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BACKGROUND: Although the short-term benefits of bilateral stimulation of the subthalamic nucleus in patients with advanced Parkinson's disease have been well documented, the long-term outcomes of the procedure are unknown. METHODS: We conducted a five-year prospective study of the first 49 consecutive patients whom we treated with bilateral stimulation of the subthalamic nucleus. Patients were assessed at one, three, and five years with levodopa (on medication) and without levodopa (off medication), with use of the Unified Parkinson's Disease Rating Scale. Seven patients did not complete the study: three died, and four were lost to follow-up. RESULTS: As compared with base line, the patients' scores at five years for motor function while off medication improved by 54 percent (P<0.001) and those for activities of daily living improved by 49 percent (P<0.001). Speech was the only motor function for which off-medication scores did not improve. The scores for motor function on medication did not improve one year after surgery, except for the dyskinesia scores. On-medication akinesia, speech, postural stability, and freezing of gait worsened between year 1 and year 5 (P<0.001 for all comparisons). At five years, the dose of dopaminergic treatment and the duration and severity of levodopa-induced dyskinesia were reduced, as compared with base line (P<0.001 for each comparison). The average scores for cognitive performance remained unchanged, but dementia developed in three patients after three years. Mean depression scores remained unchanged. Severe adverse events included a large intracerebral hemorrhage in one patient. One patient committed suicide. CONCLUSIONS: Patients with advanced Parkinson's disease who were treated with bilateral stimulation of the subthalamic nucleus had marked improvements over five years in motor function while off medication and in dyskinesia while on medication. There was no control group, but worsening of akinesia, speech, postural stability, freezing of gait, and cognitive function between the first and the fifth year is consistent with the natural history of Parkinson's disease.

CONTEXT: Vertebral fractures significantly increase lifetime risk of future fractures, but risk of further vertebral fractures in the period immediately following a vertebral fracture has not been evaluated. OBJECTIVE: To determine the incidence of further vertebral fracture in the year following a vertebral fracture. DESIGN AND SETTING: Analysis of data from 4 large 3-year osteoporosis treatment trials conducted at 373 study centers in North America, Europe, Australia, and New Zealand from November 1993 to April 1998. SUBJECTS: Postmenopausal women who had been randomized to a placebo group and for whom vertebral fracture status was known at entry (n = 2725). MAIN OUTCOME MEASURE: Occurrence of radiographically identified vertebral fracture during the year following an incident vertebral fracture. RESULTS: Subjects were a mean age of 74 years and had a mean of 28 years since menopause. The cumulative incidence of new vertebral fractures in the first year was 6.6%. Presence of 1 or more vertebral fractures at baseline increased risk of sustaining a vertebral fracture by 5-fold during the initial year of the study compared with the incidence in subjects without prevalent vertebral fractures at baseline (relative risk [RR], 5.1; 95% confidence interval [CI], 3.1-8.4; P<.001). Among the 381 participants who developed an incident vertebral fracture, the incidence of a new vertebral fracture in the subsequent year was 19.2% (95% CI, 13.6%-24.8%). This risk was also increased in the presence of prevalent vertebral fractures (RR, 9.3; 95% CI, 1.2-71.6; P =.03). CONCLUSION: Our data indicate that women who develop a vertebral fracture are at substantial risk for additional fracture within the next year.

The NCEP and NCAR are cooperating in a project (denoted “reanalysis”) to produce a 40-year record of global analyses of atmospheric fields in support of the needs of the research and climate monitoring communities. This effort involves the recovery of land surface, ship, rawinsonde, pibal, aircraft, satellite, and other data; quality controlling and assimilating these data with a data assimilation system that is kept unchanged over the reanalysis period 1957–96. This eliminates perceived climate jumps associated with changes in the data assimilation system. The NCEP/NCAR 40-yr reanalysis uses a frozen state-of-the-art global data assimilation system and a database as complete as possible. The data assimilation and the model used are identical to the global system implemented operationally at the NCEP on 11 January 1995, except that the horizontal resolution is T62 (about 210 km). The database has been enhanced with many sources of observations not available in real time for operations, provided by different countries and organizations. The system has been designed with advanced quality control and monitoring components, and can produce 1 mon of reanalysis per day on a Cray YMP/8 supercomputer. Different types of output archives are being created to satisfy different user needs, including a “quick look” CD-ROM (one per year) with six tropospheric and stratospheric fields available twice daily, as well as surface, top-of-the-atmosphere, and isentropic fields. Reanalysis information and selected output is also available on-line via the Internet (http//:nic.fb4.noaa.gov:8000). A special CDROM, containing 13 years of selected observed, daily, monthly, and climatological data from the NCEP/NCAR Reanalysis, is included with this issue. Output variables are classified into four classes, depending on the degree to which they are influenced by the observations and/or the model. For example, “C” variables (such as precipitation and surface fluxes) are completely determined by the model during the data assimilation and should be used with caution. Nevertheless, a comparison of these variables with observations and with several climatologies shows that they generally contain considerable useful information. Eight-day forecasts, produced every 5 days, should be useful for predictability studies and for monitoring the quality of the observing systems. The 40 years of reanalysis (1957–96) should be completed in early 1997. A continuation into the future through an identical Climate Data Assimilation System will allow researchers to reliably compare recent anomalies with those in earlier decades. Since changes in the observing systems will inevitably produce perceived changes in the climate, parallel reanalyses (at least 1 year long) will be generated for the periods immediately after the introduction of new observing systems, such as new types of satellite data. NCEP plans currently call for an updated reanalysis using a state-of-the-art system every five years or so. The successive reanalyses will be greatly facilitated by the generation of the comprehensive database in the present reanalysis.

BACKGROUND: Long-term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. METHODS: We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. RESULTS: Of the 150 patients who underwent randomization, 1 patient died during the 5-year follow-up period; 134 of the remaining 149 patients (90%) completed 5 years of follow-up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention-to-treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention-to-treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric-bypass and sleeve-gastrectomy groups were superior to the changes seen in the medical-therapy group with respect to body weight (-23%, -19%, and -5% in the gastric-bypass, sleeve-gastrectomy, and medical-therapy groups, respectively), triglyceride level (-40%, -29%, and -8%), high-density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (-35%, -34%, and -13%), and quality-of-life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36-Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. CONCLUSIONS: Five-year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo-Surgery and others; STAMPEDE ClinicalTrials.gov number, NCT00432809 .).

BACKGROUND AND OBJECTIVE: The original Whickham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the incidence and natural history of thyroid disease in this cohort. DESIGN, PATIENTS AND MEASUREMENTS: Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, in addition to death certificates, two-thirds had information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91% were tested for clinical, biochemical and immunological evidence of thyroid dysfunction. RESULTS: Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism in women was 0.8/1000 survivors/year (0.5-1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an increase with age in hypothyroidism but no age relation in hyperthyroidism. The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially. The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors identified at first survey. The odds ratios (with 95% confidence intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A logit model indicated that increasing values of serum TSH above 2mU/l at first survey increased the probability of developing hypothyroidism which was further increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism in women. CONCLUSIONS: This historical cohort study has provided incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease identified twenty years earlier.

Objective Despite extensive use of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and the increased bleeding risk associated with such OAC use, no handy quantification tool for assessing this risk exists. We aimed to develop a practical risk score to estimate the 1-year risk for major bleeding (intracranial, hospitalization, hemoglobin decrease >2 g/L, and/or transfusion) in a cohort of real-world patients with AF. Methods Based on 3,978 patients in the Euro Heart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analysis along with historical bleeding risk factors. A new bleeding risk score termed HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort. Results Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate increased with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (C statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar C statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with C statistics of 0.91 and 0.85, respectively. Conclusion This simple, novel bleeding risk score (HAS-BLED) provides a practical tool to assess the individual bleeding risk of real-world patients with AF, potentially supporting clinical decision making regarding antithrombotic therapy in patients with AF. Despite extensive use of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and the increased bleeding risk associated with such OAC use, no handy quantification tool for assessing this risk exists. We aimed to develop a practical risk score to estimate the 1-year risk for major bleeding (intracranial, hospitalization, hemoglobin decrease >2 g/L, and/or transfusion) in a cohort of real-world patients with AF. Based on 3,978 patients in the Euro Heart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analysis along with historical bleeding risk factors. A new bleeding risk score termed HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort. Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate increased with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (C statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar C statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with C statistics of 0.91 and 0.85, respectively. This simple, novel bleeding risk score (HAS-BLED) provides a practical tool to assess the individual bleeding risk of real-world patients with AF, potentially supporting clinical decision making regarding antithrombotic therapy in patients with AF.

BACKGROUND: Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy. METHODS: In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality. RESULTS: Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure. CONCLUSIONS: In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)

BACKGROUND: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories. RESULTS: Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). CONCLUSIONS: Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)

BACKGROUND: The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits. METHODS: At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation. RESULTS: The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001). CONCLUSIONS: A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).

We present cosmological parameter constraints based on the final nine-year WMAP data, in conjunction with additional cosmological data sets. The WMAP data alone, and in combination, continue to be remarkably well fit by a six-parameter LCDM model. When WMAP data are combined with measurements of the high-l CMB anisotropy, the BAO scale, and the Hubble constant, the densities, Omegabh2, Omegach2, and Omega_L, are each determined to a precision of ~1.5%. The amplitude of the primordial spectrum is measured to within 3%, and there is now evidence for a tilt in the primordial spectrum at the 5sigma level, confirming the first detection of tilt based on the five-year WMAP data. At the end of the WMAP mission, the nine-year data decrease the allowable volume of the six-dimensional LCDM parameter space by a factor of 68,000 relative to pre-WMAP measurements. We investigate a number of data combinations and show that their LCDM parameter fits are consistent. New limits on deviations from the six-parameter model are presented, for example: the fractional contribution of tensor modes is limited to r<0.13 (95% CL); the spatial curvature parameter is limited to -0.0027 (+0.0039/-0.0038); the summed mass of neutrinos is <0.44 eV (95% CL); and the number of relativistic species is found to be 3.84+/-0.40 when the full data are analyzed. The joint constraint on Neff and the primordial helium abundance agrees with the prediction of standard Big Bang nucleosynthesis. We compare recent PLANCK measurements of the Sunyaev-Zel'dovich effect with our seven-year measurements, and show their mutual agreement. Our analysis of the polarization pattern around temperature extrema is updated. This confirms a fundamental prediction of the standard cosmological model and provides a striking illustration of acoustic oscillations and adiabatic initial conditions in the early universe.

We present cosmological parameter constraints based on the final nine-year Wilkinson Microwave Anisotropy Probe (WMAP) data, in conjunction with a number of additional cosmological data sets. The WMAP data alone, and in combination, continue to be remarkably well fit by a six-parameter Delta CDM model. When WMAP data are combined with measurements of the high-l cosmic microwave background anisotropy, the baryon acoustic oscillation scale, and the Hubble constant, the matter and energy densities, Omega(b)h(2), Omega(c)h(2), and Omega(Lambda), are each determined to a precision of similar to 1.5%. The amplitude of the primordial spectrum is measured to within 3%, and there is now evidence for a tilt in the primordial spectrum at the 5 sigma level, confirming the first detection of tilt based on the five-year WMAP data. At the end of the WMAP mission, the nine-year data decrease the allowable volume of the six-dimensional Delta CDM parameter space by a factor of 68,000 relative to pre-WMAP measurements. We investigate a number of data combinations and show that their Delta CDM parameter fits are consistent. New limits on deviations from the six-parameter model are presented, for example: the fractional contribution of tensor modes is limited to r &lt; 0.13 (95% CL); the spatial curvature parameter is limited to Omega(k) = -0.0027(-0.0038)(+0.0039); the summed mass of neutrinos is limited to Sigma m(nu) &lt; 0.44 eV (95% CL); and the number of relativistic species is found to lie within N-eff = 3.84 +/- 0.40, when the full data are analyzed. The joint constraint on N-eff and the primordial helium abundance, Y-He, agrees with the prediction of standard big bang nucleosynthesis. We compare recent Planck measurements of the Sunyaev-Zel'dovich effect with our seven-year measurements, and show their mutual agreement. Our analysis of the polarization pattern around temperature extrema is updated. This confirms a fundamental prediction of the standard cosmological model and provides a striking illustration of acoustic oscillations and adiabatic initial conditions in the early universe.

BACKGROUND: The initial Global Burden of Disease study found that depression was the fourth leading cause of disease burden, accounting for 3.7% of total disability adjusted life years (DALYs) in the world in 1990. AIMS: To present the new estimates of depression burden for the year 2000. METHOD: DALYs for depressive disorders in each world region were calculated, based on new estimates of mortality, prevalence, incidence, average age at onset, duration and disability severity. RESULTS: Depression is the fourth leading cause of disease burden, accounting for 4.4% of total DALYs in the year 2000, and it causes the largest amount of non-fatal burden, accounting for almost 12% of all total years lived with disability worldwide. CONCLUSIONS: These data on the burden of depression worldwide represent a major public health problem that affects patients and society.

(Abridged) The 7-year WMAP data and improved astrophysical data rigorously test the standard cosmological model and its extensions. By combining WMAP with the latest distance measurements from BAO and H0 measurement, we determine the parameters of the simplest LCDM model. The power-law index of the primordial power spectrum is n_s=0.968+-0.012, a measurement that excludes the scale-invariant spectrum by 99.5%CL. The other parameters are also improved from the 5-year results. Notable examples of improved parameters are the total mass of neutrinos, sum(m_nu)<0.58eV, and the effective number of neutrino species, N_eff=4.34+0.86-0.88. We detect the effect of primordial helium on the temperature power spectrum and provide a new test of big bang nucleosynthesis. We detect, and show on the map for the first time, the tangential and radial polarization patterns around hot and cold spots of temperature fluctuations, an important test of physical processes at z=1090 and the dominance of adiabatic scalar fluctuations. With the 7-year TB power spectrum, the limit on a rotation of the polarization plane due to potential parity-violating effects has improved to Delta(alpha)=-1.1+-1.4(stat)+-1.5(syst) degrees. We report significant detections of the SZ effect at the locations of known clusters of galaxies. The measured SZ signal agrees well with the expected signal from the X-ray data. However, it is a factor of 0.5 to 0.7 times the predictions from "universal profile" of Arnaud et al., analytical models, and hydrodynamical simulations. We find, for the first time in the SZ effect, a significant difference between the cooling-flow and non-cooling-flow clusters (or relaxed and non-relaxed clusters), which can explain some of the discrepancy. This lower amplitude is consistent with the lower-than-theoretically-expected SZ power spectrum recently measured by the South Pole Telescope collaboration.

BACKGROUND: We conducted 20 years of follow-up of women enrolled in a randomized trial to compare the efficacy of radical (Halsted) mastectomy with that of breast-conserving surgery. METHODS: From 1973 to 1980, 701 women with breast cancers measuring no more than 2 cm in diameter were randomly assigned to undergo radical mastectomy (349 patients) or breast-conserving surgery (quadrantectomy) followed by radiotherapy to the ipsilateral mammary tissue (352 patients). After 1976, patients in both groups who had positive axillary nodes also received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. RESULTS: Thirty women in the group that underwent breast-conserving therapy had a recurrence of tumor in the same breast, whereas eight women in the radical-mastectomy group had local recurrences (P<0.001). The crude cumulative incidence of these events was 8.8 percent and 2.3 percent, respectively, after 20 years. In contrast, there was no significant difference between the two groups in the rates of contralateral-breast carcinomas, distant metastases, or second primary cancers. After a median follow-up of 20 years, the rate of death from all causes was 41.7 percent in the group that underwent breast-conserving surgery and 41.2 percent in the radical-mastectomy group (P=1.0). The respective rates of death from breast cancer were 26.1 percent and 24.3 percent (P=0.8). CONCLUSIONS: The long-term survival rate among women who undergo breast-conserving surgery is the same as that among women who undergo radical mastectomy. Breast-conserving surgery is therefore the treatment of choice for women with relatively small breast cancers.

The relationship between the degree of obesity and the incidence of cardiovascular disease (CVD) was reexamined in the 5209 men and women of the original Framingham cohort. Recent observations of disease occurrence over 26 years indicate that obesity, measured by Metropolitan Relative Weight, was a significant independent predictor of CVD, particularly among women. Multiple logistic regression analyses showed that Metropolitan Relative Weight, or percentage of desirable weight, on initial examination predicted 26-year incidence of coronary disease (both angina and coronary disease other than angina), coronary death and congestive heart failure in men independent of age, cholesterol, systolic blood pressure, cigarettes, left ventricular hypertrophy and glucose intolerance. Relative weight in women was also positively and independently associated with coronary disease, stroke, congestive failure, and coronary and CVD death. These data further show that weight gain after the young adult years conveyed an increased risk of CVD in both sexes that could not be attributed either to the initial weight or the levels of the risk factors that may have resulted from weight gain. Intervention in obesity, in addition to the well established risk factors, appears to be an advisable goal in the primary prevention of CVD.

BACKGROUND Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS Among patients with advanced melanoma, sustained longterm overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

On the basis of a new model of motivation, we examined the effects of 3 dimensions of teacher (n = 14) behavior (involvement, structure, and autonomy support) on 144 children's (Grades 3-5) behavioral and emotional engagement across a school year. Correlational and path analyses revealed that teacher involvement was central to children's experiences in the classroom and that teacher provision of both autonomy support and optimal structure predicted children's motivation across the school year. Reciprocal effects of student motivation on teacher behavior were also found. Students who showed higher initial behavioral engagement received subsequently more of all 3 teacher behaviors. These findings suggest that students who are behaviorally disengaged receive teacher responses that should further undermine their motivation. The importance of the student-teacher relationship, especially interpersonal involvement, in optimizing student motivation is highlighted. What are the factors that motivate children to learn? Educators and parents value motivation in school for its own sake as well as for its long-term contribution to children's learning and self-esteem. Highly motivated children are easy to identify: They are enthusiastic, interested, involved, and curious; they try hard and persist; and they actively cope with challenges and setbacks. These are the children who should stay in school longer, learn more, feel better about themselves, and continue their education after high school. Recent research has borne this out (Ames & Ames, 1984, 1985; Pintrich, 1991; Stipek, 1988). Although motivated students are easy to recognize, they are difficult to find. Research shows that across the preschool to high school years, children's intrinsic motivation decreases and they feel increasingly alienated from learning (Harter, 1981). Why is it so difficult to optimize student motivation? Decades of psychological and educational research

BACKGROUND: Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease. METHODS AND FINDINGS: Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%-10.8%) of global YLDs and dysthymia for 1.4% (0.9%-2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%-3.2%) of global DALYs and dysthymia for 0.5% (0.3%-0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%-3.8%) to 3.8% (3.0%-4.7%) of global DALYs. CONCLUSIONS: GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden. Please see later in the article for the Editors' Summary.

BACKGROUND: As more patients survive the acute respiratory distress syndrome, an understanding of the long-term outcomes of this condition is needed. METHODS: We evaluated 109 survivors of the acute respiratory distress syndrome 3, 6, and 12 months after discharge from the intensive care unit. At each visit, patients were interviewed and underwent a physical examination, pulmonary-function testing, a six-minute-walk test, and a quality-of-life evaluation. RESULTS: Patients who survived the acute respiratory distress syndrome were young (median age, 45 years) and severely ill (median Acute Physiology, Age, and Chronic Health Evaluation score, 23) and had a long stay in the intensive care unit (median, 25 days). Patients had lost 18 percent of their base-line body weight by the time they were discharged from the intensive care unit and stated that muscle weakness and fatigue were the reasons for their functional limitation. Lung volume and spirometric measurements were normal by 6 months, but carbon monoxide diffusion capacity remained low throughout the 12-month follow-up. No patients required supplemental oxygen at 12 months, but 6 percent of patients had arterial oxygen saturation values below 88 percent during exercise. The median score for the physical role domain of the Medical Outcomes Study 36-item Short-Form General Health Survey (a health-related quality-of-life measure) increased from 0 at 3 months to 25 at 12 months (score in the normal population, 84). The distance walked in six minutes increased from a median of 281 m at 3 months to 422 m at 12 months; all values were lower than predicted. The absence of systemic corticosteroid treatment, the absence of illness acquired during the intensive care unit stay, and rapid resolution of lung injury and multiorgan dysfunction were associated with better functional status during the one-year follow-up. CONCLUSIONS: Survivors of the acute respiratory distress syndrome have persistent functional disability one year after discharge from the intensive care unit. Most patients have extrapulmonary conditions, with muscle wasting and weakness being most prominent.