Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States.

INTRODUCTION: Vaginal rings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring. METHODS: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 HIV-negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three-month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow-up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three-month rings. Most participants found the ring acceptable (median = 8 on 10-point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). CONCLUSIONS: The extended duration DPV rings were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three-month DPV rings for HIV prevention.

Hemorrhage and large lipid-rich necrotic cores are independently associated with thin or ruptured fibrous caps: an in vivo 3T MRI study.

OBJECTIVE: Histological studies suggest associations between hemorrhage and large lipid-rich/necrotic cores with thin or ruptured fibrous caps in advanced atherosclerosis. We investigated these associations in carotid arteries with mild to severe stenosis by in vivo 3T MRI. METHODS AND RESULTS: Seventy-seven patients with >or=50% carotid stenosis in at least one side by duplex ultrasound underwent bilateral multi-contrast carotid MRI scans. Measurements for wall and lipid-rich/necrotic core sizes, presence of hemorrhage, and fibrous cap status (classified as intact thick, intact thin or ruptured) were recorded. Arteries with poor image quality, occlusion, or no detectable lipid-rich/necrotic core were excluded. For the 798 MRI slices included, multivariate ordinal regression analysis demonstrated larger %lipid-rich/necrotic core (odds ratio for 10% increase, 1.49; P=0.02) and presence of hemorrhage (odds ratio, 5.91; P<0.001) were independently associated with a worse (intact thin or ruptured) stage of fibrous cap status. For artery-based multivariate analysis, a larger maximum %lipid-rich/necrotic core and presence of hemorrhage independently associated with worse fibrous cap status (P<0.001, for both). No hemorrhage was detected in arteries with thick fibrous caps. CONCLUSIONS: Hemorrhage and larger %lipid-rich/necrotic core were independently associated with a thin or ruptured fibrous cap status at an early to advanced stage of carotid atherosclerosis.

Evaluation of otoscope cone disinfection techniques and contamination level in small animal private practice.

The objective of this study was to evaluate the level of bacterial contamination of otoscope cones in veterinary private practice, and to determine the most effective method of disinfection. Fifty small animal practices participated in this study, which included a detailed survey regarding otoscope cleaning, storage and usage and quantitative culture of the cleaned and stored otoscope cones. Using sterile technique, two cones from each of the 50 hospitals were swabbed and submitted for quantitative culture. Contamination was present in 29% of the samples and the following organisms were isolated: Flavobacterium brevis (10%), Pseudomonas aeruginosa (6%), Pseudomonas alcaligenes (4%), Staphylococcus intermedius (4%), Corynebacterium spp. (2%), Bacillus spp. (1%), Enterococcus faecalis (1%) Malassezia spp. (1%). There was no statistically significant difference between storage type (dry versus stored in solution) and for the instrumentation used to clean the cones (brush, cotton-tipped applicator, both versus none). There was a statistically significant difference between the different cleaning solutions (P < 0.001) and between the storage solutions (P = 0.003). A single most effective cleaning solution was unable to be determined due to the large number of solutions utilized. Cetylcide G (Cetylite Industries, Inc., Pennsauken, NJ, USA) was the most effective of the three most commonly used storage solutions (Cetylcide G, Benz-all, and 2% Chlorhexidine gluconate) when used as directed (P < 0.001). The level of contamination had a positive association with the frequency of cone use and a negative association with the frequency of storage solution replacement.

Regional lung blood flow and ventilation in upright humans studied with quantitative SPECT.

We used quantitative Single Photon Emission Computed Tomography (SPECT) to study the effect of the upright posture on regional lung blood flow and ventilation. Nine (upright) plus seven (prone and supine) healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked in sitting upright, supine and prone postures using (113m)In-labeled macroaggregates and inhaled Technegas ((99m)Tc); both remain fixed in the lung after administration. All images were obtained while supine. In comparison with horizontal postures, both blood flow and ventilation were greater in caudal regions when upright. The redistribution was greater for blood flow than for ventilation, resulting in decreasing ventilation-to-perfusion ratios down the lung when upright. We conclude that gravity redistributes regional blood flow and ventilation in the upright posture, while the influence is much less in the supine and prone postures.

Changes in arterial oxygenation and self-reported oxygen use after lung volume reduction surgery.

RATIONALE: Lung volume reduction surgery (LVRS) is inconsistently reported to improve arterial oxygenation in patients with chronic obstructive pulmonary disease. OBJECTIVES: We studied the effects of surgery on oxygenation in a large cohort and identified predictors of postoperative oxygenation improvement. METHODS: We evaluated oxygenation in 1,078 subjects with chronic obstructive pulmonary disease enrolled in the National Emphysema Treatment Trial after LVRS compared with medical control subjects, including arterial blood gases, use of supplemental oxygen during treadmill walking, and self-reported use of oxygen during rest, exertion, and sleep. MEASUREMENTS AND MAIN RESULTS: Pa(O(2)) breathing room air was equal in medical and surgical subjects at baseline (64.8 vs. 65.0 mm Hg, P = not significant), but lower in medical subjects at 6 months (63.6 vs. 70.0 mm Hg, P < 0.001), 12 months (63.9 vs. 68.7 mm Hg, P < 0.001), and 24 months (62.4 vs. 68.0 mm Hg, P < 0.001). Fewer medical subjects required oxygen for treadmill walking at baseline compared with surgical subjects (46 vs. 53%, P = 0.02). However, more medical subjects required oxygen for this activity at 6 months (49 vs. 33%, P < 0.001), 12 months (50 vs. 36%, P < 0.001), and 24 months (52 vs. 42%, P = 0.02). Self-reported oxygen use was greater in medical than in surgical subjects at 6, 12, and 24 months. Multivariate modeling of preoperative characteristics showed baseline oxygenation status was the best predictor of postoperative oxygenation. CONCLUSIONS: LVRS increases Pa(O(2)), and decreases treadmill and self-reported use of oxygen for up to 24 months post-procedure. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

Impact of implementing the Washington State ergonomics rule on employer reported risk factors and hazard reduction activity.

BACKGROUND: In Washington State an ergonomics rule was adopted in 2000 that focused on primary prevention. The implementation process followed a 6-year phase-in schedule where employers came into compliance based upon their size and industry. In late 2003 the rule was repealed by an industry-funded voter initiative. Evaluating the implementation of this rule offers a unique opportunity to observe the general deterrent effect of a new public health regulation and to study how employers and workers responded to new requirements. METHODS: Weighted survey regression methods were used to analyze the results from three employer surveys covering more than 5,000 workplaces administered in 2001, 2003, and 2005. These were compared to a baseline employer survey conducted in 1998 before the rule was promulgated. Questions covered the following topics: WMSDs experienced at the workplace; levels of employee exposure to musculoskeletal hazards; steps being taken, if any, to address these hazards; results of these steps; and sources of ergonomic information/assistance used. RESULTS: From 1998 to 2003 there was a reduction in reported exposures among workplaces in the highest hazard industries. Following the rule's repeal, however, hazard exposures increased. While more workplaces reported taking steps to reduce exposures between 1998 and 2001, this gain was reversed in 2003 and 2005. Employers who took steps reported positive results in injury and absenteeism reduction. Large workplaces in the high hazard industries were more active in taking steps and used a wide variety of resources to address ergonomics issues. Small employers relied more on trade associations and the state.

Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial.

BACKGROUND: Magnetic resonance imaging (MRI) can noninvasively assess changes in atherosclerotic plaque morphology and composition. The ORION trial assessed the effects of rosuvastatin on carotid plaque volume and composition. METHODS: The randomized, double-blind ORION trial used 1.5-T MRI to image carotid atherosclerotic plaques at baseline and after 24 months of treatment. Forty-three patients with fasting low-density lipoprotein cholesterol > or = 100 and < 250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive either a low (5 mg) or high (40/80 mg) dose of rosuvastatin. RESULTS: After 24 months, 33 patients had matched serial MRI scans to compare by reviewers blinded to clinical data, dosage, and temporal sequence of scans. Low-density lipoprotein cholesterol was significantly reduced from baseline in both the low- and high-dose groups (38.2% and 59.9%, respectively, both P < .001). At 24 months, there were no significant changes in carotid plaque volume for either dosage group. In all patients with a lipid-rich necrotic core (LRNC) at baseline, the mean proportion of the vessel wall composed of LRNC (%LRNC) decreased by 41.4% (P = .005). CONCLUSIONS: In patients with moderate hypercholesterolemia, both low- and high-dose rosuvastatin were effective in reducing low-density lipoprotein cholesterol. Furthermore, rosuvastatin was associated with a reduction in %LRNC, whereas the overall plaque burden remained unchanged over the course of 2 years of treatment. These findings provide evidence that statin therapy may have a beneficial effect on plaque volume and composition, as assessed by noninvasive MRI.

Timing of surgery in cauda equina syndrome with urinary retention: meta-analysis of observational studies.

OBJECT: The authors performed exploratory meta-analyses of observational cohort studies, evidence level III, examining whether earlier surgery makes a difference in outcome in terms of urinary function once cauda equina syndrome (CES) from a herniated lumbar disc has progressed to urinary retention (CESR). METHODS: Literature search identified 27 studies of CESR patients with clear definition of surgical timing. Relative risk (RR) could not be calculated in 11 studies, leaving 16 for meta-analysis. Urinary retention related to surgical timing at 5 breakpoints: 12, 24, 36, 48, or 72 hours. Urinary outcome was classified as Normal, Fair, or Poor. Meta-analysis was performed for "Event = Fair/Poor" or "Event = Poor." Eight studies allowed separation into CESR and incomplete CES (CESI), and 5 of these had enough data for meta-analysis to compare CESR and CESI. A random effects meta-analysis model was used because of heterogeneity across the studies. A best-evidence synthesis was performed for the 4 largest studies that had 24- and 48-hour breakpoints. RESULTS: For "Event = Fair/Poor," meta-analyses using the 5 breakpoints predicted a more likely Fair/Poor outcome for later surgery (RR range 1.77-2.19). The RR for later timing of surgery was statistically significant for 24-and 72-hour breakpoints and was elevated but not statistically significant for the other 3. For "Event = Poor," the RR range was 1.09-5.82, statistically significant for the 36 hour breakpoint only. Meta-analysis comparing CESR patients with CESI patients predicted a Fair/Poor result for CESR (RR 2.58, 95% confidence interval 0.59-11.31). The best-evidence synthesis did not disclose reasons for differences in the results of the 4 studies. CONCLUSIONS: This study supports early surgery for CES and indicates that CESR and CESI cases should not be analyzed together.

The spatial-temporal redistribution of pulmonary blood flow with postnatal growth.

The pulmonary vascular tree undergoes remarkable postnatal development and remodeling. While a number of studies have characterized longitudinal changes in vascular function with growth, none have explored regional patterns of vascular remodeling. We therefore studied six neonatal pigs to see how regional blood flow changes with growth. We selected pigs because of their rapid growth and their similarities to human development with respect to the pulmonary vascular tree. Fluorescent microspheres of varying colors were injected into the pulmonary circulation to mark regional blood on days 3, 12, 27, 43, and 71 after birth. The animals were awake and in the prone posture for all injections. The lungs were subsequently removed, air dried, and sectioned into approximately 2-cm(3) pieces. Flow on each injection day was determined for each piece. Despite the increase in the hydrostatic gradient in the lung with growth, there was a strong correlation between blood flow to the same lung piece when compared on days 3 and 71 (0.73 +/- 0.12). Although a dorsal-ventral gradient of perfusion did not exist on day 3, blood flow increased more in the dorsal region by day 12 and then gradually became more uniform by day 71. Although most of the lung pieces did not show any discernable pattern of blood flow redistribution, there were spatial patterns of blood flow redistribution that were similar across animals. Our findings suggest that local mechanisms, shared across animals, guide regional changes in vascular resistance or vasoregulation during postnatal development. In the pig, these mechanisms act to produce more uniform flow in the normal posture for an ambulating quadruped. The stimuli for these changes have not yet been identified.

Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism.

We studied the roles of endothelins in determining ventilation (Va) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (approximately 23 kg) received autologous clots (approximately 20 g) via a central venous catheter at time = 0 min. The distribution of Va and Q at five different time points (-30, -5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets (group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets (group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean Va/Q was increased, as was Va/Q heterogeneity (log SD Va/Q), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial PO2 or Va/Q mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high Va/Q regions.

Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine.

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 +/- 0.7 kg, means +/- SD) underwent incremental treadmill exercise tests in normoxia (Fi(O(2)) = 0.21) and hypoxia (Fi(O(2)) = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined Vo(2max). At steady state (~4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over approximately 30 s. Later the fluorescent intensity of each color in each 2-cm(3) lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 +/- 4.2, 4.0 +/- 4.4, and 59.4 +/- 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 +/- 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.

Pulmonary response to 3 h of hypoxia in prone pigs.

Studies in whole animals, isolated lungs and pulmonary tissue strips have shown that the pulmonary vascular resistance (PVR) to hypoxia is temporally biphasic in nature. We studied the regional temporal response to hypoxia in prone pigs. The animals were ventilated with an FIO2 of 0.21 (control), followed by an FIO2 of 0.12 for 180 min. A biphasic response in P(pa) to hypoxia was seen with the first peak between 10 and 20 min and a second rise in P(pa) starting after 30 min, which was due to an increase in cardiac output. Regional blood flow (Q ) and ventilation (V (A)) were measured using i.v. infusion of 15 microm and inhalation of 1 microm fluorescent microspheres, respectively. We grouped the lung pieces according to their temporal relative flow response to hypoxia. The five groups were each spatially distributed similarly, but not identically, among the animals. The corresponding relative ventilation to each group did not vary much. We conclude that in the prone pig, the PVR response to sustained hypoxia varies among regions of the lungs. Following an initial rise in PVR in most lung pieces, we found unexpectedly that some regions continue to increase PVR progressively and while other regions decrease PVR after the initial increase. The net effect is little change of overall PVR to hypoxia with time. Normoxic control animals had little change in their hemodynamics and the large majority of the lung pieces did not change their resistance over 3h. We speculate that the differential response of regions may be due to a differential role of nitric oxide, endothelin-1 release or K(+) channels.

Posture primarily affects lung tissue distribution with minor effect on blood flow and ventilation.

We used quantitative single photon emission computed tomography to estimate the proportion of the observed redistribution of blood flow and ventilation that is due to lung tissue shift with a change in posture. Seven healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked using radiotracers that remain fixed in the lung after administration. The radiotracers were administered in prone or supine at separate occasions, at both occasions followed by imaging in both postures. Images showed greater blood flow and ventilation to regions dependent at the time of imaging, regardless of posture at radiotracer administration. The results suggest that a shift in lung parenchyma has a major influence on the imaged distributions. We conclude that a change from the supine to the prone posture primarily causes a change in the vertical distribution of lung tissue. The effect on the vertical distribution of blood flow and ventilation within the lung parenchyma is much less.

The complex characteristics of 282 unsatisfactory shoulder arthroplasties.

The purpose of our study is to augment the knowledge of patient dissatisfaction after a shoulder arthroplasty. A total of 353 shoulders were prospectively enrolled into the Shoulder Arthroplasty Failure Experience (SAFE) project. Of these, 282 patients had complete data for the final analysis, including demographic information, medical history, physical examination, standard radiographs, and the Simple Shoulder Test (SST) scores. These data were analyzed to determine the frequency of 17 possible characteristics of an unsatisfactory arthroplasty. Pain was the most common reason for patients to seek an evaluation (241 of 282 shoulders). Shoulder function was substantially reduced at presentation, with patients only able to perform an average of 2.6 of 12 SST functions. Overall, technical factors such as component malpositioning and glenohumeral malalignment were the most common characteristics identified among all the shoulders. Loosening of glenoid components was noted in 85 of the 136 total shoulder arthroplasties, and glenoid erosion was found in 51 of 80 hemiarthroplasties performed for degenerative conditions. Patients with an unsatisfactory outcome after shoulder arthroplasty present with poor shoulder function and pain. Component malposition, glenohumeral malalignment, and glenoid failure are all prevalent features among patients with an unsatisfactory outcome.

Hypoxic pulmonary vasoconstriction is heterogeneously distributed in the prone dog.

Hypoxic pulmonary vasoconstriction (HPV) is thought to protect gas exchange by decreasing perfusion to hypoxic regions. However, with global hypoxia, non-uniformity in HPV may cause over-perfusion to some regions, leading to high-altitude pulmonary edema. To quantify the spatial distribution of HPV and regional PO2 (PRO2) among small lung regions (approximately 2.0 cm3), five prone beagles (approximately 8.3 kg) were anesthetized and ventilated (PEEP approximately 2 cm H2O) with an F1O2 of 0.21, then 0.50, 0.18, 0.15, and 0.12 in random order. Regional blood perfusion (Q), ventilation (VA) and calculated PRO2 were obtained using iv infusion of 15 microm and inhalation of 1 microm fluorescent microspheres. Lung pieces were clustered by their relative blood flow response to each F1O2. Clusters were shown to be spatially grouped within animals and across animals. Lung piece resistance increased as PRO2 decreased to 60-70 mmHg but dropped at PRO2's < 60mmHg. Regional ventilation changed little with hypoxia. HPV varied more in strength of response, rather than PRO2 response threshold. In initially homogeneous VA/Q lungs, we conclude that HPV response is heterogeneous and spatially clustered.

Prolonged combination lipid therapy is associated with reduced carotid intima-media thickness: a case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS).

BACKGROUND: Studies have documented the short-term vascular benefits of combination lipid therapy. OBJECTIVE: Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. METHODS: We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. RESULTS: Combination therapy group had a greater decrease in total cholesterol (-42 ± 14% vs -31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (-57 ± 13% vs -38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT. CONCLUSIONS: Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone.

Proximal humeral fracture as a risk factor for subsequent hip fractures.

BACKGROUND: With the aging of the world's population, the social and economic implications of osteoporotic fractures are at epidemic proportions. This study was performed to test the hypothesis that a proximal humeral fracture is an independent risk factor for a subsequent hip fracture and that the risk of the subsequent hip fracture is highest within the first five years after the humeral fracture. METHODS: A cohort of 8049 older white women with no history of a hip or humeral fracture who were enrolled in the Study of Osteoporotic Fractures was followed for a mean of 9.8 years. The risk of hip fracture after an incident humeral fracture was estimated with use of age-adjusted Cox proportional hazards regression analysis with time-varying variables; women without a humeral fracture were the reference group. Cox regression analysis was used to evaluate the timing between the proximal humeral and subsequent hip fracture. Risk factors were determined on the basis of a review of the current literature, and we chose the variables that were most predictive and easily ascertained in a clinical setting. RESULTS: Three hundred and twenty-one women sustained a proximal humeral fracture, and forty-four of them sustained a subsequent hip fracture. After adjustment for age and bone mineral density, the hazard ratio for hip fracture for subjects with a proximal humeral fracture relative to those without a proximal humeral fracture was 1.83 (95% confidence interval = 1.32 to 2.53). After multivariate adjustment, this risk appeared attenuated but was still significant (hazard ratio = 1.57; 95% confidence interval = 1.12 to 2.19). The risk of a subsequent hip fracture after a proximal humeral fracture was highest within one year after the proximal humeral fracture, with a hazard ratio of 5.68 (95% confidence interval = 3.70 to 8.73). This association between humeral and hip fracture was not significant after the first year, with hazard ratios of 0.87 (95% confidence interval = 0.48 to 1.59) between one and five years after the humeral fracture and 0.58 (95% confidence interval = 0.22 to 1.56) after five years. CONCLUSIONS: In this cohort of older white women, a proximal humeral fracture independently increased the risk of a subsequent hip fracture more than five times in the first year after the humeral fracture but was not associated with a significant increase in the hip fracture risk in subsequent years.

Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS).

We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein (LDL) cholesterol lowering and LDL cholesterol lowering plus high-density lipoprotein (HDL) cholesterol increasing. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary end points were change in mean proximal coronary diameter stenosis (Delta%S(prox)) over 3 years and the frequency of the predefined composite of coronary artery disease death, nonfatal myocardial infarction, stroke, and revascularization due to worsening ischemia. Patients with MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with a 3.5-fold increased event risk (p <0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Delta%S(prox) 0.5 vs 2.9, p <0.001) in patients with MS and induced a small net regression in those without (Delta%S(prox) -0.3 vs 2.0, p <0.001). Combination therapy decreased the event rate by 54% (13% vs 28%, p = 0.03) in those with MS and by 82% (3% vs 17%, p = 0.002) without. On average, each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was significantly associated with a 0.3 Delta%S(prox) decrease. Each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was associated with 11% (p = 0.02) or 22% (p <0.001) event risk decrease. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL cholesterol-lowering and HDL cholesterol-increasing therapies independently and significantly decrease coronary stenosis progression and decrease CV events.

Quantifying the genetic influence on mammalian vascular tree structure.

The ubiquity of fractal vascular trees throughout the plant and animal kingdoms is postulated to be due to evolutionary advantages conferred through efficient distribution of nutrients to multicellular organisms. The implicit, and untested, assertion in this theory is that the geometry of vascular trees is heritable. Because vascular trees are constructed through the iterative use of signaling pathways modified by local factors at each step of the branching process, we sought to investigate how genetic and nongenetic influences are balanced to create vascular trees and the regional distribution of nutrients through them. We studied the spatial distribution of organ blood flow in armadillos because they have genetically identical littermates, allowing us to quantify the genetic influence. We determined that the regional distribution of blood flow is strongly correlated between littermates (r(2) = 0.56) and less correlated between unrelated animals (r(2) = 0.36). Using an ANOVA model, we estimate that 67% of the regional variability in organ blood flow is genetically controlled. We also used fractal analysis to characterize the distribution of organ blood flow and found shared patterns within the lungs and hearts of related animals, suggesting common control over the vascular development of these two organs. We conclude that the geometries of fractal vascular trees are heritable and could be selected through evolutionary pressures. Furthermore, considerable postgenetic modifications may allow vascular trees to adapt to local factors and provide a flexibility that would not be possible in a rigid system.