Association between trajectories of adherence to endocrine therapy and risk of treated breast cancer recurrence among US nonmetastatic breast cancer survivors.

BACKGROUND: Endocrine therapy is the mainstay treatment for breast cancer (BC) to reduce BC recurrence risk. During the first year of endocrine therapy use, nearly 30% of BC survivors are nonadherent, which may increase BC recurrence risk. This study is to examine the association between endocrine therapy adherence trajectories and BC recurrence risk in nonmetastatic BC survivors. METHODS: This retrospective cohort study included Medicare beneficiaries in the United States (US) with incident nonmetastatic BC followed by endocrine therapy initiation in 2010-2019 US Surveillance, Epidemiology, and End Results linked Medicare data. We calculated monthly fill-based proportion of days covered in the first year of endocrine therapy. We applied group-based trajectory models to identify distinct endocrine therapy adherence patterns. After the end of the first-year endocrine therapy trajectory measurement period, we estimated the risk of time to first treated BC recurrence within 4 years using Cox proportional hazards models. RESULTS: We identified 5 trajectories of adherence to endocrine therapy in BC Stages 0-I subgroup (n = 28,042) and in Stages II-III subgroup (n = 7781). A trajectory of discontinuation before 6 months accounted for 7.0% in Stages 0-I and 5.8% in Stages II-III subgroups, and this trajectory was associated with an increased treated BC recurrence risk compared to nearly perfect adherence (Stages 0-I: adjusted hazard [aHR] = 1.84, 95% CI = 1.46-2.33; Stages II-III: aHR = 1.38, 95% CI = 1.07-1.77). CONCLUSIONS: Nearly 7% of BC survivors who discontinued before completing 6 months of treatment was associated with an increased treated BC recurrence risk compared to those with nearly perfect adherence among Medicare nonmetastatic BC survivors.

Association between trajectories of prescription opioid use and risk of opioid use disorder and overdose among US nonmetastatic breast cancer survivors.

PURPOSE: To examine the association between prescription opioid use trajectories and risk of opioid use disorder (OUD) or overdose among nonmetastatic breast cancer survivors by treatment type. METHODS: This retrospective cohort study included female nonmetastatic breast cancer survivors with at least 1 opioid prescription fill in 2010-2019 Surveillance, Epidemiology and End Results linked Medicare data. Opioid mean daily morphine milligram equivalents (MME) calculated within 1.5 years after initiating active breast cancer therapy. Group-based trajectory models identified distinct opioid use trajectory patterns. Risk of time to first OUD/overdose event within 1 year after the trajectory period was calculated for distinct trajectory groups using Cox proportional hazards models. Analyses were stratified by treatment type. RESULTS: Four opioid use trajectories were identified for each treatment group. For 38,030 survivors with systemic endocrine therapy, 3 trajectories were associated with increased OUD/overdose risk compared with early discontinuation: minimal dose (< 5 MME; adjusted hazard ratio [aHR] = 1.73 [95% CI 1.43-2.09]), very low dose (5-25 MME; 2.67 [2.05-3.48]), and moderate dose (51-90 MME; 6.20 [4.69-8.19]). For 9477 survivors with adjuvant chemotherapy, low-dose opioid use was associated with higher OUD/overdose risk (aHR = 7.33 [95% CI 2.52-21.31]) compared with early discontinuation. For 3513 survivors with neoadjuvant chemotherapy, the differences in OUD/OD risks across the 4 trajectories were not significant. CONCLUSIONS: Among Medicare nonmetastatic breast cancer survivors receiving systemic endocrine therapy or adjuvant chemotherapy, compared with early discontinuation, low-dose or moderate-dose opioid use were associated with six- to sevenfold higher OUD/overdose risk. Breast cancer survivors at high-risk of OUD/overdose may benefit from targeted interventions (e.g., pain clinic referral).

Recent Advances in Group-Based Trajectory Modeling for Clinical Research.

Group-based trajectory modeling (GBTM) identifies groups of individuals following similar trajectories of one or more repeated measures. The categorical nature of GBTM is particularly well suited to clinical psychology and medicine, where patients are often classified into discrete diagnostic categories. This review highlights recent advances in GBTM and key capabilities that remain underappreciated in clinical research. These include accounting for nonrandom subject attrition, joint trajectory and multitrajectory modeling, the addition of the beta distribution to modeling options, associating trajectories with future outcomes, and estimating the probability of future outcomes. Also discussed is an approach to selecting the number of trajectory groups.

Medication non-adherence patterns and profiles for patients with incident myocardial infarction: Observations from a large multi-morbid US population.

BACKGROUND: Consistent adherence levels to multiple long-term medications for patients with cardiovascular conditions are typically advocated in the range of 50% or higher, although very likely to be much lower in some populations. We investigated this issue in a large cohort covering a broad age and geographical spectrum, with a wide range of socio-economic disability status. METHODS: The patients were drawn from three different health plans with a varied mix of socio-economic/disability levels. Adherence patterns were examined on a monthly basis for up to 12 months past the index date for myocardial infarction (MI) using longitudinal analyses of group-based trajectory modelling. Each of the non-adherent patterns was profiled from comorbid history, demographic and health plan factors using main effect logistic regression modelling. Four medication classes were examined for MI: betablockers, statin, ACE inhibitors and anti-platelets. RESULTS: The participant population for the MI/non-MI cohorts was 1,987,605 (MI cohort: mean age 62 years, 45.9% female; non-MI cohort: mean age 45 years, 55.3% females). Cohorts characterized by medication non-adherence dominated the majority of MI population with values ranging from 74% to 82%. There were four types of consistent non-adherence patterns as a function of time for each medication class: fast decline, slow decline, occasional users and early gap followed by increased adherence. The characteristics of non-adherence profiles eligible for improvement included patients with a prior history of hypertension, diabetes mellitus and stroke as co-morbidities, and Medicare plan. CONCLUSIONS: We found consistent patterns of intermediate non-adherence for each of four drug classes for MI cohorts in the order of 56% who are eligible for interventions aimed at improving cardiovascular medication adherence levels. These insights may help improve cardiovascular medication adherence using large medication non-adherence improvement programs.

Adherence levels and patterns for multiple cardiac medications prescribed to patients with incident atrial fibrillation events.

AIMS: Using advanced longitudinal analyses, this real-world investigation examined medication adherence levels and patterns for incident atrial fibrillation (AF) patients with significant cardiovascular and noncardiovascular multimorbid conditions for each of 5 medication classes (ß-blockers, calcium channel blockers/digoxin, antiarrhythmics, anticoagulants, antiplatelets). The population was derived from a large cohort covering a wide age spectrum/diversified US geographical areas/wide range of socioeconomic-disability status. METHODS: The patients were drawn from 3 different health plans. Adherence was defined in terms of the proportion of day covered (PDC), and its patterns were modelled in terms of group-based trajectory, with each pattern profiled in terms of comorbid history, demographic variables and health plan factors using multinomial regression modelling. RESULTS: The total population consisted of 1 978 168 patients, with the AF cohort being older (average age of 64.6 years relative to 44.7 years for the non-AF cohort) and having fewer females (47.8% relative to 55.4 for the non-AF cohort). The AF cohort had significant cardiovascular/noncardiovascular multimorbidities and was much sicker than the non-AF cohort. A 6-group based trajectory solution appears to be the most logical outcome for each medication class according to assessed criteria. For each medication class, it consisted of one consistent adherent group (PDC ≥ 0.84), one fast declining group (PDC ≤ 0.11) and 4 intermediate nonadherence groups (slow decline [0.30-0.74 PDC range], occasional users [0.24-0.55 PDC range] and early gap/increased adherence [0.62-0.75]). The most consistent adherent groups were much lower than 50% of the total population and equal to 12.5-27.0% of the population, with the fast declining nonadherent pattern in the 5.6-35.0% of the population and the intermediate nonadherence equal to ~61% of the population. CONCLUSION: Our findings confirm that medication adherence is of major concern among multimorbid patients, with adherence levels lower much than those reported in the literature. There are 3 patterns of intermediate nonadherence (slow decline, occasional users, early gap/increased adherence), which were found to be eligible for interventions aimed at improving their adherence levels for each medication class. This may help improve cardiovascular medication adherence using large medication nonadherence improvement programmes.

Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism.

BACKGROUND: Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. OBJECTIVE: We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. METHODS: Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. RESULTS: Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. CONCLUSION AND RELEVANCE: This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.

Spinal pain in childhood: prevalence, trajectories, and diagnoses in children 6 to 17 years of age.

This study aimed to investigate the trajectories of spinal pain frequency from 6 to 17 years of age and describe the prevalence and frequency of spinal pain and related diagnoses in children following different pain trajectories. First through fifth-grade students from 13 primary schools were followed for 5.5 years. Occurrences of spinal pain were reported weekly via text messages. Children reporting spinal pain were physically evaluated and classified using International Classification of Disease criteria. Trajectories of spinal pain frequency were modeled from age 6 to 17 years with latent class growth analysis. We included data from 1556 children (52.4% female, mean (SD) baseline age = 9.1 (1.9) years) and identified 10,554 weeks of spinal pain in 329,756 weeks of observation. Sixty-three percent of children reported one or more occurrences of spinal pain. We identified five trajectories of spinal pain frequency. Half the children (49.8%) were classified as members of a "no pain" trajectory. The remaining children followed "rare" (27.9%), "rare, increasing" (14.5%), "moderate, increasing" (6.5%), or "early-onset, decreasing" (1.3%) spinal pain trajectories. The most common diagnoses in all trajectory groups were non-specific (e.g., "back pain"). Tissue-specific diagnoses (e.g., muscle strain) were less common and pathologies (e.g., fracture) were rare.  Conclusion: From childhood through adolescence, spinal pain was common and followed heterogeneous courses comprising stable, increasing, and early-onset trajectories. These findings accord with recommendations from adult back pain guidelines that most children with spinal pain can be reassured that they do not have a serious disease and encouraged to stay active. What is Known: • Spinal pain imposes a large burden on individuals and society. • Although many people first experience the condition in childhood, little is known about the developmental trajectories of spinal pain from childhood to adolescence. What is New: • Data from 1556 children and 329,756 participant weeks showed five unique spinal pain trajectories from 6 to 17 years: most children rarely reported spinal pain, while one in five followed increasing or early-onset trajectories. • Most pain occurrences were non-specific; pathological diagnoses were rare.

Classifying Patients with Amyotrophic Lateral Sclerosis by Changes in FVC. A Group-based Trajectory Analysis.

Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time.Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months.Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79).Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.

Adherence trajectories of buprenorphine therapy among pregnant women in a large state Medicaid program in the United States.

PURPOSE: Little is known about the longitudinal patterns of buprenorphine adherence among pregnant women with opioid use disorder, especially when late initiation, nonadherence, or early discontinuation of buprenorphine during pregnancy may increase the risk of adverse outcomes. We aimed to identify distinct trajectories of buprenorphine use during pregnancy, and factors associated with these trajectories in Medicaid-enrolled pregnant women. METHODS: A retrospective cohort study included 2361 Pennsylvania Medicaid enrollees aged 15 to 46 having buprenorphine therapy during pregnancy and a live birth between 2008 and 2015. We used group-based trajectory models to identify buprenorphine use patterns in the 40 weeks prior to delivery and 12 weeks postdelivery. Multivariable multinomial logistic regression models were used to identify factors associated with specific trajectories. RESULTS: Six distinct trajectories were identified. Four groups initiated buprenorphine during the first trimester of the pregnancy (early initiators): 31.6% with persistently high adherence, 15.1% with moderate-to-high adherence, 10.5% with declining adherence, and 16.7% with early discontinuation. Two groups did not initiate buprenorphine until midsecond or third trimester (late initiators): 13.5% had moderate-to-high adherence and 12.6% had low-to-moderate adherence. Factors significantly associated with late initiation and discontinuation were younger age, non-white race, residents of rural counties, fewer outpatient visits, more frequent emergency department visits and hospitalizations, and lower buprenorphine daily dose. CONCLUSIONS: Six buprenorphine treatment trajectories during pregnancy were identified in this population-based Medicaid cohort, with 25% of women initiating buprenorphine late during pregnancy. Understanding trajectories of buprenorphine use and factors associated with discontinuation/nonadherence may guide integration of behavioral treatment with obstetrical/gynecological care to improve buprenorphine treatment during pregnancy.

Patterns of antihypertensive and statin adherence prior to dementia: findings from the adult changes in thought study.

BACKGROUND: Detecting patients with undiagnosed dementia is an important clinical challenge. Changes in medication adherence might represent an early sign of cognitive impairment. We sought to examine antihypertensive and statin adherence trajectories in community-dwelling older adults, comparing people who went on to develop dementia to those who did not. METHODS: We analyzed data from Adult Changes in Thought (ACT), a population-based cohort study embedded within an integrated healthcare delivery system. Analyses included 4368 participants aged ≥65 years who had at least one follow-up visit. Research-quality dementia diagnoses were used to identify cases. We selected non-dementia control visits matched on age, sex, and study cohort that occurred at similar ACT follow-up time as the case's dementia onset; we treated this as the index date. Participants were included if they were prevalent users of either a statin or antihypertensive medication on the first day of follow up - 3 years prior to the index date. Using prescription fill dates and days supply, we calculated daily binary medication availability measures for each participant ('days covered') over 3 years leading up to the index date. We used group-based trajectory models to identify patterns of antihypertensive and statin adherence, and used conditional logistic regression to examine associations between adherence trajectories and dementia. RESULTS: Four trajectories were identified for antihypertensive users (292 cases, 3890 control visits), including near perfect (n = 1877, 36.6% cases, 45.5% controls), high (n = 1840, 43.2% cases, 44.1% controls), moderate (n = 365, 18.5% cases, 8.0% controls) and early poor adherence (n = 100, 1.7% cases, 2.4% controls). Odds of dementia was 3 times greater for those with moderate antihypertensive adherence compared to those with near perfect adherence (adjusted OR 3.0, 95% CI 2.0, 4.3). Four trajectories were identified for statin users (148 cases, 1131 control visits), including high (n = 1004, 75.0% cases, 79.0% controls), moderate (n = 192, 19.6% cases, 14.4% controls), early poor (n = 43, 2.0% cases, 3.5% controls), and delayed poor adherence (n = 40, 3.4% cases, 3.1% controls). No association was detected between statin adherence trajectories and dementia. CONCLUSIONS: Patterns of medication adherence may be useful to identify a subset of people at higher likelihood of developing dementia.

Using the Beta distribution in group-based trajectory models.

BACKGROUND: We demonstrate an application of Group-Based Trajectory Modeling (GBTM) based on the beta distribution. It is offered as an alternative to the normal distribution for modeling continuous longitudinal data that are poorly fit by the normal distribution even with censoring. The primary advantage of the beta distribution is the flexibility of the shape of the density function. METHODS: GBTM is a specialized application of finite mixture modeling designed to identify clusters of individuals who follow similar trajectories. Like all finite mixture models, GBTM requires that the distribution of the data composing the mixture be specified. To our knowledge this is the first demonstration of the use of the beta distribution in GBTM. A case study of a beta-based GBTM analyzes data on the neurological activity of comatose cardiac arrest patients. RESULTS: The case study shows that the summary measure of neurological activity, the suppression ratio, is not well fit by the normal distribution but due to the flexibility of the shape of the beta density function, the distribution of the suppression ratio by trajectory appears to be well matched by the estimated beta distribution by group. CONCLUSIONS: The addition of the beta distribution to the already available distributional alternatives in software for estimating GBTM is a valuable augmentation to extant distributional alternatives.

A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy.

Proline oxidase (POX) catalytically converts proline to pyrroline-5-carboxylate. This catabolic conversion generates reactive oxygen species (ROS) that triggers cellular signaling cascades including autophagy and apoptosis. This study for the first time demonstrates a role of POX in HIV-1 envelope glycoprotein (gp120)-induced neuronal autophagy. HIV-1 gp120 is a neurotoxic factor and is involved in HIV-1-associated neurological disorders. However, the mechanism of gp120-mediated neurotoxicity remains unclear. Using SH-SY5Y neuroblastoma cells as a model, this study demonstrates that gp120 treatment induced POX expression and catalytic activity. Concurrently, gp120 also increased intracellular ROS levels. However, increased ROS had a minimal effect on neuronal apoptosis. Further investigation indicated that the immediate cellular response to increased ROS paralleled with induction of autophagy markers, beclin-1 and LC3-II. These data lead to the hypothesis that neuronal autophagy is activated as a cellular protective response to the toxic effects of gp120. A direct and functional role of POX in gp120-mediated neuronal autophagy was examined by inhibition and overexpression studies. Inhibition of POX activity by a competitive inhibitor "dehydroproline" decreased ROS levels concomitant with reduced neuronal autophagy. Conversely, overexpression of POX in neuronal cells increased ROS levels and activated ROS-dependent autophagy. Mechanistic studies suggest that gp120 induces POX by targeting p53. Luciferase reporter assays confirm that p53 drives POX transcription. Furthermore, data demonstrate that gp120 induces p53 via binding to the CXCR4 co-receptor. Collectively, these results demonstrate a novel role of POX as a stress response metabolic regulator in HIV-1 gp120-associated neuronal autophagy.

Who Were the Early Adopters of Dabigatran?: An Application of Group-based Trajectory Models.

BACKGROUND: Variation in physician adoption of new medications is poorly understood. Traditional approaches (eg, measuring time to first prescription) may mask substantial heterogeneity in technology adoption. OBJECTIVE: Apply group-based trajectory models to examine the physician adoption of dabigratran, a novel anticoagulant. METHODS: A retrospective cohort study using prescribing data from IMS Xponent™ on all Pennsylvania physicians regularly prescribing anticoagulants (n=3911) and data on their characteristics from the American Medical Association Masterfile. We examined time to first dabigatran prescription and group-based trajectory models to identify adoption trajectories in the first 15 months. Factors associated with rapid adoption were examined using multivariate logistic regressions. OUTCOMES: Trajectories of monthly share of oral anticoagulant prescriptions for dabigatran. RESULTS: We identified 5 distinct adoption trajectories: 3.7% rapidly and extensively adopted dabigatran (adopting in ≤3 mo with 45% of prescriptions) and 13.4% were rapid and moderate adopters (≤3 mo with 20% share). Two groups accounting for 21.6% and 16.1% of physicians, respectively, were slower to adopt (6-10 mo post-introduction) and dabigatran accounted for <10% share. Nearly half (45.2%) of anticoagulant prescribers did not adopt dabigatran. Cardiologists were much more likely than primary care physicians to rapidly adopt [odds ratio (OR)=12.2; 95% confidence interval (CI), 9.27-16.1] as were younger prescribers (age 36-45 y: OR=1.49, 95% CI, 1.13-1.95; age 46-55: OR=1.34, 95% CI, 1.07-1.69 vs. >55 y). CONCLUSIONS: Trajectories of physician adoption of dabigatran were highly variable with significant differences across specialties. Heterogeneity in physician adoption has potential implications for the cost and effectiveness of treatment.

Trajectories of Diabetes Medication Adherence and Hospitalization Risk: A Retrospective Cohort Study in a Large State Medicaid Program.

BACKGROUND: Numerous interventions are available to boost medication adherence, but the targeting of these interventions often relies on crude measures of poor adherence. Group-based trajectory models identify individuals with similar longitudinal prescription filling patterns. Identifying distinct adherence trajectories may be more useful for targeting interventions, although the association between adherence trajectories and clinical outcomes is unknown. OBJECTIVE: To examine the association between adherence trajectories for oral hypoglycemics and subsequent hospitalizations among diabetes patients. DESIGN: Retrospective cohort study. PATIENTS: A total of 16,256 Pennsylvania Medicaid enrollees, non-dually eligible for Medicare, initiating oral hypoglycemics between 2007 and 2009. MAIN MEASURES: We used group-based trajectory models to identify trajectories of oral hypoglycemics in the 12 months post-treatment initiation, using monthly proportion of days covered (PDC) as the adherence measure. Multivariable Cox proportional hazard models were used to examine the association between trajectories and time to first diabetes-related hospitalization/emergency department (ED) visits in the following year. We used the C-index to compare prediction performance between adherence trajectories and dichotomous cutpoints (annual PDC <80 vs. ≥80 %). RESULTS: The mean annual PDC was 0.58 (SD 0.32). Seven trajectories were identified: perfect adherers (9 % of the cohort), nearly perfect adherers (31.4 %), moderate adherers (21.0 %), low adherers (11.0 %), late discontinuers (6.8 %), early discontinuers (9.7 %), and non-adherers with only one fill (11.1 %). Compared to perfect adherers, trajectories of moderate adherers (HR = 1.48, 95 % CI 1.25, 1.75), low adherers (HR = 1.51, 95 % CI 1.25, 1.83), and non-adherers with only one fill (HR = 1.35, 95 % CI 1.09, 1.67) had greater risk of diabetes-related hospitalizations/ED visits. Predictive accuracy was improved using trajectories compared to dichotomized cutpoints (C-index = 0.714 vs. 0.652). CONCLUSIONS: Oral hypoglycemic treatment trajectories were highly variable in this large Medicaid cohort. Low and moderate adherers and those filling only one prescription had a modestly higher risk of hospitalizations/ED visits compared to perfect adherers. Trajectory models may be valuable in identifying specific non-adherence patterns for targeting interventions.

Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families.

Cannabis use is common among adolescents. Identification of the factors associated with continued heavy use into young adulthood and development of cannabis abuse and dependence is of considerable importance. The role of familial risk for addiction and an associated endophenotype, P300 amplitude, has not previously been related to cannabis use and dependence. A prospective longitudinal study spanning childhood and young adulthood provided the opportunity for exploring these factors, along with genetic variation, in the cannabis use behaviors of 338 young adult offspring from high and low familial risk for alcohol dependence families (ages 19-30). P300 data were collected multiple times in childhood. The association between young adult patterns of cannabis use or cannabis abuse/dependence was tested with genetic variation in the cannabinoid gene, CNR1, the ANKK1-DRD2 gene, and childhood developmental trajectories of P300. Young adult patterns of cannabis use was characterized by three patterns: (i) no use throughout; (ii) declining use from adolescence through young adulthood; and (iii) frequent use throughout. Following the low P300 trajectory in childhood predicted cannabis abuse and dependence by young adulthood. A four SNP ANKK1-DRD2 haplotype (G-G-G-C) was found to be significantly associated with the frequency of use patterns (P = 0.0008). Although CNR1 variation overall was not significantly associated with these patterns, among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A > G minor allele conferred a 5.4-fold increase (P = 0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group.

Effectiveness of a physical activity and weight loss intervention for middle-aged women: healthy bodies, healthy hearts randomized trial.

BACKGROUND: Physical inactivity is a significant risk factor for cardiovascular disease and remains highly prevalent in middle-aged women. OBJECTIVE: We hypothesized that an interventionist-led (IL), primary-care-based physical activity (PA) and weight loss intervention would increase PA levels and decrease weight to a greater degree than a self-guided (SG) program. DESIGN: We conducted a randomized trial. PARTICIPANTS: Ninety-nine inactive women aged 45-65 years and with BMI ≥ 25 kg/m(2) were recruited from three primary care clinics. INTERVENTIONS: The interventionist-led (IL) group (n = 49) had 12 weekly sessions of 30 min discussions with 30 min of moderate-intensity PA. The self-guided (SG) group (n = 50) received a manual for independent use. MAIN MEASURES: Assessments were conducted at 0, 3, and 12 months; PA and weight were primary outcomes. Weight was measured with a standardized protocol. Leisure PA levels were assessed using the Modifiable Activity Questionnaire. Differences in changes by group were analyzed with a t-test or Wilcoxon rank-sum test. Mixed models were used to analyze differences in changes of outcomes by group, using an intention-to-treat principle. KEY RESULTS: Data from 98 women were available for analysis. At baseline, mean (SD) age was 53.9 (5.4) years and 37 % were black. Mean weight was 92.3 (17.7) kg and mean BMI was 34.7 (5.9) kg/m(2). Median PA level was 2.8 metabolic equivalent hours per week (MET-hour/week) (IQR 0.0, 12.0). At 3 months, IL women had a significantly greater increase in PA levels (7.5 vs. 1.9 MET-hour/week; p = 0.02) than SG women; there was no significant difference in weight change. At 12 months, the difference between groups was no longer significant (4.7 vs. 0.7 MET-hour/week; p = 0.38). Mixed model analysis showed a significant (p = 0.048) difference in PA change between groups at 3 months only. CONCLUSIONS: The IL intervention was successful in increasing the physical activity levels of obese, inactive middle-aged women in the short-term. No significant changes in weight were observed.

ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families.

A previous genome-wide linkage study of alcohol dependence (AD) in the Pittsburgh-based multiplex family study found suggestive evidence for linkage on Chromosome 7q, a region in which the ACN9 gene is located. Using the same two generation Pittsburgh family data in which linkage was found, data for a third generation was added. The expanded sample included 133 pedigrees with 995 individuals. Finer mapping was undertaken using six SNPs extending from rs1917939 to rs13475 with minor allele frequency (MAF) ≥0.15 and pair-wise linkage disequilibrium (LD) of r(2) <0.8 using the HapMap CEU population. Binary affection status, visual, and auditory P300 data were tested for family-based association. Family-based analyses found all six SNPs associated with affected status. Three SNPs are located upstream of the gene, two SNPs are within intron 1 and one is in Exon 4. FBAT P-values for the six SNPs ranged between 0.05 and 0.0005. Haplotype analysis revealed one four-SNP block formed by rs10499934, rs7794886, rs12056091, and rs13475 with an overall significant association at P = 0.0008. Analysis of visual P300 amplitude data, a known endophenotype of alcohol dependence risk, revealed a significant association for SNPs within intron 1 and exon 4 under a dominant model of transmission. Family-based association analysis shows the ACN9 gene significantly associated with alcohol dependence and P300 amplitude variation. The potential importance of the ACN9 gene for AD risk may be related to its role in gluconeogenesis which may be involved in the regulation of alcohol metabolism.

Characteristics of US Medicare Beneficiaries with Chronic Cough vs. Non-Chronic Cough: 2011-2018.

Background: Chronic cough (CC), characterized as a cough lasting >8 weeks, is a common multi-factorial syndrome in the community, especially in older adults. Methods: Using a pre-existing algorithm to identify patients with CC within the 2011-2018 Medicare beneficiaries, we examined trends in gabapentinoid use through repeated cross-sectional analyses and identified distinct utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Individuals without CC but with any respiratory conditions related to cough served as a comparator group. Results: Among patients with CC, gabapentinoid use increased from 18.6% in 2011 to 24.1% in 2018 (p = 0.002), with a similar upward trend observed in the non-CC cohort but with overall lower usage (14.7% to 18.4%; p < 0.001). Patients with CC had significantly higher burdens of respiratory and non-respiratory comorbidities, as well as greater healthcare service and medication use compared to the non-CC cohort. The GBTM analyses identified three distinct gabapentinoid utilization trajectories for CC and non-CC patients: no use (77.3% vs. 84.5%), low use (13.9% vs. 10.3%), and high use (8.8% vs. 5.2%). Conclusions: Future studies are needed to evaluate the safety and effectiveness of gabapentinoid use in patients with refractory or unexplained CC in real-world settings.

Association between Opioid-Benzodiazepine Trajectories and Injurious Fall Risk among US Medicare Beneficiaries.

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Pain trajectories of nursing home residents.

BACKGROUND: Understanding changes in nursing home (NH) resident pain over time would provide a more informed perspective, allowing opportunities to alter the course of illness, plan care, and set priorities. Therefore, the purpose of this analysis was to identify and characterize clinically meaningful, dynamic pain trajectories in NH residents. METHODS: Retrospective longitudinal analysis of NH resident pain scores with a length of stay >100 days (N = 4864). Group-based trajectory modeling was applied to Minimum Data Set 3.0 assessments to identify pain trajectories. Trajectories were then characterized using unadjusted and adjusted cross-sectional associations between residents' demographic and clinical characteristics and their pain trajectory. RESULTS: We identified four distinct trajectories: (1) consistent pain absence (48.9%), (2) decreasing-increasing pain presence (21.8%), (3) increasing-decreasing pain presence (15.3%), and (4) persistent pain presence (14.0%). Demographics of younger age and living in a rural area were associated with the persistent pain presence trajectory. Clinical variables of obesity and intact cognition were associated with being in the persistent pain presence trajectory. A smaller proportion of residents with moderately or severely impaired cognition were in any of the trajectory groups with pain. CONCLUSIONS: We identified and characterized four pain trajectories among NH residents, including persistent pain presence which was associated with demographic characteristics (younger, female, rural) and clinical factors (obese, fracture, contracture). Moreover, residents with a diagnosis of Alzheimer's disease or dementia were less likely to be in any of the three trajectories with pain, likely representing the difficulty in evaluating pain in these residents. It is important that NH staff understand, recognize, and respond to the factors associated with the identified pain trajectories to improve mitigation of potentially persistent pain (e.g., hip fracture, contracture) or improve proxy pain assessment skills for residents at risk for under reporting of pain (e.g., Alzheimer's Disease).