Specific Aims In the template below, I use examples from a proposal

Instructions:

The goal of this template is to help you focus your aims, one vital component of writing

a successful proposal. This template is derived directly from R01’s of mine that were

funded with scores better than the 5th percentile, and it has also been used by various

people I’ve helped, several of whom have used it to score in the top few percentile.

Bottom line is, when you combine this with some of the other aspects of a great grant

(e.g. great team, great project, etc), this approach works.

The aims are a crucial part of winning over the reviewer. Your whole proposal should be

written for a general science audience, not for just specialists in your ﬁeld. This is

particularly important in the speciﬁc aims. If you use specialized terminology without

explaining it here, you will loose your reviewer’s good will quickly, and your chances of

funding are slim to none.

Keep it general, and keep it interesting. Make sure to cover each of the four key

components: Why, Who, What, and How (Those are explained in my book, Four Steps

To Funding).

And the most important thing: you must be proposing great work that your ﬁeld cares

about. If you’re not proposing work that people care about, then great writing will not

make any difference at all.

I want to thank Dr. Marshall Edgell for his initial inspiration for this template, and Dr.

Peter Drain for his recent input to improve it.

Specific Aims

In the template below, I use examples from a proposal of mine that was

funded with a very good score.

1. 1-2 sentences: Set the big picture, central challenge of your field that lots of people

are interested in solving. For example: “Post-translational modifications (PTMs)

on proteins can significantly affect their function and their interactions with

other proteins, so a major component of mass spectrometry (MS) based

proteomic research is focused on identifying post-translational modifications

present in different cellular states.” This should be the backdrop for the “Why” (for

a complete explanation see Four Steps To Funding).

2.2-3 sentences: elaborate on the problem, and what has been going on in your field to

solving it. This is the introduction to the “What,” i.e. the theory behind what you’re

trying to do. But keep it interesting and for a general audience! Do not get bogged

For a video that walks you through this template, and for other grant writing training,

visit http://tinyurl.com/7lluvex

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down in heavy factual details here, or your reviewer will become lost and

uninterested. For example: “PTM analysis usually proceeds by one of two

methods: bottom-up is the most common, whereby all proteins are digested into

peptides and then individual peptides are analyzed by tandem mass spectrometry

to find mass-shifts associated with the presence of modification(s). The second

route is top-down analysis, where the mass of intact proteins is measured on a

high accuracy MS instrument, and from the mass, protein modifications can be

inferred due to a shift compared to the predicted mass in a protein database.”

3.1-2 sentences: Name a general bottleneck in your field that is slowing or stopping

progress towards achieving the big picture named in the first sentence. This is a

critical part of your aims! You must have a single, clear Gap that needs

solving [clearing], in order to have a good proposal. This is your framing device

for your “Why”. For example: “Both methods have limitations - with bottom-up, it

is difficult to find and analyze all the peptides associated with each protein, so

there are usually gaps in coverage. Top-down is limited because a single mass

measurement can be assigned to multiple isobaric (equal mass) combinations of

modifications, so is not definitive.”

4.1-3 sentences: elaborate on the Gap, making it more specific and focused. For

example: “To overcome these limitations, several groups including our own have

combined top-down with bottom-up (TDBU) analyses of post-translational

modifications in proteins, using top- down data to predict possible modification

scenarios, and bottom-up data to determine which scenario is correct. At present,

there is no openly available software for automatically combining these two

different types of data sets, and analysis by hand is extremely slow and time

consuming.”

5.(optional) 1-2 sentences: Discuss the theory that leads up to your proposed solution,

in general and non-technical terminology. Do not get bogged down in minute

technical details here. (For the example I’m using here, no additional theory was

presented, but many successful proposals present a bit of theory at this point,

often as a prelude to a hypothesis).

6.1-2 sentences: Propose an approach to solving the roadblock. If you are working in a

hypothesis-driven area of work, this is where you’ll state your hypothesis. If you

can tie this in with the “Who” your proposal will be stronger. From the Four Steps

To Funding model, this is your “What” - i.e. your model of how the world works

(within the area of your proposal). For example: “We are ideally positioned to

build and deliver open source software to address these limitations, having

extensive experience in both top-down and bottom-up software development, as

well as experience in applying TDBU data to an exhaustive analysis of E. coli

ribosomal proteins.” In this example, we are proposing new software, and we are

For a video that walks you through this template, and for other grant writing training,

visit http://tinyurl.com/7lluvex

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also talking about our experience in building that software in the very same

sentence. If this were a hypothesis, you’d do essentially the same thing, proposing

your hypothesis and immediately showing why you and your team have the

experience to be working on it.

7. (optional) 1-2 sentences: Explain why you and your team are the right people to

implement this solution/approach. This is another critical section, it is the

Who. You need to point out why not just anyone can do this work, and why you

are qualified and ready to jump in and solve it. The best thing is to cite one or

more previous papers of yours on the subject, or point to unpublished work, for

example: “Our established development track record includes PROCLAME for

top-down analysis (PROtein CLeavage And Modification Engine)

and GFS for

bottom-up (Genome-based peptide Fingerprint Scanning)

2-4

.”

8.1 sentence: “We are proposing to accomplish goal [or test this hypothesis] with the

following specific aims:”

9.The aims are your How. They need to be credible, meaning that it is realistic that

you can accomplish them given your skills, your budget, and your timeframe.

Each aim needs not only a how, but also a Why, as in “why do this aim? What is

its purpose for being?” The following structure is a great way to force yourself to

answer not only the How but also the Why for each aim. You may be tempted to

skip this. Do so at your own peril! This formula is proven to work. “Aim #: To X

we will Y.” - I’ve used this exact format on the last 5 funded proposals for ALL of

my aims. It forces you to clearly state WHY you will do the aim (X) and HOW you

will do it (Y). Sometimes the HOW (Y) is divided into several sub-steps, as a

numbered/lettered list, and can even be more than one sentence, if absolutely

necessary. For example: “Aim 1: To improve the identification of post-

translational modifications and amino acid substitutions on proteins by combining

top-down and bottom-up mass spectrometry data, we will enhance our

PROCLAME software to use a Markov chain Monte Carlo algorithm

that can incorporate: a) intact-mass mass data from top-down analysis,

b) peptide data from bottom-up analysis, and c) context-sensitive rules

that use but are not limited by knowledge of where modifications are

likely to occur. We will further enhance the program’s assessment of

modification frequency by ongoing analyses of protein databases like

UniProt

.” Here, I have underlined the Why and boldfaced the How. Again, for

a good aim, it must have both.

10.(optional)1-4 sentences: How clearing the hurdle fits into the big picture. For the

NIH, this big picture needs to be tied to improving health or curing disease. For

the NSF, this may be solving one of their named grand challenges. The more

For a video that walks you through this template, and for other grant writing training,

visit http://tinyurl.com/7lluvex

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people afflicted and the deadlier the disease, the easier it is to establish the

importance of the project in the big picture context. Now, in some proposals I’ve

left this off and it hasn’t hurt me, such as the one we’ve been using for an example.

But here’s an example. But here’s an example from another well-scored proposal:

“By performing a differential analysis of proteins encoded by transcripts in a

variety of tissue types, we expect to uncover knowledge about the location and

timing of protein translation in cells, information about which transcripts get

translated, and information about how many of the putative alternative exons

predicted actually encode proteins. By enhancing genome annotation with these

data, and by making the project data openly accessible to other researchers, we

expect these data sets will become a rich source of information for those studying

regulation and mis-regulation of the path from transcription to translation in

disease conditions.”

Comment on the Gestalt of this template from Peter Drain at U. Pittsburgh:

Grant writing is getting the money. Science is what you do when you get the money.

Two distinct activities. First, get the money. Second, decide on the best science to do

with that money. Getting funded and the science done with the funds are not the same.

The bottom line is that grant writing is a learned skill with some key components that are

not scientiﬁc but rather based on relating the study to the reviewers goal, in a word,

relationships.

For a video that walks you through this template, and for other grant writing training,

visit http://tinyurl.com/7lluvex

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2. Specific Aims

Chronic fatigue syndrome (CFS) is a relatively common, often disabling disorder characterized by profound

fatigue lasting at least 6 months, and other symptoms such as headache, poor sleep, myalgias, cognitive

dysfunction, post-exertional malaise, and tender glands [1]. CFS is thought to be part of a spectrum of

overlapping central sensitivity syndromes [2-4] that might share a common pathophysiologic mechanism [5].

Some suggest that central sensitization is influenced by afferent input from peripheral nerves, and that such

input may play a key role in determining the threshold of central sensitivity and symptom expression in irritable

bowel syndrome (IBS) [6], fibromyalgia (FM) [7], and possibly in other syndromes such as CFS.

We have observed that many with CFS have neuromuscular dysfunctions - specifically, restrictions in

the physiologic range of motion of the limbs and spine. Our preliminary observations also suggest that applying

a neuromuscular strain during the physical exam (via, for example, a passive straight leg raise) can amplify

CFS symptoms.

Individuals with CFS and related central sensitivity syndromes can also manifest exaggerated

sympathovagal balance (e.g., diminished heart rate variability: HRV) and impaired neural cardiac regulation

(e.g., orthostatic intolerance [8, 9]). However, the association of resting neuromuscular dysfunction with

sympathovagal balance is unknown. Moreover, the effect of exposure to an additional neuromuscular strain on

CFS symptoms, sympathovagal balance, and central sensitization has not been examined. Our long-term

goal is to understand the role of neuromuscular dysfunction in CFS and its interplay with autonomic and

central sensitization. Herein, we propose to evaluate whether individuals with CFS differ from controls

with regard to neuromuscular function, and whether applying a neuromuscular strain amplifies CFS

symptoms, sympathovagal balance, and central sensitization. Thus, our Specific Aims are:

Specific Aim 1:

To determine whether people with CFS show resting alterations in neuromuscular

function, sympathovagal balance, and central sensitivity relative to matched controls.

 We hypothesize that CFS participants will show neuromuscular dysfunctions (restricted range of motion on

limbs and spine), exaggerated sympathovagal balance (diminished HRV), and greater central sensitivity

(temporal summation) compared to controls.

Specific Aim 2:

To determine whether a neuromuscular strain manipulation (NMSM) elicits immediate

and delayed (next-day) increases in fatigue, sympathovagal balance, and central sensitivity, and

reduces neurocognitive performance.

Using a NMSM versus a sham manipulation, we hypothesize that CFS participants exposed to the NMSM

will immediately report greater fatigue, heightened central sensitivity, and poorer neurocognitive performance

compared to CFS participants exposed to the sham manipulation and to controls exposed to either the NMSM

or sham.

We also hypothesize that when assessed 24 hours later CFS participants who were exposed to the NMSM

will continue to report greater fatigue, heightened central sensitivity, and poorer neurocognitive performance

than CFS participants exposed to the sham manipulation and controls exposed to either the NMSM or sham.

Accomplishing these specific aims will allow us to determine whether neuromuscular dysfunction

represents a peripheral marker that contributes to the pathogenesis of CFS symptoms and to heightened

central sensitization.



SPECIFIC AIMS

The proposed research directly

meets the goals of the RFA-MH-12-061 – Promoting Engagement in Care

and Timely Antiretroviral Initiation Following HIV Diagnosis (R34)), which aims at reducing health disparities

and testing interventions that impact adherence to HIV therapeutic regimens and retention in medical care.

HIV-infected women have demonstrated poor engagement and retention in care, which are expected to be

due, in part, to co-morbid depression. Women consistently show higher non-adherence to antiretroviral therapy

(ART) and lower retention in care rates compared to men and consequently higher mortality rates.

4,5

(+Rumptz MH, 2007) Furthermore, HIV-infected women are particularly vulnerable to suffer from depression

compared to their male peers (19), with 69% of HIV-infected women evidencing prolonged symptoms of

depression (18) compared to only 45% of men (Wisniewski, AB, 2005). In the context of HIV disease, it is well

known that depressive disorders are one of the strongest predictors of suboptimal adherence to ART and

retention in care. If left untreated, HIV-infected patients with depressive symptoms are less likely to respond to

interventions designed to link patients to care (Gardner LI, 2009). Therefore, intervention strategies that

simultaneously reduce depressive symptoms and improve adherence and retention to clinical care among HIV-

infected women are urgently needed

6-17

(+Giordano and Gardner LI, 2009 + J. Simoni). While the proportion of

minority women infected with HIV in the United States (US), particularly in the Southeast, is increasing

significantly, little is known about effective intervention strategies and modes of intervention delivery that

address HIV-infected women’s barriers to retention and adherence to care (Ref.). Given that HIV-infected

women are more likely to live in rural areas of the US where access to diverse healthcare services are limited,

intervention strategies addressing retention to and adherence care will have to use non-traditional modes of

health care delivery. Telemedicine distributed interventions can help to overcome structural barriers to

retention and adherence to care while providing expert delivered specialty care.

Our long-term goal is to develop an effective intervention that significantly improves clinical outcomes in

HIV-infected women by decreasing depression morbidity and simultaneously increasing adherence to ART and

retention in care. The

objective of this application is to culturally adapt an established and effective cognitive-

behavioral therapy (CBT-AD) for depression and adherence and test its feasibility and acceptability to HIV

care adherence among HIV-infected minority women living in the rural South of the US (Safren, Gonzalez, &

Soroudi, 2008). CBT-AD is based on the demonstrated association between depressive symptoms and poor

ART adherence, and targets specific symptoms of depression that are seen as significantly interfering with an

individual’s ability to adhere to HIV care. Safren and colleagues (Co-investigator) previously have

demonstrated the efficacy of CBT-AD in an urban primarily male patient population, while this proposal seeks

to adapt this efficacious intervention in a rural, female population.

In the proposed study, we will adapt the CBT-AD intervention to HIV-infected women in Alabama, a state

with a significantly higher proportion of HIV-infected minority women than the national average (Ref.). We will

use telemedicine technology to increase distribution of the intervention across rural populations in Alabama.

Telemedicine has been successfully used in the delivery of mental health services - particularly in rural areas

where mental health providers are scarce (Hilty 2006 & 2007, De Las Cuevas 2006). The intervention will

provide general skills training in coping and problem solving with depressive symptoms and adherence to ART

and will be modified to address retention in care.

To accomplish our main objective above, we propose the following specific aims:

1) To evaluate the cultural relevance of CBT-AD by conducting formative research among HIV-

infected women and HIV care providers to inform the cultural adaptation of CBT-AD intervention

for HIV-infected women in rural areas of Alabama;

2) To systematically adapt the CBT-AD intervention to HIV-infected women residing in rural

Alabama and telemedicine technology, using an iterative open-label – non-randomized process.

3) To assess the feasibility, acceptibility and preliminary behavioral efficacy of the adapted CBT

intervention to address depression among HIV-infected women and retention and adherence to

care by implementing a pilot randomized controlled trial (RCT).

With respect to expected outcomes

the work proposed in specific aims 1-3 is expected to significantly

contribute to our understanding of factors impacting depression treatment as well as retention and adherence

to care interventions among HIV-infected women, in particular in underserved, rural areas that are increasingly

impacted by the HIV epidemic. Such results will

positively impact the development of an R01 scale RCT,

testing the efficacy and cost-effectiveness of CBT-AD among women across various HIV care settings, as will

be detailed in the next section.

“Developments in research on placebos suggest that the

time has come to translate the science of placebo effects

and knowledge regarding techniques for promoting

placebo responses into clinical practice and medical

education.” Brody & Miller: Lessons from Recent

Research about the Placebo Effect - From Art

to Science. JAMA 2011; 306: 2612-2613.

2. Specific Aims

In response to PA-12-179: Exploratory/Developmental Clinical Research Grants in Obesity,

we propose

a pilot randomized-controlled trial to evaluate the feasibility and effects of the non-deceptive (open-label)

administration of placebo pills on objective (weight, physical activity) and subjective (quality of life,

psychological well-being) outcomes in obese adults seeking weight loss.

Although the placebo effect is well-established

[1-5], using placebos in clinical practice is considered

unethical because deception (“intentional ignorance”)

is thought necessary to elicit positive responses.

However, two recent open-label placebo studies—

where patients were told they were receiving placebo

pills—significantly reduced symptoms both in adults

with Irritable Bowel Syndrome (IBS) and depression

scores in adults with Major Depressive Disorder (MDD) [6, 7]. These non-deceptive placebo clinical studies,

which involved a single intervention visit, applied the perspective that placebo effects are not merely the

result of ingesting an inert pill but also the effects embedded within the patient–clinician encounter;

including a persuasive rationale for benefit, attention, ritual, and the modulation of expectations and

perceptions. While these studies indicate that open-label placebos can influence subjective (patient-reported)

outcomes, it is unknown whether they can also influence objective (e.g., weight) and behavioral outcomes

(e.g., physical activity, dietary intake).

Obesity is a major public health problem and current behavioral treatments, even very intensive ones, often

produce modest and short-lived weight loss [e.g., 8-11]. Thus, identifying alternative approaches that enhance

obesity treatment outcomes is desirable. We will examine the feasibility and effects of open-label placebos (OLP)

for obese adults seeking weight loss. Specifically, we will conduct a pilot trial to evaluate whether, in obese

adults given the identical self-directed weight loss program, the open-label administration of placebo

pills—in the context of the patient-clinician relationship of education, reassurance, and positive

expectation—produces greater weight loss compared to those who do not receive placebo pills (NO OLP).

Specific Aim 1: Examine the feasibility of OLP for treating obesity.

Hypothesis 1a: OLP will be perceived by the majority of obese adults screened as credible and acceptable.

Hypothesis 1b: Those randomized to OLP will adhere >80% to the placebo pills “prescription.”

Specific Aim 2: Evaluate whether OLP reduces weight.

Hypothesis 2: The OLP group will show greater weight reduction compared to NO OLP.

Specific Aim 3: Evaluate whether OLP has beneficial effects on behavioral (i.e., physical activity, dietary

intake) and psychosocial (i.e., weight-related quality of life, well-being) outcomes.

Hypothesis 3: The OLP group will show greater benefits on these outcomes compared to NO OLP.

Sixty obese adults will be randomized to either: (1) OLP (where participants will be told that "placebo pills

made of an inert substance, like sugar pills, have been shown in studies to produce significant improvements

in many people by activating mind-body healing and self-management processes”), or (2) NO OLP. Prior to

randomization, participants will be given the identical self-directed weight loss program and take part in a

placebo orientation meeting. Within the context of a natural “give and take” interaction with a weight loss

specialist, this meeting will provide the rationale for positive expectations that placebo treatment may increase

their ability to lose weight. All participants will have the same quantity and quality of interaction with providers.

Those randomized to OLP will take two placebo pills twice a day (adherence will be measured by Medication

Events Monitoring Systems (MEMS) caps) over the course of the 12-week study, while those randomized to

NO OLP will not. Change in body weight will be the primary outcome. Secondary outcomes will be physical

activity (measured by accelerometer), dietary intake, psychological well-being, and weight-related quality of

life. We will also assess the perceived effectiveness and global satisfaction with OLP.

This pilot trial will provide information on the feasibility of OLP for obesity, as well as on study design,

retention, effect sizes, and outcomes assessment. Our long-term goals are to determine whether OLPs are

beneficial for treating obesity, and, if so, to identify: (1) participant characteristics associated with positive

response, (2) the mechanisms by which OLP operates, and (3) the best methods of administering OLPs to

maximally harness its effects.

II. Specific Aims

In order to eliminate new pediatric HIV infections, save maternal lives, and simplify antiretroviral therapy (ART)

implementation, current WHO guidance emphasizes triple ART for all pregnant and breastfeeding women

regardless of CD4 count or clinical stage, called Option B.

The guidelines further recommend lifelong ART for

these women in countries with generalized epidemics (Option B+). This recommendation provides the

opportunity to achieve prevention of mother-to-child transmission (PMTCT) of HIV, treatment of HIV-infected

pregnant women for their own health, and reduction of new HIV infections in sero-discordant couples.

Despite the promise of Option B+ to remove logistical barriers—such as the need to obtain CD4 counts prior to

prescribing ART for pregnant women—and to promote maternal health through life-long ART, this strategy

brings challenges. Early reports from Malawi indicate 20-30% loss-to-follow-up in the first 3-6 months after

ART initiation for pregnant and lactating women.

3-6

Additionally, a meta-analysis of 51 studies, many in sub-

Saharan Africa, found that only 73.5% of pregnant women achieved adequate (>80%) ART adherence, with

the proportion of postpartum women with adequate adherence being only 53%.

Evidence-based strategies to

promote adherence to ART and retention of mother-baby pairs in HIV care during pregnancy, breastfeeding,

and beyond are urgently needed in order to achieve the potential benefits of Option B+.

Barriers to PMTCT adherence and retention in care occur at the individual, interpersonal, community, and

health facility levels.

On the individual level, women may lack information and motivation; while on the

interpersonal and community levels, a woman may fear negative reactions, HIV-related stigma, and

discrimination. At the health facility level, low quality services, including health care workers who hold negative

views about women living with HIV and/or who do not recognize and help women to overcome social barriers

to adherence, may contribute to high drop-out rates from PMTCT programs.

9-11

However, there is limited

knowledge of specific facilitators and barriers to uptake and retention in care for Option B+.

We propose to gain understanding of and address potential barriers at three levels and rigorously test two

evidence-based interventions that alone or in combination are likely to maximize ART adherence and retention

in care among HIV-infected pregnant women and HIV-exposed infants in rural Kenya, using a cluster

randomized 2x2 factorial design. The evidence-based interventions to be tested will include 1) community-

based mentor mothers (MM) who will support HIV-positive women in the community and 2) individually

tailored, theory-based mobile phone text messages to help retain women, and infants in HIV care. There is

evidence that both of these interventions enhance uptake and retention in PMTCT and HIV services in sub-

Saharan Africa,

12,13

14-17

but they have not been investigated in the context of Option B+.

The proposed study will be conducted in rural Nyanza Province, Kenya at 20 low-resource primary health care

facilities and associated communities supported by Family AIDS Care and Education Services (FACES), a

PEPFAR-funded HIV prevention, care, and treatment program. We will assess both process and outcome

indicators using a 2x2 factorial design, in which equal numbers of clusters will be randomized to one of the

interventions, both interventions, or standard of care. The interventions will be added to fully integrated high-

quality HIV and antenatal, maternal, neonatal, and child health (ANC/MNCH) services already offered at

these sites. Our overall goal is to determine which intervention (or combination of interventions)

maximizes ART adherence and retention in care in the context of Option B+ and thus improves

maternal and infant health outcomes. This goal will be achieved through the following specific aims:

Aim 1: To evaluate the acceptability of lifelong triple ARV therapy given to HIV-infected pregnant women

both for their own health and for PMTCT (Option B+), as well as facilitators, barriers, and acceptability of

potential interventions for ART adherence and retention in care, using qualitative research methods.

Aim 2: To compare service utilization outcomes (pregnant women’s adherence to ART, women’s retention

in HIV care, and uptake of early infant diagnosis) in four study conditions (community MM intervention only,

text message intervention only, both interventions, and control) using a 2X2 factorial design.

Aim 3: To examine effects of the individual and combined interventions on maternal and infant health

outcomes, including maternal CD4 counts/viral loads, and MTCT at 6 weeks, 12 months, and 18 months.

There is an urgent need to evaluate service models that maximize ART adherence and retention in care

among women and infants in order for Option B+ to achieve its full potential. This study will support the scale-

up of Option B+ in Kenya by identifying effective interventions and combinations of interventions that can

reduce barriers and increase facilitators of optimal ART adherence and retention in care with the aims of

reaching the elimination of mother to child transmission of HIV and significantly improving maternal health.

“Achieving and maintaining normal body composition

will be a key end point for optimal treatment of patients

with JIA.” Bechtold & Roth (2009), Natural History

of Growth and Body Composition in Juvenile

Idiopathic Arthritis

“There is great potential for weight-bearing exercise to

help combat the musculoskeletal changes of JIA.” Long &

Rouster-Stevens (2010), The role of exercise

therapy in the management of juvenile idiopathic

arthritis

2. Specific Aims

We propose to evaluate the safety and feasibility of resistance exercise (RE) on body composition in children

with Juvenile Idiopathic Arthritis (JIA).

Determining whether RE is safe, well-

tolerated and whether it improves the

outcome of arthritis is explicitly stated as

one of the research areas of clinical and

public health need and interest for

Program Announcement 10-282: Pilot

and Feasibility Clinical Research

Grants in Arthritis and

Musculoskeletal and Skin Diseases.

JIA is the most common chronic

inflammatory autoimmune disease in

children and a significant cause of childhood

and long-term disability (1). Its prevalence ranges from 16 to 150 per 100,000 (1, 2), and symptoms include

joint pain and tenderness, fatigue, and loss of range of motion. As a consequence of the disease, physical

inactivity, and the medications used to treat JIA, these children often have reduced muscle mass and strength,

and bone cross-sectional area and bone mineral density [BMD]. Although the newer disease modifying

antirheumatic drugs (DMARDs) may minimize long-term sequelae of JIA, these patients still tend to experience

considerable muscle and bone loss which may predispose them to experience health problems and

accelerated functional decline in later years (3-6).

The American College of Rheumatology (ACR) recommends exercise for patients with arthritis. A recent

Cochrane Review (7) of exercise in JIA shows that there have only been 3 randomized-controlled trials, all of

which involved aerobic exercise only. Though improvements in functional ability, quality of life, and aerobic

capacity all favored aerobic exercise, none were statistically significant compared to controls. Moreover,

these studies did not investigate the effects of the exercise on body composition and muscle

strength, the primary outcomes in our proposed study, or symptoms or disease activity, the

secondary outcomes in this study.

Resistance exercise (RE) has been shown to be safe and well-tolerated in adults with rheumatoid arthritis

(RA) and idiopathic inflammatory myopathies (e.g., dermatomyositis). Moreover, RE improves strength,

reduces disease activity and impairment, and in some cases, reduces inflammation (e.g., 8-13). However, RE

has not been rigorously studied in JIA. Because children with JIA suffer musculoskeletal disturbances driven

by inflammation, we hypothesize that they would derive similar benefits from RE to those obtained in adults

with inflammatory rheumatic diseases. Thus, we will conduct a randomized-controlled pilot study to

evaluate the safety, feasibility, and effects of 12-weeks of RE in children with polyarticular JIA. The

trial will be conducted in our exercise facility where the participants will be individually supervised and

adherence will be closely monitored and documented.

Specific Aim 1: To investigate the safety and feasibility and effects of RE on the following primary outcomes:

body composition, muscle strength, flexibility, and range of motion.

We will test the primary hypothesis that those randomized to RE will have significantly

greater improvement in body composition (i.e., fat-free mass [FFM]), muscle strength,

flexibility, and range of motion compared to those randomized to the control condition.

Specific Aim 2: To investigate the effects of RE on the following secondary outcomes: disease activity,

aerobic capacity, inflammatory markers, pain, fatigue, functional ability, and quality of life.

We will examine if RE produces greater improvements in these outcomes compared to controls. Because of

the absence of previous studies on these outcomes with RE, effects sizes are unknown. As an alternative to

hypothesis testing, we will determine 95% confidence intervals in response to the interventions that will

provide evidence worthy of further investigation in children with JIA.

This novel “proof of principle” pilot study will be the first randomized-controlled trial to evaluate the safety,

feasibility, and effects of RE in children with polyarticular JIA. This innovative study should provide

preliminary insights into the mechanisms by which RE might modify body composition, muscle strength,

symptoms, and disease activity. The data will also provide preliminary data to inform an RO1 grant.

SPECIFIC AIMS

Adherence to HIV treatment recommendations—including adherence to both antiretroviral therapy (ART) and

HIV care visits—is essential for persons living with HIV (PLHIV) to achieve health, longevity, and an

undetectable viral load. Yet, only 20-25% of PLHIV in the United States (US) are virally suppressed.

Even

among PLHIV who are followed regularly in interval cohort studies, ART adherence varies and is inadequate,

especially in certain disadvantaged sub-groups, including women.

2,3

There is evidence that HIV-infected

women may have worse adherence to ART than men,

and higher morbidity and mortality.

4,5

Women of color

are at particularly high risk of acquiring HIV,

and have worse health outcomes once infected compared to

White women.

Southern states in the US have the highest rates of new infections, particularly among Black,

female, and poor populations, and the highest HIV case-fatality rates in the country.

8-10

There is an urgent need

to identify barriers to engagement in care and to ART adherence among women living with HIV, particularly

among minority women from diverse geographic regions of the country, in order to understand existing health

disparities and develop responsive interventions.

One potentially important barrier to adherence to HIV treatment recommendations is HIV-related stigma.

Studies suggest that stigma and discrimination not only threaten quality of life for PLHIV, but also impede ART

adherence and engagement in care. Specifically, research has found that persons who perceive high levels of

HIV-related stigma have lower acceptance of HIV testing,

lower access to medical care,

poorer ART

adherence,

and lower utilization of HIV care.

However, there is need for further studies to determine the

magnitude of these effects longitudinally, to identify environmental factors that may underlie geographic

differences in these associations, and to elucidate temporal relationships to provide further evidence for

causality. There are also limited longitudinal data on links between HIV stigma and immunologic and virologic

outcomes—key consequences of poor adherence to HIV treatment recommendations. Furthermore, there are

notable gaps in the literature on the roles of specific dimensions of stigma, as well as the interpersonal,

psychological, mental health, and biological mechanisms that may explain the observed relationships.

There

are also indications that stigma may directly affect health through pathways other than treatment adherence–

via chronic activation of stress-responsive biological systems.

Finally, only a few studies have examined the

intersection of HIV-related stigma with other forms of stigma and discrimination due to race, gender, socio-

economic status, and other factors, which may exacerbate the effects of HIV-related stigma.

17,18

While these

issues are particularly salient for minority women in the US, there are limited data examining the roles of HIV-

related stigma and other intersecting stigmas in adherence and clinical outcomes for this population.

To address these gaps in knowledge, we will leverage the resources of the national Women’s Interagency HIV

Study (WIHS), which has been collecting data on HIV-infected women’s treatment adherence, mental health,

and immunologic and virologic outcomes for 20 years. In 2013, WIHS added new sites from the Southern US

in response to shifts in the HIV epidemic. We have recently collaborated to add brief measures of internalized

stigma and serostatus disclosure to national WIHS data collection, and the proposed study will enable us to

fund the continuation of those measures in order to establish longitudinal effects (n=2100). We also propose a

yearly supplementary visit at 3 WIHS sites (n=500) representing different parts of the country—California (San

Francisco), the Deep South (Alabama/Mississippi), and the Southeast (Georgia)—to collect additional

measures of theoretically important dimensions of stigma (anticipated, experienced, community), validated

measures of hypothesized interpersonal, psychological, and mental health mechanisms, measures of other

intersecting stigmas and discrimination (due to race, gender, and socio-economic status), as well as hair

samples for assessment of cortisol (a biomarker for chronic stress). We propose the following specific aims:

AIM 1) To elucidate longitudinal associations between internalized HIV-related stigma, women’s adherence

to HIV treatment recommendations, and corresponding immunologic and virologic outcomes in the entire

national WIHS cohort, and to examine factors underlying geographic differences in these associations.

AIM 2) To examine the effects of additional dimensions of HIV-related stigma (experienced, anticipated, and

community) on adherence and HIV clinical outcomes, and to elucidate potential interpersonal, psychological,

mental health, and biological mediating mechanisms in the relationships between dimensions of stigma,

adherence, and HIV outcomes, using additional quantitative longitudinal data collected at 3 WIHS sites.

AIM 3) To examine the link between intersectional stigma—including stigma related to HIV, race/ethnicity,

poverty, and gender—and adherence to HIV treatment recommendations using mixed methods research.

The findings from this study will have important theoretical implications for the field of stigma research and will

provide crucial information for policy and programs aiming to improve outcomes for women living with HIV.

Knowledge about the effects of specific dimensions of stigma, the mechanisms for those effects, and

intersectional stigma can be used to tailor interventions to maximize benefits for adherence and health.