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.

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).

Patterns of Cough Medication Prescribing among Patients with Chronic Cough in Florida: 2012-2021.

Among patients with chronic cough (CC) in the 2012-2021 statewide OneFlorida Clinical Research Consortium database, we examined trends in cough medication (CM) prescribing prevalence over time in repeated cross-sectional analyses and identified distinct CM utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Among eligible adults (≥18 years) without cancer/benign respiratory tumor diagnoses, we identified CC patients and non-CC patients with any cough-related diagnosis. In the GBTM analysis, we calculated the number of monthly prescriptions for any CMs (excluding gabapentinoids) during the 12 months from the first qualifying cough event to identify distinct utilization trajectories. From 2012 to 2021, benzonatate (9.6% to 26.1%), dextromethorphan (5.2% to 8.6%), and gabapentinoid (5.3% to 14.4%) use increased among CC patients, while opioid antitussive use increased from 2012 to 2015 and decreased thereafter (8.4% in 2012, 14.7% in 2015, 6.7% in 2021; all p < 0.001). Of 15,566 CC patients and 655,250 non-CC patients identified in the GBTM analysis, CC patients had substantial burdens of respiratory/non-respiratory comorbidities and healthcare service and concomitant medication use compared to non-CC patients. Among CC patients, GBTM identified three distinct CM utilization trajectories: (1) no CM use (n = 11,222; 72.1%); (2) declining CM use (n = 4105; 26.4%); and (3) chronic CM use (n = 239; 1.5%). CC patients in Florida had limited CM use with increasing trends in use of benzonatate, dextromethorphan, and gabapentinoids and a decreasing trend in opioid antitussive use. CC patients, particularly with chronic prescription CM use, experienced substantial disease burden.

Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group-based multi-trajectory models.

BACKGROUND AND AIMS: One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. DESIGN: Retrospective cohort study. SETTING: US Medicare. PARTICIPANTS: Using a 5% national Medicare data sample (2013-16) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). MEASUREMENTS: During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25-50 MME), moderate (51-90 MME), high (91-150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10-20 DME), moderate (21-40 DME), high (41-60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment-weighted Cox proportional hazards models. FINDINGS: We identified nine distinct OPI-BZD trajectories: group A: very low OPI (early discontinuation)-very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)-very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)-medium BZD (n = 4997; 13.2%); D: low OPI-low BZD (n = 5083; 13.4%); E: low OPI-high BZD (n = 3906; 10.3%); F: medium OPI-low BZD (n = 3948; 10.4%); G: very high OPI-high BZD (n = 1371; 3.6%); H: very high OPI-very high BZD (n = 957; 2.5%); and I: very high OPI-low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: E: low OPI-high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61-6.63]; F: medium OPI-low BZD (HR = 4.04, 95% CI = 2.06-7.95); G: very high OPI-high BZD (HR = 6.98, 95% CI = 3.11-15.64); H: very high OPI-very high BZD (HR = 4.41, 95% CI = 1.51-12.85); and I: very high OPI-low BZD (HR = 6.50, 95% CI = 3.15-13.42). CONCLUSIONS: Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very high-dose opioid use (MME > 150), high-dose benzodiazepine use (DME > 40) or medium-dose opioid with low-dose benzodiazepine use.

Trajectories of Opioid Coverage After Long-Term Opioid Therapy Initiation Among a National Cohort of US Veterans.

PURPOSE: The objective of this study was to identify the trajectories that patients take after initiating long-term opioid therapy (LTOT). MATERIALS AND METHODS: Using a retrospective cohort design, veterans with chronic non-cancer pain (CNCP) initiating LTOT were identified. Group-based trajectory models were used to identify opioid therapy trajectories based on days of opioid supply (primary outcome) and average daily morphine milligram equivalent dose (AMME; secondary outcome) in each 180-day period following initiation of LTOT. RESULTS: A total of 438,398 veterans with CNCP initiated LTOT. Nine trajectories were identified: 33.7% with persistent, high days covered, 17.7% with persistent, moderate days covered, 16.6% with slow, persistent days-covered reduction, 2.4% with days-covered reduction followed by increase, 4.6% with delayed days-covered reduction, 4.1% with rapid days-covered reduction, 10.9% with moderate-paced discontinuation, 3.4% with delayed discontinuation, and 6.5% with rapid discontinuation. Patients following discontinuation trajectories were more likely to be younger, persons of color, use more supportive services (eg, physical therapy), and received less opioid days' supply and lower doses prior to initiating LTOT as compared to patients following persistent opioid days-covered trajectories. AMME trajectories were similar to days-covered trajectories. CONCLUSION: Among persons initiating LTOT, nine opioid trajectories emerged which can be broadly characterized into three main trajectory groups: persistent opioid therapy (2 trajectories), reductions in opioid therapy (4 trajectories), and discontinuation (3 trajectories). A majority of patients (51.4%) maintained persistent opioid therapy. Further research is needed to assess the risks of opioid-related adverse outcomes among the identified trajectories.

Trajectories of mental and physical functioning among spouse caregivers of cancer survivors over the first five years following the diagnosis.

OBJECTIVE: Identify the trajectories of physical and mental functioning among spouse caregivers of patients with cancer over the first five years post-diagnosis and variables associated with low or deteriorating functioning. METHODS: Caregivers completed a survey at 6 months and 1, 2, 3.5, and 5 years post-patient diagnosis, including the SF-12 for quality of life (QOL). SF-12 Mental Component Summary (MCS, n=299) and Physical Component Summary (PCS, n=300) scores were analyzed using SAS. RESULTS: Five trajectories for PCS were identified, the top three were: (a) high PCS (53.0%); (b) steady decline in PCS (17.0%); and (c) steady increase, but remaining below population norm (16.7%). Five trajectories for MCS were also identified, the top two being: (a) high MCS (45.8%) and (b) MCS comparable to population norm (27.8%). Variables associated with low or deteriorating QOL included depression, social support, coping, burden, and/or unmet needs. CONCLUSIONS: This is the first study to document spouse caregivers' QOL over the first five years post-patient diagnosis. Although many participants experienced high functioning, almost a third reported low or deteriorating mental or physical functioning. PRACTICE IMPLICATIONS: Variables associated with low or deteriorating mental and physical functioning can be targeted in future interventions.

Lifetime use of cannabis from longitudinal assessments, cannabinoid receptor (CNR1) variation, and reduced volume of the right anterior cingulate.

Lifetime measures of cannabis use and co-occurring exposures were obtained from a longitudinal cohort followed an average of 13 years at the time they received a structural MRI scan. MRI scans were analyzed for 88 participants (mean age=25.9 years), 34 of whom were regular users of cannabis. Whole brain voxel based morphometry analyses (SPM8) were conducted using 50 voxel clusters at p=0.005. Controlling for age, familial risk, and gender, we found reduced volume in Regular Users compared to Non-Users, in the lingual gyrus, anterior cingulum (right and left), and the rolandic operculum (right). The right anterior cingulum reached family-wise error statistical significance at p=0.001, controlling for personal lifetime use of alcohol and cigarettes and any prenatal exposures. CNR1 haplotypes were formed from four CNR1 SNPs (rs806368, rs1049353, rs2023239, and rs6454674) and tested with level of cannabis exposure to assess their interactive effects on the lingual gyrus, cingulum (right and left) and rolandic operculum, regions showing cannabis exposure effects in the SPM8 analyses. These analyses used mixed model analyses (SPSS) to control for multiple potentially confounding variables. Level of cannabis exposure was associated with decreased volume of the right anterior cingulum and showed interaction effects with haplotype variation.

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.

Trajectories of childhood weight gain: the relative importance of local environment versus individual social and early life factors.

OBJECTIVE: To determine the association between local environmental factors with child weight status in a longitudinal study, using a semi-parametric, group-based method, while also considering social and early life factors. METHODS: Standardized, directly measured BMI from 4-10 y of age, and group-based trajectory modeling (PROC TRAJ) were used to estimate developmental trajectories of weight change in a Québec birth cohort (n = 1,566). Associations between the weight trajectories and living location, social cohesion, disorder, and material and social deprivation were estimated after controlling for social and early life factors. RESULTS: FOUR WEIGHT TRAJECTORY GROUPS WERE ESTIMATED: low-increasing (9.7%); low-medium, accelerating (36.2%); medium-high, increasing (43.0%); and high-stable (11.1%). In the low-increasing and medium-high trajectory groups, living in a semi-urban area was inversely related to weight, while living in a rural area was positively related to weight in the high-stable group. Disorder was inversely related to weight in the low-increasing group only. Other important risk factors for high-stable weight included obesity status of the mother, smoking during pregnancy, and overeating behaviors. CONCLUSIONS: In this study, associations between local environment factors and weight differed by trajectory group. Early life factors appear to play a more consistent role in weight status. Further work is needed to determine the influence of place on child weight.

Distressed partners and caregivers do not recover easily: adjustment trajectories among partners and caregivers of cancer survivors.

BACKGROUND: Although a number of cross-sectional studies document the distress experienced by partners and caregivers of cancer survivors, few have considered their potential differential patterns of adjustment over time. PURPOSE: Identify distinct trajectories of anxiety and depression among partners and caregivers of cancer survivors and predictors of these trajectories. METHODS: Participants completed a survey to examine the impact of caring for, or living with, a cancer survivor at 6, 12, and 24 months post-survivor diagnosis. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (N(anxiety) = 510; N(depression) = 511). RESULTS: Anxiety trajectories included: no anxiety (15.1% scored <3; 37.8% scored 3-5); chronic, borderline anxiety (33.2%); and chronic, clinical anxiety (13.9%). The depression trajectories were: no depression (38.9% scored <2; 31.5% scored around 3); a sustained score of 7 (25.5%); and chronic, clinical depression (4.1%). Variables associated with the trajectories included most of the psychosocial variables. CONCLUSIONS: Findings highlight that most caregivers maintained their baseline level of distress, which is particularly concerning for participants reporting chronic anxiety or depression.

Maternal and cord serum cytokine changes with continuous and intermittent labor epidural analgesia: a randomized study.

BACKGROUND: Maternal fever during labor epidural analgesia (LEA) may cause increased maternal and cord serum inflammatory cytokines. We report the effects of intermittent and continuous LEA on these cytokines. METHODS: Ninety-two women were randomly assigned to continuous (CLEA) or intermittent (ILEA) groups, 46 in each. Maternal temperature was checked and blood drawn at epidural insertion (baseline) and four-hourly until 4 h postpartum (4 PP). Cord blood was drawn after placental delivery. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte macrophage-colony stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) were measured and analyzed according to group randomization, and then combined and reanalyzed as febrile (temperature ≥ 38 °C) or afebrile groups. RESULTS: Significant intragroup changes from baseline were noted in some groups. Data are pg/mL, median (Q1/Q3). IL-6 rose at all time points in all groups. CLEA: baseline: 18.5 (12.5/31.1), 4 h: 80.0 (46.3/110.8), 8 h: 171.9 (145.3/234.3), and 4 PP: 81 (55.7/137.4). ILEA: baseline: 15.7 (10.2/27.1), 4 h: 68.2 (33.3/95.0), 8 h: 125.0 (86.3/195.0), and 4 PP: 70.2 (54.8/103.6). Febrile group: baseline: 21.6 (13.8/40.9), 4 h: 83.9 (47.5/120.8), 8 h: 186.7 (149.6/349.9), and 4 PP: 105.8 (65.7/158.8). Afebrile group: baseline: 10.9 (2.1/17.4), 4 h: 38.2 (15.0/68.2), 8 h: 93.8 (57.1/135.7), and 4 PP: 52.9 (25.1/78). IL-8 rose at all time points in CLEA: baseline: 2.68 (0.0/4.3), 4 h: 3.7 (0.0/6.5), 8 h: 6.0 (3.3/9.6), 4 PP: 5.6 (0.8/8.0), and afebrile group baseline: 2.5 (0.0/4.7), 4 h: 3.3 (0.0/6.2), 8 h: 5.3 (1.9/9.8), and 4 PP: 4.7 (0.0/7.6). It fell at 4 PP in febrile group: baseline: 4.1 (0.0/6.4), 4 h: 3.8 (0.0/6.5), 8 h: 5.2 (2.5/8.0), and 4 PP: 2.9 (0.0/4.0). GM-CSF increased at 8 h and decreased at 4 PP in ILEA baseline: 2.73 (0.0/7.2), 4 h: 2.73 (0.0/7.9), 8 h: 3.9 (2.7/11.5), and 4 PP: 2.0 (0.0/7.2). It increased at 4 h and 8 h and decreased at 4 PP in febrile group: baseline: 2.6 (0.0/4.2), 4 h: 3.2 (2.1/7.0), 8 h: 4.0 (3.2/12.3), and 4 PP: 2.4 (1.7/12.6). There were no intergroup cytokine changes in maternal or cord serum in CLEA versus ILEA or febrile versus afebrile groups. CONCLUSIONS: Some cytokines, especially IL-6, rise physiologically during labor epidural analgesia.

Trajectories of drug use and mortality outcomes among adults followed over 18 years.

BACKGROUND: For adults in general population community settings, data regarding long-term course and outcomes of illicit drug use are sparse, limiting the formulation of evidence-based recommendations for drug use screening of adults in primary care. OBJECTIVE: To describe trajectories of three illicit drugs (cocaine, opioids, amphetamines) among adults in community settings, and to assess their relation to all-cause mortality. DESIGN: Longitudinal cohort, 1987/88-2005/06. SETTING: Community-based recruitment from four cities (Birmingham, Chicago, Oakland, Minneapolis). PARTICIPANTS: Healthy adults, balanced for race (black and white) and gender were assessed for drug use from 1987/88-2005/06, and for mortality through 12/31/2008 (n = 4301) MEASUREMENTS: Use of cocaine, amphetamines, and opioids (last 30 days) was queried in the following years: 1987/88, 1990/91, 1992/93, 1995/96, 2000/01, 2005/06. Survey-based assessment of demographics and psychosocial characteristics. Mortality over 18 years. RESULTS: Trajectory analysis identified four groups: Nonusers (n = 3691, 85.8%), Early Occasional Users (n = 340, 7.9%), Persistent Occasional Users (n = 160, 3.7%), and Early Frequent/Later Occasional Users (n = 110, 2.6%). Trajectories conformed to expected patterns regarding demographics, other substance use, family background and education. Adjusting for demographics, baseline health status, health behaviors (alcohol, tobacco), and psychosocial characteristics, Early Frequent/Later Occasional Users had greater all-cause mortality (Hazard Ratio, HR = 4.94, 95% CI = 1.58-15.51, p = 0.006). LIMITATIONS: Study is restricted to three common drugs, and trajectory analyses represent statistical approximations rather than identifiable "types". Causal inferences are tentative. CONCLUSIONS: Four trajectories describe illicit drug use from young adulthood to middle age. Two trajectories, representing over one third of adult users, continued use into middle age. These persons were more likely to continue harmful risk behaviors such as smoking, and more likely to die.

Myocardial extravascular extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow infusion versus bolus.

BACKGROUND: Myocardial extravascular extracellular volume fraction (Ve) measures quantify diffuse fibrosis not readily detectable by conventional late gadolinium (Gd) enhancement (LGE). Ve measurement requires steady state equilibrium between plasma and interstitial Gd contrast. While a constant infusion produces steady state, it is unclear whether a simple bolus can do the same. Given the relatively slow clearance of Gd, we hypothesized that a bolus technique accurately measures Ve, thus facilitating integration of myocardial fibrosis quantification into cardiovascular magnetic resonance (CMR) workflow routines. Assuming equivalence between techniques, we further hypothesized that Ve measures would be reproducible across scans. METHODS: In 10 volunteers (ages 20-81, median 33 yr, 3 females), we compared serial Ve measures from a single short axis slice from two scans: first, during a constant infusion, and second, 12-50 min after a bolus (0.2 mmol/kg gadoteridol) on another day. Steady state during infusion was defined when serial blood and myocardial T1 data varied <5%. We measured T1 on a 1.5 T Siemens scanner using a single-shot modified Look Locker inversion recovery sequence (MOLLI) with balanced SSFP. To shorten breath hold times, T1 values were measured with a shorter sampling scheme that was validated with spin echo relaxometry (TR = 15 sec) in CuSO4-Agar phantoms. Serial infusion vs. bolus Ve measures (n = 205) from the 10 subjects were compared with generalized estimating equations (GEE) with exchangeable correlation matrices. LGE images were also acquired 12-30 minutes after the bolus. RESULTS: No subject exhibited LGE near the short axis slices where Ve was measured. The Ve range was 19.3-29.2% and 18.4-29.1% by constant infusion and bolus, respectively. In GEE models, serial Ve measures by constant infusion and bolus did not differ significantly (difference = 0.1%, p = 0.38). For both techniques, Ve was strongly related to age (p < 0.01 for both) in GEE models, even after adjusting for heart rate. Both techniques identically sorted older individuals with higher mean Ve values. CONCLUSION: Myocardial Ve can be measured reliably and accurately 12-50 minutes after a simple bolus. Ve measures are also reproducible across CMR scans. Ve estimation can be integrated into CMR workflow easily, which may simplify research applications involving the quantification of myocardial fibrosis.

The return to smoking: 1-year relapse trajectories among female smokers.

Research has demonstrated that a lapse in cigarette abstinence often leads smokers to fully relapse (i.e., return to daily smoking). However, patterns of smoking resumption beyond the point at which relapse occurs have not been examined in systematic follow-up studies. Daily cigarette intake data for 108 female adult smokers who participated in a smoking cessation trial were recorded at several points during the 365 days following the participants' quit date. SAS Proc Traj, a group-based mixture modeling procedure, was used to determine cigarette-use trajectories over time (i.e., patterns of smoking resumption). Over the 365 days, 27% of the sample maintained abstinence. Among the 73% who relapsed, four distinct trajectories emerged: low-level users (8% of the overall sample), moderate users (17%), slow-returners (15%), and quick-returners (33%). A few individual characteristics differentiated these groups. Overall, the findings illustrate that, after relapsing, smokers do not follow a unitary course of smoking resumption; rather, they exhibit more variable resumption patterns than previously assumed.