The impact of COVID-19 vaccination prior to SARS-CoV-2 infection on prevalence of long COVID among a population-based probability sample of Michiganders, 2020-2022.

PURPOSE: To estimate the association between COVID-19 vaccination status at the time of COVID-19 onset and long COVID prevalence. METHODS: We used data from the Michigan COVID-19 Recovery Surveillance Study, a population-based probability sample of adults with COVID-19 (n = 4695). We considered 30-day and 90-day long COVID (illness duration ≥30 or ≥90 days, respectively), using Poisson regression to estimate prevalence ratios (PRs) comparing vaccinated (completed an initial series ≥14 days before COVID-19 onset) to unvaccinated individuals (received 0 doses before COVID-19 onset), accounting for differences in age, sex, race and ethnicity, education, employment, health insurance, and rurality/urbanicity. The full unvaccinated comparison group was further divided into historic and concurrent comparison groups based on timing of COVID-19 onset relative to vaccine availability. We used inverse probability of treatment weights to account for sociodemographic differences between groups. RESULTS: Compared to the full unvaccinated comparison group, the adjusted prevalence of 30-day and 90-day long COVID were lower among vaccinated individuals [PR30-day= 0.57(95%CI:0.49,0.66); PR90-day= 0.42(95%CI:0.34,0.53)]. Estimates were consistent across comparison groups (full, historic, and concurrent). CONCLUSIONS: Long COVID prevalence was 40-60% lower among adults vaccinated (vs. unvaccinated) prior to their COVID-19 onset. COVID-19 vaccination may be an important tool to reduce the burden of long COVID.

Estimating the effect of latent time-varying count exposures using multiple lists.

A major challenge in longitudinal built-environment health studies is the accuracy of commercial business databases that are used to characterize dynamic food environments. Different databases often provide conflicting exposure measures on the same subject due to different source credibilities. As on-site verification is not feasible for historical data, we suggest combining multiple databases to correct the bias in health effect estimates due to measurement error in any 1 datasource. We propose a joint model for the time-varying health outcomes, observed count exposures, and latent true count exposures. Our model estimates the time-specific quality of sources and incorporates time dependence of true count exposure by Poisson integer-valued first-order autoregressive process. We take a Bayesian nonparametric approach to flexibly account for location-specific exposures. By resolving the discordance between different databases, our method reduces the bias in the longitudinal health effect of the true exposures. Our method is demonstrated with childhood obesity data in California public schools with respect to convenience store exposures in school neighborhoods from 2001 to 2008.

Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation.

Background: Boiling histotripsy (BH), a mechanical focused ultrasound ablation strategy, can elicit intriguing signatures of anti-tumor immunity. However, the influence of BH on dendritic cell function is unknown, compromising our ability to optimally combine BH with immunotherapies to control metastatic disease. Methods: BH was applied using a sparse scan (1 mm spacing between sonications) protocol to B16F10-ZsGreen melanoma in bilateral and unilateral settings. Ipsilateral and contralateral tumor growth was measured. Flow cytometry was used to track ZsGreen antigen and assess how BH drives dendritic cell behavior. Results: BH monotherapy elicited ipsilateral and abscopal tumor control in this highly aggressive model. Tumor antigen presence in immune cells in the tumor-draining lymph nodes (TDLNs) was ~3-fold greater at 24h after BH, but this abated by 96h. B cells, macrophages, monocytes, granulocytes, and both conventional dendritic cell subsets (i.e. cDC1s and cDC2s) acquired markedly more antigen with BH. BH drove activation of both cDC subsets, with activation being dependent upon tumor antigen acquisition. Our data also suggest that BH-liberated tumor antigen is complexed with damage-associated molecular patterns (DAMPs) and that cDCs do not traffic to the TDLN with antigen. Rather, they acquire antigen as it flows through afferent lymph vessels into the TDLN. Conclusion: When applied with a sparse scan protocol, BH monotherapy elicits abscopal melanoma control and shapes dendritic cell function through several previously unappreciated mechanisms. These results offer new insight into how to best combine BH with immunotherapies for the treatment of metastatic melanoma.

Distress about social problems and tobacco and cannabis use outcomes among young adults in Los Angeles County.

OBJECTIVE: To examine associations of concern, worry, and stress about discrimination, shootings/violence, and police brutality and exclusive and dual tobacco and cannabis use among young adults. METHODS: A prospective, racially/ethnically diverse cohort of young adults (n = 1960) living in Los Angeles, California completed a baseline survey in 2020 (age range: 19-23) and a follow-up survey in 2021. Exploratory factor analysis (EFA) was employed on nine variables assessing levels of concern, worry, and stress about societal discrimination, societal shootings/violence, and community police brutality at baseline. Past 30-day tobacco and cannabis use at follow-up was categorized as current exclusive tobacco, exclusive cannabis, and dual tobacco and cannabis (vs never/former) use based on eleven use variables. Multinomial logistic regressions estimated adjusted associations between each factor score (translated to standard deviation units) with exclusive and dual tobacco and cannabis use. RESULTS: The EFA produced four factor scores representing concern/worry/stress (i.e., distress) about community police brutality (F1), distress about societal shootings/violence (F2), and distress about societal discrimination (F3), as well as generalized stress about police brutality, shootings/violence, and discrimination (F4). F1, F2, and F3 were associated with subsequent exclusive current cannabis use, with F1 having the strongest association (OR: 1.35, 95% CI: 1.18-1.55), while only F1 (OR: 1.51, 95% CI: 1.27-1.78) was associated with dual tobacco and cannabis use. None of the factors were associated with exclusive tobacco use. CONCLUSIONS: Young adult concern, worry, and/or stress about social problems may increase risk of cannabis use with or without concurrent tobacco use 6-12 months later.

Discrimination and Tobacco Use Outcomes Among US Adults: Effect Modification by Race/Ethnicity.

INTRODUCTION: Racial/ethnic discrimination (hereafter, discrimination) is associated with tobacco use. However, little is known about the relationship between discrimination and dual/polytobacco use and tobacco use disorder (TUD), including how these relationships vary by race/ethnicity. METHODS: Data on adults 18 and older come from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (n = 35,881). Past-year discrimination was measured using the Experiences of Discrimination scale. Past 30-day exclusive, dual, and polytobacco use was measured as the mutually exclusive use of any combination of four types of tobacco products: cigarettes, electronic nicotine delivery systems, other combustibles (i.e., cigars and pipe), and smokeless tobacco. Past-year TUD was defined according to DSM-5 criteria. Associations between discrimination and exclusive, dual, and polytobacco use and discrimination and TUD were estimated using multinomial logistic regression and logistic regression, respectively. Models were stratified by race/ethnicity (i.e., Hispanic, non-Hispanic (NH) White, NH Black, another race/ethnicity) to assess effect modification. RESULTS: Adults who used tobacco and who had TUD was 24.2% and 19.2%, respectively. More discrimination was associated with higher odds of exclusive, dual, and polytobacco use as well as TUD. Models stratified by race/ethnicity suggest that discrimination was associated with dual/polytobacco use among NH Black adults (OR: 1.05, 95% CI: 1.002-1.11) and NH White adults (OR: 1.18, 95% CI: 1.13-1.22). While more discrimination was associated with TUD among all racial/ethnic groups, the relationship was the strongest for NH White adults. CONCLUSIONS: Discrimination was associated with more severe tobacco use outcomes among multiple racial/ethnic groups, but associations were the strongest for NH White adults.

Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation.

Background: Boiling histotripsy (BH), a mechanical focused ultrasound ablation strategy, can elicit intriguing signatures of anti-tumor immunity. However, the influence of BH on dendritic cell function is unknown, compromising our ability to optimally combine BH with immunotherapies to control metastatic disease. Methods: BH was applied using a sparse scan (1 mm spacing between sonications) protocol to B16F10-ZsGreen melanoma in bilateral and unilateral settings. Ipsilateral and contralateral tumor growth was measured. Flow cytometry was used to track ZsGreen antigen and assess how BH drives dendritic cell behavior. Results: BH monotherapy elicited ipsilateral and abscopal tumor control in this highly aggressive model. Tumor antigen presence in immune cells in the tumor-draining lymph nodes (TDLNs) was ~3-fold greater at 24h after BH, but this abated by 96h. B cells, macrophages, monocytes, granulocytes, and both conventional dendritic cell subsets (i.e. cDC1s and cDC2s) acquired markedly more antigen with BH. BH drove activation of both cDC subsets, with activation being dependent upon tumor antigen acquisition. Our data also suggest that BH-liberated tumor antigen is complexed with damage-associated molecular patterns (DAMPs) and that cDCs do not traffic to the TDLN with antigen. Rather, they acquire antigen as it flows through afferent lymph vessels into the TDLN. Conclusion: When applied with a sparse scan protocol, BH monotherapy elicits abscopal melanoma control and shapes dendritic cell function through several previously unappreciated mechanisms. These results offer new insight into how to best combine BH with immunotherapies for the treatment of metastatic melanoma.

Surrogacy validation for time-to-event outcomes with illness-death frailty models.

A common practice in clinical trials is to evaluate a treatment effect on an intermediate outcome when the true outcome of interest would be difficult or costly to measure. We consider how to validate intermediate outcomes in a causally-valid way when the trial outcomes are time-to-event. Using counterfactual outcomes, those that would be observed if the counterfactual treatment had been given, the causal association paradigm assesses the relationship of the treatment effect on the surrogate outcome with the treatment effect on the true, primary outcome. In particular, we propose illness-death models to accommodate the censored and semicompeting risk structure of survival data. The proposed causal version of these models involves estimable and counterfactual frailty terms. Via these multistate models, we characterize what a valid surrogate would look like using a causal effect predictiveness plot. We evaluate the estimation properties of a Bayesian method using Markov chain Monte Carlo and assess the sensitivity of our model assumptions. Our motivating data source is a localized prostate cancer clinical trial where the two survival outcomes are time to distant metastasis and time to death.

Past-Year Use Prevalence of Cannabidiol, Cannabigerol, Cannabinol, and Δ8-Tetrahydrocannabinol Among US Adults.

This survey study characterizes past-year use prevalence and factors associated with use of cannabidiol, cannabigerol, cannabinol, and Δ8-tetrahydrocannabinol among US adults.

Cigarette Prices and Disparities in Cessation in the United States.

INTRODUCTION: Achieving cessation in people with established smoking patterns remains a challenge. Increasing cigarette prices has been one of the most effective strategies for lowering smoking rates. It remains unclear how effective it has been in encouraging cessation among adults in recent years and how the effectiveness varies by sociodemographic characteristics. METHODS: Using repeated cross-sectional data collected by the Tobacco Use Supplement of the Current Population Survey, we investigate the relationship between cigarette prices and cessation from 2003 to 2019 in adults 25+. We examine the associations between price and cessation in the population overall and by sex, race/ethnicity, and socioeconomic status. RESULTS: We found mixed support for associations between greater local prices and cessation. Unadjusted models showed that greater local prices were associated with greater odds of cessation, but the associations did not persist after controlling for sociodemographic characteristics. The associations did not significantly differ by respondent characteristics. Sensitivity analysis using alternative specifications and retail state price as the main predictor showed similar results. Sensitivity analysis with controls for e-cigarette use in the 2014-2019 period showed that greater local price was associated with cessation among adults with less than a high school degree. When stratified by year of data collection, results show that greater local prices were associated with cessation after 2009. CONCLUSIONS: Overall, the study adds to the conflicting evidence on the effectiveness of increasing prices on smoking cessation among adults with established smoking patterns. IMPLICATIONS: Higher cigarette prices have been one of the most effective tools for lowering smoking prevalence. It remains unclear how effective they are in encouraging adults with established smoking patterns to quit. Results show that greater local prices were associated with higher odds of cessation, but the association did not persist after sociodemographic adjustment. In a sensitivity analysis, greater local price was associated with cessation among people with less than a high school degree in models controlling for e-cigarette use. We also found evidence that greater local price was associated with cessation after 2009. More comprehensive smoke-free coverage was also associated with greater odds of cessation. The study's results highlight that encouraging cessation among adults with an established smoking pattern remains a challenging policy problem even when cigarette prices rise.

An experimental evaluation of a stopping rule aimed at maximizing cost-quality trade-offs in surveys.

Surveys face difficult choices in managing cost-error trade-offs. Stopping rules for surveys have been proposed as a method for managing these trade-offs. A stopping rule will limit effort on a select subset of cases to reduce costs with minimal harm to quality. Previously proposed stopping rules have focused on quality with an implicit assumption that all cases have the same cost. This assumption is unlikely to be true, particularly when some cases will require more effort and, therefore, more costs than others. We propose a new rule that looks at both predicted costs and quality. This rule is tested experimentally against another rule that focuses on stopping cases that are expected to be difficult to recruit. The experiment was conducted on the 2020 data collection of the Health and Retirement Study (HRS). We test both Bayesian and non-Bayesian (maximum-likelihood or ML) versions of the rule. The Bayesian version of the prediction models uses historical data to establish prior information. The Bayesian version led to higher-quality data for roughly the same cost, while the ML version led to small reductions in quality with larger reductions in cost compared to the control rule.

A statewide population-based approach to examining Long COVID symptom prevalence and predictors in Michigan.

OBJECTIVE: The current broad definition of Long COVID, and an overreliance on clinical and convenience samples, is leading to a wide array of Long COVID estimates with limited generalizability. Our objective was to examine Long COVID symptoms using a statewide population-based probability sample. METHODS: Among 8000 sampled adults with polymerase-chain-reaction-confirmed SARS-CoV-2 between June 2020 and July 2021 in the Michigan Disease Surveillance System, 2533 completed our survey (response rate 32.2%). Using modified Poisson regression, we examined sociodemographic, behavioral, and clinical predictors of eight Long COVID symptom clusters, defined as at least one applicable symptom lasting 90 or more days post COVID-19 onset. RESULTS: Neuropsychiatric Long COVID symptoms, including brain fog, were most prevalent (23.7%), followed by systemic symptoms (17.1%), including fatigue, musculoskeletal (11.4%), pulmonary (10.4%), dermatologic (6.7%), cardiovascular (6.1%), gastrointestinal (5.4%), and ear, nose, and throat symptoms (5.3%). In adjusted analyses, female sex, a pre-existing psychological condition, and intensive care unit admission were strong predictors of most Long COVID symptom clusters. Older age was not associated with a higher prevalence of all symptoms - cardiovascular and dermatologic symptoms were most prevalent among middle-aged adults and age was not associated with neuropsychiatric or gastrointestinal symptoms. Additionally, there were fewer associations between pre-existing conditions and cardiovascular, neuropsychiatric, and dermatologic symptoms compared to other symptom clusters. CONCLUSIONS: While many predictors of Long COVID symptom clusters were similar, the relationship with age and pre-existing conditions varied across clusters. Cardiovascular, neuropsychiatric, and dermatologic symptoms require further study as potentially distinct from other Long COVID symptoms.

Improving transportability of randomized controlled trial inference using robust prediction methods.

Randomized trials have been the gold standard for assessing causal effects since their introduction by Fisher in the 1920s, since they can eliminate both observed and unobserved confounding. Estimates of causal effects at the population level from randomized controlled trials can still be biased if there are both effect modification and systematic differences between the trial sample and the ultimate population of inference with respect to these modifiers. Recent advances in the survey statistics literature to improve inference in nonprobability samples by using information from probability samples can provide an avenue for improving population causal inference in randomized controlled trials when relevant probability samples of the patient population are available. We review some recent work in "transporting" causal effect estimates from trials to populations, focusing on the setting where there is a "benchmark" or population-representative sample along with the RCT sample. We then propose estimators using either inverse probability weighting (IPWT) or prediction that can accommodate unequal probability of selection in the "benchmark" or population, and use Bayesian additive regression trees for both inverse probability of treatment weighting and prediction estimation that do not require specification of functional form or interaction. We also consider how the assumption of ignorability may be assessed from observed data and propose a sensitivity analysis under the failure of this assumption. We compare our proposed approach with existing methods in simulation and apply these alternative approaches to a study of pulmonary artery catheterization in critically ill patients. We also suggest next steps for future work.

Racial and Ethnic Disparities in Mental Health Problems and Tobacco and Cannabis Use Among US Emerging Adults.

INTRODUCTION: Mental health problems in emerging adulthood are linked to tobacco and cannabis use, but whether race and ethnicity modifies these associations is unclear. METHODS: We used data from wave 4 of the Population Assessment of Tobacco and Health Study (youth n = 6898, young adult n = 10,304) to conduct latent class analysis (LCA) of six past 30-day tobacco and cannabis use indicators (i.e., cigarettes, electronic nicotine delivery systems (ENDS), cigars, blunts, cannabis vaping, other cannabis). We estimated associations between past 30-day internalizing and externalizing (i.e., low (referent), moderate, high) problems and latent classes of tobacco/cannabis use (vs. never/former use) using adjusted multinomial logistic regression. We explored whether associations varied by race and ethnicity through stratification. RESULTS: We identified four exclusive use latent classes and two dual/poly use latent classes for both youth and young adult samples. Race/ethnicity-stratified models identified associations between internalizing/externalizing problems and most use classes for Hispanic and non-Hispanic White youth/young adults, with mixed results for non-Hispanic Black youth/young adults. For example, Hispanic (OR: 2.50, 95% CI: 1.09-5.74) and non-Hispanic White (OR: 1.90, 95% CI: 1.18-3.06) youth with high internalizing problems had higher odds of ENDS + cannabis vaping. Externalizing problems were not associated with use among non-Hispanic Black youth while internalizing problems were not associated with use among non-Hispanic Black young adults. CONCLUSION: We observed racial/ethnic variation in mental health problems and tobacco and cannabis use. Understanding mental health problem and tobacco product and cannabis use comorbidity may better inform culturally relevant interventions aimed to prevent and reduce use.

Incorporating Covariates into Measures of Surrogate Paradox Risk.

Clinical trials often collect intermediate or surrogate endpoints other than their true endpoint of interest. It is important that the treatment effect on the surrogate endpoint accurately predicts the treatment effect on the true endpoint. There are settings in which the proposed surrogate endpoint is positively correlated with the true endpoint, but the treatment has opposite effects on the surrogate and true endpoints, a phenomenon labeled "surrogate paradox". Covariate information may be useful in predicting an individual's risk of surrogate paradox. In this work, we propose methods for incorporating covariates into measures of assessing the risk of surrogate paradox using the meta-analytic causal association framework. The measures calculate the probability that a treatment will have opposite effects on the surrogate and true endpoints and determine the size of a positive treatment effect on the surrogate endpoint that would reduce the risk of a negative treatment effect on the true endpoint as a function of covariates, allowing the effects of covariates on the surrogate and true endpoint to vary across trials.

Differential care-seeking behaviors during the beginning of the COVID-19 pandemic in Michigan: a population-based cross-sectional study.

BACKGROUND: At the beginning of the COVID-19 pandemic in the United States in the spring of 2020, many Americans avoided the healthcare system, while those with COVID-19 symptoms were faced with decisions about seeking healthcare services for this novel virus. METHODS: Using a probability sample (n = 1088) from the Michigan adult population of PCR-confirmed COVID-19 cases who were diagnosed prior to July 31, 2020, we used logistic regression to examine sociodemographic and symptom severity predictors of care-seeking behaviors. The analyses examined three different outcomes: (1) whether respondents sought care and, among those who sought care, whether they sought care from (2) a primary care provider or (3) an emergency room. Final models were adjusted for sex, age, race and ethnicity, income, education, marital status, living arrangement, health insurance, and self-reported symptom severity. RESULTS: We found that participants ages 65 and older had 4.00 times higher odds of seeking care than 18-34-year-olds (95% CI: 2.21, 7.24), while adults reporting very severe symptoms had roughly 15 times higher odds of seeking care than those with mild symptoms (95% CI: 7.73, 27.01). Adults who were non-Hispanic Black or were uninsured had lower odds of seeking care from a primary care physician versus seeking care from other locations in comparison to adults who were non-Hispanic White or were privately insured, respectively (non-Hispanic Black: aOR = 0.27, 95% CI: 0.16, 0.44; Uninsured: aOR = 0.19, 95% CI: 0.09, 0.42). Conversely, adults who were older or reported more severe symptoms had higher odds of seeking care from an emergency room versus other locations in comparison to adults who were younger or reported less severe symptoms (Age 65+: aOR = 2.96, 95% CI: 1.40, 6.28; Very Severe Symptoms: aOR = 6.63, 95% CI: 3.33, 13.20). CONCLUSIONS: Our results suggest differential utilization of healthcare services early in the COVID-19 pandemic. Further analyses are needed to examine the reasons for these differences.

Network Types and Functional Health in Old Age: It is Not Just the Size of the Network That Matters.

OBJECTIVES: Findings on the effect of network size and support on functional health are mixed. We examine whether network types, that simultaneously incorporate multiple network characteristics, are associated with functional health in late life. METHODS: Data are from the National Social Life, Health, and Aging Project (N = 3005). We estimated the longitudinal effect of membership in five multidimensional network types on disability in six activities of daily living using negative binomial regression, and on mobility (assessed using a timed walk test) using a generalized linear mixed model. RESULTS: Compared to those in the large without strain network, older adults in the small, restricted, high contact network had fewer disabilities but worse mobility, while those in the large network with strain also had worse mobility. DISCUSSION: Care plans focusing on function and mobility should consider multiple aspects of older adults' social networks including network size, diversity, and relationship strain.

Driving Skills at Licensure and Time to First Crash.

BACKGROUND AND OBJECTIVES: Young drivers are overrepresented in crashes, and newly licensed drivers are at high risk, particularly in the months immediately post-licensure. Using a virtual driving assessment (VDA) implemented in the licensing workflow in Ohio, this study examined how driving skills measured at the time of licensure contribute to crash risk post-licensure in newly licensed young drivers. METHODS: This study examined 16 914 young drivers (<25 years of age) in Ohio who completed the VDA at the time of licensure and their subsequent police-reported crash records. By using the outcome of time to first crash, a Cox proportional hazard model was used to estimate the risk of a crash during the follow-up period as a function of VDA Driving Class (and Skill Cluster) membership. RESULTS: The best performing No Issues Driving Class had a crash risk 10% lower than average (95% confidence interval [CI] 13% to 6%), whereas the Major Issues with Dangerous Behavior Class had a crash risk 11% higher than average (95% CI 1% to 22%). These results withstood adjusting for covariates (age, sex, and tract-level socioeconomic status indicators). At the same time, drivers licensed at age 18 had a crash risk 16% higher than average (95% CI 6% to 27%). CONCLUSIONS: This population-level study reveals that driving skills measured at the time of licensure are a predictor of crashes early in licensure, paving the way for better prediction models and targeted, personalized interventions. The authors of future studies should explore time- and exposure-varying risks.

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling.

The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.