COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy.

BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Riesgo de infección del sitio quirúrgico, según tiempo operatorio en cirugía maxilofacial mayor limpia contaminada: estudio observacional analítico / Risk of surgical site infection according to operating time in major clean-contaminated maxillofacial surgery. Observational analytical study

Introducción: La infección del sitio quirúrgico (ISQ) sigue generando gran morbimortalidad, a pesar de los avances en control de infecciones y técnicas quirúrgicas. Objetivos Determinar si en cirugía maxilofacial mayor limpia contaminada el aumento del tiempo operatorio incrementa la proporción de infección del sitio quirúrgico. Materiales y método Estudio observacional analítico en pacientes ASA I intervenidos en cirugía maxilofacial mayor limpia contaminada entre los años 1997 y 2010 en el Hospital Clínico San Borja Arriarán (Santiago, Chile). Las variables medidas fueron género, edad, tiempo operatorio e ISQ. Se realizó un análisis estadístico mediante prueba de Chi cuadrado, test de la t de Student y regresión logística simple, con un IC del 95 por ciento y el paquete estadístico SPSS. Resultados De un total de 522 pacientes presentaron ISQ 36 (6,9 por ciento). Al comparar los 2 grupos, con ISQ y sin ISQ, no hubo diferencias significativas según género (p = 0,319) y edad (p = 0,238), pero sí según tiempo operatorio (p = 0,046). Se obtuvo un OR = 1,003 (IC 95 por ciento = 1,000-1,006) entre el tiempo operatorio y la infección del sitio quirúrgico. Conclusión Se encontraron diferencias significativas en la proporción de ISQ al aumentar el tiempo operatorio. Sin embargo, esta asociación no es clínicamente significativa.

Introduction: Despite advances in infection control and surgical techniques, surgical site infection (SSI) continues to be a cause of high morbidity and mortality. Objectives To determine if operating time increases the proportion of surgical site infections in clean-contaminated maxillofacial surgery. Materials and method This was an observational analytical study, including ASA I patients undergoing clean-contaminated maxillofacial surgery between 1997 and 2010 at the Clinical Hospital San Borja Arriarán (Santiago, Chile). The outcome variable was surgical site infection. Predictor variables were gender, age, operating time and SSI. Statistical analysis was performed using chi-squared test, Student t test, and simple logistic regression. Results A total of 522 patients met the inclusion criteria. The infection rate was 6.9 percent. Statistically significant differences were only observed in the operation time (P = .046) with an Odds ratio of 1.003 (95 percent CI = 1.000-1.006). Conclusion Significant differences in the proportion of SSI were found when operation time increased. However, this association is not clinically significant.

Intermediary quantitative traits--an alternative in the identification of disease genes in asthma?

Intermediary quantitative traits are a possible alternative for the identification of disease genes. This may be particularly relevant when diagnostic criteria are not very well defined as described for asthma. We analyzed serum samples from 944 individuals of 218 asthma families for 17 cytokines (eotaxin, GM-CSF, IFNγ, IL1B, IL1RA, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p40), IL-13, IL-17, IL-23, IL-33, TSLP and TNF-α) and determined the heritability. Linked chromosomal regions were identified by a genome-wide analysis using 334 autosomal microsatellite marker and association tested by further 550 SNP marker at genes implicated earlier with immune response. Heritability varied with TNF-α and IL-8 levels having the highest and TSLP having the lowest heritability. Linkage was significantly increased only for IL-12(p40) at D17S949. There were multiple significant single-nucleotide polymorphisms (SNP) associations (P<0.05) as found in the transmission disequilibrium test, whereas only a few replicated in parents or children only. These include SNPs in IL1RN that were associated with IL-33 and TSLP levels, and a SNP in NR3C2 that was associated with eotaxin, IL-13 and IFN-γ levels. Circulating level of serum cytokines exhibits genetic associations with asthma traits that are otherwise not detected using clinical diagnosis or when the clinical details are ambiguous.

Irradiation-induced morphea: x-rays as triggers of autoimmunity.

We report on 3 females with breast cancer who developed morphea at the site of post-surgery radiotherapy. One was suffering from other autoimmune skin diseases before the diagnosis and treatment of breast cancer. Postirradiation morphea is a potential complication after radiotherapy, particularly radiotherapy for cancer. This troublesome skin disease can occur months to years after treatment, and is associated with remarkable morbidity and pain, and also cosmetic aspects. Therefore, it is crucial to be aware of this condition, and to try to identify patients who might be at an increased risk of developing morphea.

Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene.

In the present report we have determined the molecular mechanisms, which govern the expression of the human IL-10 gene when induced by the glucocorticoid Methyl-Prednisolone (MP). Treatment of cells with MP at 10(-6) M will readily induce IL-10 in CD19+ primary B cells and in a human B cell line. Analysis of the IL-10 promoter showed a robust 18-fold induction and demonstrated that a potential GRE motif was not required, while mutation of the -120 STAT-motif strongly reduced MP-induced trans-activation. A strong induction was also seen with a trimeric STAT-motif and over-expression of dominant-negative STAT3 could block MP induction of IL-10 mRNA. Finally, MP treatment induced binding of STAT3 to the promoter as shown by gelshift, supershift and by chromatin-immunoprecipitation. These data show that glucocorticoid-induced expression of the IL-10 gene is mediated by the transcription factor STAT3.

Dose-controlled exposure of A549 epithelial cells at the air-liquid interface to airborne ultrafine carbonaceous particles.

The geometry of commercially available perfusion chambers designed for harbouring three membrane-based cell cultures was modified for reliable and dose-controlled air-liquid interface (ALI) exposures. Confluent A549 epithelial cells grown on membranes were integrated in the chamber system and supplied with medium from the chamber bottom. Cell viability was not impaired by the conditions of ALI exposure without particles. Expression of the inflammatory cytokines interleukin 6 and interleukin 8 by A549 cells during ALI exposure to filtered air for 6h and subsequent stimulation with tumor necrosis factor was not altered compared to submersed controls, indicating that the cells maintained their functional integrity. Ultrafine carbonaceous model particles with a count median mobility diameter of about 95+/-5 nm were produced by spark discharge at a stable concentration of about 2 x 10(6) cm(-3) and continuously monitored for accurate determination of the exposure dose. Delivery to the ALI exposure system yielded a homogeneous particle deposition over the membranes with a deposition efficiency of 2%. Mid dose exposure of A549 cells to this aerosol for 6h yielded a total particle deposition of (2.6+/-0.4) x 10(8) cm(-2) corresponding to (87+/-23) ng cm(-2). The 2.7-fold (p < or = 0.05) increased transcription of heme oxygenase-1 indicated a sensitive antioxidant and stress response, while cell viability did not reveal a toxic mechanism.

Projections of demand and capacity for colonoscopy related to increasing rates of colorectal cancer screening in the United States.

BACKGROUND: There is debate about the optimal colorectal cancer screening test, partly because of concerns about colonoscopy demand. AIM: To quantify the demand for colonoscopy with different screening tests, and to estimate the ability of the United States health care system to meet demand. METHODS: We used a previously published Markov model and the United States census data to estimate colonoscopy demand. We then used an endoscopic database to compare current rates of screening-related colonoscopy with those projected by the model, and to estimate the number of endoscopists needed to meet colonoscopy demand. RESULTS: Annual demand for colonoscopy ranges from 2.21 to 7.96 million. Based on current practice patterns, demand exceeds current supply regardless of screening strategy. We estimate that an increase of at least 1360 gastroenterologists would be necessary to meet demand for colonoscopic screening undergone once at age 65, while colonoscopy every 10 years could require 32 700 more gastroenterologists. A system using dedicated endoscopists could meet demand with fewer endoscopists. CONCLUSIONS: Colorectal cancer screening leads to demand for colonoscopy that outstrips supply. Systems to train dedicated screening endoscopists may be necessary in order to provide population-wide screening. The costs and feasibility of establishing this infrastructure should be studied further.

The measurement of active errors: methodological issues.

The value of research in any topic area turns on its validity. Patient safety research has revealed--or, at least, given renewed urgency to--a raft of methodological issues. The meaning and thus the value of empirical research in this field is contingent on getting the methodology right. The need for good methods for the measurement of error is necessary whenever an inference is intended and, since inferences lie at the heart of research and management, there is a huge need to understand better how to make measurements that are meaningful, precise, and accurate. In this paper we consider issues relating to the measurement of error and the need for more research.

[Malignant skin tumours in a private dermatology practice. A quality control study]. / Hautmalignome in der dermatologischen Praxis. Eine Qualitätskontrolle.

BACKGROUND AND OBJECTIVE: The campaign for early detection of malignant melanoma and the increase in people with photodamaged skin have a remarkable influence on the daily dermatological routine. Could these factors lead to the introduction of quality control in a private dermatology practice? PATIENTS AND METHODS: Over a period of one year the diagnoses of all patients were registered. The clinical diagnosis of any skin tumour undergoing surgical removal was compared with the final histopathological diagnosis. RESULTS: 56% of 3004 diagnoses involved females; 44%, males. In 40.5%, the possibility of a pigmented or non-pigmented skin tumour was raised. 49% of the 291 tumours removed were malignant (107 basal cell carcinoma, 20 squamous cell carcinoma, 16 melanoma) while 11.7% were malignant precursor lesions. 48% of 44 melanocytic naevi with clinical atypia showed histopathological dysplasia but none were a malignant melanoma. No cancers were detected among 59 clinically benign tumors. In 71.8% of cases, the clinical diagnosis agreed with the result of the histopathological examination. CONCLUSIONS: This study shows, in concordance with literature, that a dermatologist can provide high quality treatment and prophylaxis of malignant skin tumours. With an optimal cost-performance ratio, he or she is the most competent partner for patients and health insurance companies.

The effectiveness of budesonide therapy for Crohn's disease.

AIM: To assess the effectiveness and safety of budesonide in comparison to corticosteroids, 5-aminosalicylic acid (5-ASA), or placebo for inducing remission of active Crohn's disease and for maintaining remission. STUDY SELECTION CRITERIA: Randomized controlled trials comparing budesonide to corticosteroids, 5-ASA products or placebo were included. Trials had to report on the effectiveness of treatment (defined as decreasing or maintaining Crohn's Disease Activity Index, CDAI, scores < or = 150) or adverse events. DATA ANALYSIS: After assessing the validity of study design and independent, duplicate data extraction from selected trials, summary relative risks (RR) were calculated for each outcome. A test of heterogeneity was also calculated for each outcome using a random effects model. RESULTS: Budesonide was more likely to induce remission than placebo (RR=1.82, 95% CI: 1.15-2.88) or 5-ASA (RR=1.73, 95% CI: 1.26-2.39), although only one trial compared budesonide to 5-ASA products. Although budesonide induced remission less frequently than conventional corticosteroids (RR=0.87, 95% CI: 0.76-0.995), there was no significant difference between conventional corticosteroids and budesonide for inducing remission among patients with a low disease activity (initial CDAI=200-300). Budesonide was significantly less likely to cause corticosteroid-associated adverse events than conventional corticosteroids (RR=0.65, 95% CI: 0.53-0.80). No significant difference in total adverse events or corticosteroid-associated adverse events was demonstrated between budesonide and 5-ASA or placebo. CONCLUSION: Budesonide is significantly more effective than placebo or 5-ASA for inducing remission of active Crohn's disease. Although budesonide is 13% less effective for the induction of remission in active Crohn's disease than conventional corticosteroids, it is less likely to cause corticosteroid-related adverse effects. Budesonide is ineffective in maintaining remission.

[Myerson nevus as a primary patch of Gibert pityriasis rosea. A case report]. / Meyerson-Nävus als Primärmedaillon einer Pityriasis rosea Gibert. Eine Kasuistik.

UNLABELLED: There are only few articles in literature which discuss the association between Meyerson's naevi and Pityriasis rosea. And when so, the discussion is done in a controversial way. Here an 18 year old man is presented who visits the outpatient clinic. He has a ten day history of a solitary Meyerson's naevus on his back. Over the next three weeks this naevus will develop to the typical herold patch followed by the classical exantheme of Pityriasis rosea. CONCLUSION: Halo dermatitis associated with Pityriasis rosea don't represent Meyerson's naevi. But they reflect the rare "nevocentric" property of a not so rare dermatose.

Palmar digital vein thromboses: their different expressions.

There have only been a few reports about thrombotic events in the volar digital veins. The observation of 2 such cases gives reason to discuss this rare symptomatology. Thrombosis of the digital veins can be categorised into three subtypes: the first shows clinical similarity to thrombotic events in veins or varicose veins of the limbs and may be related to a hypercoagulable state; the second group develops in a pre-existing normal vein or an acquired venous cavernoma and does not show clinical or histological signs of inflammation; the third category resembles Mondor's disease and may be named Mondor's phlebitis of the finger; histopathological examination has yet to be done. In any case of thrombosis of the volar digital veins, an inherited or acquired hypercoagulable state must be ruled out.

Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain.

The key elements of circadian clockwork and oxygen homeostasis are the PAS protein family members PER and CLOCK and hypoxia-inducible factor 1alpha (HIF-1alpha). The PAS domain serves as an interface for protein-protein interactions. We asked whether a cross-talk exists between the PAS components of hypoxic and circadian pathways. We found several isoforms of PER1 protein that exhibit tissue-specific size differences. In the mouse brain, a predominantly nuclear 48 kDa isoform that followed a daily rhythm was observed. The 48 kDa form was found in the nuclear fractions derived from mouse liver, Swiss3T3 fibroblasts, and N2A neuroblastoma cells. In mouse kidney and human 293 kidney cells, a 55 kDa PER1 form was detected. CLOCK was observed as a predicted 100 kDa protein in rat-1 cells and in all analyzed mouse tissues including brain, liver, kidney, and spleen. In contrast to PER1, CLOCK protein expression was not rhythmic. Exposure to hypoxia led to increased PER1 and CLOCK protein levels in mice. Based on coimmunoprecipitation experiments that showed protein-protein interaction between PER1 and the alpha subunit of HIF-1, we suggest that these hypoxic effects may be modulated by HIF-1alpha.-Chilov, D., Hofer, T., Bauer, C., Wenger, R. H., Gassmann, M. Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain.

The role of hospital volume in coronary artery bypass grafting: is more always better?

OBJECTIVES: The goal of this study was to determine whether outcomes of nonemergent coronary artery bypass grafting (CABG) differed between low- and high-volume hospitals in patients at different levels of surgical risk. BACKGROUND: Regionalizing all CABG surgeries from low- to high-volume hospitals could improve surgical outcomes but reduce patient access and choice. "Targeted" regionalization could be a reasonable alternative, however, if subgroups of patients that would clearly benefit from care at high-volume hospitals could be identified. METHODS: We assessed outcomes of CABG at 56 U.S. hospitals using 1997 administrative and clinical data from Solucient EXPLORE, a national outcomes benchmarking database. Predicted in-hospital mortality rates for subjects were calculated using a logistic regression model, and subjects were classified into five groups based on surgical risk: minimal (< 0.5%), low (0.5% to 2%), moderate (2% to 5%), high (5% to 20%), and severe (> or =20%). We assessed differences in in-hospital mortality, hospital costs and length of stay between low- and high-volume facilities (defined as > or =200 annual cases) in each of the five risk groups. RESULTS: A total of 2,029 subjects who underwent CABG at 25 low-volume hospitals and 11,615 subjects who underwent CABG at 31 high-volume hospitals were identified. Significant differences in in-hospital mortality were seen between low- and high-volume facilities in subjects at moderate (5.3% vs. 2.2%; p = 0.007) and high risk (22.6% vs. 11.9%; p = 0.0026) but not in those at minimal, low or severe risk. Hospital costs and lengths of stay were similar across each of the five risk groups. Based on these results, targeted regionalization of subjects at moderate risk or higher to high-volume hospitals would have resulted in an estimated 370 transfers and avoided 16 deaths; in contrast, full regionalization would have led to 2,029 transfers and avoided 20 deaths. CONCLUSIONS: Targeted regionalization might be a feasible strategy for balancing the clinical benefits of regionalization with patients' desires for choice and access.

[Acne inversa: a dapsone-sensitive dermatosis]. / Acne inversa. Eine Dapson-sensitive Dermatose.

Acne inversa is a chronic disease with a major impact on the quality of life. Therapeutic options were long restricted to local disinfectants and systemic antibiotics, as well as repeated incision and drainage which produce only short term benefits. Retinoids, antiandrogens and radiation therapy are only partially successful. The best approach appears to be surgical removal of the entire apocrine sweat gland apparatus. Dapsone is used in dermatology to treat inflammatory dermatoses such as dermatitis herpetiformis and pyoderma gangrenosum, and was formerly the treatment of choice for acne conglobata. We report its successful use in acne inversa. Five female patients aged 23-40 years with acne inversa for a mean of 9.6 years were included. All patients showed an almost complete resolution of their symptoms within 2-4 weeks. All patients rated the treatment results with dapsone as good or very good. The treatment was well tolerated and no important side effects occurred. Because of its lack of teratogenicity, dapsone may be the most favorable treatment option in young women with acne inversa.

Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1alpha activation cascade: implications for HIF-1alpha gene therapy.

The heterodimeric hypoxia-inducible factor (HIF)-1 is a master transcriptional regulator of oxygen homeostasis and a possible target for gene therapy of ischemic disease. Although the role of oxygen concentration in HIF-1a protein stabilization is well established, it is less clear whether and how oxygen-regulated mechanisms contribute to HIF-1a protein modifications, nuclear translocation, heterodimerization with the b-subunit, recruitment of cofactors, and gene trans-activation. Because the HIF-1a protein is proteolytically degraded under normoxic conditions, we established two HeLa Tet-Off cell lines (HT42 and HT43), which inducibly overexpress high levels of HIF-1a under normoxic conditions, allowing to distinguish hypoxia-dependent from hypoxia-independent activation mechanisms. Using these cells, we found that normoxically induced HIF-1a is localized to the nucleus, binds DNA, and trans-activates reporter and endogenous target genes. The levels of p53 expression remained unaffected. The MAP kinase inhibitor PD98059 attenuated HIF-1a protein modifications and trans-activation ability but not protein stabilization and DNA-binding activity. Because overexpressed HIF-1a is fully localized to the nucleus but displays only partial DNA-binding and trans-activation activity, mitogen-activated protein kinase-dependent phosphorylation might be required for full HIF-1 activation. HIF-1a protein was also overexpressed in vivo, following the transplantation of HT42 cells into nude mice, demonstrating the feasibility of HIF-1a gene transfer.

Estimating hospital deaths due to medical errors: preventability is in the eye of the reviewer.

CONTEXT: Studies using physician implicit review have suggested that the number of deaths due to medical errors in US hospitals is extremely high. However, some have questioned the validity of these estimates. OBJECTIVE: To examine the reliability of reviewer ratings of medical error and the implications of a death described as "preventable by better care" in terms of the probability of immediate and short-term survival if care had been optimal. DESIGN: Retrospective implicit review of medical records from 1995-1996. SETTING AND PARTICIPANTS: Fourteen board-certified, trained internists used a previously tested structured implicit review instrument to conduct 383 reviews of 111 hospital deaths at 7 Department of Veterans Affairs medical centers, oversampling for markers previously found to be associated with high rates of preventable deaths. Patients considered terminally ill who received comfort care only were excluded. MAIN OUTCOME MEASURES: Reviewer estimates of whether deaths could have been prevented by optimal care (rated on a 5-point scale) and of the probability that patients would have lived to discharge or for 3 months or more if care had been optimal (rated from 0%-100%). RESULTS: Similar to previous studies, almost a quarter (22.7%) of active-care patient deaths were rated as at least possibly preventable by optimal care, with 6.0% rated as probably or definitely preventable. Interrater reliability for these ratings was also similar to previous studies (0.34 for 2 reviewers). The reviewers' estimates of the percentage of patients who would have left the hospital alive had optimal care been provided was 6.0% (95% confidence interval [CI], 3.4%-8.6%). However, after considering 3-month prognosis and adjusting for the variability and skewness of reviewers' ratings, clinicians estimated that only 0.5% (95% CI, 0.3%-0.7%) of patients who died would have lived 3 months or more in good cognitive health if care had been optimal, representing roughly 1 patient per 10 000 admissions to the study hospitals. CONCLUSIONS: Medical errors are a major concern regardless of patients' life expectancies, but our study suggests that previous interpretations of medical error statistics are probably misleading. Our data place the estimates of preventable deaths in context, pointing out the limitations of this means of identifying medical errors and assessing their potential implications for patient outcomes.

Which colon cancer screening test? A comparison of costs, effectiveness, and compliance.

PURPOSE: Recent media reports have advocated the use of colonoscopy for colorectal cancer screening. However, colonoscopy is expensive compared with other screening modalities, such as fecal occult blood testing and flexible sigmoidoscopy. We sought to determine the cost effectiveness of different screening strategies for colorectal cancer at levels of compliance likely to be achieved in clinical practice. METHODS: A Markov decision model was used to examine screening strategies, including fecal occult blood testing alone, fecal occult blood testing combined with flexible sigmoidoscopy, flexible sigmoidoscopy alone, and colonoscopy. The timing and frequency of screening was varied to assess optimal screening intervals. Sensitivity analyses were conducted to assess the factors that have the greatest effect on the cost effectiveness of screening. RESULTS: All strategies are cost effective versus no screening, at less than $20,000 per life-year saved. Direct comparison suggests that the most effective strategies are twice-lifetime colonoscopy and flexible sigmoidoscopy combined with fecal occult blood testing. Assuming perfect compliance, flexible sigmoidoscopy combined with fecal occult blood testing is slightly more effective than twice-lifetime colonoscopy (at ages 50 and 60 years) but is substantially more expensive, with an incremental cost effectiveness of $390,000 per additional life-year saved. However, compliance with primary screening tests and colonoscopic follow-up for polyps affect screening decisions. Colonoscopy at ages 50 and 60 years is the preferred test regardless of compliance with the primary screening test. However, if follow-up colonoscopy for polyps is less than 75%, then even once-lifetime colonoscopy is preferred over most combinations of flexible sigmoidoscopy and fecal occult blood testing. Costs of colonoscopy and proportion of cancer arising from polyps also affect cost effectiveness. CONCLUSIONS: Colonoscopic screening for colorectal cancer appears preferable to current screening recommendations. Screening recommendations should be tailored to the compliance levels achievable in different practice settings.

Estimating the microvascular benefits of screening for type 2 diabetes mellitus.

OBJECTIVE: To define the relative benefits of screening for diabetes and improved treatment programs and ways of improving the efficiency of screening for a population-based cohort derived from the Third National Health and Nutrition Examination Survey (NHANES III). METHODS: A Markov decision model is used to estimate microvascular benefits of glucose control for four different screening and treatment scenarios, including either universal screening or improved glucose control of known diabetic subjects, neither, or both. RESULTS: A population cohort of subjects with recent onset of diabetes (< 5 years) was derived from NHANES III (of whom close to half were unaware that they had diabetes). In this population-based cohort, the total benefit achievable by universal screening and improved treatment (limiting HbA1c to less than 9%) is a reduction of about 30,000 cases of blindness over the lifetime of the cohort. Screening alone results in 7% of this benefit, and improved treatment alone provides 65%. Screening a targeted group of patients with three or more risk factors for developing diabetes would reduce the number of required fasting glucose measurements needed by 82% and provide 50% of the total benefit of screening the entire population with a fasting glucose measurement. CONCLUSIONS: Morbidity from type 2 diabetes can be most effectively reduced by developing ways to modestly improve the glycemic control of known diabetic subjects, particularly those with high A1c's and early onset of disease. Targeting can significantly reduce the number of persons who need to be screened with a fasting blood test while preserving a large component of the benefit of screening.