Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis--meta-analysis.

OBJECTIVE: To evaluate the therapeutic trajectory of intra-articular hyaluronic acid (IAHA) vs placebo for knee osteoarthritis (OA). DESIGN: Our data sources include Medline, EMBASE, CINAHL, BIOSIS, Web of Science, Google Scholar, Cochrane database; hand searched reviews, manuscripts, and, supplements; author contacts for unpublished data. Randomized trials that reported effects of IAHA vs placebo on knee OA were selected based on inclusion criteria. We computed effect sizes for change from baseline at 4, 8, 12, 16, 20 and 24 weeks, using Bayesian random effects model. We performed multivariate analyses adjusting for correlation between time points. Meta-regressions were performed adjusting for potential confounders. RESULTS: The 54 eligible trials included 7545 participants. The conduct and quality of these trials varied in number of aspects. The effect size (ES) favored IAHA by week 4 (0.31; 95% CI 0.17, 0.45), reaching peak at week 8 (0.46; 0.28, 0.65), and then trending downwards, with a residual detectable effect at week 24 (0.21; 0.10, 0.31). This therapeutic trajectory was consistent among the subset of high quality trials and on multivariate analysis adjusting for correlation between time points. CONCLUSIONS: Our meta-analysis highlights a therapeutic trajectory of IAHA for knee OA pain over 6 months post-intervention. With this additional perspective, we are able to infer that IAHA is efficacious by 4 weeks, reaches its peak effectiveness at 8 weeks and exerts a residual detectable at 24 weeks. On the other hand, the peak effect size (0.46; 0.28, 0.65), is greater than published effects from other OA analgesics [acetaminophen (ES=0.13; 0.04, 0.22); NSAIDs (ES=0.29; 0.22, 0.35); COX-2 inhibitors (ES=0.44; 0.33, 0.55)]. An effect size above 0.20 is considered to be clinically relevant on an individual patient basis in chronic pain conditions such as knee OA. Thus, its properties could have utility for certain clinical situations, or in combination with other therapies.

Maternal obesity and risk of cesarean delivery: a meta-analysis.

Despite numerous studies reporting an increased risk of cesarean delivery among overweight or obese compared with normal weight women, the magnitude of the association remains uncertain. Therefore, we conducted a meta-analysis of the current literature to provide a quantitative estimate of this association. We identified studies from three sources: (i) a PubMed search of relevant articles published between January 1980 and September 2005; (ii) reference lists of publications selected from the search; and (iii) reference lists of review articles published between 2000 and 2005. We included cohort designed studies that reported obesity measures reflecting pregnancy body mass, had a normal weight comparison group, and presented data allowing a quantitative measurement of risk. We used a Bayesian random effects model to perform the meta-analysis and meta-regression. Thirty-three studies were included. The unadjusted odd ratios of a cesarean delivery were 1.46 [95% confidence interval (CI): 1.34-1.60], 2.05 (95% CI: 1.86-2.27) and 2.89 (95% CI: 2.28-3.79) among overweight, obese and severely obese women, respectively, compared with normal weight pregnant women. The meta-regression found no evidence that these estimates were affected by selected study characteristics. Our findings provide a quantitative estimate of the risk of cesarean delivery associated with high maternal body mass.

Cumulative illness severity and progression from moderate to severe retinopathy of prematurity.

OBJECTIVE: To test cumulative neonatal illness severity (IS) and IS fluctuation as predictors of progression from moderate to severe retinopathy of prematurity (ROP). METHODS: Data from research databases and medical record review were collected for infants from four neonatal intensive care unit (NICUs) admitted between 1995 and 2001 and diagnosed with prethreshold ROP. Cumulative neonatal IS measured using daily Scores for Neonatal Acute Physiology (SNAP) for the first 28 days of life, and IS fluctuation as assessed by summing changes between daily SNAP scores, were tested as predictors of progression to threshold ROP using logistic regression. RESULTS: Infants progressing to threshold (n=79), compared to those not progressing to threshold (n=130), had significantly (P<0.05) lower gestational ages (25.2+/-1.1 versus 25.8+/-1.4 weeks), higher cumulative neonatal SNAP (255+/-77 versus 224+/-63 weeks) and had more severe hospitalizations as indicated by diagnoses and medical management. In regression analysis, gestational age, chronological age and presence of plus disease at first diagnosis of prethreshold were associated with development of threshold. After adjusting for these factors, cumulative neonatal SNAP was significantly associated with progression to threshold. However, addition of cumulative SNAP to the model only increased receiver-operating characteristic curve area from 0.77 to 0.78 (NS). Other factors, including SNAP fluctuation, were not associated with progression to threshold after adjustment using this model. CONCLUSIONS: Cumulative neonatal IS, as measured by cumulative SNAP, is an independent risk factor for progression from moderate to severe ROP. However, cumulative IS does not enhance assessment of risk for ROP progression after adjusting for simpler clinical factors.

Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus.

BACKGROUND: Obesity is closely related to type 2 diabetes and long-term weight reduction is an important part of the care delivered to obese persons with diabetes. OBJECTIVES: To assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. SEARCH STRATEGY: Computerized searches were performed of MEDLINE (January 1966 to May 2004), EMBASE (January 1974 to May 2004, Web of Science (January 1981 to May 2004, and other electronic bibliographic databases, supplemented with hand searches of reference lists and selected journals. SELECTION CRITERIA: Randomized, controlled trials were included where pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished literature in any language and with any study design was included. DATA COLLECTION AND ANALYSIS: Two reviewers abstracted data and the quality of included studies was evaluated by assessing potential attrition, as well as selection and measurement bias, and a Jadad score was obtained. Effects were combined using a random effects model. MAIN RESULTS: A sufficient number of studies were available for a quantitative synthesis for fluoxetine, orlistat, and sibutramine. Twenty two randomized controlled trials were included in the review, with a total of 296 participants for fluoxitine, 2036 for orlistat, and 1047 for sibutramine. Pharmacotherapy produced modest reductions in weight for fluoxetine (5.1 kg (95% confidence interval [CI], 3.3 - 6.9) at 24 to 26 weeks follow up; orlistat 2.0 kg (CI, 1.3 - 2.8) at 12 to 57 weeks follow-up, and sibutramine 5.1 kg (CI, 3.2 - 7.0) at 12 to 52 weeks follow-up. Glycated hemoglobin also modestly and significantly reduced for fluoxetine and orlistat. Gastrointestinal side effects were common with orlistat; tremor, somnolence and sweating with fluoxetine; and palpitations with sibutramine. Some studies, using a variety of study designs, were available on other drugs and a significant decrease in weight was noted in three studies of mazindol, one of phenmetrazine, two of phentermine. No studies were identified that fit inclusion criteria for pseudophedrine, ephedra, sertraline, yohimbine, amphetamine or its derivatives, bupropion, topiramate, benzocaine, threachlorocitric acid, sertraline, and bromocriptine. AUTHORS' CONCLUSIONS: Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes.

Long-term non-pharmacological weight loss interventions for adults with prediabetes.

BACKGROUND: Most persons with prediabetes (impaired glucose tolerance or impaired fasting glucose) are overweight, and obesity worsens the metabolic and physiologic abnormalities associated with this condition. Prediabetes is an important risk factor for the development of type 2 diabetes. OBJECTIVES: The objective of this review was to assess the effectiveness of dietary, physical activity, and behavioral weight loss, and weight control interventions for adults with prediabetes. SEARCH STRATEGY: Studies were obtained from computerized searches of multiple electronic bibliographic databases, supplemented by hand searches of selected journals, and consultation with experts in obesity research. The last search was conducted May, 2004. SELECTION CRITERIA: Studies were included if they were published or unpublished randomized controlled trials in any language and examined weight loss or weight control strategies using one or more dietary, physical activity, or behavioral interventions, with a follow-up interval of at least 12 months. DATA COLLECTION AND ANALYSIS: Effects were combined using a random-effects model. MAIN RESULTS: Nine studies were identified, with a total of 5,168 participants. Follow-up ranged from 1 to 10 years. Quantitative synthesis was limited by the heterogeneity of populations, settings, and interventions and by the small number of studies that examined outcomes other than weight. Overall, in comparisons with usual care, four studies with a follow-up of one year reduced weight by 2.8 kg (95 % confidence interval (CI) 1.0 to 4.7) (3.3% of baseline body weight) and decreased body mass index by 1.3 kg/m(2) (95% CI 0.8 to 1.9). Weight loss at two years was 2.6 kg (95% CI 1.9 to 3.3) (three studies). Modest improvements were noted in the few studies that examined glycemic control, blood pressure, or lipid concentrations (P > 0.05). No data on quality of life or mortality were found. The incidence of diabetes was significantly lower in the intervention groups versus the controls in three of five studies examining this outcome at 3 to 6 years follow-up. AUTHORS' CONCLUSIONS: Overall, weight loss strategies using dietary, physical activity, or behavioral interventions produced significant improvements in weight among persons with prediabetes and a significant decrease in diabetes incidence. Further work is needed on the long-term effects of these interventions on morbidity and mortality and on how to implement these interventions in diverse community settings.

Long-term non-pharmacologic weight loss interventions for adults with type 2 diabetes.

BACKGROUND: Most persons with type 2 diabetes are overweight and obesity worsens the metabolic and physiologic abnormalities associated with diabetes. OBJECTIVES: The objective of this review is to assess the effectiveness of lifestyle and behavioral weight loss and weight control interventions for adults with type 2 diabetes. SEARCH STRATEGY: Studies were obtained from computerized searches of multiple electronic bibliographic databases, supplemented with hand searches of selected journals and consultation with experts in obesity research. The last search was conducted May, 2004. SELECTION CRITERIA: Studies were included if they were published or unpublished randomized controlled trials in any language, and examined weight loss or weight control strategies using one or more dietary, physical activity, or behavioral interventions, with a follow-up interval of at least 12 months. DATA COLLECTION AND ANALYSIS: Effects were combined using a random effects model. MAIN RESULTS: The 22 studies of weight loss interventions identified had a 4,659 participants and follow-up of 1 to 5 years. The pooled weight loss for any intervention in comparison to usual care among 585 subjects was 1.7 kg (95 % confidence interval [CI] 0.3 to 3.2), or 3.1% of baseline body weight among 517 subjects. Other main comparisons demonstrated nonsignificant results: among 126 persons receiving a physical activity and behavioral intervention, those who also received a very low calorie diet lost 3.0 kg (95% CI -0.5 to 6.4), or 1.6% of baseline body weight, more than persons receiving a low-calorie diet. Among 53 persons receiving identical dietary and behavioral interventions, those receiving more intense physical activity interventions lost 3.9 kg (95% CI -1.9 to 9.7), or 3.6% of baseline body weight, more than those receiving a less intense or no physical activity intervention. Comparison groups often achieved significant weight loss (up to 10.0 kg), minimizing between-group differences. Changes in glycated hemoglobin generally corresponded to changes in weight and were not significant when between-group differences were examined. No data were identified on quality of life and mortality. AUTHORS' CONCLUSIONS: Weight loss strategies using dietary, physical activity, or behavioral interventions produced small between-group improvements in weight. These results were minimized by weight loss in the comparison group, however, and examination of individual study arms revealed that multicomponent interventions including very low calorie diets or low calorie diets may hold promise for achieving weight loss in adults with type 2 diabetes.

Safety of nifedipine in patients with hypertension: a meta-analysis.

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.

Safety of nifedipine in angina pectoris: a meta-analysis.

-Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (P=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (P=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.

Prognostic factors for local and distant recurrence in stage I and II cervical carcinoma.

PURPOSE: The effects of tumor size, parametrial involvement, and other variables on treatment outcome for patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage I or II cervical carcinoma, as well as treatment complications, were analyzed retrospectively. METHODS AND MATERIALS: Records of 125 patients with FIGO Stage I or II carcinoma of the uterine cervix selected for curative radiotherapy between January 1980 and December 1990 were reviewed. Twelve patients (9.9%) underwent adjuvant extrafascial hysterectomy and 8 patients (6.4%) received chemotherapy. Median age was 55 years. Median follow-up time was 40 months, and minimum follow-up time was 24 months. The data were analyzed for site of first relapse, survival, overall incidence of complications, and incidence of grade 4 complications. RESULTS: The overall 5-year survival was: Stage IA: 100%, Stage IB: 72%, Stage IIA: 90%, and Stage IIB: 72%. The 5-year survival with no evidence of disease (NED) was: Stage IA: 100%, Stage IB: 67%, Stage IIA: 90%, and Stage IIB: 50%. Patients with bulky (> 5 cm) tumors had a shorter overall and NED survival than patients with nonbulky tumors (53% vs. 83%; p = 0.0008 and 44% vs. 78%; p = 0.0001, respectively). Thirty-nine tumor recurrences (39 out of 125 = 31%) occurred and were scored as local (23 out of 125 = 18.3%), if initial failure had a local component, or distant (16 out of 125 = 12.7%), if initial failure was distant only. Patients with bulky (more than 5 cm) tumors (32 out of 125) were more likely to experience a recurrence (18 out of 32 = 56%) than patients with nonbulky tumors (21 out of 93 = 22%; p = 0.0004). The initial site of recurrence was more likely to be local for bulky tumors (14 out of 18 = 78%) than for nonbulky tumors (9 out of 21 = 43%; p = 0.03). The probability of a recurrence increased with the number of involved parametria (none: 20 out of 78 = 25%; one: 12 out of 34 = 35%; two: 7 out of 13 = 54%; p = 0.04 for linear trend), as did the probability that the initial failure was distant rather than local (none: 4 out of 20 = 20%; one: 7 out of 12 = 58%; two: 5 out of 7 = 71%; p = 0.01 for linear trend). Positive lymph nodes, vessel invasion, and low hemoglobin level all correlated with an increased risk of a recurrence (RR 2.41, p = 0.004; RR 2.20, p = 0.01; OR 2.02, p = 0.01, respectively). There were 46 complications among 37 (29%) patients. The incidence of grade 4 complications was 8.8% (11 out of 125). History of pelvic surgery and bulky tumor were significant predictors of a grade 4 complication (p < 0.0001 and 0.021, respectively). Also, a dose rate to point A of > 0.6 Gy/h increased the chance of a grade 4 complication (p = 0.007). CONCLUSION: For patients with FIGO Stage I or II cervical carcinoma, tumor size was more predictive of local recurrence than was overall stage, and the extent of parametrial involvement was strongly predictive of distant recurrence, as was the stage. These findings suggest that tumor size and extent of parametrial involvement should be incorporated into the staging system. Patients with bulky tumors had a shorter survival and were more likely to experience a grade 4 toxicity of therapy. Dose rate to point A of > 0.6 Gy/h was associated with the increased risk of grade 4 complications.

The value of breast lumpectomy margin assessment as a predictor of residual tumor burden.

PURPOSE: Margin assessment is commonly used as a guide to the relative aggressiveness of therapy for breast conserving treatment (BCT), though its value as a predictor of the presence, type, or extent of residual tumor has not been conclusively studied. Controversy continues to exist as to what constitutes a margin that is "positive," "close," or "negative." We attempt to address these issues through an analysis of re-excision specimens. PATIENTS AND METHODS: As part of an institutional prospective practice approach for BCT, 265 cases with AJCC Stage I/II carcinoma with an initial excision margin that was < or = 2 mm or indeterminate were subjected to re-excision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype, relative closeness of the measured margin, the extent of margin positivity graded as focal, minimal, moderate, or extensive, and the extent of specimen processing as reflected in the number of cut sections per specimen volume (S:V ratio). The amount of residual tumor was graded as microscopic, small, medium, or large. The histopathologic subtype of tumor in the re-excision specimen was classified as having an invasive component (ICa) or pure DCIS (DCIS). RESULTS: The primary excision margin was positive, > 0 < or = 1 mm, 1.1-2 mm, and indeterminate in 60%, 18%, 5%, and 17%, respectively. The predominant histopathologies in the initial excision specimens were invasive ductal (IDC) (50%) and tumors with an extensive intraductal component (EIC) (43%). The histopathology of the initial excision specimen was highly predictive of the histopathology of tumor found on re-excision, as residual DCIS was found in 60% of +RE specimens with initial histopathology of EIC compared to 26% for IDC (p = 0.001). Neither the extent of margin positivity nor the extent of tumor in the re-excision were significantly related to the initial histopathologic subtype; however, a +RE was seen in 59% of EIC, 43% of IDC, and 32% of invasive lobular ILC cases (p = 0.01). The extent of margin positivity was significantly related to the size of the tumor such that tumor size < or = 20 mm was associated with a greater probability of focal or minimal margin involvement. Positive margins graded as focal, minimal, moderate/extensive were associated with a +RE in 26%, 58%, and 84%, respectively (p = 0.001). Further, the extent of positivity was significantly correlated with the extent of residual tumor such that focal/minimal positivity was more commonly associated with micro/small +RE, whereas moderate/extensive positivity was associated with medium/large +RE. When the closest margin of the initial excision specimen was positive, > 0 < or = 1 mm, or 1.1-2 mm, a +RE was found in 56%, 41%, and 17%, respectively (p = 0.01) but did not correlate with the amount of residual tumor. The extent of specimen processing as reflected in the S:V ratio did not correlate with the probability of defining a measured margin as positive nor the probability of a +RE. In a univariate model, the extent of tumor in the re-excision and the histologic type of tumor in the re-excision were significantly associated with margin status and initial histopathology, respectively. The probability of finding a +RE, based on a multivariate model, was associated with the closeness and extent of margin involvement and initial histopathology of an EIC. CONCLUSION: The relative closeness of tumor to the specimen edge and the extent of margin positivity are predictive for residual tumor, though with an error consistent with its limitations as a sampling procedure. The histopathology of tumor in the initial excision is predictive of the type of residual tumor and the extent of margin positivity was correlated with the amount of residual tumor.

Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed.

PURPOSE: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of therapy directed at the tumor-bearing quadrant. METHODS AND MATERIALS: From 1982-1994, there were 509 treated Stage I and II breast carcinomas with a median follow-up of 72 months. For operational purposes, tumor excision margins were prospectively defined as: > 5 mm, 2.1-5 mm, > 0 < or = 2 mm, and positive. If a margin was assessed as < or = 2 mm or indeterminate, and it was deemed cosmetically feasible, a reexcision of the tumor bed would be performed. All patients received whole breast irradiation to 50-50.4 Gy. The following scheme for tumor bed boost irradiation as a function of final margin status (FMS) was observed: (a) Minimal risk = no tumor found on reexcision, no boost performed; (b) low risk = FMS > 5 mm, boost of 10 Gy; intermediate risk = FMS 2.1-5 mm, boost to 14 Gy; high risk = FMS < or = 2 mm or positive, boost to 20 Gy. Cases were analyzed for local failure (LF) with respect to histology (invasive ductal (IDC), IDC with associated DCIS (IDC/DCIS), invasive lobular (ILC)), age, tumor size, total excision volume, reexcision, total dose, tamoxifen therapy, and chemotherapy. RESULTS: There were 19 breast recurrences for a Kaplan-Meier local failure rate for all cases at 5 and 10 years of 2.7% and 7.1%, respectively. Local failure in the first 4 years of follow-up was rare, with a mean annual incidence rate of 0.25% that rose to a mean of 1.1% in subsequent years. Univariate results of Cox proportional hazards regression survival models found positive FMS (p = 0.02), IDC/DCIS (p = 0.04) and age (0.0006) as significantly associated with local failure. In a multivariable model of FMS and IDC/DCIS, FMS retained significance (p = 0.01) but IDC/DCIS was borderline (p = 0.06). When FMS and age were included in a multivariable model, there was a significant interaction (p = 0.01) between the two variables. There was a significant increase in the relative risk of LF for age < or = 45 years (range 11.1-17.4), irrespective of FMS category. Although excellent overall control rates were achieved for patients > 45 years, for younger patients LF rates appeared to remain proportional to the relative closeness of the FMS, despite rigorous dose escalation. CONCLUSIONS: Graded tumor-bed dose escalation in response to FMS results in an exceptionally low risk of "early" local recurrence within the first 5 years of follow-up. However, this strategy is unable to completely overcome the longer term adverse influence of young age and positive FMS.

The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation.

Controversy exists regarding the impact of pretransplantation HCV infection on the outcome of renal transplantation. We compared the prevalence of posttransplantation liver disease and graft and patient survival among kidney transplant recipients with and without anti-HCV at the time of transplantation. Pretransplantation sera from 103 randomly selected recipients of kidneys from anti-HCV-negative donors were tested for anti-HCV using a second generation ELISA. Twenty-three (22%) were positive for anti-HCV and 80 (78%) were negative. Anti-HCV-positive recipients had a longer time on dialysis (P = 0.003) and had a higher number of previous transplants (P = 0.01). Further, 61% of anti-HCV-positive patients had a history of liver disease compared with 13% of anti-HCV-negative patients (P < 0.001). HCV RNA was detected in the pretransplantation serum in 61% of anti-HCV positive recipients compared with 5% of anti-HCV-negative recipients (P < 0.001). Clinical follow-up on both anti-HCV-positive and -negative patients was obtained until December, 1993. Median posttransplantation follow-up among recipients with anti-HCV prior to transplantation (45 months) was shorter (P = 0.05) than that for recipients without anti-HCV (66 months). For recipients with anti-HCV prior to transplantation, the relative risk of posttransplantation liver disease was 5.0 (95% confidence intervals of 2.4 to 10.5); the relative risk of graft loss was 1.3 (95% confidence intervals of 0.6 to 2.6); the relative risk of death was 3.3 (95% confidence intervals of 1.4 to 7.9), and the relative risk of death due to sepsis was 9.9 (95% confidence intervals of 2.6 to 38.3). The results of this study demonstrate that pretransplantation HCV infection is associated with an increased risk of liver disease and death after renal transplantation. These results raise the question of whether anti-HCV-positive patients on dialysis should be offered renal transplantation as opposed to continuing dialysis.

Long-term follow-up of hepatitis C virus infection among organ transplant recipients: implications for policies on organ procurement.

BACKGROUND: Hepatitis C virus (HCV) infection causes slowly progressive liver disease. Therefore, the full impact of HCV infection after transplantation may require 5-10 years of follow-up. METHODS: We have previously reported the effect of HCV infection, acquired from the donor (study 1) or acquired before transplantation (study 2), on the incidence of liver disease, and on patient and graft survival with a median follow-up of 3-5 years. In study 1, we compared 24 recipients of organs from donors who were positive to antibody to HCV (anti-HCV) to 74 recipients of organs from anti-HCV-negative donors. In study 2, we compared 23 anti-HCV-positive recipients to 80 anti-HCV-negative recipients of kidneys from anti-HCV-negative donors. In this report, we extend the median follow-up period for patient and graft survival to 6-7 years, and discuss the implications of our finding on policies for organ procurement. RESULTS: In study 2, after extended follow-up, there continued to be no significant difference between groups with respect to graft loss, but mortality remained significantly higher among recipients with anti-HCV before transplantation. Compared with recipients without anti-HCV before transplantation, the relative risk of graft loss among recipients with anti-HCV before transplantation was 1.30 (0.66-2.58), the relative risk of death was 2.60 (1.15-5.90), and the relative risk of death due to sepsis was 6.30 (1.99-20). In study 1, after extended follow-up, there continued to be no significant differences between groups, with respect to graft loss or death. Compared with recipients of organs from anti-HCV-negative donors, the relative risk of graft loss among recipients of organs from anti-HCV-positive donors was 0.95 (0.54-1.67), and the relative risk of death was 1.00 (0.49-2.02). CONCLUSIONS: The two studies presented in this report provide an apparent paradox, with respect to the impact of HCV infection acquired at the time of transplantation versus before transplantation on posttransplantation clinical outcomes. However, the increased mortality among recipients who acquired HCV infection before transplantation, but not among recipients who acquired HCV at the time of transplantation, could be explained by the longer duration of HCV infection in the former group. These findings are consistent with the known slowly progressive nature of HCV infection. However, in the absence of definitive evidence for an adverse effect on patient or graft survival, we believe that the decision to accept a kidney from an anti-HCV-positive donor should be made by the patient, after discussion with the treating physician.

GB hepatitis agent in cadaver organ donors and their recipients.

BACKGROUND: The cloning of yet another hepatitis virus, GB virus-C (GBV-C), has provided the opportunity to study the prevalence, and clinical and laboratory characteristics, associated with GBV-C infection among cadaver organ donors and recipients of organs from infected donors. METHODS: Stored sera from a cohort of cadaver organ donors from eight organ procurement organizations, representing different geographic regions of the United States previously screened for hepatitis C virus (HCV) infection, were tested for GBV-C RNA by polymerase chain reaction using degenerate primers derived from the NS3 helicase and 5'-untranslated regions of the GBV-C genome. Pre- and posttransplantation clinical data, and prevalence of GBV-C RNA among recipients of organs from GBV-C RNA-positive and -negative donors, were studied at one of the organ procurement organizations. RESULTS: Twenty-one of 76 (27.6%) anti-HCV ELISA1-positive donors tested positive for GBV-C RNA compared with 6 of 82 (7.3%) ELISA1-negative donors (P=0.001). The prevalence of GBV-C RNA, extrapolated to all cadaver organ donors, was 8.3% (95% confidence interval [CI]: 5.6-11.1%) and was higher than the prevalence of HCV RNA (2.4%). Among ELISA1-positive donors, GBV-C RNA was present in 13 of 35 (37%) donors with HCV RNA, compared with 8 of 41 (20%) donors without HCV RNA (odds ratio [OR]=2.44, P=0.09). Blood alcohol level of more than 100 mg/dl (OR=9.43, P=0.05) and a positive anti-HCV ELISA2 (OR=4.58, P=0.001) were significantly associated with GBV-C infection. In addition, there was a trend toward an association between history of drug abuse (OR=5.23, P=0.06) and younger age (OR=0.97/year, P=0.06) with GBV-C infection. Organs from four GBVC-positive donors and 47 GBV-C-negative donors procured by the New England Organ Bank (Newton, MA) were transplanted into 6 and 79 recipients, respectively. Among recipients of organs from GBV-C RNA. positive donors, the posttransplantation prevalence of GBV-C RNA (25%) was not significantly higher than among recipients of organs from GBV-C RNA-negative donors (23%). Among recipients in whom both pre- and posttransplantation sera were available, one of three (33%) recipients of kidneys from GBV-C RNA-positive donors acquired GBV-C RNA after transplantation, compared with 4 of 40 (10%) recipients of kidneys from GBV-C RNA-negative donors. After a median follow up of 6 years, the posttransplantation prevalence of liver disease, and graft and patient survival, were not significantly different between recipients of organs from GBV-C RNA-positive and -negative donors. CONCLUSIONS: Although GBV-C could be transmitted by organ transplantation, the results of this study preclude definitive conclusions. Further studies are required to determine the risk of transmission of GBV-C by organ transplantation and its role in posttransplantation liver disease.

Fate of mitral regurgitation following repair of atrioventricular septal defect.

The purpose of this study was to evaluate the fate of mitral regurgitation (MR) following repair of atrioventricular septal defects (AVSDs). Echocardiograms of all survivors of isolated AVSD surgery between 1986 and 1996, who had had > or =2 postoperative color Doppler studies (39 patients), were reviewed. On each study, MR severity was graded on a 1+ to 4+ scale, based upon the size of the MR jet. Median age at surgery was 9 months (range 3 to 169); median age at postoperative follow-up was 45 months (range 3 to 107). Mild deterioration of mitral valve function was fairly common. MR severity increased by > or =1 grade in 16 patients (41%) during the course of the study. However, the deterioration in mitral valve function occurred primarily during the early postoperative time intervals. After the initial 32 postoperative months, MR worsened on only 4 occasions and in each instance worsened by only 1 grade. Deterioration to 4+ MR occurred in only 3 patients, and was not observed after the initial 30 postoperative months. Survival curve analysis predicted a 90% probability of not having severe (4+) MR after 30 months (lower 95% confidence bound: 80%). Postoperative MR remains fairly stable following AVSD repair. Serious deterioration is rare, especially after the initial 30 postoperative months.

Serologic and virologic profiles of hepatitis C infection in renal transplant candidates. New England Organ Bank Hepatitis C Study Group.

The development of policies to prevent nosocomial transmission of hepatitis C virus (HCV) infection in hemodialysis units is critically dependent on the understanding of the relationship between tests for anti-HCV, HCV RNA, and HCV genotype and the patients' clinical characteristics. We tested sera from all patients on the renal transplant waiting list at the New England Organ Bank between November 1986 and June 1990 for anti-HCV by a third-generation enzyme-linked immunosorbent assay (ELISA3) and a third-generation recombinant immunoblot assay (RIBA3). All ELISA3-positive sera were tested for HCV RNA by reverse transcriptase "nested" polymerase chain reaction, and the genotype was characterized by restriction fragment length polymorphism. Sera were available in 1,544 of 3,243 (48%) patients on the waiting list, of whom 287 (19%) tested positive for anti-HCV by ELISA3. Two hundred eighty-six randomly selected, anti-HCV-negative patients served as controls. Compared with anti-HCV-negative controls, anti-HCV-positive patients had a longer duration since initiation of renal replacement therapy, higher number of previous kidney transplants and blood transfusions, higher proportion of patients with anti-HBc, history of liver disease, history of non-A, non-B hepatitis, and elevated serum alanine aminotransferase, and lower serum albumin concentrations. Of the 287 anti-HCV-positive sera, 261 (91%) were reactive by RIBA3, 21 (7%) were indeterminate, and five (2%) were nonreactive. HCV RNA was detected in 224 of 275 (81%) ELISA3-positive patients, in whom additional sera were available. There were no significant differences in clinical or laboratory characteristics between ELISA3-positive patients with and without HCV RNA. Genotypes 1a, 1b, 2a, 2b, 3a, and 4 were present in 53%, 23%, 8%, 10%, 4%, and 2% of patients, respectively. Infection with one, two, or three different HCV genotypes was present in 92%, 7%, and 1%, respectively. There was no significant association between the type or number of HCV genotypes and RIBA3 reactivity. There were no major differences in clinical or laboratory characteristics between genotypes or between single and mixed infection. In summary, this study provides detailed information regarding the relationship between tests for anti-HCV, HCV RNA, and HCV genotypes and the clinical and laboratory characteristics of a large, well-characterized cohort of patients referred for renal transplant.

Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care.

Cumulative meta-analysis of clinical trials (a Bayesian interpretation for accumulating evidence) will profoundly affect medical care by summarizing evidence in the assessment of technology innovations. Application of the technique to the randomized control trials (RCTs) of streptokinase treatment of acute myocardial infarction, reduction of peri-operative mortality by antibiotic prophylaxis, and prevention of death from bleeding peptic ulcers has revealed efficacy years before it was suspected by any other means. Arrangement of the trials according to event rate in the controls, effect sizes, quality of the trials or according to covariables of interest has supplied unique information. If carried out prospectively the technique supplies invaluable information regarding indications for another trial, the number of patients necessary to determine the validity of past trends, and the type of patients who might be benefitted. Careful examination in a cumulative manner of the prior trials can reduce the need for future large trials.

A logistic regression model when some events precede treatment: the effect of thrombolytic therapy for acute myocardial infarction on the risk of cardiac arrest.

When outcomes occur in clinical trials before treatment can be given, neither intent-to-treat nor according-to-protocol analyses give optimal estimates of the treatment effect. A better approach employs a time-dependent variable for treatment. Intent-to-treat analyses are conservative, biasing against treatment; according-to-protocol analyses bias in favor of treatment. We show how to measure the effect of a time-dependent variable in a logistic regression using person-time intervals as units of measurement and describe appropriate methods for reporting model performance. The method is applied to develop a model to predict the probability that a patient with a myocardial infarction will have a sudden cardiac arrest within 48 hours of presentation to emergency medical services both when treated with thrombolysis and when not treated. We use a time-dependent treatment variable because many patients went into cardiac arrest while awaiting treatment. This technique has been programmed into an electrocardiograph for real-time use in an emergency department.

Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment.

When treating individual patients, physicians may face difficulties using the evidence from center-based randomized control trials (RCTs) due to limitations in these studies generalizability. Therefore, they often perform their own "informal" tests of treatment effectiveness. Single patient ("N-of-1") trials provide a structured design for more rigorous assessment of medical treatments of chronic diseases, but are applied only to the index patient. We present a hierarchical Bayesian random effects model to combine N-of-1 studies to obtain an estimate of treatment effectiveness for the population and to use this population information to aid in the evaluation of an individual patient's trial results. The model's treatment effect estimates are adjustments between the population estimate and the individual's observed results. This adjustment is based upon the within-patient and between-patient heterogeneity. We demonstrate this patient-focused method using published data from 23 N-of-1 trial results comparing amitriptyline and placebo for the treatment of fibromyalgia.

Lansoprazole compared with histamine2-receptor antagonists in healing gastric ulcers: a meta-analysis.

To compare the gastric ulcer healing rates of lansoprazole with histamine2-receptor antagonists (H2RAs) (ranitidine, famotidine, cimetidine, and roxatidine), a meta-analysis was performed using data from five published and eight unpublished randomized controlled trials. Analyses were performed using (1) both evaluable patients (n = 1527) and all randomized patients (n = 1655) (assuming that patients lost to follow-up were treatment failures); (2) all studies and a subset of studies that received high methodologic quality scores; and (3) fixed-effects, random-effects, and Bayesian statistical models. In all cases, lansoprazole was associated with a significantly higher rate of endoscopic healing at both 4 and 8 weeks compared with the H2RAs. When the most conservative Bayesian statistical model and intent-to-treat analysis were used, lansoprazole was associated with a 33% higher healing rate at 4 weeks (risk ratio = 1.33; 95% confidence interval [CI] = 1.19 to 1.49) and a 12% higher healing rate at 8 weeks (risk ratio = 1.12; 95% CI = 1.06 to 1.19) than were the H2RA agents. Similar results were obtained when the meta-analysis was performed on evaluable rather than all randomized patients and using the three different analytical techniques noted above. Slightly lower, though still highly significant, improvement in ulcer healing rates was obtained when the meta-analysis was performed using a subset of six studies that received high methodologic quality scores. These results support the conclusion that lansoprazole heals ulcers more quickly than do the H2RAs and also achieves higher overall rates of healing. The eradication of Helicobacter pylori associated with gastric ulcers was not assessed in individual studies.