Search

ObjectiveBoth obesity and synovitis are independently associated with knee osteoarthritis (KOA) progression. We examined whether synovitis mediates the relationship between body mass index (BMI) and KOA radiographic progression in the Osteoarthritis Initiative (OAI) cohort.DesignWe conducted a case-control study within the OAI. Cases (n = 315) were right knees with an increase of ≥1 Kellgren-Lawrence from baseline to 48 months of follow-up. Controls (n = 315) were right knees with no KL change. Cases and controls were matched by age, sex, race, and baseline KL. MRI Osteoarthritis Knee Score (MOAKS) at baseline and at 2 years was used for a semi-quantitative scoring (0-3) of effusion-synovitis and Hoffa-synovitis. Conditional logistic regression estimated associations between BMI and synovitis with KOA progression. Mediation analysis was used to assess the mediating effects of synovitis.ResultsThe mean age of participants was 61 years, 70.8% were women, and 87% were White. KOA progression was associated with higher BMI (adjusted OR 1.05; 95%CI 1.01-1.09) and effusion-synovitis relative to no effusion-synovitis (adjusted OR 2.2; 95%CI 1.6-3.1). Associations between effusion-synovitis worsening and KOA progression were more pronounced among obese individuals (OR 34.1; 95%CI 4.2-274.8; P = 0.001) compared to normal weight (OR 3.2; 95%CI 0.8-12.8, P=0.096) individuals. Effusion-synovitis at 2 years, but not at baseline, mediated the relationship between BMI and KOA progression over a 4-year period.ConclusionsWe found that effusion-synovitis worsening mediated the association between BMI and KOA progression and was associated with increased risk of KOA progression, particularly among obese individuals.

We examined the prospective associations of social isolation and loneliness with incident cardiovascular disease (CVD) among aging nonveteran and veteran women, and effect modification by veteran status. Participants with no history of myocardial infarction (MI), stroke, coronary heart disease (CHD), or coronary heart failure from the Women's Health Initiative Extension Study II self-reported social isolation, loneliness, health behaviors, health status, and veteran status. CVD and CVD subevents were physician adjudicated. Hazard ratios (HR) and 95% confidence intervals (CI) for the Interquartile Range (IQR) in social isolation (IQR = 1) and loneliness (IQR=.33) were calculated using Cox proportional hazard models adjusting for sociodemographic, health behavior, and health status characteristics. Veteran status was tested as an effect modifier. Among 52,442 women (Mean age = 79 ± 6.1; veterans n  = 1023; 89.2% non-Hispanic White), 3579 major CVD events occurred over an average 5.8 follow-up years. Compared to nonveterans, veteran women reported higher levels of social isolation ( p < .01) and loneliness ( p < .01). The CVD HR was 1.07 (95% CI, 1.04-1.10) for the IQR in social isolation and 1.03 (95% CI, 1.10-1.06) for the IQR in loneliness. The HR for the IQR in both social isolation and loneliness was 1.10 (95% CI, 1.05-1.15). Social isolation was associated with CHD (HR = 1.12; 95% CI, 1.03-1.21). The CHD HR for the IQR in social isolation was 1.12 (95% CI, 1.03-1.21). Associations did not differ by veteran status (all p -interactions > 0.08). Findings suggest that the adverse associations of social isolation and loneliness with CVD are similar among veteran and nonveteran women.

Objectives: Adipose tissue has been associated with knee osteoarthritis (KOA) pathogenesis, but the longitudinal changes in adipose tissue with KOA progression have not been carefully evaluated. This study aimed to determine if longitudinal changes of systemic and local adipose tissue is associated with radiographic progression of KOA., Methods: This case-control study used data from the Osteoarthritis Initiative (OAI) and included 315 cases (all the right knees with a minimum of Kellgren-Lawrence score (KL) of 0 and an increase of ≥ 1 KL from baseline to 48 months) and 315 controls matched by age, sex, race, and baseline KL. Cross sectional area of IPFP (IPFP CSA) and subcutaneous adipose tissue around the distal thigh (SCATthigh) were measured using MRI images at baseline and 24 months. Conditional logistic regression models were fitted to estimate associations of obesity markers, IPFP CSA, and SCATthigh with radiographic KOA progression. Mediation analysis was used to assess whether IPFP CSA or SCATthigh mediates the relationships between baseline BMI and radiographic KOA progression., Results: 24-month changes of IPFP CSA (ΔIPFP CSA) and SCATthigh (ΔSCATthigh) were significantly greater in cases compared to controls, whereas Δ BMI and Δ abdominal circumference were similar in both groups during follow-up. Adjusted ORs for radiographic KOA progression were 9.299, 95% CI (5.357-16.141) per 1 SD increase of Δ IPFP CSA and 1.646, 95% CI (1.288-2.103) per 1 SD increase of Δ SCATthigh. ΔIPFP CSA mediated the association between baseline BMI and radiographic KOA progression (87%)., Conclusions: Subjects with radiographic progression of KOA, had significant increases in IPFP CSA and subcutaneous adipose tissue while BMI and abdominal circumference remained stable. Additional studies are needed to confirm these associations., (© 2024. The Author(s).)

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study entry = 57.9 years, range = 51-71 years; 97.6% non-Hispanic; 92.5% White) collected from 2003 to 2019, who had complete information on prior TBI. Participants completed a comprehensive neuropsychological assessment at up to three visits over up to a 12-year follow-up period during which they also self-reported their history of TBI. Multivariable, linear mixed-effects models were used to assess associations between TBI and cognitive performance trajectories. Effect measure modification by apolipoprotein E ( APOE ) epsilon 4 ( ε4 ) genotype status was assessed in a subset of participants. Thirty-one percent of participants reported a history of TBI; 29.4% were APOE ε4 carriers. There were no statistically significant associations of TBI with decline in episodic memory, executive function, or processing speed among participants overall. In models stratified by APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carriers (β = -0.0181; 95% confidence interval [CI] -0.0335, -0.0027) compared to noncarriers (β = -0.0031; 95% CI -0.0128, 0.0067; P Interaction = 0.03). In sensitivity analyses, TBI earlier in life (before military induction, average age = 20 years) was associated with faster declines in executive function compared to no TBI, irrespective of APOE ε4 status. In this sample of middle-to-older aged men, TBI was associated with faster declines in executive function among APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging., (© Alexander Ivan B. Posis et al., 2024; Published by Mary Ann Liebert, Inc.)

The association of leukocyte telomere length (LTL) with survival to late life with intact mobility has not been adequately studied. This prospective cohort study consisted of 1451 postmenopausal women from a Women's Health Initiative ancillary study, who were eligible, because of birth year, to survive to age 90 as of March 6, 2021. LTL was measured by Southern blot at baseline (1993-1998). Associations between LTL and survival to age 90 were evaluated using logistic regression models adjusted for socio-demographic characteristics, health factors, and lifestyle factors. Multinominal logistic regression was utilized to examine associations of LTL with survival to age 90 with or without intact mobility. Mediation analysis examined the extent to which incident coronary heart disease and stroke-mediated the association between LTL and longevity. Overall, 76.7% of women were White, and 23.3% were Black; average age at baseline was 70.4±3.5 years. Relative to death before age 90, the odds of survival to age 90 were 60% higher (OR, 1.60; 95% CI, 1.28-2.01), the odds of survival to age 90 with mobility limitation were 72% higher (OR, 1.72; 95% CI, 1.33-2.21), and the odds of survival to age 90 with intact mobility were 44% higher (OR, 1.44; 95% CI, 1.06-1.95) for every one kilobase longer LTL. Absence of CHD, stroke, or CHD/stroke mediated the association of LTL with survival to age 90 by 11.1%, 37.4%, and 31.3%, respectively; however, these findings were not significant. Longer LTL was associated with higher odds of survival to age 90 among older women., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Introduction: Secondhand and thirdhand tobacco smoke exposure most often occur at home, but little is known about occurrences of in-home cannabis smoking. We ascertained in-home cannabis smoking reported by all cannabis-using (i.e., used in the last 12 months) respondents to the Global Drug Survey (GDS; international-GDS sample), and among U.S. cannabis-using respondents (US-GDS sample). Materials and Methods: We used data collected November 2019-January 2020 for the 2020 GDS, an annual anonymous, cross-sectional survey; respondents were 16+ years old, from 191 countries. We estimated any and daily in-home cannabis smoking in the last 30 days among international-GDS respondents ( n =63,797), using mixed effects logistic regression. US-GDS respondents ( n =6,580) were weighted to the covariate distribution of the nationally representative 2018 National Survey on Drug Use and Health cannabis-using sample, using inverse odds probability weighting, to make estimates more generalizable to the U.S. cannabis-using population. Results: For the international-GDS cannabis-using respondents, any in-home cannabis smoking was reported by 63.9% of men, 61.9% of women, and 68.6% of nonbinary people; and by age (<25 years old=62.7%, 25-34 years old=65.0%, and 35+ years old=62.8%). Daily in-home cannabis smoking was highest among nonbinary (28.7%) and respondents 35+ years of age (28.0%). For the weighted US-GDS cannabis-using respondents, any in-home cannabis smoking was reported by 49.8% of males and 61.2% of females; and by age (<25 years old=62.6%, 25-34 years old=41.8%, 35+ years old=57.9%). Weighted daily in-home smoking was 23.2% among males and 37.1% among females; by age (<25 years old=34.8%, 25-34 years old=27.8%, and 35+ years old=21.6%). Conclusions: There was high daily cannabis smoking in homes of international-GDS and US-GDS respondents who used cannabis in the last 12 months. In part, due to cannabis legalization, the number of users worldwide has increased over the past decade. Criminal stigma historically associated with cannabis continues to drive those users indoors. In this context, our findings support further investigation of cannabis use behavior to understand how often people are exposed to secondhand and thirdhand cannabis smoke and the consequences of that exposure.

Background: Multimorbidity is associated with increased rate of cognitive decline with age. It is unknown whether social engagement, which is associated with reduced risk of dementia, modifies associations between multimorbidity and cognitive decline., Objective: To examine the associations of multimorbidity with longitudinal cognitive test performance among community-dwelling older adults, and to determine whether associations differed by levels of social engagement., Methods: We used data from the Rancho Bernardo Study of Healthy Aging, a community-based prospective cohort study. Starting in 1992-1996, participants completed a battery of cognitive function tests at up to 6 study visits over 23.7 (mean = 7.2) years. Multimorbidity was defined as≥2 of 14 chronic diseases. Social engagement was assessed using items based on the Berkman-Syme Social Network Index. Multivariable linear mixed-effects models were used to test associations of multimorbidity and cognitive performance trajectories. Effect measure modification by social engagement was evaluated., Results: Among 1,381 participants (mean age = 74.5 years; 60.8% women; 98.8% non-Hispanic White), 37.1% had multimorbidity and 35.1% had low social engagement. Multimorbidity was associated with faster declines in Mini-Mental State Examination (MMSE; β= -0.20; 95% CI -0.35, -0.04), Trail-Making Test Part B (β= 10.02; 95% CI 5.77, 14.27), and Category Fluency (β= -0.42; 95% CI -0.72, -0.13) after adjustment for socio-demographic and health-related characteristics. Multimorbidity was associated with faster declines in MMSE among those with low compared to medium and high social engagement (p-interaction < 0.01)., Conclusions: Multimorbidity was associated with faster declines in cognition among community-dwelling older adults. Higher social engagement may mitigate multimorbidity-associated cognitive decline.

Background: Positive affect and emotional resources, such as optimism, may play a major role in women's health and promote healthy well-being later in life. However, positive affect and optimism measures have not been psychometrically assessed in older women, despite relations to health. Therefore, the objective of this study was to psychometrically assess measures of positive affect and optimism and test their association with other measures of well-being. Methods: In a Women's Health Initiative subcohort of 58,810 women (mean age [standard deviation] 79.0 [6.1]; 89% White), positive affect and optimism were measured using the modified Differential Emotions Scale (mDES) and Life Orientation Test-Revised (LOT-R), respectively. Reliability was tested using Cronbach's alpha and McDonald's omega. Performance was assessed using item response theory. Factor analysis was used to explore the construct validity of the LOT-R. Convergent and divergent validity with other well-being measures was tested. Results: Results suggest good reliability (mDES: Cronbach's alpha = 0.90 and omega total = 0.92; LOT-R: Cronbach's alpha = 0.79, omega hierarchical = 0.61, and omega total = 0.83). Item response analyses indicate mDES's ability to discriminate across positive affect; LOT-R was skewed toward lower optimism levels. Exploratory factor analyses suggest a two-factor solution for the LOT-R. Significant, but small correlations in expected directions to well-being measures confirmed validity hypotheses. Conclusions: The mDES and LOT-R measured positive affect and optimism with good reliability, item performance, and validity in a large sample of older postmenopausal women, supporting use of these measures to quantify effects of positive affect and optimism-promoting interventions.

Background: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia., Objective: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women., Methods: This prospective cohort study included 6,670 women from the Women's Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average 10.7 (SD = 6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support., Results: Among 6,670 women (average age = 70 years [SD = 3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR = 0.85, 95% CI 0.74-0.99; ptrend = 0.08). Associations were significant for emotional/information support (T3 versus T1: HR = 0.84, 95% CI 0.72-0.97; ptrend = 0.04) and positive social interaction (T3 versus T1: HR = 0.85, 95% CI 0.73-0.99; ptrend = 0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity., Objective: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women.

Objective: The association of pregnancy with later-life cognition is not well understood. We examined whether full-term and incomplete pregnancies were associated with cognition in a sample of postmenopausal women, and whether socioeconomic status (SES) factors mediated these relationships., Methods: A total of 1016 cognitively normal women from the National Health and Nutrition Examination Survey (NHANES) were examined. Cognitive measures included the Digit Symbol Substitution Test (DSST), Animal Fluency (AF) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tasks. Analyses examined the relationship between the number of term and incomplete pregnancies with cognitive performance, as well as the mediating effects of education and the federal income-to-poverty ratio (PIR)., Results: A greater number of term pregnancies was associated with worse performance on the DSST ( β  = -0.09, 95% confidence interval [CI]: -0.12, -0.06), AF ( β  = -0.03, 95% CI: -0.07, 0.00) and CERAD-DR ( β  = -0.04, 95% CI: -0.08, -0.01). More incomplete pregnancies were associated with better CERAD-DR performance ( β  = 0.07, 95% CI: 0.01, 0.13), and 28% (95% CI: 0.17, 0.42) of the association of term pregnancies with the DSST was mediated by the PIR., Conclusions: A higher number of term pregnancies was associated with worse cognitive performance, whereas a higher number of incomplete pregnancies was associated with better cognitive performance. Results indicate the necessity to consider SES factors when studying the relationship between pregnancy and cognition.

The goal of this study was to examine associations between accelerometer-measured physical activity (PA) and sedentary time (ST) with mortality by a genetic risk score (GRS) for longevity. Among 5,446 women, (mean [SD]: age, 78.2 [6.6] years), 1,022 deaths were observed during 33,350 person-years of follow-up. Using multivariable Cox proportional hazards models, higher light PA and moderate to vigorous PA were associated with lower mortality across all GRS for longevity categories (low/medium/high; all ptrend < .001). Higher ST was associated with higher mortality (ptrend across all GRS categories < .001). Interaction tests for PA and ST with the GRS were not statistically significant. Findings support the importance of higher PA and lower ST for reducing mortality risk in older women, regardless of genetic predisposition for longevity.

Purpose of the Research: Early evidence from studies of home smoking policies suggests that in-home cannabis smoking is more often allowed than in-home tobacco smoking, but there are not yet data on whether cannabis is more often smoked in the home compared to tobacco, or whether in-home cannabis and tobacco smoking differs by usage status. Using cross-sectional data from over 100,000 sentinel drug users from 17 countries, we compared cannabis and tobacco smoking in the homes of Global Drug Survey 2019 respondents who currently used cannabis only, tobacco only, both tobacco and cannabis, or neither., Principal Results: Complete data on cannabis and tobacco use and in-home smoking were available for 107,272 adults (average age = 30 ± 12, 34% women, countries with the three highest response rates; Germany = 32%, USA = 10%, New Zealand = 9%). In total, 53.6% and 50.6% of respondents reported past-year cannabis and tobacco smoking in their home respectively. Stratifying respondents into current cannabis-only users, tobacco-only users, dual users, and non-users, past-year in-home cannabis smoking was more prevalent (78.8%) among cannabis-only users than was in-home tobacco smoking (67.9%) among tobacco-only users. Among dual users, past-year in-home cannabis smoking (82.8%; 95%CI = 80%-86%) was higher than in-home tobacco smoking (75.9%; 95%CI = 69%-81%; p < 0.001). In-home cannabis and tobacco smoking was similar among non-users (20.2% and 20.5%, respectively)., Major Conclusions: Past-year in-home cannabis smoking was more prevalent than tobacco smoking in the homes of participants who used cannabis and/or tobacco, supporting our speculation that in-home cannabis smoking might be more socially acceptable than in-home tobacco smoking., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos., Objective: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos., Methods: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change., Results: Anticholinergic use was associated with lower cognitive global cognition (β= -0.21; 95% CI [-0.36; -0.05]), learning (β= -0.27; 95% CI [-0.47; -0.07]), memory (β= -0.22; 95% CI [-0.41; -0.03]), and executive functioning (β= -0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (β: -0.28 [95% CI: -0.55, -0.01]; β: -0.28 [95% CI: -0.55, -0.01]; β: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3 = 3.59, F3 = 2.84, F3 = 3.88, respectively)., Conclusion: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

Objectives: To quantify postsmoking waterpipe tobacco (WPT) waste and describe postsmoking waterpipe (WP) device cleaning practices and disposal of associated waste in home settings., Methods: We analysed data from a US convenience sample of 50 exclusive WPT smokers, mean age 25.3 years. Data were collected at a home visit during which participants smoked one WPT head and completed a self-administered questionnaire on WP cleaning practices and disposal of waste associated with WPT use. Research assistants provided and prepared a WP for participants by weighing and loading 10 g of WPT in the WP head and placing 470 mL of water in the WP bowl. At the completion of the smoking session, research assistants measured the remaining WPT and water. Descriptive analyses were performed., Results: Of the 10 g of fresh WPT used for each smoking session, 70.1% (mean=7.01 g) was discarded postsmoking as waste; for each 470 mL of water used in the WP bowl, 94.3% (mean=443 mL) was discarded. WP device cleaning practices ranged from never cleaning the device to cleaning it after each smoking session. Respondents reported discarding smoked WPT residue in the trash (81.6%) or the kitchen sink (14.3%) and discarding postsmoking charcoal in the trash (57.6%), the kitchen sink (27.3%) or backyard soil (9.1%). Respondents reported discarding smoked WP water in the kitchen sink (76.5%), bathroom sink (14.7%), toilet (2.9%) and backyard soil (5.9%)., Conclusions: Interventions and regulations are needed to inform proper WP device cleaning practices and disposal of waste associated with WPT use., Trial Registration Number: NCT03253653., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We examined college students' beliefs and behavior regarding sharing when smoking a hookah, a practice that may involve substantial risk of disease transmission. Methods: We carried out a cross-sectional Web-based survey of undergraduate ever users of hookah (N = 970) at a US university in 2007. Results: Hookah sharing started at initiation of hookah use. The first-time participants smoked hookah, 96.9% shared it, and 97.5% were with friends either in a hookah lounge (59.5%) or at a friend's home (30%). Participants shared a hookah when they first smoked it because sharing was acceptable with friends, family, or trusted others, normative etiquette, not problematic/harmful, cheaper, or the only smoking option. Participants did not use a mouth tip when they first smoked a hookah because it is not necessary with friends/family, there was no tip available, they were unaware of tips, or did not want to use one. Conclusions: Overwhelmingly, hookah sharing started at smoking initiation. Efforts are needed to create an environment in which sharing hookah practices are less acceptable such as increasing awareness of potential health risks of sharing, particularly among youth, and providing disposable hoses, disposable mouth tips, and proper hookah device cleaning practices in private and public hookah venues settings.

Background: Nicotine, an addictive drug, is present in all forms of tobacco products, including hookah tobacco, which is not yet regulated in the United States., Objectives: This study aimed to investigate the uptake of nicotine in hookah smokers and non-smokers exposed to secondhand smoke (SHS) at indoor hookah social events in natural settings where hookah tobacco was smoked exclusively., Patients and Methods: We quantified cotinine, a metabolite of nicotine, in the urine of 105 hookah smokers and 103 non-smokers. Participants provided spot urine samples the morning of and the morning after attending an indoor hookah-only smoking social event at a hookah lounge or in a private home., Results: Following a social event where exclusively hookah tobacco was smoked, urinary cotinine levels increased significantly 8.5 times (geometric mean (GM): 16.0 ng/mg to 136.1 ng/mg) among hookah smokers, and 2.5 times (GM: 0.4 ng/mg to 1.0 ng/mg) among non-smokers exposed exclusively to hookah tobacco SHS. Among hookah smokers, the highest increase in urinary cotinine levels post a hookah event was found in occasional hookah smokers in which GM levels increased significantly 31.2 times post smoking (from 2.0 ng/mg to 62.3 ng/mg). Reported reasons for preference to smoke hookah at home by hookah smokers who attended a hookah social event in a private home included recreational purposes, socializing with friends and family, 'Me' time and relaxing at home, more comfortable to smoke hookah at home, owning a hookah and hookah tobacco, eating and drinking while smoking hookah, and saving money by smoking at home and not going to hookah lounges., Conclusions: Hookah tobacco smoke is a source of substantial nicotine exposure. Our results call for protecting hookah smokers' and non-smokers' health by requiring accurate hookah tobacco labels, raising taxes on hookah tobacco, reducing the spread of hookah lounges, and encouraging voluntary bans on smoking hookah tobacco in private homes., Competing Interests: Declaration of Interests: The authors declare no competing interests associated with this study.