopt and modify the study (as long as it does not 
compromise the science) if deemed required by community feedback during the start-up period in year 1 and during 
the study if such a need arises. Other pitfalls are described in individual subsections.  
Outreach Activities and Knowledge Dissemination  
A social ecological approach88 will be used to translate the findings of the study into health-promoting actions that 
can be taken by older adults, family caregivers, housing managers, health care providers, and policy makers to reduce 
the health risks of exposure to air pollution in congregate housing for the elderly. Common values of community-
based health promotion include:  
• 
Stakeholder engagement in the design and evaluation of translation strategies89,90  
• 
A comprehensive evaluation of process, implementation, and sustainability91  
• 
A dissemination plan90  
Evaluation strategies applied to the health education materials and methods will include process evaluation, 
assessment of short term learning outcomes, and a six-month follow-up on the extent of adoption and maintenance 
of behavioral or environmental changes among selected housing communities. Evaluation criteria for selected target 
audiences (housing managers; community-based network) will address standards of utility, feasibility, propriety, and 
accuracy (fidelity)90. The study team will:  
1. Consult with study participants and key stakeholders throughout the study to help develop the strategies and 
media for educating older adults and providers of housing for the elderly.  
2. Conduct tailored, one-to-one educational sessions with study participants to share results and implications, 
and to develop educational materials and methods.  
3. Design and conduct communications to address potential mobility, cognitive, and sensory limitations of older 
adults (e.g., access to group meetings; impaired vision and hearing), and health literacy.  
4. Develop and evaluate fact sheets in cooperation with the Residents' Council and Activities coordinators for 
distribution through existing channels (e.g., meetings, flyers).  

Page 16 of 24 
5. Schedule meetings for presentations by study team members89 to the residents, staff and key associates.  
6. Utilize the network of community-based organizations and advocacy groups92 to reach the larger population 
of managers of senior housing communities, health care providers and policy makers via presentations at 
professional meetings. Key dissemination networks include marketing and networking trade meetings of 
senior housing providers; the Area Agencies on Aging, and the Michigan Association of Homes and Services 
to the Aging.  
7. Disseminate findings for broader application by health professionals through channels of peer-reviewed 
publications and presentations at conferences on aging.  
 
Statistical Analyses and Data Management  
Sample size, power considerations, and statistical analysis plans are provided in full in the Study Record: the PHS 
Human Subjects and Clinical Trials Information document.  
Project Management and Schedule  
As described in the multiple PI leadership plan, Drs. Brook and Morishita together will provide oversight of the entire 
project. Since the proposed research is interdisciplinary and involves multiple schools/departments, a governance 
structure will be implemented in order to ensure effective management and coordination. The proposed research 
will follow a work plan that will meet the milestones shown in the “Study Timeline” attached to the Study Record: the 
PHS Human Subjects and Clinical Trials Information document. We will hold bi-monthly general project meetings 
involving all staff and investigators to present the latest data and to coordinate study logistics and analysis. The team 
of investigators on this proposal is well-poised to integrate their various disciplines and ensure a high probability of 
success for accomplishing the proposed specific aims. 
 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS 
Study Power and Analysis Plans:  
With 50 subjects randomized to blocks 2 (“bedroom alone AFU”), and (“control”) in a random sequence, we 
anticipate adequate power using our proposed cross-over study design for observing significant reductions in 
average systolic BP (primary endpoint). With the repeated BP measurements collected in this cross-over design, we 
will do paired analysis for power calculations, since each subject can serve as their own control given sufficient 
washout periods and because we have a prori pre-specified the group comparison hypothesis for each aim clearly 
beforehand. We will be able to achieve 90.3% power in Aim 1a for detecting a 3 mm Hg in mean systolic BP 
difference comparing the “bedroom AFU” to the “control” group  at both the acute (4-day) and chronic (4-week) time 
periods, assuming that the standard deviation (SD) of systolic BP is 8.2 mm Hg. The detectable mean difference of 
systolic BP between “bedroom FU” vs “control” with the corresponding statistical powers that we can achieve is as 
follows: 
Detectable mean BP difference between 
“active intervention” vs. “control” (Hg) 
2.4 mm  
2.6 
mm  
2.8 
mm  
3 mm 
Hg 
3.2 mm  
3.4 mm  
Statistical Power 
75.4% 
81.9% 
86.1% 
90.3% 
93.6% 
95.4% 
 
Within the range of the SD of systolic BP measurements from 6.2 to 9.8, the statistical power for aim 1a we can 
achieve ranges between 72.1% and 97.5% to detect a 3 mm Hg change in mean systolic BP. Similar powers will be 
achieved for Aim 2a as well, comparing “bedroom alone AFU” (block 2) versus “control” (block 3) group. In our 
previous AFU study (RAPIDS, see: Progress Report) we observed a 3.2 mm Hg reduction in systolic BP by active versus 
control intervention. Therefore, the pre-specified effect size (3 mm Hg systolic BP reduction) for which we have 
designed this renewal proposal to have adequate power to observe is well justified. The study is a priori designed and 

Page 17 of 24 
powered to determine the pre-specified outcomes in aims 1a, 2a, and 2b. Other comparisons evaluated in aims 1b 
(24-hr personal-PM2.5 exposures); 1c (secondary health endpoints); 2c (24-hr personal-PM2.5 exposures); 2d 
(secondary health endpoints); as well as in aims 3a (differences in steroid levels between blocks) and 3b (mediation 
analyses) are all deemed secondary study outcomes. We will collect the data as proposed and analyze the results 
using the same statistical methods as outlined for the primary study outcomes. However, since these are secondary 
endpoints only (i.e., hypothesis generating results), we will analyze the data for trends and for “nominal” statistical 
significance.  We will also not perform a priori power calculations for all secondary endpoints.  
Both the primary endpoints and the secondary measures such as diastolic BP, 24-hour BP levels and HOMA-IR will be 
reported as mean (median) ± SD (IQR). One-sample paired t-test will be performed to compare each outcome 
variable between active intervention group and the control group. In case there are extreme values or that the 
variables are not normally distributed, Wilcoxon signed-rank test, a non-parametric test for comparing repeated 
measurements’ mean ranks, will be performed for robustness1. When the distribution of an outcome variable is not 
anticipated to follow a normal distribution, we will transform it to meet normality assumptions as best as possible 
before we fit regression models to adjust for confounders (age, sex, BMI, dose of BP tablets, type of BP control 
medication). Non-parametric correlation coefficients, such as Kendall’s tau7 or spearman’s rho8, between the 
principal outcomes and exposure measures will be calculated at each time point. Such measures provide robust 
inferences. Multiple hypothesis testing will be adjusted through the Holm’s procedure9. 
More specifically, to adjust for other confounders, we will use linear mixed models2-4 to evaluate the effect of 
interventions on the outcomes (e.g. BP levels) adjusting for confounders. The mixed models will fully represent the 
structure of the data by taking into account the within-subject correlations of the outcome variables measured 
repeatedly at different time points over the study design. We will also evaluate the impact of other variables that 
may impact the results. To be more specific, a mixed effect model with a random intercept and a random slope2-4 will 
be fit for the longitudinal measurement of the outcomes: Yij = a0 + a1tij + a2𝐼𝐼(Bij = 1) + a3𝐼𝐼(Bij = 2) + a4Xij +
bi0 + bi1tij + eij, where Yij denotes the repeated average BP outcomes for subject i at block j, Bij denotes what 
intervention is subject i randomized to at occasion j, and Xij are the other covariates that would be controlled in the 
model (age, sex, BMI, dose of BP tablets, type of BP control medication).  So in Aim 1a, we hypothesize a2 ≠0 and 
test for H0 ：a2＝0, and in Aim 2a, we hypothesize a3 ≠0 and test for H0 ：a3＝0 , and in Aim 2b, we are testing 
a2＝a3. Similar models will be fit for other secondary outcome variables, such as ABPM, HOMA-IR, etc. When it 
happens some outcome variables have inflated zero measures, we will adopt zero-inflated regression models or a 
two-part mixture regression (tobit) model5,6 on the outcome changes between “active intervention” vs. “control”.  
 
Other statistical considerations:  
Missing data: We will try to avoid missing data when collecting data through the study design. When missing data 
happens, we will test if the data are missing completely at random (MCAR). If it is MCAR or the amount of missing 
data is less than 10%, analysis will be performed based on the complete data. If the amount of missing data is more 
than 10%, multiple imputations (5-10 times) will be utilized through mi package in R10. The analysis will be performed 
on each imputed data set, and later merged through mitools package in R11. Multiple imputations are based upon the 
missing-at-random (MAR) assumption12. Sensitivity analysis13 will be examined when inferences depart from the MAR 
assumption. 
Data Monitoring and Coordination: The Data Coordinating Center (DCC) at U-M will ensure the proposed research 
collect and manage data in a confidential and secure manner. U-M DCC will review data to control its data quality 
and integrity, organize data using uniform formats and vocabulary to facilitate analysis and document protocols for 
collecting, filtering and formatting the data. All files stored at the U-M database will be managed by Dr. Wang as was 
done previously for other successful grants. The database provides a central location for disseminating and retrieving 
study information, including codebooks, common data element definitions, synopses of studies, data collection forms 
(if necessary), and analyses in progress. We will create and maintain a webpage for any distributed software 
packages, with detailed documentation as well as contact information. We will also archive all relevant publications 
from the proposed research by following the law of copyrights.  

Page 18 of 24 
Quality Management Plan: All study outcomes have been performed by our research team in prior studies and are 
well-established research endpoints using in hundreds of prior experiments. We will follow the developed protocols 
used in our prior experiments and established manual of operations (Dr. Brook, available on request). All proposed 
blood outcomes will be measured in accredited clinical laboratories. We will plan regular (quarterly) group meetings 
during the trial to identify and mitigate any unanticipated study pitfalls that develop during the trial. 
 
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Page 21 of 24 
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50. Brook RD, Kousha T. Air Pollution and Emergency Department Visits for Hypertension in Edmonton and 
Calgary, Canada: A Case-Crossover Study. Am J Hypertens 2015;28:1121-6.  
51. Coogan PF, White LF, Jerrett M, Brook RD, Su GC, Seto E, Burnett RT, Palmar JR, Rosenberg L. Air 
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10.  
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Jerrett M. Long term exposure to NO2 and diabetes incidence in the Black Women’s Health Study. Environ 
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Long-Term Exposure to NO2 and Ozone and Hypertension Incidence in the Black Women's Health Study. 
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concentrations. Build Environ 2017; 126: 266-275.  
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conventional blood pressure medications improves management of hypertension and reduces 
cardiovascular and stroke risks. Hypertens Res 2016; 39: 277-92.  

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63. Tsai DH, Riediker M, Wuerzner G, Maillard M, Marques-Vidal P, Paccaud F, Vollenweider P, Burnier M, 
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64. Hashimoto J. Central hemodynamics for management of atherosclerotic diseases. J Atheroscler 
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Protocol Modifications to the RAPIDS-YPSI Clinical Trial 
In light of COVID-19 and the high-risk nature of the study population (elderly adults >60-65 
years of age living in a low-income senior home and many with pre-existing high-risk 
conditions), our objective is to modify the protocol to eliminate all direct in-person contact 
between study research personnel and participants.  
All interactions will be via email, mail, and telephone and can be accomplished without 
detrimental impact to the study primary objective. Several secondary aims that involve more 
complicated endpoints, including 24-hour ambulatory blood pressure (BP) and blood draws, that 
necessitate direct subject contact will be removed from the protocol. 
Summary of changes: 
Visits/participant interactions: All communication with subjects, including study enrollment and 
informed consent and all study visits, will be conducted through remote visits via the telephone.  
Endpoints: Remove blood draws, heart rate variability, BpTRU BP measurements, WatchPAT, 
and 24-hour ambulatory BP monitoring endpoints. Continue home BP monitoring using the 
same protocol as original trial. However, we will change BP measurements to be performed 
twice per day (AM+PM) of days 2-5 (Tues – Fri) of week 1 and week 4 of both study blocks. 
PM2.5 monitoring: Continue with in-room (PurpleAir) monitoring per original study design for full 
4 weeks of both study blocks. We will use personal-PM2.5 monitoring (pDR-1500); however, it 
will not occur during week-1 but only at end of week-4 for both study blocks (once per study 
block). 
Air filter intervention: No changes. We will continue the protocol using portable air cleaners 
(PACs) in the bedroom without change for 4 weeks in active and sham conditions.  
Study flow: All study devices (home BP monitors, pDR-1500 personal PM2.5 monitors, 
PurpleAir in-room PM monitors, PACs) will be cleaned and sterilized (per COVID-19 protocols) 
before they are provided to each subject. The devices will be provided to the subjects without 
any contact with the research team members. At the appropriate time in the protocol, the 
subjects will be notified by phone and the equipment and instructions for usage and set up will 
dropped off for the participants at their doorway at a pre-arranged time.  
 
Advanced Covid Restrictions: 
Study staff will not enter residences or have any personal contact with any subject or potential 
subject. In the event of elevated Covid concerns the study staff will not enter hallways and will 
deliver equipment to the front doorway to Carpenter Place. In cases where the subject agrees, 
the study staff may enter apartments to set up the equipment. Our 2021 experience has proven 
that some subjects have physical limitations to moving the equipment (frailty, walkers and small 
apartments, etc)  
 
Study Protocol: 

Recruitment: Advertisements and recruitment will be done without personal contact. We will 
provide fliers for recruitment with a contact number to the research coordinator for interested 
residents. The staff members who work and are present at Carpenter Place will post the fliers in 
Carpenter place bulletin boards and notify residents that the study is active and has been 
modified to be simpler and to eliminate any contact with the research team. Advertisements will 
continue in the residential newsletter. 
Enrollment: Interested residents will call the study research coordinator. Study 
inclusion/exclusion criteria will be reviewed (no changes). All subjects must attest to be non-
smokers living in non-smoking household. Consents will be left at the office or subjects will be 
emailed or mailed the consent form and subjects will be given ample time to review the consent 
and consider their participation independently. Study team will review the consent document 
over the telephone just as they would during a face to face meeting.  Signature will be obtained 
on the consent form and provided to the study staff via mail or left for pickup by study staff in the 
same manner as equipment is dropped off with no contact. This cohort is unlikely to benefit from 
electronic consenting procedures based on the lack of internet access, the poor internet 
provided by Carpenter Place, the willingness of the participants, and the added burden it would 
place on this older population of subjects participating in a low risk study. 
 
Study Flow: The modified trial will be conducted per the original design except for no face-to-
face interactions between research staff and subjects and the protocol has been simplified. 
Subjects will be assigned a research ID number. They will be randomized in a blinded fashion to 
either active vs sham PAC use for intervention block 1. After completing block 1, they will 
washout for 1 week and then crossover to block 2 and undergo the same trial randomized to the 
alternative PAC intervention (sham vs active). 
BLOCK 1 (2) 
 
Week 1  
(6) 
Wk 2-3 
(7-8) 
Week 4 
(9) 
Washout 
 
Day 
 
Day 
 
1 
M 
2 
T 
3 
W 
4 
Th 
5 
F 
 
1 
M 
2 
T 
3 
W 
4 
Th 
5 
F 
PAC INTERVENTION (2 limb x-over) 
Randomized PAC 
↓ 
x 
x 
x 
x 
----------> 
x 
x 
x 
x 
↑ 
TESTING 
Home BP: AM  
 
 
 
 
 
 
 
 
 
 
 
                   PM  
 
 
 
 
 
 
 
 
 
 
 
PM MONITORING 
In-room PM 
(Purple Air) 
↓ 
x 
x 
x 
x 
----------> 
x 
x 
x 
x 
↑ 
Personal PM 
(PDR1500) 
 
 
 
 
 
 
 
 
 
↓ 
↑ 
↓ = start; x = continue; ↑ = stop;  = check BP; -----------> = continues throughout period 
Week-1/day-1: PAC Intervention/bedroom PM monitoring: Start in subject’s bedroom at 9 am 
Home BP: am= when first wake up in bedroom; pm=just before going to sleep in bedroom 
Personal PM monitoring: Wear/have on person during daytime. Put by bedside at night-time. 
 

Week-1/day-1: Staff will drop off the study equipment between 8-9 AM. The equipment will all 
have been cleaned and sterilized beforehand. It includes a home BP monitor (and instructions), 
the blinded-randomized (active or sham) indoor PAC (and instructions for its use), and a 
PurpleAir monitor (and instructions for positioning and use).  
At 9 AM, the subject will position the PAC in their bedroom per instructions, plug it in and turn it 
on. They will keep the PAC running at the highest tolerated setting (per protocol and 
instructions) and keep it running throughout weeks 1-4 in their bedroom. The subject will also 
plug in the PurpleAir and position it at least 6 feet away from the PAC in their bedroom per 
instructions (off the floor on a table). They will make sure it is running for continued air pollution 
monitoring throughout weeks 1-4 in their bedroom per provided instructions.  
Home BP monitoring: The subject will measure home BP upon awakening in the morning and 
just before bedtime on week-1 (days 2-5 = Tuesday through Friday) and on week-4 (days 2-5 = 
Tuesday through Friday). They will follow instructions for home BP monitoring without change 
from original protocol. They will sit 5 minutes prior to measurement with right arm resting at 
heart level on a table. They will measure BP in triplicate on right arm. The Omron-10 series will 
be set to measure BP in triplicate at 1-minute intervals. The device stores all time-stamped BP 
readings and subjects will record on a log for safekeeping of data. 
Subject reminders: The study coordinator will contact the subject week-4/day-1 (mon) to remind 
the subject to begin home BP monitoring on week-4/day-2 for the next 4 days.  
Personal PM-monitoring (week 4): The study coordinator will call the subjects and Carpenter 
Place staff to remind them about personal PM monitoring which will occur on week-4/day-4 
starting at 9-AM and continue for 24-hours through day-5 at 9-AM. The coordinator will drop off 
the pDR-1500 (with instructions for use) before 9-AM on day-4 at the front lobby of Carpenter 
Place. The subject will pick-up the monitor, turn it on, and wear it (on belt or strap) for the next 
24-hours as per instructions. During sleep or showering the monitor can be kept close to their 
person (bedside). 
Week-4/Day-5: On the final day of each study block, the coordinator will contact the subject. 
They subject will be instructed to place the equipment (randomized PAC, PurpleAir, pDR-1500, 
and home BP device) in the bin with wheels and bring it to the front lobby of Carpenter Place. 
The coordinator will then pick-up the equipment.  
Data collection: The coordinator will collect/data-base the time-stamped home BP readings from 
week-1 and week-4. They will download all the time/date-stamped PM2.5 data from the 
PurpleAir and data-base the results. They will also download and data-base the 24-hour 
personal PM2.5 exposure results from the pDR-1500.  
As-needed visits: During the study period, the subject can call and schedule an as-needed 
telephone or video visit with the research coordinator at any time to discuss any study-related 
issues or problems.  
Washout-period. During the washout period the coordinator will clean and sterilize all the 
equipment. They will change the PAC to the alternative randomized blinded mode (active vs 
sham). They will call the subject and schedule the timeline for Block-2 (week-1/visit-1). 
Block-2: This block will proceed exactly as block-1, except the subject will be provided the 
alternative randomized (blinded) PAC intervention.