Cancer in General Responders Participating in World Trade Center Health Programs, 2003-2013.

BACKGROUND: Following the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure. METHODS: The study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer. RESULTS: Restricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer. CONCLUSION: Our analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure.

Effect of Palliative Care-Led Meetings for Families of Patients With Chronic Critical Illness: A Randomized Clinical Trial.

IMPORTANCE: Family caregivers of patients with chronic critical illness experience significant psychological distress. OBJECTIVE: To determine whether family informational and emotional support meetings led by palliative care clinicians improve family anxiety and depression. DESIGN, SETTING, AND PARTICIPANTS: A multicenter randomized clinical trial conducted from October 2010 through November 2014 in 4 medical intensive care units (ICUs). Adult patients (aged ≥21 years) requiring 7 days of mechanical ventilation were randomized and their family surrogate decision makers were enrolled in the study. Observers were blinded to group allocation for the measurement of the primary outcomes. INTERVENTIONS: At least 2 structured family meetings led by palliative care specialists and provision of an informational brochure (intervention) compared with provision of an informational brochure and routine family meetings conducted by ICU teams (control). There were 130 patients with 184 family surrogate decision makers in the intervention group and 126 patients with 181 family surrogate decision makers in the control group. MAIN OUTCOMES AND MEASURES: The primary outcome was Hospital Anxiety and Depression Scale symptom score (HADS; score range, 0 [best] to 42 [worst]; minimal clinically important difference, 1.5) obtained during 3-month follow-up interviews with the surrogate decision makers. Secondary outcomes included posttraumatic stress disorder experienced by the family and measured by the Impact of Events Scale-Revised (IES-R; total score range, 0 [best] to 88 [worst]), discussion of patient preferences, hospital length of stay, and 90-day survival. RESULTS: Among 365 family surrogate decision makers (mean age, 51 years; 71% female), 312 completed the study. At 3 months, there was no significant difference in anxiety and depression symptoms between surrogate decision makers in the intervention group and the control group (adjusted mean HADS score, 12.2 vs 11.4, respectively; between-group difference, 0.8 [95% CI, -0.9 to 2.6]; P = .34). Posttraumatic stress disorder symptoms were higher in the intervention group (adjusted mean IES-R score, 25.9) compared with the control group (adjusted mean IES-R score, 21.3) (between-group difference, 4.60 [95% CI, 0.01 to 9.10]; P = .0495). There was no difference between groups regarding the discussion of patient preferences (intervention, 75%; control, 83%; odds ratio, 0.63 [95% CI, 0.34 to 1.16; P = .14]). The median number of hospital days for patients in the intervention vs the control group (19 days vs 23 days, respectively; between-group difference, -4 days [95% CI, -6 to 3 days]; P = .51) and 90-day survival (hazard ratio, 0.95 [95% CI, 0.65 to 1.38], P = .96) were not significantly different. CONCLUSIONS AND RELEVANCE: Among families of patients with chronic critical illness, the use of palliative care-led informational and emotional support meetings compared with usual care did not reduce anxiety or depression symptoms and may have increased posttraumatic stress disorder symptoms. These findings do not support routine or mandatory palliative care-led discussion of goals of care for all families of patients with chronic critical illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01230099.

Cancer in World Trade Center responders: Findings from multiple cohorts and options for future study.

BACKGROUND: Three longitudinal studies of cancer incidence in varied populations of World Trade Center responders have been conducted. METHODS: We compared the design and results of the three studies. RESULTS: Separate analyses of these cohorts revealed excess cancer incidence in responders for all cancers combined and for cancers of the thyroid and prostate. Methodological dissimilarities included recruitment strategies, source of cohort members, demographic characteristics, overlap between cohorts, assessment of WTC and other occupational exposures and confounders, methods and duration of follow-up, approaches for statistical analysis, and latency analyses. CONCLUSIONS: The presence of three cohorts strengthens the effort of identifying and quantifying the cancer risk; the heterogeneity in design might increase sensitivity to the identification of cancers potentially associated with exposure. The presence and magnitude of an increased cancer risk remains to be fully elucidated. Continued long-term follow up with minimal longitudinal dropout is crucial to achieve this goal.

Mortality among World Trade Center rescue and recovery workers, 2002-2011.

BACKGROUND: Rescue and recovery workers responding to the 2001 collapse of the World Trade Center (WTC) sustained exposures to toxic chemicals and have elevated rates of multiple morbidities. METHODS: Using data from the World Trade Center Health Program and the National Death Index for 2002-2011, we examined standardized mortality ratios (SMR) and proportional cancer mortality ratios (PCMR) with indirect standardization for age, sex, race, and calendar year to the U.S. general population, as well as associations between WTC-related environmental exposures and all-cause mortality. RESULTS: We identified 330 deaths among 28,918 responders (SMR 0.43, 95%CI 0.39-0.48). No cause-specific SMRs were meaningfully elevated. PCMRs were elevated for neoplasms of lymphatic and hematopoietic tissue (PCMR 1.76, 95%CI 1.06-2.75). Mortality hazard ratios showed no linear trend with exposure. CONCLUSIONS: Consistent with a healthy worker effect, all-cause mortality among responders was not elevated. There was no clear association between intensity and duration of exposure and mortality. Surveillance is needed to monitor the proportionally higher cancer mortality attributed to lymphatic/hematopoietic neoplasms.

Risk factors for radiation exposure in newly diagnosed IBD patients.

PURPOSE: Patients with inflammatory bowel disease (IBD) may be exposed to high doses of diagnostic radiation. The purpose of this study is to identify subsets of this population at risk for significant radiation exposure. METHODS: This HIPAA compliant, IRB approved study consists of 336 patients (237 adult and 99 pediatric) within the Ocean State Crohn's & Colitis Area Registry (OSCCAR). All were newly diagnosed with IBD and prospectively enrolled between 1/2008 and 12/2012. Comprehensive chart review was performed. RESULTS: 207 (61.6%) patients were diagnosed with Crohn's disease (CD), 120 (35.7%) with ulcerative colitis (UC), and 9 (2.7%) with inflammatory bowel disease, type unspecified (IBDU). 192 (57.1%) patients were exposed to GI-specific radiation. Average GI-specific radiation dose for adult IBD patients was 14.1 mSV and was significantly greater among adult CD than adult UC patients (p = 0.01). Pediatric patients underwent fewer CT scans (p < 0.0001). Risk factors for increased radiation exposure include: GI surgery (p = 0.003), biologic therapy (p = 0.01), pain-predominant symptoms (as compared to diarrhea-predominant symptoms; p < 0.05), and isolated ileal disease (p = 0.02). Patients with stricturing or penetrating disease received higher radiation doses than patients with non-stricturing, non-penetrating disease (p < 0.0001). CONCLUSIONS: A variety of risk factors are associated with increased exposure to ionizing radiation after diagnosis of IBD. Knowledge of these risk factors can help physicians prospectively identify patients at risk for elevated radiation exposure and consider low-dose or radiation-free imaging.

Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis.

The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6 months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF-AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF.

Standardized cancer incidence disparities in Upper Manhattan New York City neighborhoods: the role of race/ethnicity, socioeconomic status, and known risk factors.

We examined the effects of race/ethnicity and neighborhood, a proxy of socioeconomic status, on cancer incidence in New York City neighborhoods: East Harlem (EH), Central Harlem (CH), and Upper East Side (UES). In this ecological study, Community Health Survey data (2002-2006) and New York State Cancer Registry incidence data (2007-2011) were stratified by sex, age, race/ethnicity, and neighborhood. Logistic regression models were fitted to each cancer incidence rate with race/ethnicity, neighborhood, and Community Health Survey-derived risk factors as predictor variables. Neighborhood was significantly associated with all cancers and 14 out of 25 major cancers. EH and CH residence conferred a higher risk of all cancers compared with UES (OR=1.34, 95% CI 1.07-1.68; and OR=1.39, 95% CI 1.12-1.72, respectively). The prevalence of diabetes and tobacco smoking were the largest contributors toward high cancer rates. Despite juxtaposition and similar proximity to medical centers, cancer incidence disparities persist among EH, CH, and UES neighborhoods. Targeted, neighborhood-specific outreach may aid in reducing cancer incidence rates.

How well do medical oncologists manage chronic cancer pain? A national survey.

BACKGROUND: Cancer pain is usually managed by oncologists, occasionally with input from specialists in hospice and palliative medicine (PLM) or pain medicine (PMD). We evaluated the knowledge of cancer pain management in these three specialty groups. METHODS: Eight vignettes depicting challenging scenarios of patients with poorly controlled pain were developed; each had five or six treatment choices. Respondents indicated choices likely to be safe and efficacious as "true" and choices likely to be unsafe or inefficacious as "false." Two questionnaires were created, each with four vignettes. Three anonymous mailings targeted geographically representative U.S. samples of 570 oncologists, 266 PMD specialists, and 280 PLM specialists, each randomly assigned one version of the questionnaire. Vignette scores were normalized to a 0-100 numeric rating scale (NRS); a score of 50 indicates that the number of correct choices equals the number of incorrect choices (consistent with guessing). RESULTS: Overall response rate was 49% (oncologists, 39%; PMD specialists, 48%; and PLM specialists, 70%). Average vignette score ranges were 53.2-66.5, 45.6-65.6, and 50.8-72.0 for oncologists, PMD specialists, and PLM specialists, respectively. Oncologists scored lower than PLM specialists on both questionnaires and lower than PMD specialists on one. On a 0-10 NRS, oncologists rated their ability to manage pain highly (median 7, with an interquartile range [IQR] of 5-8). Lower ratings were assigned to pain-related training in medical school (median 3, with an IQR of 2-5) and residency/fellowship (median 5, with an IQR of 4-7). Oncologists older than 46-47 years rated their training lower than younger oncologists. CONCLUSION: These data suggest that oncologists and other medical specialists who manage cancer pain have knowledge deficiencies in cancer pain management. These gaps help clarify the need for pain management education.

Cancer incidence in world trade center rescue and recovery workers, 2001-2008.

BACKGROUND: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. OBJECTIVE: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. METHODS: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. RESULTS: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. CONCLUSION: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders.

Maternal active and passive smoking and hypertensive disorders of pregnancy: risk with trimester-specific exposures.

BACKGROUND: The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking. METHODS: We conducted an analysis of 74,439 singleton pregnancies with completed second- and third- trimester questionnaires. Active and passive smoke exposure by trimester were determined by maternal self-report, and covered the period of preconception through approximately 30 weeks' gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Rates of active smoking declined dramatically during pregnancy: for trimester 1, 23%; trimester 2, 9%; and trimester 3, 8%. Active smoking in the third trimester was associated with reduced odds of preeclampsia and gestational hypertension, with the strongest association among continuous smokers (for preeclampsia, OR= 0.57 [95% CI = 0.46-0.70]). Women who quit smoking before the third trimester had approximately the same risk of preeclampsia and gestational hypertension as nonsmokers. There was some evidence of dose-response, with the heaviest smokers (more than eight cigarettes per day) having the lowest risks of preeclampsia (0.48 [0.32-0.73]) and gestational hypertension (0.51 [0.28-0.95]). There was little evidence of an association with passive smoking exposure. CONCLUSION: The association between smoking and preeclampsia varies substantially according to the timing and intensity of exposure. A better understanding of the biologic pathways that underlie these associations may provide important clues to the etiology of preeclampsia and the development of effective clinical interventions.

Diabetes, glucose control, glucose lowering medications, and cancer risk: a 10-year population-based historical cohort.

BACKGROUND: Both diabetes and glucose-lowering medications have been associated with an increased risk of cancer incidence. This study will compare cancer incidence rates in individuals with and without diabetes; and will investigate, in individuals with diabetes, an association between glucose control and cancer incidence; and between the use of specific glucose-lowering medications, as well as no drug exposure, and cancer incidence. METHODS/DESIGN: This is a population based historical cohort study of all individuals aged 21 years or older (about 2,300,000) who were insured by Clalit Health Services, the largest health maintenance organization in Israel during a ten-year study period. Four study groups will be established according to the status of diabetes and cancer at study entry, Jan 1, 2002: cancer free, diabetes free; cancer free, diabetes prevalent; cancer prevalent, diabetes free; and cancer prevalent, diabetes prevalent. Individuals without diabetes at study entry will be followed for diabetes incidence, and all four groups will be followed for specific cancer incidence, including second primary neoplasms. Glucose control will be assessed by HbA1c and by fasting plasma glucose levels. Time dependent regression models for cancer incidence will account for glucose-lowering medications as they are added and changed over the follow-up period. A large number of demographic and clinical variables will be considered, including: age, gender, BMI, smoking status, concomitant medications, glucose control (assessed by HbA1c and by fasting plasma glucose) and cancer screening tests. DISCUSSION: Strengths of this study include the large population; high quality comprehensive data; comparison to individuals without diabetes, and to those with diabetes but not treated with glucose-lowering medications; and the extensive range of variables available for analysis. The great increases in diabetes prevalence and in treatment options render this study particularly relevant and timely. The Israeli national healthcare system, characterized by high standard and uniform healthcare, offers an advantageous environment for its conduct.

Meeting standards of high-quality intensive care unit palliative care: clinical performance and predictors.

OBJECTIVES: High-quality care for intensive care unit patients and families includes palliative care. To promote performance improvement, the Agency for Healthcare Research and Quality's National Quality Measures Clearinghouse identified nine evidence-based processes of intensive care unit palliative care (Care and Communication Bundle) that are measured through review of medical record documentation. We conducted this study to examine how frequently the Care and Communication Bundle processes were performed in diverse intensive care units and to understand patient factors that are associated with such performance. DESIGN: Prospective, multisite, observational study of performance of key intensive care unit palliative care processes. SETTINGS: A surgical intensive care unit and a medical intensive care unit in two different large academic health centers and a medical-surgical intensive care unit in a medium-sized community hospital. PATIENTS: Consecutive adult patients with length of intensive care unit stay ≥5 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between November 2007 and December 2009, we measured performance by specified day after intensive care unit admission on nine care process measures: Identify medical decision-maker, advance directive and resuscitation preference, distribute family information leaflet, assess and manage pain, offer social work and spiritual support, and conduct interdisciplinary family meeting. Multivariable regression analysis was used to determine predictors of performance of five care processes. We enrolled 518 (94.9%) patients and 336 (83.6%) family members. Performances on pain assessment and management measures were high. In contrast, interdisciplinary family meetings were documented for <20% of patients by intensive care unit day 5. Performance on other measures ranged from 8% to 43%, with substantial variation across and within sites. Chronic comorbidity burden and site were the most consistent predictors of care process performance. CONCLUSIONS: Across three intensive care units in this study, performance of key palliative care processes (other than pain assessment and management) was inconsistent and infrequent. Available resources and strategies should be utilized for performance improvement in this area of high importance to patients, families, and providers.

"Sarcoid like" granulomatous pulmonary disease in World Trade Center disaster responders.

BACKGROUND: More than 20,000 responders have been examined through the World Trade Center (WTC) Medical Monitoring and Treatment Program since September 11, 2001. Studies on WTC firefighters have shown elevated rates of sarcoidosis. The main objective of this study was to report the incidence of "sarcoid like" granulomatous pulmonary disease in other WTC responders. METHODS: Cases of sarcoid like granulomatous pulmonary disease were identified by: patient self-report, physician report and ICD-9 codes. Each case was evaluated by three pulmonologists using the ACCESS criteria and only "definite" cases are reported. RESULTS: Thirty-eight patients were classified as "definite" cases. Six-year incidence was 192/100,000. The peak annual incidence of 54 per 100,000 person-years occurred between 9/11/2003 and 9/11/2004. Incidence in black responders was nearly double that of white responders. Low FVC was the most common spirometric abnormality. CONCLUSIONS: Sarcoid like granulomatous pulmonary disease is present among the WTC responders. While the incidence is lower than that reported among firefighters, it is higher than expected.

Multiple myeloma in World Trade Center responders: a case series.

OBJECTIVES: We report on cases of multiple myeloma (MM) observed in World Trade Center (WTC) responders registered in the WTC Medical Program. METHODS: Possible cases of MM diagnosed between September 11, 2001, and September 10, 2007, in responders were confirmed if they met the World Health Organization and Mayo Clinic diagnostic criteria. RESULTS: Among 28,252 responders of known sex and age, eight cases of MM were observed (6.8 expected). Four of these cases were observed in responders younger than 45 years at the time of diagnosis (1.2 expected). A slight deficit of MM cases was observed in responders older than 45 years (4 observed, 5.6 expected). CONCLUSION: In this case series, we observe an unusual number of MM cases in WTC responders under 45 years. This finding underscores the importance of maintaining surveillance for cancer and other emerging diseases in this highly exposed population.

Gene expression profiles of the one-carbon metabolism pathway.

One-carbon metabolism plays a critical role in both DNA methylation and DNA synthesis. Accumulating evidence has shown that interruptions of this pathway are associated with many disease outcomes including cardiovascular diseases and cancers. Mechanistic studies have been performed on genetic polymorphisms involved in one-carbon metabolism. However, expression profiles of these inter-related genes are not well-known. In this study, we examined the gene expression profiles of 11 one-carbon metabolizing genes by quantifying the mRNA level of the lymphocyte among 54 healthy individuals and explored the correlations of these genes. We found these genes were expressed in lymphocytes at moderate levels and showed significant inter-person variations. We also applied principle component analysis to explore potential patterns of expression. The components identified by the program agreed with existing knowledge about one-carbon metabolism. This study helps us better understand the biological functions of one-carbon metabolism.

BRCA1 promoter methylation is associated with increased mortality among women with breast cancer.

Promoter-CpG island hypermethylation has been proposed as an alternative mechanism to inactivate BRCA1 in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996-1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (P = 0.02) and among premenopausal cases (P = 0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05-2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02-2.18). Neither dietary methyl intakes in the year prior to the baseline interview nor the functional polymorphisms in one-carbon metabolism were associated with BRCA1 methylation status. Our study is the first epidemiological investigation on the prognostic value of BRCA1 promoter methylation in a large population-based cohort of breast cancer patients. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival.

Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression.

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.

Temporal surveillance using scan statistics.

We describe two classes of statistics for testing an arbitrary model of disease incidence over time against an alternative model involving a spike (pulse) superimposed on this background. The statistics are each based on taking the maximum of some function comparing observed and expected numbers of events in a window of width w. One approach applies p-values for scan statistics calculated for a constant background rate to this more general problem. For a fixed window, w, the approach gives a simple formula to determine p-values for retrospective analysis, or to sound an alarm for either continuous or grouped prospective data. The latter application involves a new approximation for the distribution of the maximum number of cases in w consecutive intervals. The second approach based on generalized likelihood ratio tests (GLRTs), sounds an alarm for a higher than anticipated rate of events in a scanning window of fixed length, or for window sizes that lie in a region. GLRTs are constructed for continuous observations, for grouped data, or for a sequence of trials. As for GLRTs used in retrospective evaluations, simulation is required to implement the prospective procedure. For grouped surveillance data, we compare by simulation, operating characteristics of the P-scan with fixed windows (both correctly specified and not), the fixed-window GLRT, the variable-window GLRT, and a variant of the CUSUM. The simulations demonstrate a very high correlation between the P-scan and corresponding fixed-window GLRT.