PRODIG (Prevention of new onset diabetes after transplantation by a short term treatment of Vildagliptin in the early renal post-transplant period) study: study protocol for a randomized controlled study.

BACKGROUND: Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make it possible to target a population at risk of developing de novo diabetes. We hypothesized that a short-term treatment with vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. METHODS/DESIGN: This is a multicenter, double-blind, placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included from ten French transplant centers. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating theatres) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, and/or with an abnormal oral glucose tolerance test. Secondary outcomes include glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months, and 12 months after transplantation. Outcomes will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, health-related quality of life, and the cost-effectiveness of prevention of diabetes with vildagliptin. DISCUSSION: We have scarce data on the pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02849899 . Registered on 8 February 2016.

Early effects of liver regeneration on endocrine pancreas: in vivo change in islet morphology and in vitro assessment of systemic effects on ß-cell function and viability in the rat model of two-thirds hepatectomy.

Liver and pancreas share key roles in glucose homeostasis. Liver regeneration is associated with systemic modifications and depends especially on pancreatic hormones. The aim of the study was to investigate the role of systemic factors released after two-thirds hepatectomy (2/3H) on early possible consequences of liver regeneration on endocrine pancreas structure and function. The pancreas and serum were harvested 1, 2, or 3 days after 2/3H or sham operation in Lewis rats. The HGF and VEGF serum concentrations and plasma microparticles levels were measured. The fate of endocrine pancreas was examined through islets histomorphometry and function in sham and 2/3H rats. ß-Cell line RIN-m5F viability was assessed after 24 h of growth in media supplemented with 10% serum from 2/3H or sham rats instead of FCS. Three days after surgery, the pancreas was heavier in 2/3H compared to sham rats (0.56 vs. 0.40% of body weight, p < 0.05) and the proportion of islets of intermediate size was lower in 2/3H rats (5 vs. 15%, p < 0.05). Compared to Sham, sera obtained 3 days after hepatectomy were more efficient to maintain the viability of RIN-m5F cells (99 vs. 67%, p < 0.01). Three days after surgery, no significant differences in serum HGF, a trend to significant increase in VEGF concentration and a significant increase in microparticles levels, were observed in 2/3H vs. sham rats (9.8 vs. 6.5 nM Phtd Ser Eq., p < 0.05). Liver regeneration is associated with early effects on islets and could influence ß-cell viability and function by systemic effect.

Early assessment of glucose abnormalities during continuous glucose monitoring associated with lung function impairment in cystic fibrosis patients.

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is correlated with a decline in lung function. Under certain circumstances, oral glucose tolerance test (OGTT) screening, used to diagnose CFRD, fails to reveal early glucose tolerance abnormalities. In this situation, continuous glucose monitoring (CGM) could be a useful tool for evaluating early abnormalities of glucose tolerance in CF patients. We aimed to study the CGM glucose profile in CF patients with normal OGTT screening results and to evaluate lung function and nutritional status according to the CGM glucose profile. METHODS: We assessed glycemic control, the CGM glucose profile, nutritional status, lung function antibiotic courses and colonization (P. aeruginosa and S. aureus) in CF patients, aged 10 years and over, with normal screening OGTT results (blood glucose at T120 min < 7.8 mmol/l). Two groups were identified according to the max CGM glucose value: Group 1<11 mmol/l and Group 2 ≥ 11 mmol/l. RESULTS: Among the 38 patients with normal OGTT, 12 (31.6%) were in Group 2. Compared to Group 1, Group 2 patients exhibited a significant impairment in lung function: FEV1, 68.2 ± 25.6% vs. 87.3 ± 17%, p = 0.01 and FVC, 86.1% ± 19.4% vs. 99.3% ± 13.4%, p=0.021, as well as a higher rate of colonization by P. aeruginosa: 83.3% vs. 44%, p=0.024. Nevertheless, there were no differences in nutritional status (BMI standard deviation score: p = 0.079; prealbumin: p = 0.364). CONCLUSIONS: CGM reveals early abnormalities of glucose tolerance that remain undiagnosed by OGTT screening and are associated with worse lung function and a higher prevalence of P. aeruginosa colonization in patients with CF. CLINICAL TRIAL REGISTRATION NUMBER: NCT00476281.

Study design in the evaluation of breast cancer imaging technologies.

RATIONALE AND OBJECTIVES: Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. MATERIALS AND METHODS: The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. CONCLUSION: Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

Pulmonary artery catheterization and clinical outcomes: National Heart, Lung, and Blood Institute and Food and Drug Administration Workshop Report. Consensus Statement.

OBJECTIVE: The efficacy and safety of the pulmonary artery catheter are under scrutiny because of its association with increased morbidity and mortality in observational studies. In response, the National Heart, Lung, and Blood Institute (NHLBI) and the US Food and Drug Administration (FDA) conducted the Pulmonary Artery Catheterization and Clinical Outcomes workshop in Alexandria, Va, on August 25 and 26, 1997, to develop recommendations regarding actions to improve pulmonary artery catheter utility and safety. PARTICIPANTS: The NHLBI and FDA planning task force selected a workshop chairperson, subcommittee chairs, and participants. Approximately 85 participants were selected for their collective expertise in critical care, pulmonary medicine, cardiovascular medicine and surgery, pediatrics, nursing, biostatistics, and medical economics. The meeting was open to industry representatives and other government and lay observers. This workshop was funded by the NHLBI and the FDA's Division of Devices. EVIDENCE: Published reports relating to the efficacy and safety of the pulmonary artery catheter, especially consensus documents developed by professional societies. CONSENSUS PROCESS: The planning task force disseminated materials, held teleconferences, and developed draft position papers prior to the workshop. These were modified during the workshop and thereafter in the course of several teleconferences, and presented to the entire group for final modifications and approval. CONCLUSIONS: A need exists for collaborative education of physicians and nurses in performing, obtaining, and interpreting information from the use of pulmonary artery catheters. This effort should be led by professional societies, in collaboration with federal agencies, with the purpose of developing and disseminating standardized educational programs. Areas given high priority for clinical trials were pulmonary artery catheter use in persistent/refractory congestive heart failure, acute respiratory distress syndrome, severe sepsis and septic shock, and low-risk coronary artery bypass graft surgery. JAMA. 2000;283:2568-2572

Sources of influence on intention to breastfeed among African-American women at entry to WIC.

To examine how individuals within a woman's life influence her infant feeding intention, we interviewed 441 African-American women on the breastfeeding attitudes and experiences of their friends, relatives, mother, and the baby's father. Women were interviewed at entry into prenatal care at clinics associated with one of four Baltimore WIC clinics chosen for a breastfeeding promotion project. Qualitative data were also collected among 80 women. Friends and "other" relatives were not influential. Grandmothers' opinions and experiences were important, but their influence was reduced after considering the opinion of the baby's father. The opinion of the woman's doctor was an independent predictor of infant feeding intention. Breastfeeding promotion programs should recognize the separate influence of fathers, health providers, and grandmothers in women's infant feeding decisions.

Early introduction of solid foods among urban African-American participants in WIC.

OBJECTIVE: To compare infant feeding practices among low-income, urban, African-American women enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) with current recommendations for infant feeding. DESIGN: Longitudinal follow-up of women and their infants who participated in a WIC-based breast-feeding promotion project. Women enrolled prenatally at or before 24 weeks of gestation were followed up until 16 weeks postpartum. SUBJECTS/SETTING: Two hundred seventeen African-American WIC participants in an urban area. METHODS: Data related to infant feeding practices were collected by interviewers who used a structured questionnaire to determine when nonmilk liquids or solids were introduced to the infant. Reported practices were compared with current recommendations. STATISTICAL ANALYSIS PERFORMED: Contingency table analysis, including chi 2 tests, and multivariate analysis using logistic regression. RESULTS: By 7 to 10 days postpartum, approximately a third of infants were receiving some nonmilk liquids or solids; this escalated to 77% by 8 weeks and 93% by 16 weeks postpartum. Women breast-feeding exclusively (i.e., not adding nonmilk liquids or solids) were least likely, and women providing mixed feeding (breast milk and formula) were more likely, than women feeding formula exclusively to introduce nonmilk liquids and solids at each data collection time period. APPLICATIONS/CONCLUSIONS: WIC participants who receive instruction about infant feeding nutrition are no more likely than mothers who do not participate in WIC to follow infant feeding guidelines recommended by the American Academy of Pediatrics in regard to the time when solids should be introduced to infants' diet. Our findings suggest the need for WIC to implement more powerful and innovative educational and motivational strategies to help mothers delay the introduction of nonmilk liquids and solid foods until their infants are 4 to 6 months old, as recommended.

The partial testing design: a less costly way to test equivalence for sensitivity and specificity.

We propose a new, less costly, design to test the equivalence of digital versus analogue mammography in terms of sensitivity and specificity. Because breast cancer is a rare event among asymptomatic women, the sample size for testing equivalence of sensitivity is larger than that for testing equivalence of specificity. Hence calculations of sample size are based on sensitivity. With the proposed design it is possible to achieve the same power as a completely paired design by increasing the number of less costly analogue mammograms and not giving the more expensive digital mammograms to some randomly selected subjects who are negative on the analogue mammogram. The key idea is that subjects who are negative on the analogue mammogram are unlikely to have cancer and hence contribute less information for estimating sensitivity than subjects who are positive on the analogue mammogram. To ascertain disease state among subjects not biopsied, we propose another analogue mammogram at a later time determined by a natural history model. The design differs from a double sampling design because it compares two imperfect tests instead of combining information from a perfect and imperfect test.

Technology assessment of medical devices at the Center for Devices and Radiological Health.

We reviewed the Food and Drug Administration's regulatory process for medical devices and described the issues that arise in assessing device safety and effectiveness during the postmarket period. The Center for Devices and Radiological Health (CDRH), an organization within the Food and Drug Administration, has the legal authority and responsibility for ensuring that medical devices marketed in the United States are both reasonably safe and effective for their intended use. This is an enormous challenge given the diversity of medical devices and the large number of different types of devices on the market. Many scientific and regulatory activities are necessary to ensure device safety and effectiveness, including technology assessment, albeit in a manner quite different from that of conventional technology assessment. The basic approach taken at the CDRH to ensure device safety and effectiveness is to develop an understanding of the way in which a medical device works and how it will perform in clinical situations.

WIC-based interventions to promote breastfeeding among African-American Women in Baltimore: effects on breastfeeding initiation and continuation.

We evaluated the single and combined effects of introducing a motivational video and peer counseling into four matched WIC clinics on breastfeeding initiation and continuation at 7-10 days among African-American WIC participants. Of the 242 women with complete data, 48% initiated breastfeeding, but only 31% were still breastfeeding at 7-10 days. Initiation was associated with cesarean delivery, infant feeding instruction, no artificial milk discharge pack, attending the peer counselor only-intervention site, and intention to breastfeed. Continuation was influenced by infant feeding instruction, no artificial milk discharge pack, and intention to breastfeed. Overall, trends toward a positive impact of the breastfeeding promotion activities were evident but weak, and largely gone by 7-10 days postpartum.

Medical coverage for local national employees in the Czech Republic, Hungary, Poland and Russia.

Employers that must provide medical benefits for employees in Russia and other Eastern European countries cannot try to match the coverage they provide in the United States. This article, which focuses on the Czech Republic, Hungary, Poland and Russia, summarizes the medical benefits provided by each government's social security system, describes other means of accessing medical care in these countries and outlines the insured supplemental benefit plans that may be available to employers in the local market.

Counseling and motivational videotapes increase duration of breast-feeding in African-American WIC participants who initiate breast-feeding.

OBJECTIVE: To evaluate the relative effects introducing motivational videotapes and/or peer counseling in Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinics serving African-American women have on breast-feeding duration. DESIGN: Experimental intervention study. Pregnant women were enrolled at or before 24 weeks gestation and were followed up until postpartum week 16. Women were interviewed at enrollment, 7 to 10 days, 8 weeks, and 16 weeks postpartum. SUNJECTS/SETTING: One hundred fifteen African-American WIC participants who initiated breast-feeding and who had been enrolled in 1 of 4 clinics. INTERVENTION: Two-by-two factorial design, in which 4 clinics were randomly assigned to receive either no intervention, a motivational video package intervention, a peer-counseling intervention, or both interventions. MAIN OUTCOME MEASURES: Breast-feeding duration in weeks and relative risk ratios for breast-feeding cessation before 16 weeks postpartum. STATISTICAL ANALYSIS PERFORMED: Contingency table analysis, including chi2 tests and log-rank tests; multivariate analysis using Cox proportional hazards regression analysis. RESULTS: A higher proportion of women were breast-feeding at 8 and 16 weeks postpartum in the intervention clinics than in the control clinic. The proportion of women reporting breast-feeding declined at 8 and 16 weeks postpartum, but the rate of decline was slower in the 3 intervention clinics than in the control clinic. Being younger than 19 years of age or older than 25 years of age, having a male infant, and returning to work or school all negatively affected breastfeeding duration, whereas previous breast-feeding experience positively influenced breast-feeding duration. APPLICATIONS/CONCLUSIONS: WIC-based peer counselor support and motivational videos can positively affect the duration of breast-feeding among African-American women. WIC nutritionists and other health professionals in contact with this population should expand their efforts toward promoting increased duration of breast-feeding.

Screening for Wilms' tumor in children with high-risk congenital syndromes: considerations for an intervention trial.

Screening for cancer in children is uncommon. However, in children with congenital syndromes associated with Wilms' tumor, conditions exist that potentially make screening effective. This select population of children 1) are relatively easily identified; 2) have a high incidence of Wilms' tumor; 3) if identified before development of Wilms' tumor, may have a decrement in morbidity/mortality; and 4) are amenable to a simple and acceptable screening technology, renal sonography exams. Many clinicians have recommended screening for cancer in children with congenital syndromes associated with Wilms' tumor. However, neither costs nor effectiveness of such recommendations have been evaluated systematically. The strongest evidence for or against Wilms' tumor screening in this select population would be provided by a randomized screening trial. Prior to undertaking such a trial, the key parameters that dominate the cost and effectiveness of screening should be identified. Simulation models, such as cost effectiveness analysis, offer a starting point for deciding whether cancer screening is appropriate, and if so, under what set of conditions. We review basic conditions required for a successful screening trial in children with syndromes that are at increased risk of Wilms' tumor. We also discuss the use of cost-effectiveness analysis as a preliminary step in determining the feasibility of an intervention trial.

Use of gene tests to detect hereditary predisposition to cancer: what do we know about cost effectiveness?

Mutations in 4 genes associated with DNA repair have been shown to be associated with hereditary non-polyposis colon cancer (HNPCC) in families which display unusually high risk for colorectal cancer. Laboratory tests for mutations in these genes will soon be commercially available, raising the possibility that population-wide gene testing to identify individuals with an inherited susceptibility to colorectal cancer could be conducted. The purpose of our report is to explore the economic implications of conducting a program of population-wide screening for HNPCC compared with alternative programs which would be restricted to families already known to be at high risk for HNPCC. Rather than provide a definitive answer to these questions, our purpose is to indicate priority areas of research which need to be conducted before such a definitive analysis can be done. An exploratory analysis has been conducted to determine which factors are most important in determining the cost-effectiveness of a genetic testing program for HNPCC. The base case analysis focuses on current uncertainty about the population prevalence of the HNPCC genotype and phenotype, factors which are central to the cost-effectiveness of population-wide screening. Uncertainty in parameters related to the cost and effectiveness of screening and preventive interventions for HNPCC were explored using additional sensitivity analyses. Favorable levels of cost-effectiveness for population-wide screening are achieved only when the most favorable assumptions about HNPCC prevalence and the cost and effectiveness of screening and preventive interventions are made.

The use of gene tests to detect hereditary predisposition to cancer: economic considerations.

Several mutations recently have been shown to be associated with hereditary nonpolyposis colon cancer (HNPCC) in families displaying unusually strong predisposition to colorectal cancer. Laboratory tests to detect such gene mutations soon will be commercially available, raising the possibility for population-wide screening. The purpose of this study was to explore the economic implications of conducting a population-wide screening for HNPCC compared with restricted screening among members of the families at high risk. An exploratory analysis was performed to determine which factors are most important in determining the cost-effectiveness of such a testing program. The base-case analysis focuses on current uncertainty about the population prevalence of the HNPCC genotype and phenotype. The uncertainty with regard to parameters related to the cost-effectiveness of screening and preventive interventions for HNPCC were explored, using additional sensitivity analyses. Cost-effectiveness is achieved for population-wide screening only when assumptions most favorable to that outcome are made regarding the HNPCC prevalence, the cost and effectiveness of screening, and preventive intervention. Information on the population prevalence of HNPCC genotypes and the penetrance of these genotypes is essential for making policy decisions. Additional information is needed regarding the determinants of the cost of genetic testing and counseling, the efficacy of preventive regimens for individuals at high risk, and the accuracy and cost of alternative methods of identifying families at risk.

Medicare payments from diagnosis to death for elderly cancer patients by stage at diagnosis.

Although extensive resources go to cancer care, national population-based data on the costs of such care at the patient level have been unavailable. Medicare payments subsequent to diagnosis of cancer for elderly enrollees with five common cancers were estimated using tumor registry data from the Surveillance, Epidemiology, and End Results Program linked to Medicare claims from 1984 to 1990. The time between diagnosis and death was divided into four phases corresponding to the clinical course of solid tumors, average payments for each phase were estimated (including payments for services not related to cancer), then phase-specific payment data were aggregated. Average payments by phase varied among cancer sites, especially in the initial care phase, where payments were highest for lung and colorectal cancers ($17,500 in 1990 dollars) and lowest for female breast cancer ($8,913). Total Medicare payments from diagnosis to death were highest for persons with bladder cancer ($57,629) and lowest for those with lung cancer ($29,184). Low payments for persons with lung cancer corresponded to brief survival times. Persons diagnosed at earlier stages incurred higher total payments between diagnosis and death than those diagnosed at later stages, reflecting their longer survival. This implies that early detection may increase total Medicare expenditures by extending beneficiaries' lives. However, Medicare payments per year of survival were lower for earlier stages. Data on Medicare payments subsequent to diagnosis of cancer are useful for identifying the cost implications of differences in treatment patterns by demographic characteristics, geography, and delivery systems; comparing the financial impact of alternative therapies; evaluating the long-term cost impacts of screening and prevention programs; and risk-adjusting payments to health plans.

Potential for cancer related health services research using a linked Medicare-tumor registry database.

The National Cancer Institute and the Health Care Financing Administration share a strong research interest in cancer costs, access to cancer prevention and treatment services, and cancer patient outcomes. To develop a database for such research, the two agencies have undertaken a collaborative effort to link Medicare Program data with the Surveillance, Epidemiology, and End Results (SEER) Program database. The SEER Program is a system of 9 population-based tumor registries that collect standardized clinical information on cases diagnosed in separate, geographically defined areas covering approximately 10% of the US population. Using a deterministic matching algorithm, the records of 94% of SEER registry cases diagnosed at age 65 or older between 1973 to 1989, or more than 610,000 persons, were successfully linked with Medicare claims files. The resulting database, combining clinical characteristics with information on utilization and costs, will permit the investigation of the contribution of various patient and health care setting factors to treatment patterns, costs, and medical outcomes.

A model for making project funding decisions at the National Cancer Institute.

This paper describes the development of a model for making project funding decisions at The National Cancer Institute (NCI). The American Stop Smoking Intervention Study (ASSIST) is a multiple-year, multiple-site demonstration project, aimed at reducing smoking prevalence. The initial request for ASSIST proposals was answered by about twice as many states as could be funded. Scientific peer review of the proposals was the primary criterion used for funding decisions. However, a modified Delphi process made explicit several criteria of secondary importance. A structured questionnaire identified the relative importance of these secondary criteria, some of which we incorporated into a composite preference function. We modeled the proposal funding decision as a zero-one program, and adjusted the preference function and available budget parametrically to generate many suitable outcomes. The actual funding decision, identified by our model, offers significant advantages over manually generated solutions found by experts at NCI.

Cancer awareness among African Americans: a survey assessing race, social status, and occupation.

Knowledge of cancer prevention and control was defined in terms of prevention, etiology, treatment, symptoms, cancer rates, screening, and detection examinations. A survey of 86 African Americans and 68 white Americans in Alameda County, California was completed in 1985. An index comprised of 69 knowledge items was assessed. A multivariate analysis of race, education, socioeconomic status, and occupation confirmed that these characteristics were independent predictors of knowledge. Blue collar work status was the most important predictor of low knowledge levels. African Americans were less knowledgeable than white Americans with regard to diet in preventing cancer and treatment modalities for cancer, and were most likely to perceive surgery as contributing to metastases. Low education and income status predicted low levels of knowledge. An important consideration in changing knowledge levels is the need to translate technical information about treatment and metastases in ways that are effective in reaching target populations at risk for low levels of knowledge. Cancer prevention and control programs need to develop materials and strategies that are responsive to communities whose members are predominantly African Americans or blue collar workers, or have low levels of education and income.