Respiratory Viral Shedding in Healthcare Workers Reinfected with SARS-CoV-2, Brazil, 2020.

We documented 4 cases of severe acute respiratory syndrome coronavirus 2 reinfection by non-variant of concern strains among healthcare workers in Campinas, Brazil. We isolated infectious particles from nasopharyngeal secretions during both infection episodes. Improved and continued protection measures are necessary to mitigate the risk for reinfection among healthcare workers.

The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

Group comparisons involving missing data in clinical trials: a comparison of estimates and power (size) for some simple approaches.

When using 'intent-to-treat' approaches to compare outcomes between groups in clinical trials, analysts face a decision regarding how to account for missing observations. Most model-based approaches can be summarized as a process whereby the analyst makes assumptions about the distribution of the missing data in an attempt to obtain unbiased estimates that are based on functions of the observed data. Although pointed out by Rubin as often leading to biased estimates of variances, an alternative approach that continues to appear in the applied literature is to use fixed-value imputation of means for missing observations. The purpose of this paper is to provide illustrations of how several fixed-value mean imputation schemes can be formulated in terms of general linear models that characterize the means of distributions of missing observations in terms of the means of the distributions of observed data. We show that several fixed-value imputation strategies will result in estimated intervention effects that correspond to maximum likelihood estimates obtained under analogous assumptions. If the missing data process has been correctly characterized, hypothesis tests based on variances estimated using maximum likelihood techniques asymptotically have the correct size. In contrast, hypothesis tests performed using the uncorrected variance, obtained by applying standard complete data formula to singly imputed data, can provide either conservative or anticonservative results. Surprisingly, under several non-ignorable non-response scenarios, maximum likelihood based analyses can yield equivalent hypothesis tests to those obtained when analysing only the observed data.

The impact of requisition design on laboratory utilization.

Laboratory utilization by clinician specialty groups serving outpatients was monitored before and after requisition redesign. Requisition changes were designed to address compliance and utilization issues and included implementation of test groupings and cascades or ordering algorithms. Data collected included the number of selected tests and test sets ordered during both time intervals and the number of patient office visits. Selected tests for monitoring included CBC counts, metabolic panels, thyroid function tests, hepatic function tests, urine analysis, and send-out testing. Statistical significance was measured using Poisson rates for test ordering. The composite effect was a significant decrease in the overall number of tests ordered per outpatient visit for most specialties, with a shift in ordering practices from panels to individual tests. Utilization rates by specialty groups were characterized by average number of laboratory tests ordered per patient visit.

Cervical spine imaging in patients with trauma: determination of fracture risk to optimize use.

PURPOSE: To develop a method to use clinically apparent factors to determine cervical spine fracture risk to guide selection of optimal imaging strategies. MATERIALS AND METHODS: Records from 472 patients with trauma (168 with fractures, 304 control patients) who visited the emergency department in 1994 and 1995 were reviewed for 20 potential predictors of cervical spine fracture in this retrospective case-control study. Simple logistic regression was used to determine predictors of cervical spine fracture. Prediction rules were formulated by using multiple logistic regression and recursive partitioning with bootstrap validation. Posttest fracture probabilities were calculated from base prevalence and likelihood ratios derived for predictors by using Bayes theorem. RESULTS: Predictors of cervical spine fracture included severe head injury (adjusted odds ratio [OR] = 8.5, 95% CI: 4.0, 17.0), high-energy cause (OR = 11.6, 95% CI: 5.4, 25.0), and focal neurologic deficit (OR = 58, 95% CI: 12, 283). The prediction rule was used to stratify patients into groups with fracture probabilities of 0.04%-19.70%. After adjusting for overfitting, the area under the receiver operating characteristic curve was 0.87. CONCLUSION: Clinically apparent factors, including cause of injury, associated injuries, and age, can be used to determine the probability of cervical spine fracture. Development of evidence-based imaging guidelines should incorporate knowledge of fracture probability.

A unifying family of group sequential test designs.

Currently, the design of group sequential clinical trials requires choosing among several distinct design categories, design scales, and strategies for determining stopping rules. This approach can limit the design selection process so that clinical issues are not fully addressed. This paper describes a family of designs that unifies previous approaches and allows continuous movement among the previous categories. This unified approach facilitates the process of tailoring the design to address important clinical issues. The unified family of designs is constructed from a generalization of a four-boundary group sequential design in which the shape and location of each boundary can be independently specified. Methods for implementing the design using error-spending functions are described. Examples illustrating the use of the design family are also presented.

The efficacy of silver alloy-coated urinary catheters in preventing urinary tract infection: a meta-analysis.

PURPOSE: Indwelling urinary catheters are implicated in most cases of nosocomial urinary tract infection. Silver-coating of catheters may reduce the risk of these infections; however, trials have provided mixed results. We performed a meta-analysis to estimate the effectiveness of silver-coated urinary catheters. SUBJECTS AND METHODS: Published or unpublished articles were sought using MEDLINE, reference review, and correspondence with original authors, catheter manufacturers, and experts. Trials using silver-coated urinary catheters in the treatment group and uncoated urinary catheters in the control group were included. Bacteriuria, as evaluated by urine culture, was the outcome variable used to indicate urinary tract infection. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel methods with a fixed-effects model. RESULTS: Of 117 reports retrieved, eight trials with a total of 2,355 patients satisfied inclusion criteria. The summary OR for urinary tract infection was 0.59 (95% CI, 0.42 to 0.84) indicating a significant benefit in the patients receiving silver-coated catheters. A test of heterogeneity, however, indicated that the odds ratios varied significantly among studies. Silver alloy catheters (OR = 0.24; 95% CI, 0.11 to 0.52) were significantly more protective against bacteriuria than silver oxide catheters (OR = 0.79; 95% CI, 0.56 to 1.10). CONCLUSIONS: This meta-analysis clarifies discrepant results among trials of silver-coated urinary catheters by revealing that silver alloy catheters are significantly more effective in preventing urinary tract infections than are silver oxide catheters. Though silver alloy urinary catheters cost about $6 more than standard urinary catheters, they may be worth the extra cost since catheter-related infection is a common cause of nosocomial infection and bacteremia.

Predictors of bile leaks after T-tube removal in orthotopic liver transplant recipients.

Bile leaks after T-tube removal are a frequent cause of morbidity in orthotopic liver transplant recipients. The aim of this study was to determine factors that predict the development of these leaks in liver transplant recipients. Records of all patients who had undergone liver transplantation at the University of Washington Medical Center between January 1990 and September 1993 were reviewed. The following were excluded: patients with a Roux-en-Y anastomosis or inadvertent early T-tube removal and patients who died or underwent retransplantation before T-tube removal. All T-tube cholangiograms were reviewed blindly by two authors. Using logistic regression, several variables were assessed for possible association with bile leaks after T-tube removal; these included patient demographics, intraoperative variables, and clinical and cholangiographic variables related to T-tube removal. Of the 166 liver transplants performed in 150 patients, 99 transplants in 97 patients were evaluable for bile leak after T-tube removal. Thirty-three patients developed symptomatic bile leaks, and 21 underwent endoscopic or operative intervention for persistent symptoms. Only duct mural irregularities on the final cholangiogram were strongly associated with the development of a bile leak after T-tube removal (P = 0.001). In conclusion, bile leaks after T-tube removal occurred in one-third of patients undergoing orthotopic liver transplantation; the majority of these patients required some intervention. Duct mural irregularities were associated with bile leaks.

Histological and clinical outcome after liver transplantation for hepatitis C.

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.

Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials.

We performed an independent meta-analysis of all available randomized clinical trials of interferon alfa-2b in patients with chronic hepatitis C. Articles published between 1986 and 1996 had to include previously untreated patients who were randomly allocated to therapy with at least 2 million units (MU) of interferon alfa-2b three times weekly for 24 weeks. A total of 32 trials met the inclusion criteria. Of these, 20 compared interferon-treated patients to placebo recipients or untreated patients and were used in the primary meta-analysis that compared rates of end-of-treatment and 6-month post-treatment sustained biochemical (normal alanine aminotransferase [ALT] levels) responses, end-of-treatment and 6-month sustained virological responses (absence of hepatitis C virus [HCV] RNA), and end-of-treatment histological responses in patients with paired biopsies. An additional 12 trials compared different doses, duration, or strategies of treatment. In comparison with no treatment, interferon alfa-2b therapy was associated with significant improvement in all end points measured. End-of-treatment biochemical responses were seen in 47% of treated patients compared with 4% of controls (odds ratio, 25.1; P < .0001). The biochemical responses were sustained for at least 6 months in 23% of treated patients compared with 2% of controls (odds ratio, 17.8; P < .0001). End-of-treatment virologic responses were observed in 29% of treated patients compared with 5% of controls (odds ratio, 9.4; P < .001) and 6-month sustained virologic responses were documented in 8% of treated patients compared with 1% of controls (odds ratio, 8.6; P < .001). Histological responses were recorded in 73% of treated patients compared with 38% of controls (odds ratio, 4.8; P < .0001). Extended therapy for 12 to 24 months resulted in significant improvement in 6-month sustained responses: 27% versus 14% (odds ratio, 2.9; P < .001). Higher dose therapy also resulted in modest increases in end-of-treatment (61% vs. 52%; odds ratio, 1.8; P < .02) and 6-month sustained responses (28% vs. 19%; odds ratio, 2.2; P < .01).

A computationally simpler algorithm for the UMVUE of a normal mean following a group sequential trial.

When using data collected in a group sequential clinical trial, the sample mean is no longer the uniform minimum variance unbiased estimator (UMVUE) of the mean of a normal distribution. Emerson (1993, Computers and Biomedical Research, 26, 68-73) described an algorithm for computing the UMVUE in this setting. This algorithm, although computationally expensive, used only the basic software necessary for deriving group sequential boundaries. In this paper, we present an improved algorithm that results in greatly decreased computation times.

Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials.

Surrogate end-point biomarkers (SEBs) have become widely used in short-term cancer chemoprevention trials in place of cancer end points. This paper discusses criteria relevant to the selection and validation of SEBs for colon cancer risk and the use of SEBs in colon cancer chemoprevention trials. As with a number of other cancers, colon carcinogenesis is the result of a multistep process in which an increasing number of alterations, including specific gene mutations, occur as cells progress from normal to precancerous states of increasing size and dysplasia to cancer and finally to metastatic disease. Ideally, a SEB would show differential expression between the various phases of colon carcinogenesis (i.e., normal, premalignant, and malignant tissues) and be associated with risk of colon cancer. Some SEBs that do not meet these criteria may still be useful for demonstrating the effect of a particular agent. It is also necessary that a SEB be measured in tissues (or other sample material) accessible for multiple and sequential sampling and allow for development of appropriate quality control procedures. Some SEBs must have the potential for modulation by chemopreventive agents. Validation of SEBs for use in chemoprevention studies requires that a relationship between the marker and subsequent risk of cancer be established. Also, the assay reliability and accuracy for each SEB must be determined adequately in well-designed prospective studies.

Stopping a clinical trial very early based on unplanned interim analyses: a group sequential approach.

In the conduct of a clinical trial, unexpectedly high rates of toxicity may cause a researcher to want to terminate the trial early even though no formal stopping rule had been specified. The experience of one such clinical trial is used as an example of the ways in which group sequential methodology can be applied in deciding to stop the study, as well as in reporting the results of the clinical trial. This approach is then compared to a Bayesian analysis.

Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps.

BACKGROUND: alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal models, DFMO has been especially active in preventing carcinogen-induced epithelial cancers, including those of the skin, colon, breast, and urinary bladder. Although DFMO is known to exert its diverse biological effects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, induced by DFMO, suppresses carcinogenesis is unknown. PURPOSE: The specific aim of our study was to determine the lowest dose of DFMO that would deplete target tissue (colorectal mucosa) levels of these polyamines in humans who had undergone prior removal of colon polyps while producing minimal toxic effects. METHODS: A dose de-escalation chemoprevention trial of DFMO was conducted in 111 patients (36 female and 75 male) who were in generally good health, aged 39-79, and who had undergone colonoscopy for surgical removal of an adenomatous colon polyp greater than 3 mm within 5 years prior to entering the study. Groups of patients (12-20 patients per group) were orally treated with single, daily doses of DFMO ranging from 3.0 to 0.1 g/m2 for 4 weeks (28 days). Prior to initiation of DFMO treatment and at the end of treatment, six colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end points. Samples for analysis of plasma DFMO levels were also collected during this time period on the day after the last day of drug administration. RESULTS: DFMO caused a decrease in both putrescine content and the ratio of spermidine to spermine for all dose groups down to 0.25 g/m2. Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decreased as a function of donor age. None of the 30 patients receiving either 0.25 or 0.5 g/m2 experienced any clinical ototoxicity in this trial. CONCLUSIONS: DFMO is both safe and effective in reducing colorectal mucosal polyamine contents when it is administered orally to patients at doses as low as 0.25 g/m2 for 28 days. No ototoxicity was observed at doses up to twice this amount. IMPLICATIONS: If DFMO is also found to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epithelial cancers, including those of the prostate and breast.

Sources of variability in estimating ornithine decarboxylase activity and polyamine contents in human colorectal mucosa.

The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is elevated during epithelial carcinogenesis. Since this enzyme is a target for colon and other cancer chemoprevention strategies, we sought to identify sources of variability affecting the measurement of tissue ODC activities and polyamine contents. Multiple colorectal biopsies were obtained from 39 patients undergoing colonoscopy. Biopsy size affected polyamine but not ODC values. Spermidine (spd):spermine (spm) ratios varied less than the contents of the individual amines. Bowel preparation methods did not affect any of the measurements. ODC activities and spd:spm ratios did not vary with bowel location. Lab assay methods contributed to sources of error. Variability was greatest for polyamine content measurements but was reduced when polyamine contents were analyzed as spd:spm ratios. Intrapatient variability of these parameters was as great or greater than interpatient variability. When measured in apparently unaffected colorectal mucosa, none of these parameters were significantly correlated with prior polyp history, number of prevalent polyps found at current colonoscopy, or polyp size. Thus, neither ODC activity nor polyamine contents of normal mucosa appear to be discriminatory markers of colorectal carcinogenesis. However, spd:spm ratios, which show the least variability among measures of polyamine contents, should be a good marker of the consequence of polyamine synthesis inhibition in chemoprevention trials.

Gastrointestinal tissue polyamine contents of patients with Barrett's esophagus treated with alpha-difluoromethylornithine.

alpha-Difluoromethylornithine (DFMO), an investigational chemopreventive agent, suppresses polyamine contents and decreases epithelial carcinogenesis in experimental models. The ability of this drug to decrease polyamine contents in human esophageal tissues has not yet been determined. Eight patients with Barrett's esophagus were treated with DFMO at a dose of 1.5 g/m2/day for 12 weeks. Four sites (Barrett's lesion, adjacent normal squamous esophagus, gastric tissue, and small bowel) were biopsied in each patient before, during, and after DFMO treatment in order to assess the effects of this drug on tissue polyamine levels. Ornithine decarboxylase activities and polyamine contents varied in each site analyzed. The rank orders were Barrett's > small bowel congruent to normal esophagus > gastric tissue for ODC activities, and small bowel > or = Barrett's congruent to normal esophagus > gastric tissue for putrescine contents. Spermidine, but not spermine, contents in the Barrett's lesions and normal squamous esophageal tissue were suppressed by systemic DFMO treatment and recovered to untreated control values when DFMO therapy was discontinued. Systemic DFMO treatment did not affect the levels of either of these two amines in gastric tissue and small bowel. Since DFMO can suppress polyamine contents in several gastrointestinal tissues, including Barrett's mucosa, we conclude that it is an effective agent with which to test the hypothesis that depletion of spermidine contents may prevent the development of adenocarcinoma of the esophagus in this specific patient group.

Antibody levels and response to pneumococcal vaccine in steroid-dependent asthma.

Immunization with pneumococcal vaccine is recommended for patients with chronic respiratory diseases, and is also used to evaluate antibody responses to polysaccharide antigens. We determined the effect of chronic prednisone treatment on immunoglobulin levels, pneumococcal antibody levels, and on the serologic response to pneumococcal vaccination. We studied 14 adult steroid-dependent asthmatics receiving daily or alternate day prednisone, 10 to 35 mg, and 14 age-matched, nonsteroid dependent asthmatic patients. Immunoglobulin levels were within the normal range in all patients. There was no difference in the pre-immunization antipneumococcal polysaccharide antibody levels against serotypes 3, 7F, 9N, and 14 between steroid-dependent and nonsteroid-dependent asthmatic patients. All patients had increases in antipneumococcal antibody levels 4 weeks after pneumococcal immunization. Mean post-immunization pneumococcal antibody titers were similar in steroid-dependent and nonsteroid-dependent asthmatic patients. All patients either had or developed levels > or = 300 ng Ab N/mL against one or more pneumococcal serotypes. We conclude that chronic prednisone treatment in steroid-dependent asthmatic adults does not significantly affect immunoglobulin levels, pneumococcal antibody levels, or specific antibody responses to pneumococcal immunization.

Are endoscopic measurements of colonic polyps reliable?

Many clinical studies of colorectal adenomatous polyps rely on endoscopic estimation of polyp size. To examine the reliability of such measurements, we conducted a study using artificial polyps in an endoscopy teaching model. Eight experienced endoscopists estimated the size of 13 polyps in two separate sessions 2 wk apart. Endoscopic estimates of polyp size tended to be significantly lower than the true polyp size for all polyps and all endoscopists at both sessions. We also found a statistically significant difference in the magnitude of the underestimation between the first and second session (p < 0.0001). At the first session, polyps tended to be estimated at 64% of their true size, and at the second session, the estimates tended to be at 77% of the actual polyp size. We estimate the magnitude of the variation in polyp measurements due to individual polyps, endoscopist, and examination session, and discuss the impact these sources of variation have in planning of clinical trials.

Design and analysis of studies to reduce the incidence of colon polyps.

Decisions regarding the design and analysis of a phase III study to reduce the incidence of colorectal polyps must take into account two complicating factors: the possibility that polyps are missed during screening exams, and variable lengths of follow-up. In this paper we investigate the effects due to misclassification on the power of statistical tests to detect a change in polyp recurrence rates. We also use Monte Carlo studies to examine the relative efficiency of different methods of adjusting for variable times of follow-up.

Computation of the uniform minimum variance unbiased estimator of a normal mean following a group sequential trial.

The sampling distribution of data collected in a group sequential trial is such that the usual fixed-sample estimates of treatment effect are biased. Improved estimates can be obtained by taking the group sequential stopping rule into account. In particular, in the case of inference about the mean of a normal distribution, the sample mean is no longer the uniform minimum variance unbiased estimator (UMVUE). In this paper, I present a way in which the UMVUE for a normal mean can be calculated using software capable of determining the operating characteristics of a group-sequential test.