Objective To assess possible outcome benefits of prone positioning in patients with moderate and severe hypoxemia who are affected by ARDS.
Design, Setting, and Patients The Prone-Supine II Study, a multicenter, unblinded, randomized controlled trial conducted in 23 centers in Italy and 2 in Spain. Patients were 342 adults with ARDS receiving mechanical ventilation, enrolled from February 2004 through June 2008 and prospectively stratified into subgroups with moderate (n = 192) and severe (n = 150) hypoxemia.
Interventions Patients were randomized to undergo supine (n = 174) or prone (20 hours per day; n = 168) positioning during ventilation.
Main Outcome Measures The primary outcome was 28-day all-cause mortality. Secondary outcomes were 6-month mortality and mortality at intensive care unit discharge, organ dysfunctions, and the complication rate related to prone positioning.
Results Prone and supine patients from the entire study population had similar 28-day (31.0% vs 32.8%; relative risk [RR], 0.97; 95% confidence interval [CI], 0.84-1.13; P = .72) and 6-month (47.0% vs 52.3%; RR, 0.90; 95% CI, 0.73-1.11; P = .33) mortality rates, despite significantly higher complication rates in the prone group. Outcomes were also similar for patients with moderate hypoxemia in the prone and supine groups at 28 days (25.5% vs 22.5%; RR, 1.04; 95% CI, 0.89-1.22; P = .62) and at 6 months (42.6% vs 43.9%; RR, 0.98; 95% CI, 0.76-1.25; P = .85). The 28-day mortality of patients with severe hypoxemia was 37.8% in the prone and 46.1% in the supine group (RR, 0.87; 95% CI, 0.66-1.14; P = .31), while their 6-month mortality was 52.7% and 63.2%, respectively (RR, 0.78; 95% CI, 0.53-1.14; P = .19).
Conclusion Data from this study indicate that prone positioning does not provide significant survival benefit in patients with ARDS or in subgroups of patients with moderate and severe hypoxemia.
Trial Registration clinicaltrials.gov Identifier:
Objective To examine prevalence of and factors associated with persistent pain after surgical treatment for breast cancer.
Design, Setting, and Patients A nationwide cross-sectional questionnaire study of 3754 women aged 18 to 70 years who received surgery and adjuvant therapy (if indicated) for primary breast cancer in Denmark between January 1, 2005, and December 31, 2006. A study questionnaire was sent to the women between January and April 2008.
Main Outcome Measures Prevalence, location, and severity of persistent pain and sensory disturbances in 12 well-defined treatment groups assessed an average of 26 months after surgery, and adjusted odds ratio (OR) of reported pain and sensory disturbances with respect to age, surgical technique, chemotherapy, and radiotherapy.
Results By June 2008, 3253 of 3754 eligible women (87%) returned the questionnaire. A total of 1543 patients (47%) reported pain, of whom 201 (13%) had severe pain, 595 (39%) had moderate pain, and 733 (48%) had light pain. Factors associated with chronic pain included young age (18-39 years: OR, 3.62; 95% confidence interval [CI], 2.25-5.82; P < .001) and adjuvant radiotherapy (OR, 1.50; 95% CI, 1.08-2.07; P = .03), but not chemotherapy (OR, 1.01; 95% CI, 0.85-1.21; P = .91). Axillary lymph node dissection (ALND) was associated with increased likelihood of pain (OR, 1.77; 95% CI, 1.43-2.19; P < .001) compared with sentinel lymph node dissection. Risk of sensory disturbances was associated with young age (18-39 years: OR, 5.00; 95% CI, 2.87-8.69; P < .001) and ALND (OR, 4.97; 95% CI, 3.92-6.30; P < .001). Pain complaints from other parts of the body were associated with increased risk of pain in the surgical area (P < .001). A total of 306 patients (20%) with pain had contacted a physician within the prior 3 months for pain complaints in the surgical area.
Conclusion Two to 3 years after breast cancer treatment, persistent pain and sensory disturbances remain clinically significant problems among Danish women who received surgery in 2005 and 2006.
]]>Objective To assess major lipids and apolipoproteins in vascular risk.
Design, Setting, and Participants Individual records were supplied on 302 430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes.
Main Outcome Measures Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 loge triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non–HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis.
Results The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non–HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non–HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non–HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non–HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non–HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non–HDL-C.
Conclusion Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
]]>Objective To study the association between the use of statins, fibrates, or other lipid-lowering agents and the risk of incident gallstone disease followed by cholecystectomy.
Design, Setting, and Participants Case-control analysis using the UK-based General Practice Research Database. Incident patients between 1994 and 2008 and 4 controls per each patient were identified and matched on age, sex, general practice, calendar time, and years of history in the database. The study population was 76% women and the mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic regression was used to estimate the odds ratio (OR) of developing gallstones followed by cholecystectomy in relation to exposure to lipid-lowering agents, stratified by exposure timing and duration. The ORs and 95% confidence intervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogen use.
Main Outcome Measure The adjusted OR (AOR) for developing gallstone disease followed by cholecystectomy in relation to exposure to lipid-lowering agents.
Results A total of 27 035 patients with cholecystectomy and 106 531 matched controls were identified, including 2396 patients and 8868 controls who had statin use. Compared with nonuse, current statin use (last prescription recorded within 90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for controls (AOR, 1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, 0.85; 95% CI, 0.77-0.93) for 5 to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; 95% CI, 0.59-0.70) for 20 or more prescriptions. The AORs for current use of statins defined as 20 or more prescriptions were similar (around 0.6) across age, sex, and body mass index categories, and across the statin class.
Conclusion Long-term use of statins was associated with a decreased risk of gallstones followed by cholecystectomy.
]]>Objective To compare the surgical mask with the N95 respirator in protecting health care workers against influenza.
Design, Setting, and Participants Noninferiority randomized controlled trial of 446 nurses in emergency departments, medical units, and pediatric units in 8 tertiary care Ontario hospitals.
Intervention Assignment to either a fit-tested N95 respirator or a surgical mask when providing care to patients with febrile respiratory illness during the 2008-2009 influenza season.
Main Outcome Measures The primary outcome was laboratory-confirmed influenza measured by polymerase chain reaction or a 4-fold rise in hemagglutinin titers. Effectiveness of the surgical mask was assessed as noninferiority of the surgical mask compared with the N95 respirator. The criterion for noninferiority was met if the lower limit of the 95% confidence interval (CI) for the reduction in incidence (N95 respirator minus surgical group) was greater than –9%.
Results Between September 23, 2008, and December 8, 2008, 478 nurses were assessed for eligibility and 446 nurses were enrolled and randomly assigned the intervention; 225 were allocated to receive surgical masks and 221 to N95 respirators. Influenza infection occurred in 50 nurses (23.6%) in the surgical mask group and in 48 (22.9%) in the N95 respirator group (absolute risk difference, –0.73%; 95% CI, –8.8% to 7.3%; P = .86), the lower confidence limit being inside the noninferiority limit of –9%.
Conclusion Among nurses in Ontario tertiary care hospitals, use of a surgical mask compared with an N95 respirator resulted in noninferior rates of laboratory-confirmed influenza.
Trial Registration clinicaltrials.gov Identifier:
Published online October 1, 2009 (doi:10.1001/jama.2009.1466).
]]>Objective To describe the clinical and epidemiologic features of pandemic 2009 influenza A(H1N1) cases that led to hospitalization or death.
Design, Setting, and Participants Statewide enhanced public health surveillance of California residents who were hospitalized or died with laboratory evidence of pandemic 2009 influenza A(H1N1) infection reported to the California Department of Public Health between April 23 and August 11, 2009.
Main Outcome Measure Characteristics of hospitalized and fatal cases.
Results During the study period there were 1088 cases of hospitalization or death due to pandemic 2009 influenza A(H1N1) infection reported in California. The median age was 27 years (range, <1-92 years) and 68% (741/1088) had risk factors for seasonal influenza complications. Sixty-six percent (547/833) of those with chest radiographs performed had infiltrates and 31% (340/1088) required intensive care. Rapid antigen tests were falsely negative in 34% (208/618) of cases evaluated. Secondary bacterial infection was identified in 4% (46/1088). Twenty-one percent (183/884) received no antiviral treatment. Overall fatality was 11% (118/1088) and was highest (18%-20%) in persons aged 50 years or older. The most common causes of death were viral pneumonia and acute respiratory distress syndrome.
Conclusions In the first 16 weeks of the current pandemic, the median age of hospitalized infected cases was younger than is common with seasonal influenza. Infants had the highest hospitalization rates and persons aged 50 years or older had the highest mortality rates once hospitalized. Most cases had established risk factors for complications of seasonal influenza.
]]>Objective To describe characteristics, treatment, and outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection.
Design, Setting, and Patients A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009.
Main Outcome Measures The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay.
Results Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The median time from symptom onset to hospital admission was 4 days (interquartile range [IQR], 2-7 days) and from hospitalization to ICU admission was 1 day (IQR, 0-2 days). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean [SD] score of 6.8 [3.6] on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean [SD] ratio of Pa
Conclusion Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.
Published online October 12, 2009 (doi:10.1001/jama.2009.1496).
]]>Objective To describe baseline characteristics, treatment, and outcomes of consecutive critically ill patients in Mexico hospitals that treated the majority of such patients with confirmed, probable, or suspected 2009 influenza A(H1N1).
Design, Setting, and Patients Observational study of 58 critically ill patients with 2009 influenza A(H1N1) at 6 hospitals between March 24 and June 1, 2009. Demographic data, symptoms, comorbid conditions, illness progression, treatments, and clinical outcomes were collected using a piloted case report form.
Main Outcome Measures The primary outcome measure was mortality. Secondary outcomes included rate of 2009 influenza (A)H1N1–related critical illness and mechanical ventilation as well as intensive care unit (ICU) and hospital length of stay.
Results Critical illness occurred in 58 of 899 patients (6.5%) admitted to the hospital with confirmed, probable, or suspected 2009 influenza (A)H1N1. Patients were young (median, 44.0 [range, 10-83] years); all presented with fever and all but 1 with respiratory symptoms. Few patients had comorbid respiratory disorders, but 21 (36%) were obese. Time from hospital to ICU admission was short (median, 1 day [interquartile range {IQR}, 0-3 days]), and all patients but 2 received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia (median day 1 ratio of Pa
Conclusion Critical illness from 2009 influenza A(H1N1) in Mexico occurred in young individuals, was associated with severe acute respiratory distress syndrome and shock, and had a high case-fatality rate.
Published online October 12, 2009 (doi:10.1001/jama.2009.1536).
]]>Objectives To describe the characteristics of all patients with 2009 influenza A(H1N1)–associated ARDS treated with ECMO and to report incidence, resource utilization, and patient outcomes.
Design, Setting, and Patients An observational study of all patients (n = 68) with 2009 influenza A(H1N1)–associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand between June 1 and August 31, 2009.
Main Outcome Measures Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival.
Results Sixty-eight patients with severe influenza-associated ARDS were treated with ECMO, of whom 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8), representing an incidence rate of 2.6 ECMO cases per million population. An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs. The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) Pa
Conclusions During June to August 2009 in Australia and New Zealand, the ICUs at regional referral centers provided mechanical ventilation for many patients with 2009 influenza A(H1N1)–associated respiratory failure, one-third of whom received ECMO. These ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.
Published online October 12, 2009 (doi:10.1001/jama.2009.1535).
]]>Objective To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN).
Design, Setting, and Participants Cluster randomized controlled trial involving 89 784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49 222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40 562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008.
Intervention Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result).
Main Outcome Measures Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period).
Results The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity.
Conclusion This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.
Trial Registration trialregister.nl Identifier:
Objective To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure.
Design, Setting, and Patients Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients who completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group.
Intervention Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.
Main Outcome Measures Weight gain and changes in lipid and metabolic parameters.
Results After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval [CI], 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, –1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL [95% CI, 6.9 to 24.3 mg/dL] P < .001 and 9.1 mg/dL [95% CI, 0.4 to 17.7 mg/dL] P = .046), triglycerides (24.3 mg/dL [95% CI, 9.8 to 38.9 mg/dL] P = .002 and 37.0 mg/dL [95% CI, 10.1 to 63.8 mg/dL] P = .01), non–high-density lipoprotein (HDL) cholesterol (16.8 mg/dL [95% CI, 9.3 to 24.3 mg/dL] P < .001 and 9.9 mg/dL [95% CI, 1.4 to 18.4 mg/dL] P = .03), and ratio of triglycerides to HDL cholesterol (0.6 [95% CI, 0.2 to 0.9] P = .002 and (1.2 [95% CI, 0.4 to 2.0] P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL [95% CI, 0.5 to 19.0 mg/dL]; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group.
Conclusions First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.
]]>Objective To estimate the proportion of the US population living within 1 and 2 hours by rotary air transport (helicopter) or ground transport of a burn care facility.
Design and Setting A cross-sectional analysis of geographic access to US burn centers utilizing the 2000 US census, road and speed limit data, the Atlas and Database of Air Medical Services database, and the 2008 American Burn Association Directory.
Main Outcome Measure The proportion of state, regional, and national population living within 1 and 2 hours by air transport or ground transport of a burn care facility.
Results In 2008, there were 128 self-reported burn centers in the United States including 51 American Burn Association–verified centers. An estimated 25.1% and 46.3% of the US population live within 1 and 2 hours by ground transport, respectively, of a verified burn center. By air, 53.9% and 79.0% of the population live within 1 and 2 hours, respectively, of a verified center. There was significant regional variation in access to verified burn centers by both ground and rotary air transport. The greatest proportion of the population with access was highest in the northeast region and lowest in the southern United States.
Conclusion Nearly 80% of the US population lives within 2 hours by ground or rotary air transport of a verified burn center; however, there is both state and regional variation in geographic access to these centers.
]]>Objective To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased.
Design, Setting, and Patients Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association–European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123 407]) was compared with the European general population (Eurostat).
Main Outcome Measures Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated.
Results Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16 654 deaths (39%) were cardiovascular and 21 654 (51%) were noncardiovascular. In the general population, 7 041 747 deaths (40%) were cardiovascular and 10 183 322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43).
Conclusion Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.
]]>Objective To estimate pancreatic cancer risk in families with germline MMR gene mutations.
Design, Setting, and Patients Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment.
Main Outcome Measures Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk.
Results Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population.
Conclusions Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.
]]>Objective To compare the immune response in wild-type mice after immunization with DNA Aβ42 trimer and Aβ42 peptide.
Design and Intervention Wild-type mice received either 4 µg of DNA Aβ42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 µg of human Aβ42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Aβ42-specific antibodies were analyzed.
Main Outcome Measures Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Aβ42-specific antibodies, and T-cell activation.
Results DNA Aβ42 trimer immunization resulted in antibody titers with a mean of 15 µg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a TH2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed TH1/TH2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03).
Conclusion In this preliminary study in a wild-type mouse model, DNA Aβ42 trimer immunization protocol produced a TH2 immune response and appeared to have low potential to cause an inflammatory T-cell response.
]]>Objective To determine whether omega-3 improves the response to sertraline in patients with major depression and coronary heart disease (CHD).
Design, Setting, and Participants Randomized controlled trial. Between May 2005 and December 2008, 122 patients in St Louis, Missouri, with major depression and CHD were randomized.
Interventions After a 2-week run-in period, all patients were given 50 mg/d of sertraline and randomized in double-blind fashion to receive 2 g/d of omega-3 acid ethyl esters (930 mg of eicosapentaenoic acid [EPA] and 750 mg of docosahexaenoic acid [DHA]) (n=62) or to corn oil placebo capsules (n=60) for 10 weeks.
Main Outcome Measures Scores on the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HAM-D).
Results Adherence to the medication regimen was 97% or more in both groups for both medications. There were no differences in weekly BDI-II scores (treatment x time interaction = 0.02; 95% confidence interval [CI], –0.33 to 0.36; t112 = 0.11; P = .91), pre-post BDI-II scores (placebo, 14.8 vs omega-3, 16.1; 95% difference-in-means CI, –4.5 to 2.0; t116 = –0.77; P = .44), or HAM-D scores (placebo, 9.4 vs omega-3, 9.3; 95% difference-in-means CI, –2.2 to 2.4; t115 = 0.12; P = .90). The groups did not differ on predefined indicators of depression remission (BDI-II ≤8: placebo, 27.4% vs omega-3, 28.3%; odds ratio [OR], 0.96; 95% CI, 0.43-2.15; t113 = –0.11; P = .91) or response (>50% reduction in BDI-II from baseline: placebo, 49.0% vs omega-3, 47.7%; OR, 1.06; 95% CI, 0.51-2.19; t112 = 0.15; P = .88).
Conclusions Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks, compared with sertraline and placebo. Whether higher doses of omega-3 or sertraline, a different ratio of EPA to DHA, longer treatment, or omega-3 monotherapy can improve depression in patients with CHD remains to be determined.
Trial Registration clinicaltrials.gov Identifier:
Objective To examine aldosterone antagonist prescription based on HF management guideline criteria, investigator-defined appropriateness criteria, and trends over time in patients hospitalized with heart failure.
Design, Setting, and Patients Observational analysis of 43 625 patients admitted with HF and discharged home from 241 hospitals participating in the Get With The Guidelines–HF quality improvement registry between January 2005 and December 2007.
Main Outcome Measures Prescription and predictors of use of aldosterone antagonists, based on guideline criteria.
Results Among 12 565 patients eligible for aldosterone antagonist therapy, 4087 (32.5%) received an aldosterone antagonist at discharge, and treatment increased modestly from 28% to 34% over the study period. There was also wide variation in aldosterone antagonist use among hospitals (0%-90.6%). Aldosterone antagonist use in eligible patients was associated with younger age (adjusted odds ratio [OR], 0.85; 95% confidence interval [CI], 0.82-0.88), African American race/ethnicity (adjusted OR, 1.17; 95% CI, 1.04-1.32), lower systolic blood pressure (adjusted OR, 0.94; 95% CI, 0.92-0.95), history of implantable cardioverter-defibrillator use (adjusted OR, 1.51; 95% CI, 1.34-1.69), depression (adjusted OR, 1.15; 95% CI, 1.01-1.30), alcohol use (adjusted OR, 1.23; 95% CI, 1.02-1.50), and pacemaker implantation (adjusted OR, 1.21; 95% CI, 1.06-1.38), and with having no history of renal insufficiency (adjusted OR, 0.85; 95% CI, 0.75-0.96). Applying serum creatinine and potassium appropriateness criteria, inappropriate and potentially inappropriate use of aldosterone antagonist therapy was low and did not change over the 3-year study period.
Conclusions Less than one-third of eligible patients hospitalized for HF and participating in a quality improvement registry received HF guideline–recommended aldosterone antagonist therapy. Use of aldosterone antagonist therapy among patients with documented contraindications was low.
]]>Objectives To examine the relation between CVD and risk of hip fracture in twins and evaluate the relative importance of genetics and lifestyle factors in this association.
Design, Setting, and Participants A cohort of all 31 936 Swedish twins born from 1914-1944 was followed up from the age of 50 years. The National Patient Registry identified twins with CVDs and fractures from 1964 through 2005. Time-dependent exposures using Cox proportional hazard regression models were evaluated.
Main Outcome Measure Time to hip fracture after diagnosis of CVD.
Results The crude absolute rate of hip fractures was 12.6 per 1000 person-years after a diagnosis of heart failure, 12.6 per 1000 person-years after a stroke, 6.6 per 1000 person-years after a diagnosis of peripheral atherosclerosis, and 5.2 per 1000 person-years after a diagnosis of ischemic heart disease compared with 1.2 per 1000 person-years for those without a CVD diagnosis. The multivariable-adjusted hazard ratio (HR) of hip fracture after a diagnosis of heart failure was 4.40 (95% confidence interval [CI], 3.43-5.63); after a stroke, the HR was 5.09 (95% CI, 4.18-6.20); after a diagnosis of peripheral atherosclerosis, the HR was 3.20 (95% CI, 2.28-4.50); and after an ischemic heart disease event, the HR was 2.32 (95% CI, 1.91-2.84). Identical twins without heart failure and stroke also had, after their co-twins had been exposed to these respective diseases, an increased rate of hip fracture. These sibling twins pseudoexposed for heart failure had a multivariable-adjusted HR of 3.74 (95% CI, 1.97-7.10) for hip fracture, whereas pseudoexposure for stroke had an HR of 2.29 (95% CI, 1.20-4.35).
Conclusions A diagnosis of CVD was significantly associated with risk of subsequent hip fracture. Increased risks in co-twins without an index diagnosis suggest genetic factors in the association between CVD and osteoporotic fractures.
]]>Objective To compare physician workforce estimates and supply projections using the American Medical Association Physician Masterfile (Masterfile) data with estimates and projections using data from the US Census Bureau Current Population Survey (CPS).
Design, Setting, and Participants Parallel retrospective cohort analyses of employment trends of the number of active physicians by age and sex using annual data from the Masterfile and the CPS between 1979 and 2008. Recent workforce trends were used to project future physician supply by age.
Main Outcome Measure Annual number of physicians working at least 20 hours per week in 10-year age categories.
Results In an average year in the sample period, the CPS estimated 67 000 (10%) fewer active physicians than did the Masterfile (95% confidence interval [CI], 57 000-78 000; P < .001), almost entirely due to fewer active physicians aged 55 years or older. The CPS estimated more young physicians (ages 25-34 years) than did the Masterfile, with the difference increasing to an average of 17 000 (12%) during the final 15 years (95% CI, 13 000-22 000; P < .001). The CPS estimates of more young physicians were consistent with historical growth observed in the number of first-year residents, and the CPS estimates of fewer older physicians were consistent with lower Medicare billing by older physicians. Projections based on both the CPS and the Masterfile data indicate that the number of active physicians will increase by approximately 20% between 2005 and 2020. However, projections for 2020 using CPS data estimate nearly 100 000 (9%) fewer active physicians than projections using the Masterfile data (957 000 vs 1 050 000), and estimate that a smaller proportion of active physicians will be 65 years or older (9% vs 18%). The increasing proportion of female physicians had little effect on physician supply projections because, unlike male physicians, female physicians were found to maintain their work activity after age 55 years.
Conclusion Compared with the Masterfile data, estimates using the CPS data found more young physicians entering the workforce and fewer older physicians remaining active, resulting in estimates of a smaller and younger physician workforce now and in the future.
]]>Objective To report the clinical circumstances and implication of hypertrophic cardiomyopathy (HCM) transmitted by sperm donation to recipients.
Setting Voluntary sperm donation through a US Food and Drug Administration–approved tissue bank.
Main Outcome Measure Incidence of genetically affected offspring and clinical outcomes to date.
Results An asymptomatic 23-year-old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel β-myosin heavy-chain mutation that caused HCM, after an offspring was clinically diagnosed with this disease. Of the 24 children known to be offspring of the donor, including 22 who were products of fertilization via sperm donation and 2 conceived by the donor's wife, a total of 9 genetically affected offspring, 2 to 16 years of age and 6 males, have been identified with HCM (2005-2009). Three of the 9 gene-positive children have currently expressed phenotypic evidence of HCM, including one who died at age 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at age 15 years. The latter 2 children and the donor are judged likely to be at increased risk for sudden death.
Conclusions This case series underscores the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (eg, HCM) such as consideration for 12-lead electrocardiograms.
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