Dartmouth–Hitchcock Medical Center

IMPORTANCE: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. EVIDENCE REVIEW: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results. FINDINGS: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant. CONCLUSION AND RELEVANCE: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.

UNLABELLED: This study predicts the burden of incident osteoporosis-related fractures and costs in the United States, by sex, age group, race/ethnicity, and fracture type, from 2005 to 2025. Total fractures were >2 million, costing nearly $17 billion in 2005. Men account for >25% of the burden. Rapid growth in the disease burden is projected among nonwhite populations. INTRODUCTION: The aging of the U.S. population will likely lead to greater prevalence of osteoporosis. Policy makers require precise projections of the disease burden by demographic subgroups and skeletal sites to effectively target osteoporosis intervention and treatment programs. MATERIALS AND METHODS: A state transition Markov decision model was used to estimate total incident fractures and costs by age, sex, race/ethnicity, and skeletal site for the U.S. population 50 years of age for 2005-2025. RESULTS: More than 2 million incident fractures at a cost of $17 billion are predicted for 2005. Total costs including prevalent fractures are more than $19 billion. Men account for 29% of fractures and 25% of costs. Total incident fractures by skeletal site were vertebral (27%), wrist (19%), hip (14%), pelvic (7%), and other (33%). Total costs by fracture type were vertebral (6%), hip (72%), wrist (3%), pelvic (5%), and other (14%). By 2025, annual fractures and costs are projected to rise by almost 50%. The most rapid growth is estimated for people 65-74 years of age, with an increase>87%. An increase of nearly 175% is projected for Hispanic and other subpopulations. CONCLUSIONS: Osteoporosis prevention, treatment, and education efforts should address all skeletal sites, not just hip and vertebral, and appropriate attention is warranted for men and diverse race/ethnicity subgroups.

Several soluble factors have recently been associated with the proliferation and differentiation of thymus-derived lymphocytes. One of these factors present in medium conditioned by T cell mitogen-stimulated lymphocytes has the ability to promote the long-term culture of normal and antigen-specific cytotoxic T cells. We report a method to test for this proliferative stimulus in the form of a sensitive microassay based upon the tritiated-thymidine incorporation of continuous murine tumor-specific cytotoxic T cell lines (CTLL). The microassay requires microliter quantitites of sample fluid and is amenable to quantitative analysis. This highly reproducible, quantitative assay for T cell growth factor (TCGF) has allowed investigation as to the kinetics of TCGF generation and has revealed that T lymphocytes are required for its production. Further investigation has supported the notion that this nonspecies-specific factor is actively removed from tissue culture medium by the proliferation of either T cell mitogen-activated lymphocytes or CTLL.

BACKGROUND: Although the relation between hospital volume and surgical mortality is well established, for most procedures, the relative importance of the experience of the operating surgeon is uncertain. METHODS: Using information from the national Medicare claims data base for 1998 through 1999, we examined mortality among all 474,108 patients who underwent one of eight cardiovascular procedures or cancer resections. Using nested regression models, we examined the relations between operative mortality and surgeon volume and hospital volume (each in terms of total procedures performed per year), with adjustment for characteristics of the patients and other characteristics of the providers. RESULTS: Surgeon volume was inversely related to operative mortality for all eight procedures (P=0.003 for lung resection, P<0.001 for all other procedures). The adjusted odds ratio for operative death (for patients with a low-volume surgeon vs. those with a high-volume surgeon) varied widely according to the procedure--from 1.24 for lung resection to 3.61 for pancreatic resection. Surgeon volume accounted for a large proportion of the apparent effect of the hospital volume, to an extent that varied according to the procedure: it accounted for 100 percent of the effect for aortic-valve replacement, 57 percent for elective repair of an abdominal aortic aneurysm, 55 percent for pancreatic resection, 49 percent for coronary-artery bypass grafting, 46 percent for esophagectomy, 39 percent for cystectomy, and 24 percent for lung resection. For most procedures, the mortality rate was higher among patients of low-volume surgeons than among those of high-volume surgeons, regardless of the surgical volume of the hospital in which they practiced. CONCLUSIONS: For many procedures, the observed associations between hospital volume and operative mortality are largely mediated by surgeon volume. Patients can often improve their chances of survival substantially, even at high-volume hospitals, by selecting surgeons who perform the operations frequently.

The 16S rRNA gene has been a mainstay of sequence-based bacterial analysis for decades. However, high-throughput sequencing of the full gene has only recently become a realistic prospect. Here, we use in silico and sequence-based experiments to critically re-evaluate the potential of the 16S gene to provide taxonomic resolution at species and strain level. We demonstrate that targeting of 16S variable regions with short-read sequencing platforms cannot achieve the taxonomic resolution afforded by sequencing the entire (~1500 bp) gene. We further demonstrate that full-length sequencing platforms are sufficiently accurate to resolve subtle nucleotide substitutions (but not insertions/deletions) that exist between intragenomic copies of the 16S gene. In consequence, we argue that modern analysis approaches must necessarily account for intragenomic variation between 16S gene copies. In particular, we demonstrate that appropriate treatment of full-length 16S intragenomic copy variants has the potential to provide taxonomic resolution of bacterial communities at species and strain level.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

CONTEXT: There are few randomized controlled trials on the effectiveness of palliative care interventions to improve the care of patients with advanced cancer. OBJECTIVE: To determine the effect of a nursing-led intervention on quality of life, symptom intensity, mood, and resource use in patients with advanced cancer. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted from November 2003 through May 2008 of 322 patients with advanced cancer in a rural, National Cancer Institute-designated comprehensive cancer center in New Hampshire and affiliated outreach clinics and a VA medical center in Vermont. INTERVENTIONS: A multicomponent, psychoeducational intervention (Project ENABLE [Educate, Nurture, Advise, Before Life Ends]) conducted by advanced practice nurses consisting of 4 weekly educational sessions and monthly follow-up sessions until death or study completion (n = 161) vs usual care (n = 161). MAIN OUTCOME MEASURES: Quality of life was measured by the Functional Assessment of Chronic Illness Therapy for Palliative Care (score range, 0-184). Symptom intensity was measured by the Edmonton Symptom Assessment Scale (score range, 0-900). Mood was measured by the Center for Epidemiological Studies Depression Scale (range, 0-60). These measures were assessed at baseline, 1 month, and every 3 months until death or study completion. Intensity of service was measured as the number of days in the hospital and in the intensive care unit (ICU) and the number of emergency department visits recorded in the electronic medical record. RESULTS: A total of 322 participants with cancer of the gastrointestinal tract (41%; 67 in the usual care group vs 66 in the intervention group), lung (36%; 58 vs 59), genitourinary tract (12%; 20 vs 19), and breast (10%; 16 vs 17) were randomized. The estimated treatment effects (intervention minus usual care) for all participants were a mean (SE) of 4.6 (2) for quality of life (P = .02), -27.8 (15) for symptom intensity (P = .06), and -1.8 (0.81) for depressed mood (P = .02). The estimated treatment effects in participants who died during the study were a mean (SE) of 8.6 (3.6) for quality of life (P = .02), -24.2 (20.5) for symptom intensity (P = .24), and -2.7 (1.2) for depressed mood (P = .03). Intensity of service did not differ between the 2 groups. CONCLUSION: Compared with participants receiving usual oncology care, those receiving a nurse-led, palliative care-focused intervention addressing physical, psychosocial, and care coordination provided concurrently with oncology care had higher scores for quality of life and mood, but did not have improvements in symptom intensity scores or reduced days in the hospital or ICU or emergency department visits. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00253383.

The microRNAs (miRNAs) are an extensive class of small noncoding RNAs (18 to 25 nucleotides) with probable roles in the regulation of gene expression. In Caenorhabditis elegans, lin-4 and let-7 miRNAs control the timing of fate specification of neuronal and hypodermal cells during larval development. lin-4, let-7 and other miRNA genes are conserved in mammals, and their potential functions in mammalian development are under active study. In order to identify mammalian miRNAs that might function in development, we characterized the expression of 119 previously reported miRNAs in adult organs from mouse and human using northern blot analysis. Of these, 30 miRNAs were specifically expressed or greatly enriched in a particular organ (brain, lung, liver or skeletal muscle). This suggests organ- or tissue-specific functions for miRNAs. To test if any of the 66 brain-expressed miRNAs were present in neurons, embryonal carcinoma cells were treated with all-trans-retinoic acid to promote neuronal differentiation. A total of 19 brain-expressed miRNAs (including lin-4 and let-7 orthologs) were coordinately upregulated in both human and mouse embryonal carcinoma cells during neuronal differentiation. The mammalian ortholog of C. elegans lin-28, which is downregulated by lin-4 in worms via 3' untranslated region binding, was also repressed during neuronal differentiation of mammalian embryonal carcinoma cells. Mammalian lin-28 messenger RNAs contain conserved predicted binding sites in their 3' untranslated regions for neuron-expressed miR-125b (a lin-4 ortholog), let-7a, and miR-218. The identification of a subset of brain-expressed miRNAs whose expression behavior is conserved in both mouse and human differentiating neurons implicates these miRNAs in mammalian neuronal development or function.

Ulcerative colitis (UC) is an idiopathic inflammatory disorder. These guidelines indicate the preferred approach to the management of adults with UC and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the evidence was not appropriate for GRADE, but there was consensus of significant clinical merit, "key concept" statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.

BACKGROUND: Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. METHODS: We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. RESULTS: Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004). CONCLUSIONS: Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

PURPOSE: To provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs published from August 1, 2014, through December 4, 2018. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. RESULTS: The systematic review included 35 publications on VTE prophylaxis and treatment and 18 publications on VTE risk assessment. Two RCTs of direct oral anticoagulants (DOACs) for the treatment of VTE in patients with cancer reported that edoxaban and rivaroxaban are effective but are linked with a higher risk of bleeding compared with low-molecular-weight heparin (LMWH) in patients with GI and potentially genitourinary cancers. Two additional RCTs reported on DOACs for thromboprophylaxis in ambulatory patients with cancer at increased risk of VTE. RECOMMENDATIONS: Changes to previous recommendations: Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE.Additional information is available at www.asco.org/supportive-care-guidelines.

BACKGROUND: Barrett's esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett's esophagus and decrease the rate of neoplastic progression. METHODS: In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barrett's esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barrett's esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS: In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS: In patients with dysplastic Barrett's esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

BACKGROUND: Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. METHODS: We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. RESULTS: Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23). CONCLUSIONS: Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel.

We consider how to combine several independent studies of the same diagnostic test, where each study reports an estimated false positive rate (FPR) and an estimated true positive rate (TPR). We propose constructing a summary receiver operating characteristic (ROC) curve by the following steps. (i) Convert each FPR to its logistic transform U and each TPR to its logistic transform V after increasing each observed frequency by adding 1/2. (ii) For each study calculate D = V - U, which is the log odds ratio of TPR and FPR, and S = V + U, an implied function of test threshold; then plot each study's point (Si, Di). (iii) Fit a robust-resistant regression line to these points (or an equally weighted least-squares regression line), with V - U as the dependent variable. (iv) Back-transform the line to ROC space. To avoid model-dependent extrapolation from irrelevant regions of ROC space we propose defining a priori a value of FPR so large that the test simply would not be used at that FPR, and a value of TPR so low that the test would not be used at that TPR. Then (a) only data points lying in the thus defined north-west rectangle of the unit square are used in the data analysis, and (b) the estimated summary ROC is depicted only within that subregion of the unit square. We illustrate the methods using simulated and real data sets, and we point to ways of comparing different tests and of taking into account the effects of covariates.

BACKGROUND: Little is known about how physician time is allocated in ambulatory care. OBJECTIVE: To describe how physician time is spent in ambulatory practice. DESIGN: Quantitative direct observational time and motion study (during office hours) and self-reported diary (after hours). SETTING: U.S. ambulatory care in 4 specialties in 4 states (Illinois, New Hampshire, Virginia, and Washington). PARTICIPANTS: 57 U.S. physicians in family medicine, internal medicine, cardiology, and orthopedics who were observed for 430 hours, 21 of whom also completed after-hours diaries. MEASUREMENTS: Proportions of time spent on 4 activities (direct clinical face time, electronic health record [EHR] and desk work, administrative tasks, and other tasks) and self-reported after-hours work. RESULTS: During the office day, physicians spent 27.0% of their total time on direct clinical face time with patients and 49.2% of their time on EHR and desk work. While in the examination room with patients, physicians spent 52.9% of the time on direct clinical face time and 37.0% on EHR and desk work. The 21 physicians who completed after-hours diaries reported 1 to 2 hours of after-hours work each night, devoted mostly to EHR tasks. LIMITATIONS: Data were gathered in self-selected, high-performing practices and may not be generalizable to other settings. The descriptive study design did not support formal statistical comparisons by physician and practice characteristics. CONCLUSION: For every hour physicians provide direct clinical face time to patients, nearly 2 additional hours is spent on EHR and desk work within the clinic day. Outside office hours, physicians spend another 1 to 2 hours of personal time each night doing additional computer and other clerical work. PRIMARY FUNDING SOURCE: American Medical Association.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

OBJECTIVE: To quantify the incidence of anemia and red blood cell (RBC) transfusion practice in critically ill patients and to examine the relationship of anemia and RBC transfusion to clinical outcomes. DESIGN: Prospective, multiple center, observational cohort study of intensive care unit (ICU) patients in the United States. Enrollment period was from August 2000 to April 2001. Patients were enrolled within 48 hrs of ICU admission. Patient follow-up was for 30 days, hospital discharge, or death, whichever occurred first. SETTING: A total of 284 ICUs (medical, surgical, or medical-surgical) in 213 hospitals participated in the study. PATIENTS: A total of 4,892 patients were enrolled in the study. MEASUREMENTS AND MAIN RESULTS: The mean hemoglobin level at baseline was 11.0 +/- 2.4 g/dL. Hemoglobin level decreased throughout the duration of the study. Overall, 44% of patients received one or more RBC units while in the ICU (mean, 4.6 +/- 4.9 units). The mean pretransfusion hemoglobin was 8.6 +/- 1.7 g/dL. The mean time to first ICU transfusion was 2.3 +/- 3.7 days. More RBC transfusions were given in study week 1; however, in subsequent weeks, subjects received one to two RBC units per week while in the ICU. The number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality. Patients who received transfusions also had more total complications and were more likely to experience a complication. Baseline hemoglobin was related to the number of RBC transfusions, but it was not an independent predictor of length of stay or mortality. However, a nadir hemoglobin level of <9 g/dL was a predictor of increased mortality and length of stay. CONCLUSIONS: Anemia is common in the critically ill and results in a large number of RBC transfusions. Transfusion practice has changed little during the past decade. The number of RBC units transfused is an independent predictor of worse clinical outcome.