John Orav

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

Effect of Endothelial Shear Stress on the Progression of Coronary Artery Disease, Vascular Remodeling, and In-Stent Restenosis in Humans In Vivo 6-Month Follow-Up Study

Background—Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium controls local arterial responses by transduction of shear stress. Characterization of endothelial shear stress (ESS) may allow for prediction of progression of atherosclerosis and in-stent restenosis. Methods and Results—By using intracoronary ultrasound, biplane coronary angiography, and measurement of coronary blood flow, we represented the artery in accurate 3D space and determined detailed characteristics of ESS and arterial wall/plaque morphology. Patients who underwent stent implantation and who had another artery with luminal obstruction <50% underwent intravascular profiling initially and after 6-month follow-up. Twelve arteries in 8 patients were studied: 6 native and 6 stented arteries. In native arteries, regions of abnormally low baseline ESS exhibited a significant increase in plaque thickness and enlargement of the outer vessel wall, such that lumen radius remained unchanged (outward remodeling). Regions of physiological ESS showed little change. Regions with increased ESS exhibited outward remodeling with normalization of ESS. In stented arteries, there was an increase in intima-medial thickness, a decrease in lumen radius, and an increase in ESS at all levels of baseline ESS. Conclusions—The present study represents the first experience in humans relating ESS to subsequent outcomes in native and stented arteries. Regions of low ESS develop progressive atherosclerosis and outward remodeling, areas of physiological ESS remain quiescent, and areas of increased ESS exhibit outward remodeling. ESS may have a limited role in in-stent restenosis. This technology can predict areas of minor plaque likely to exhibit progression of atherosclerosis.

Depression in Multiple Sclerosis

Standardized interview techniques, diagnostic criteria, and rating scales were used to assess 50 moderately disabled multiple sclerosis (MS) patients. Fifty-four percent met lifetime Research Diagnostic Criteria for major depression, with a significant increase in the rate from before to after the onset of MS symptoms. The MS patients were significantly more depressed than other medical patients described in the literature. Major depressions were associated with steroid-treated exacerbations and a history of major depression. Symptoms of depression may be easily confused with those of MS, resulting in inadequate diagnosis and treatment.

The Impact of Postoperative Pain on the Development of Postoperative Delirium

We performed a prospective observational study to examine the role of postoperative pain and its treatment on the development of postoperative delirium.Pain was measured in direct patient interviews using a visual analog scale (VAS) and was assessed for pain at rest, pain with movement, and maximal pain over the previous 24 h. Postoperative delirium was diagnosed during these interviews by using the confusion assessment method (CAM) and/or by using data from the medical record and the hospitals nursing intensity index. The method of postoperative analgesia, type of opioid, and cumulative opioid dose were also recorded. After controlling for known preoperative risk factors for delirium (age, alcohol abuse, cognitive function, physical function, serum chemistries, and type of surgery), higher pain scores at rest was associated with an increased risk of delirium over the first 3 postoperative days (adjusted risk ratio 1.20, P = 0.04). Pain with movement and maximal pain were not associated with delirium. Method of postoperative analgesia, type of opioid, and cumulative opioid dose were not associated with an increased risk of delirium. We conclude that more effective control of postoperative pain reduces the incidence of postoperative delirium. Implications: We performed daily interviews in a large population of patients undergoing noncardiac surgery to measure their level of pain and development of delirium. We found an association between higher pain levels at rest and the development of delirium. Our results suggest that better control of postoperative pain may reduce this serious complication. (Anesth Analg 1998;86:781-5)

Impact of Age on Perioperative Complications and Length of Stay in Patients Undergoing Noncardiac Surgery

As the U.S. population ages, major surgical procedures are being performed in elderly patients with increasing frequency (1), but few data are available to guide preoperative risk stratification. Several studies have described correlates of cardiac morbidity and mortality in patients undergoing noncardiac surgery (2-8), but the number of elderly patients in most series has been small. Furthermore, few data are available on noncardiac complications, the overall complication rate, and length of stay. We describe the influence of age on perioperative complication and mortality rates in a large cohort of patients undergoing noncardiac surgery. As discussed elsewhere, age was not an independent correlate of major cardiac complications in this cohort (7). This analysis tests the hypothesis that advanced age is a correlate of the overall rate of complications, after adjustment for functional status. Methods Patients All patients 50 years of age or older who underwent major nonemergent noncardiac procedures at Brigham and Womens Hospital, Boston, Massachusetts, from 18 July 1989 to 28 February 1994 were eligible for the study. Major noncardiac procedures were defined as those with an expected length of stay of 2 or more days. Procedures were electively scheduled or were performed nonemergently during inpatient admissions. Eligibility criteria included the ability to speak English and adequate cognitive function to give informed consent. The enrollment and clinical data collection protocols were approved by the institutional review board of Brigham and Womens Hospital. The full study protocol included preoperative interviews by clinical study personnel (physicians or research nurses). Of the 4315 patients who provided informed consent to participate, 621 (14.4%) did not provide consent before surgery for the serial interview portion of the study, which included interviews 1 and 6 months after surgery. Patients who were not interviewed before surgery were not excluded on the basis of age or clinical status, but solely according to the availability of study personnel. Data Collection The data collection protocol is described elsewhere (7, 9, 10). In brief, patients who provided informed consent to the full study protocol underwent preoperative evaluation by clinical investigators (physicians or research nurses) using a structured data form. These evaluations included detailed medical histories, physical examinations, and laboratory tests. For patients who did not undergo this evaluation because they could not be approached or because they declined participation in the interview portion of the study, we obtained clinical data from the structured evaluation by the anesthesiologist found in the medical record. This data source was also used to obtain American Society of Anesthesiologists classification for all patients. Hence, prospectively recorded clinical data were available for all patients. Consenting patients agreed to postoperative sampling of creatine kinase and, if total creatine kinase levels were elevated, measurement of creatine kinaseMB immediately after surgery, at 8 p.m. on the evening of surgery, and on the next two mornings. In all other enrolled patients, creatine kinaseMB was measured according to the physicians orders. Among all participants, the mean (SD) number of cardiac enzyme samples obtained was 4.0 2.2. Electrocardiography was performed in the recovery room and on the first, third, and fifth postoperative days if the patient remained hospitalized. The Charlson Comorbidity Index, a weighted comorbidity score based on the number and the severity of 16 selected medical diseases, was used to quantify the burden of medical comorbid conditions (11). The mean number of other common comorbid conditions in this population was calculated for all patients. Preoperative functional status was assessed in 3890 patients by performing structured interviews using the Specific Activity Scale, an ordinally scaled, four-class instrument based on metabolic expenditure in various personal care, housework, occupational, and recreational activities (12, 13). This group included 196 patients who consented to preoperative interviews but did not consent to the full study protocol, including long-term follow-up. Classification of Outcomes The occurrence of major cardiac events postoperatively was classified by a single reviewer who was blinded to preoperative clinical data and who evaluated only postoperative clinical information, including cardiac enzyme measurements, electrocardiograms, and clinical events. Myocardial infarction was diagnosed on the basis of creatine kinaseMB levels and electrocardiographic findings (10). Major cardiac complications were unstable angina (postoperative typical chest pain associated with ischemic electrocardiographic changes), myocardial infarction, cardiogenic pulmonary edema, documented ventricular tachycardia, ventricular fibrillation or primary cardiac arrest, and sustained complete heart block requiring pacemaker. Major noncardiac events were pulmonary embolism documented by autopsy, angiography, or a high-probability ventilationperfusion scan; respiratory failure requiring intubation for more than 2 days or reintubation; noncardiogenic pulmonary edema; lobar pneumonia confirmed by chest radiography and requiring antibiotic therapy; acute renal failure requiring dialysis; or cerebrovascular accident with new neurologic deficit. In-hospital mortality was also recorded, and the combined end point of major cardiac or noncardiac complications or death was used in these analyses. Statistical Analysis To evaluate the impact of age on postoperative complications, we performed analyses in which age was considered as a continuous variable and as four categories (50 to 59 years, 60 to 69 years, 70 to 79 years, and 80 years). Because age was not linearly associated with the risk for outcomes, categorized age variables are used throughout this report. Univariate correlations between clinical characteristics and age category were analyzed by using the chi-square test and the Fisher exact test for categorical variables and a t-test or Wilcoxon test for continuous variables. Because several clinical and laboratory variables are associated with age and because it is difficult to exclude the association of age with the event of interest, we included all relevant clinical variables in the multivariate analysis. Logistic regression analysis was used to determine the independent association of age with postoperative complications while controlling for the presence of comorbid conditions, sex, ethnicity, functional status as measured by Specific Activity Scale class, type of procedure, and preoperative laboratory data. Patients for whom data on selected variables were missing were excluded from the model. Clinically relevant variables from the regression model were analyzed for potential interactions, and potentially significant interaction terms were considered in the regression models. A two-sided P value less than 0.05 was considered statistically significant in all analyses. Linear regression models were used to estimate the independent variation in length of stay attributable to age, controlling for sex, ethnicity, preoperative clinical characteristics, American Society of Anesthesiologists classification, type of procedure, postoperative events, and in-hospital mortality. The logarithmic transformation of length of stay was used because of the non-normal distribution of this variable. The percentage change in the geometric mean of length of stay in the final model was used to estimate the numbers of adjusted hospital days attributable to age groups. All analyses were performed by using SAS statistical software for Windows, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The funding source had no role in data collection and analysis or in subsequent decisions about publication of manuscripts. Results Patients The study sample constituted 4315 patients who had a mean age of 67 9 years; 2096 patients (48%) were male and 3903 (90%) were white. Twenty-four percent (1015 patients) were younger than 59 years, 38% (1646 patients) were 60 to 69 years of age, 31% (1341 patients) were 70 to 79 years of age, and 7% (313 patients) were older than 80 years of age. These patients undergoing elective surgery had a low prevalence of comorbid conditions, and 3187 (74%) patients had Charlson Comorbidity Index scores of 0 through 2. The types of procedures performed were orthopedic (35%), intrathoracic (12%), abdominal (12%), abdominal aortic aneurysm (5%), other vascular (17%), and other general surgical procedures (33%). In the oldest age group, significantly fewer patients were male and nonwhite compared with the younger age groups (Table 1). The number of comorbid conditions and the average Charlson Comorbidity Index scores increased with increasing age. The distribution of Specific Activity Scale class and American Society of Anesthesiology class was also significantly worse in the older age groups; a greater proportion of patients 70 to 79 years of age and 80 years of age was classified as class 3 or 4. As expected, the type of surgical procedure performed varied among age groups. Higher percentages of older patients underwent orthopedic procedures, aortic aneurysm repair, and other vascular surgeries (Table 1). Table 1. Patient Characteristics Perioperative Complications Major or fatal perioperative complications occurred in 44 (4.3%) patients younger than 59 years of age, 93 (5.7%) patients 60 to 69 years of age, 129 (9.6%) patients 70 to 79 years of age, and 39 (12.5%) patients 80 years of age or older (P<0.001) (Figure). Age was significantly associated with a higher risk for cardiogenic pulmonary edema, myocardial infarction, ventricular arrhythmias, bacterial pneumonia, respiratory failure requiring intubation, and in-hospital mortality. All other major complications e

Hemoconcentration is an early marker for organ failure and necrotizing pancreatitis.

In a previous retrospective case-control study, hemoconcentration was associated with the development of pancreatic necrosis. The aim of the present study was to determine in a cohort study whether hemoconcentration is a marker for both organ failure and necrotizing pancreatitis. A cohort study was performed on patients admitted with acute pancreatitis from February 1996 to April 1997. Pancreatic necrosis was defined by findings on dynamic contrast-enhanced computed tomography scan or magnetic resonance imaging. Of 128 total patients with acute pancreatitis, 53 underwent computed tomography or magnetic resonance imaging. Eighteen of 53 had necrotizing pancreatitis. Logistic regression identified an admission hematocrit ≥44% and a failure of admission hematocrit to decrease at 24 hours as the best binary predictors of necrotizing pancreatitis and organ failure. By 24 hours, 17 of 18 patients with necrotizing pancreatitis versus 11 of 35 with interstitial pancreatitis met one or the other criterion for necrosis (p < 0.001). By 24 hours, 13 of 15 with organ failure versus 36 of 104 without organ failure met one or the other criterion (p < 0.001). The negative predictive value by 24 hours was 96% for necrotizing pancreatitis and 97% for organ failure. Hemoconcentration with an admission hematocrit ≥44% and/or failure of admission hematocrit to decrease at approximately 24 hours was associated with the development of necrotizing pancreatitis and organ failure. Patients who did not experience hemoconcentration were very unlikely to develop pancreatic necrosis or organ failure.

Dietary Calcium and Serum 25‐Hydroxyvitamin D Status in Relation to BMD Among U.S. Adults

A higher calcium intake is still the primary recommendation for the prevention of osteoporosis, whereas vitamin D deficiency is often not addressed. To study the relative importance of dietary calcium intake and serum 25‐hydroxyvitamin D [25(OH)D] status in regard to hip BMD, 4958 community‐dwelling women and 5003 men ≥20 yr of age from the U.S. NHANES III population‐based survey were studied. Calcium supplement users and individuals with a prior radius or hip fracture were excluded. We calculated standardized means for BMD by quartiles of sex‐specific calcium intake for three 25(OH)D categories (<50, 50–74, and 75+ nM) among men and women, separately controlling for other important predictors of BMD. A higher calcium intake was significantly associated with higher BMD (p value for trend: p = 0.005) only for women with 25(OH)D status <50 nM, whereas calcium intake beyond the upper end of the lowest quartile (>566 mg/d) was not significantly associated with BMD at 25(OH)D concentrations >50 nM. Among men, there was no significant association between a higher calcium intake beyond the upper end of the lowest quartile (626 mg/d) and BMD within all 25(OH)D categories. Among both sexes, BMD increased stepwise and significantly with higher 25(OH)D concentrations (<50, 50–74, 75+ nM; p value for trend: women < 0.0001; men = 0.0001). Among men and women, 25(OH)D status seems to be the dominant predictor of BMD relative to calcium intake. Only women with 25(OH)D concentrations <50 nM seem to benefit from a higher calcium intake.

Hemoconcentration as an early risk factor for necrotizing pancreatitis

Objective:The aim of our study was to determine whether measurement of serum hematocrit during the first 24 h helps in distinguishing necrotizing from mild pancreatitis.Methods:From May 1992 to June 1996, a case-control study was performed with cases of patients with necrotizing pancreatitis. We selected as a control the next patient admitted with mild pancreatitis.Results:There were 32 patients in each group. Logistic regression identified an admission hematocrit of ≥ 47% and a failure of admission hematocrit to decrease at 24 h as the best binary risk factors for necrotizing pancreatitis. At admission, more patients with necrotizing pancreatitis than with mild pancreatitis had a hematocrit ≥ 47% (11/32 vs 3/32; p= 0.03). At 24 h, 15 additional patients with necrotizing pancreatitis versus only one with mild pancreatitis showed no decrease in admission hematocrit (p < 0.01). Thus, by 24 h, 26 of 32 patients with necrotizing pancreatitis versus only four of 32 patients with mild pancreatitis met one or the other criterion (p < 0.01). The sensitivity and specificity at admission were 34% and 91%; at 24 h, 81% and 88%.Conclusions:Hemoconcentration with an admission hematocrit ≥ 47% or failure of admission hematocrit to decrease at approximately 24 h were strong risk factors for the development of pancreatic necrosis.

Memory impairment in multiple sclerosis.

We compared the performance of 50 multiple sclerosis (MS) patients and 35 normal controls on a variety of memory tasks to determine the nature and severity of memory deficits in the MS patients and the proportion of patients affected. We also determined the relationship between memory and other cognitive functions, demographic factors, disease characteristics, depression, and psychoactive medication. We found significant differences between patients and controls on almost all memory tests. Patterns of learning, effects of interference, and improvement with cuing were similar for both groups. Thirty percent of patients showed severe memory impairment, 30% were moderately impaired, and 40% were mildly or not impaired. Memory dysfunction was related to impairment of other cognitive functions, lower socioeconomic status, chronic progressive type of MS, and use of antianxiety medication, but not to severity of disability, duration of MS symptoms or depression.

Effects of asymptomatic ischemia on long-term prognosis in chronic stable coronary disease.

BackgroundIschemia on ambulatory electrocardiographic monitoring has been shown to adversely affect short-term prognoses in patients with unstable angina, after myocardial infarction, and with chronic stable angina. Methods and ResultsIn this long-term study, we followed 138 patients (mean age, 59±9 years) with chronic stable angina and positive exercise tests for cardiac events (e.g., death, myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery). In 105 patients, ambulatory electrocardiographic monitoring was performed after all antianginal medication was withheld for 48 hours. In 26 patients, the diagnostic tests were repeated while on their usual medication. In addition to the 105 patients, 33 patients had their monitoring performed only while on their usual medication. During 37±17 months of follow-up, there were nine deaths, nine myocardial infarctions, and 35 revascularization procedures. In patients monitored off medication, Cox survival analysis showed that the occurrence of ischemia on electrocardiographic monitoring was the most significant predictor of death and myocardial infarction in the subsequent 2 years (p = 0.02) and of all adverse events for 5 years p = 0.009). Patients who were monitored on medication and did not have ischemia (n =18) appeared to have more adverse events than patients who had no ischemia while being monitored off medication (n =43). ConclusionsAsymptomatic ischemia on ambulatory electrocardiographic monitoring in patients with stable angina predicts death and myocardial infarction for 2 years and all adverse events for 5 years. Monitoring performed while on medication may show no ischemia; however, this may not indicate low risk of future coronary events.