A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

Health impacts of a randomized biomass cookstove intervention in northern Ghana.

BACKGROUND: Household air pollution (HAP) from cooking with solid fuels has adverse health effects. REACCTING (Research on Emissions, Air quality, Climate, and Cooking Technologies in Northern Ghana) was a randomized cookstove intervention study that aimed to determine the effects of two types of "improved" biomass cookstoves on health using self-reported health symptoms and biomarkers of systemic inflammation from dried blood spots for female adult cooks and children, and anthropometric growth measures for children only. METHODS: Two hundred rural households were randomized into four different cookstove groups. Surveys and health measurements were conducted at four time points over a two-year period. Chi-square tests were conducted to determine differences in self-reported health outcomes. Linear mixed models were used to assess the effect of the stoves on inflammation biomarkers in adults and children, and to assess the z-score deviance for the anthropometric data for children. RESULTS: We find some evidence that two biomarkers of oxidative stress and inflammation, serum amyloid A and C-reactive protein, decreased among adult primary cooks in the intervention groups relative to the control group. We do not find detectable impacts for any of the anthropometry variables or self-reported health. CONCLUSIONS: Overall, we conclude that the REACCTING intervention did not substantially improve the health outcomes examined here, likely due to continued use of traditional stoves, lack of evidence of particulate matter emissions reductions from "improved" stoves, and mixed results for HAP exposure reductions. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov (National Institutes of Health); Trial Registration Number: NCT04633135 ; Date of Registration: 11 November 2020 - Retrospectively registered. URL: https://clinicaltrials.gov/ct2/show/NCT04633135?term=NCT04633135&draw=2&rank=1.

Plasma protein patterns as comprehensive indicators of health.

Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3-10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12-16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.

New Emission Factors and Efficiencies from in-Field Measurements of Traditional and Improved Cookstoves and Their Potential Implications.

Household cooking using solid biomass fuels is a major global health and environmental concern. As part of the Research on Emissions Air quality Climate and Cooking Technologies in Northern Ghana study, we conducted 75 in-field uncontrolled cooking tests designed to assess emissions and efficiency of the Gyapa woodstove, Philips HD4012, threestone fire and coalpot (local charcoal stove). Emission factors (EFs) were calculated for carbon monoxide (CO), carbon dioxide (CO2), and particulate matter (PM). Moreover, modified combustion (MCE), heat transfer (HTE) and overall thermal efficiencies (OTE) were calculated across a variety of fuel, stove and meal type combinations. Mixed effect models suggest that compared to traditional stove/fuel combinations, the Philips burning wood or charcoal showed significant fuel and energy based EF differences for CO, but no significant PM changes with wood fuel. MCEs were significantly higher for Philips wood and charcoal-burning stoves compared to the threestone fire and coalpot. The Gyapa emitted significantly higher ratios of elemental to organic carbon. Fuel moisture, firepower and MCE fluctuation effects on stove performance were investigated with mixed findings. Results show agreement with other in-field findings and discrepancies with some lab-based findings, with important implications for estimated health and air quality impacts.

Flexible modeling of the hazard rate and treatment effects in long-term survival studies.

The effects of predictors on time to failure may be difficult to assess in cancer studies with longer follow-up, as the commonly used assumption of proportionality of hazards holding over an extended period is often questionable. Motivated by a long-term prostate cancer clinical trial, we contrast and compare four powerful methods for estimation of the hazard rate. These four methods allow for varying degrees of smoothness as well as covariates with effects that vary over time. We pay particular attention to an extended multiresolution hazard estimator, which is a flexible, semi-parametric, Bayesian method for joint estimation of predictor effects and the hazard rate. We compare the results of the extended multiresolution hazard model to three other commonly used, comparable models: Aalen's additive model, Kooperberg's hazard regression model, and an extended Cox model. Through simulations and the analysis of a large-scale randomized prostate cancer clinical trial, we use the different methods to examine patterns of biochemical failure and to estimate the time-varying effects of androgen deprivation therapy treatment and other covariates.

Exposures to and origins of carbonaceous PM2.5 in a cookstove intervention in Northern Ghana.

REACCTING (Research on Emissions Air Quality, Climate, and Cooking Technologies in Northern Ghana) was a 200-home cookstove intervention study from 2013 to 2015. Study households were divided into four groups: a control group, a group given two locally made rocket stoves, a group given two Philips forced draft stoves, and a group given a locally made rocket stove and a Philips stove. In a subset of study households, 48-hour PM2.5 exposure samples were collected for adults and children, as well as in the primary cooking area. Further, weekly ambient background PM2.5 samples were collected for the first nine months of the study. All PM2.5 samples were analyzed for elemental and organic carbon (EC/OC), and a subset was also analyzed for organics. Mixed effects modeling was applied to quantify differences in PM exposures between the groups and to assess relationships between exposures and cooking area measurements. Results showed that personal OC exposure for the intervention groups was 56.6% lower than the control group (p≤0.01). Both intervention groups given Philips stoves had significantly lower EC exposure than the control group (60.6% reduction, p≤0.02). Only weak relationships were found between personal and cooking area EC or OC. Source apportionment modeling was performed on both the personal/microenvironment and the ambient organics PM2.5 data sets to assess the sources of the observed PM. We identified six PM sources. The identified source factors were similar among the data sets, as well as with previous work in Navrongo. Two sources, one characterized by the presence of methoxyphenols, and one by the presence of polyaromatic hydrocarbons and EC, were associated with biomass burning, and accounted for a median of 9.2% of OC and 15.3% of EC personal exposure. Here, we demonstrate the utility of using the cooking-related source apportionment factors within a mixed effects model for more precise estimation of exposures due to cooking, rather than other combustion sources unrelated to the intervention.

A multivariate cure model for left-censored and right-censored data with application to colorectal cancer screening patterns.

We develop a multivariate cure survival model to estimate lifetime patterns of colorectal cancer screening. Screening data cover long periods of time, with sparse observations for each person. Some events may occur before the study begins or after the study ends, so the data are both left-censored and right-censored, and some individuals are never screened (the 'cured' population). We propose a multivariate parametric cure model that can be used with left-censored and right-censored data. Our model allows for the estimation of the time to screening as well as the average number of times individuals will be screened. We calculate likelihood functions based on the observations for each subject using a distribution that accounts for within-subject correlation and estimate parameters using Markov chain Monte Carlo methods. We apply our methods to the estimation of lifetime colorectal cancer screening behavior in the SEER-Medicare data set. Copyright © 2016 John Wiley & Sons, Ltd.

Research on Emissions, Air quality, Climate, and Cooking Technologies in Northern Ghana (REACCTING): study rationale and protocol.

BACKGROUND: Cooking over open fires using solid fuels is both common practice throughout much of the world and widely recognized to contribute to human health, environmental, and social problems. The public health burden of household air pollution includes an estimated four million premature deaths each year. To be effective and generate useful insight into potential solutions, cookstove intervention studies must select cooking technologies that are appropriate for local socioeconomic conditions and cooking culture, and include interdisciplinary measurement strategies along a continuum of outcomes. METHODS/DESIGN: REACCTING (Research on Emissions, Air quality, Climate, and Cooking Technologies in Northern Ghana) is an ongoing interdisciplinary randomized cookstove intervention study in the Kassena-Nankana District of Northern Ghana. The study tests two types of biomass burning stoves that have the potential to meet local cooking needs and represent different "rungs" in the cookstove technology ladder: a locally-made low-tech rocket stove and the imported, highly efficient Philips gasifier stove. Intervention households were randomized into four different groups, three of which received different combinations of two improved stoves, while the fourth group serves as a control for the duration of the study. Diverse measurements assess different points along the causal chain linking the intervention to final outcomes of interest. We assess stove use and cooking behavior, cooking emissions, household air pollution and personal exposure, health burden, and local to regional air quality. Integrated analysis and modeling will tackle a range of interdisciplinary science questions, including examining ambient exposures among the regional population, assessing how those exposures might change with different technologies and behaviors, and estimating the comparative impact of local behavior and technological changes versus regional climate variability and change on local air quality and health outcomes. DISCUSSION: REACCTING is well-poised to generate useful data on the impact of a cookstove intervention on a wide range of outcomes. By comparing different technologies side by side and employing an interdisciplinary approach to study this issue from multiple perspectives, this study may help to inform future efforts to improve health and quality of life for populations currently relying on open fires for their cooking needs.

Survival Analysis with Electronic Health Record Data: Experiments with Chronic Kidney Disease.

This paper presents a detailed survival analysis for chronic kidney disease (CKD). The analysis is based on the EHR data comprising almost two decades of clinical observations collected at New York-Presbyterian, a large hospital in New York City with one of the oldest electronic health records in the United States. Our survival analysis approach centers around Bayesian multiresolution hazard modeling, with an objective to capture the changing hazard of CKD over time, adjusted for patient clinical covariates and kidney-related laboratory tests. Special attention is paid to statistical issues common to all EHR data, such as cohort definition, missing data and censoring, variable selection, and potential for joint survival and longitudinal modeling, all of which are discussed alone and within the EHR CKD context.

Shock index and early recognition of sepsis in the emergency department: pilot study.

INTRODUCTION: Screening for severe sepsis in adult emergency department (ED) patients may involve potential delays while waiting for laboratory testing, leading to postponed identification or over-utilization of resources. The systemic inflammatory response syndrome (SIRS) criteria are inaccurate at predicting clinical outcomes in sepsis. Shock index (SI), defined as heart rate / systolic blood pressure, has previously been shown to identify high risk septic patients. Our objective was to compare the ability of SI, individual vital signs, and the systemic inflammatory response syndrome (SIRS) criteria to predict the primary outcome of hyperlactatemia (serum lactate ≥ 4.0 mmol/L) as a surrogate for disease severity, and the secondary outcome of 28-day mortality. METHODS: We performed a retrospective analysis of a cohort of adult ED patients at an academic community trauma center with 95,000 annual visits, from February 1st, 2007 to May 28th, 2008. Adult patients presenting to the ED with a suspected infection were screened for severe sepsis using a standardized institutional electronic order set, which included triage vital signs, basic laboratory tests and an initial serum lactate level. Test characteristics were calculated for two outcomes: hyperlactatemia (marker for morbidity) and 28-day mortality. We considered the following covariates in our analysis: heart rate >90 beats/min; mean arterial pressure < 65 mmHg; respiratory rate > 20 breaths/min; ≥ 2 SIRS with vital signs only; ≥2 SIRS including white blood cell count; SI ≥ 0.7; and SI ≥ 1.0. We report sensitivities, specificities, and positive and negative predictive values for the primary and secondary outcomes. RESULTS: 2524 patients (89.4%) had complete records and were included in the analysis. 290 (11.5%) patients presented with hyperlactatemia and 361 (14%) patients died within 28 days. Subjects with an abnormal SI of 0.7 or greater (15.8%) were three times more likely to present with hyperlactatemia than those with a normal SI (4.9%). The negative predictive value (NPV) of a SI ≥ 0.7 was 95%, identical to the NPV of SIRS. CONCLUSION: In this cohort, SI ≥ 0.7 performed as well as SIRS in NPV and was the most sensitive screening test for hyperlactatemia and 28-day mortality. SI ≥ 1.0 was the most specific predictor of both outcomes. Future research should focus on multi-site validation, with implications for early identification of at-risk patients and resource utilization.

Interfraction motion of the vaginal apex during postoperative intensity modulated radiation therapy: are we missing the target?

OBJECTIVE: This study aimed to evaluate changes in vaginal cuff position and rectal distention during whole pelvic intensity modulated radiation therapy using daily image guidance for patients with gynecologic malignancies. MATERIALS AND METHODS: We reviewed 145 daily images from 5 patients treated with intensity modulated radiation therapy after total abdominal hysterectomy for endometrial or cervical cancer. A fiducial marker was placed in the vaginal cuff tissue before computed tomographic simulation. The 2008 ASTRO consensus guidelines for delineation of clinical target volumes were used to deliver 45 to 50 Gy to the target structures. Daily megavoltage computed tomographic images were reviewed and changes in position of the fiducial marker as compared to the initial planning scan were recorded in the anterior-posterior (AP), lateral, and superior-inferior dimensions. Changes in rectal distention were also recorded. The position of the fiducial marker relative to the planning target volumes was reviewed on each daily image. RESULTS: The average shifts of the gold seed in the AP, lateral, and superior-inferior dimensions were 7 mm (range, 0-28 mm), 3 mm (range, 0-7 mm), and 2.9 mm (range, 0-12 mm), respectively. Distention of the rectum ranged from 20.5 to 60.1 mm and correlated with movement of the gold seed in the AP dimension (R = 0.53). For 2 patients, the fiducial marker was within 5 mm of the planning target volume margin on 8/40 treatments, or outside the planning target volume on 4/40 treatments. This did not significantly impact total delivered dose to the planning target volume. CONCLUSIONS: Daily image guidance confirms significant interfraction movement of the vaginal cuff tissue, which may exceed suggested guidelines for clinical target volume margins.

Hyperlactatemia affects the association of hyperglycemia with mortality in nondiabetic adults with sepsis.

BACKGROUND: Admission hyperglycemia has been reported as a mortality risk factor for septic nondiabetic patients; however, hyperglycemia's known association with hyperlactatemia was not addressed in these analyses. OBJECTIVES: The objective was to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia. METHODS: This was a post hoc, nested analysis of a retrospective cohort study performed at a single center. Providers had identified study subjects during their emergency department (ED) encounters; all data were collected from the electronic medical record (EMR). Nondiabetic adult ED patients hospitalized for suspected infection, two or more systemic inflammatory response syndrome (SIRS) criteria, and simultaneous lactate and glucose testing in the ED were enrolled. The setting was the ED of an urban teaching hospital from 2007 to 2009. To evaluate the association of hyperglycemia (glucose > 200 mg/dL) with hyperlactatemia (lactate ≥ 4.0 mmol/L), a logistic regression model was created. The outcome was a diagnosis of hyperlactatemia, and the primary variable of interest was hyperglycemia. A second model was created to determine if coexisting hyperlactatemia affects hyperglycemia's association with mortality; the main outcome was 28-day mortality, and the primary risk variable was hyperglycemia with an interaction term for simultaneous hyperlactatemia. Both models were adjusted for demographics; comorbidities; presenting infectious source; and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction. RESULTS: A total of 1,236 ED patients were included, and the median age was 77 years (interquartile range [IQR] = 60 to 87 years). A total of 115 (9.3%) subjects were hyperglycemic, 162 (13%) were hyperlactatemic, and 214 (17%) died within 28 days of their initial ED visits. After adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (odds ratio [OR] = 4.14, 95% confidence interval [CI] = 2.65 to 6.45). Hyperglycemia and concurrent hyperlactatemia were associated with increased mortality risk (OR = 3.96, 95% CI = 2.01 to 7.79), but hyperglycemia in the absence of simultaneous hyperlactatemia was not (OR = 0.78, 95% CI = 0.39 to 1.57). CONCLUSIONS: In this cohort of septic adult nondiabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. The previously reported association of hyperglycemia with mortality in nondiabetic sepsis may be due to the association of hyperglycemia with hyperlactatemia.

Impact of metformin use on the prognostic value of lactate in sepsis.

OBJECTIVE: The objective of this study is to determine if metformin use affects the prevalence and prognostic value of hyperlactatemia to predict mortality in septic adult emergency department (ED) patients. METHODS: This is a single-center retrospective cohort study. Emergency department providers identified study subjects; data were collected from the medical record. PATIENTS: Adult ED patients with suspected infection and 2 or more systemic inflammatory response syndrome criteria were included. The outcome was 28-day mortality. The primary risk variable was serum lactate (<2.0, 2.0-3.9, ≥ 4.0 mmol/L) categorized by metformin use; covariates: demographics, Predisposition, Infection, Response, Organ Dysfunction score and metformin use contraindications. SETTING: The study was conducted at an urban teaching hospital; February 1, 2007 to October 31, 2008. RESULTS: A total of 1947 ED patients were enrolled; 192 (10%) were taking metformin; 305 (16%) died within 28 days. Metformin users had higher median lactate levels than nonusers (2.2 mmol/L [interquartile range, 1.6-3.2] vs 1.9 mmol/L [interquartile range, 1.3-2.8]) and a higher, although nonsignificant, prevalence of hyperlactatemia (lactate ≥ 4.0 mmol/L) (17% vs 13%) (P = .17). In multivariate analysis (reference group nonmetformin users, lactate <2.0 mmol/L), hyperlactatemia was associated with an increased adjusted 28-day mortality risk among nonmetformin users (odds ratio [OR], 3.18; P < .01) but not among metformin users (OR, 0.54; P = .33). In addition, nonmetformin users had a higher adjusted mortality risk than metformin users (OR, 2.49; P < .01). These differences remained significant when only diabetic patients were analyzed. CONCLUSIONS: In this study of adult ED patients with suspected sepsis, metformin users had slightly higher median lactate levels and prevalence of hyperlactatemia. However, hyperlactatemia did not predict an increased mortality risk in patients taking metformin.

The prevalence, rate of progression, and treatment of elbow flexion contracture in children with brachial plexus birth palsy.

BACKGROUND: Elbow flexion contracture is a well-known complication of brachial plexus birth palsy that adversely affects upper-extremity function. The prevalence, risk factors, and rate of progression of elbow flexion contracture associated with brachial plexus birth palsy have not been established, and the effectiveness of nonoperative treatment involving nighttime splinting or serial casting has not been well studied. METHODS: The medical records of 319 patients with brachial plexus birth palsy who had been seen at our institution between 1992 and 2009 were retrospectively reviewed to identify patients with an elbow flexion contracture (≥10°). The chi-square test for trend and the Kaplan-Meier estimator were used to evaluate risk factors for contracture, including age, sex, and the extent of brachial plexus involvement. Longitudinal models were used to estimate the rate of contracture progression and the effectiveness of nonoperative treatment. RESULTS: An elbow flexion contracture was present in 48% (152) of the patients with brachial plexus birth palsy. The median age of onset was 5.1 years (range, 0.25 to 14.8 years). The contracture was ≥30° in 36% (fifty-four) of these 152 patients and was accompanied by a documented radial head dislocation in 6% (nine). The prevalence of contracture increased with increasing age (p < 0.001) but was not significantly associated with sex or with the extent of brachial plexus involvement. The magnitude of the contracture increased by 4.4% per year before treatment (p < 0.01). The magnitude of the contracture decreased by 31% when casting was performed (p < 0.01) but thereafter increased again at the same rate of 4.4% per year. The magnitude of the contracture did not improve when splinting was performed but the rate of increase thereafter decreased to <0.1% per year (p = 0.04). CONCLUSIONS: The prevalence of elbow flexion contracture in children with brachial plexus birth palsy may be greater than clinicians perceive. The prevalence increased with patient age but was not significantly affected by sex or by the extent of brachial plexus involvement. Serial casting may initially improve severe contractures, whereas nighttime splinting may prevent further progression of milder contractures.

The natural history of cardiac and pulmonary function decline in patients with duchenne muscular dystrophy.

STUDY DESIGN: Retrospective review of scoliosis progression, pulmonary and cardiac function in a series of patients with Duchenne Muscular Dystrophy (DMD). OBJECTIVE: To determine whether operative treatment of scoliosis decreases the rate of pulmonary function loss in patients with DMD. SUMMARY OF BACKGROUND DATA: It is generally accepted that surgical intervention should be undertaken in DMD scoliosis once curve sizes reach 35° to allow intervention before critical respiratory decline has occurred. There are conflicting reports, however, regarding the effect of scoliosis stabilization on the rate of pulmonary function decline when compared to nonoperative cohorts. METHODS: We reviewed spinal radiographs, echocardiograms, and spirometry, hospital, and operative records of all patients seen at our tertiary referral center from July 1, 1992 to June 1, 2007. Data were recorded to Microsoft Excel (Microsoft, Redmond, WA) and analyzed with SAS (SAS Institute, Cary, NC) and R statistical processing software (www.r-project.org). RESULTS: The percent predicted forced vital capacity (PPFVC) decreased 5% per year before operation. The mean PPFVC was 54% (SD = 21%) before operation with a mean postoperative PPFVC of 43% (SD = 14%). Surgical treatment was associated with a 12% decline in PPFVC independent of other treatment variables. PPFVC after operation declined at a rate of 1% per year and while this rate was lower, it was not significantly different than the rate of decline present before operation (P = 0.18). Cardiac function as measured by left ventricular fractional shortening declined at a rate of 1% per year with most individuals exhibiting a left ventricular fractional shortening rate of more than 30 before operation. CONCLUSION: Operative treatment of scoliosis in DMD using the Luque Galveston method was associated with a reduction of forced vital capacity related to operation. The rate of pulmonary function decline after operation was not significantly reduced when compared with the rate of preoperative forced vital capacity decline.

Differential maintenance of cortical and cancellous bone strength following discontinuation of bone-active agents.

Osteoporotic patients treated with antiresorptive or anabolic agents experience an increase in bone mass and a reduction in incident fractures. However, the effects of these medications on bone quality and strength after a prolonged discontinuation of treatment are not known. We evaluated these effects in an osteoporotic rat model. Six-month-old ovariectomized (OVX) rats were treated with placebo, alendronate (ALN, 2 µg/kg), parathyroid hormone [PTH(1-34); 20 µg/kg], or raloxifene (RAL, 2 mg/kg) three times a week for 4 months and withdrawn from the treatments for 8 months. Treatment with ALN, PTH, and RAL increased the vertebral trabecular bone volume (BV/TV) by 47%, 53%, and 31%, with corresponding increases in vertebral compression load by 27%, 51%, and 31%, respectively (p < .001). The resulting bone strength was similar to that of the sham-OVX control group with ALN and RAL and higher (p < .001) with PTH treatment. After 4 months of withdrawal, bone turnover (BFR/BS) remained suppressed in the ALN group versus the OVX controls (p < .001). The vertebral strength was higher than in the OVX group only in ALN-treated group (p < .05), whereas only the PTH-treated animals showed a higher maximum load in tibial bending versus the OVX controls (p < .05). The vertebral BV/TV returned to the OVX group level in both the PTH and RAL groups 4 months after withdrawal but remained 25% higher than the OVX controls up to 8 months after withdrawal of ALN (p < .05). Interestingly, cortical bone mineral density increased only with PTH treatment (p < .05) but was not different among the experimental groups after withdrawal. At 8 months after treatment withdrawal, none of the treatment groups was different from the OVX control group for cortical or cancellous bone strength. In summary, both ALN and PTH maintained bone strength (maximum load) 4 months after discontinuation of treatment despite changes in bone mass and bone turnover; however, PTH maintained cortical bone strength, whereas ALN maintained cancellous bone strength. Additional studies on the long-term effects on bone strength after discontinuation and with combination of osteoporosis medications are needed to improve our treatment of osteoporosis.

Longitudinal influences of partner depression on cognitive functioning in latino spousal pairs.

BACKGROUND/AIMS: While social factors may influence the trajectories of cognitive aging, the influence of spousal characteristics (i.e. health or mental health) on cognitive decline has received little attention. This study examined the influence of baseline depressive symptoms in one spouse on cognitive functioning in the other. METHODS: We conducted a longitudinal study of 279 Latino spousal pairs (558 people) taken from a cohort study (n = 1,789) in California's central valley with assessments every 12-18 months. RESULTS: Higher husband baseline depression was significantly associated with lower cognitive scores maintained across time for both husbands (p < 0.001) and wives (p = 0.01). Wives with higher baseline depression scores showed significantly worse cognitive function over time (p = 0.007). CONCLUSIONS: Husbands' cognitive function was more strongly linked to their own level of depression, whereas wives' cognitive function was influenced by both their own and their partners' level of baseline depression. Our study further documents the public health significance of depression and our need to look beyond the individual to the reverberating effects of depression on the family.