Comparative effectiveness of faecal microbiota transplant by route of administration.

The optimal route of delivery for faecal microbiota transplant (FMT) is unknown. This observational single-centre study analysed the two-week cure rates for all patients who received FMT from 2013 to 2016 according to route of delivery. Overall, nasogastric delivery of FMT was less effective than lower endoscopic delivery. When patients were stratified by illness severity, nasogastric delivery achieved similar cure rates in healthier individuals, whereas lower endoscopic delivery was preferred for relatively ill individuals. Nasogastric delivery may be less effective than lower endoscopic delivery; however, when taking the cost, preparation and potential risk into account, this difference may not be clinically significant for patients with mild disease.

Predictors of smear-negative pulmonary tuberculosis in HIV-infected patients, Battambang, Cambodia.

DESIGN: Retrospective data analysis of human immunodeficiency virus (HIV) infected patients attending an HIV clinic (referral hospital), Cambodia. Chest X-rays (CXRs) were read independently by onsite and offsite physicians. RESULTS: Data on 881 patients were analyzed (smear-negative = 776, smear-positive = 105). Overall, the prevalence of culture-confirmed pulmonary tuberculosis (PTB) was 17% (150/881, smear-negative = 62/150). For those with any positive culture, a smear-negative case was four times more likely to be mycobacteria other than tuberculosis (MOTT) than Mycobacterium tuberculosis (P = 0.001). Median CD4 count was higher in smear-negative than smear-positive PTB patients (92.5 vs. 42, P = 0.24). Age, symptoms (cough >3 weeks or hemoptysis or fever >1 month) (aOR 2.6, P = 0.02) and an abnormal CXR (offsite reading) (aOR 4.9, P < 0.001) were significant predictors of smear-negative PTB. CXR was no longer significant in the model using the onsite reading (aOR 1.6, P = 0.11). The combination of age >or=30 years plus symptoms had a sensitivity of 100% but a positive predictive value (PPV) of 9%. CXR (offsite), as the next diagnostic test, had a sensitivity of 50% and specificity of 83%. The sensitivity of smear microscopy was 59% and its specificity 97%. CONCLUSIONS: While age and symptoms are useful both in screening smear-negative PTB suspects and in predicting smear-negative PTB cases, they have limited PPV. Given the limitations of smear microscopy, culture is required to diagnose smear-negative disease. Where culture is unavailable, CXR is an important adjunct for diagnosis. However, inaccurate CXR interpretation can impact case detection.

Pulmonary tuberculosis among patients visiting a voluntary confidential counseling and testing center, Cambodia.

SETTING: Voluntary counseling and confidential testing center (VCCT), Battambang District, Cambodia. OBJECTIVES: To determine newly diagnosed pulmonary tuberculosis (PTB) prevalence and predicting factors, and assess the utility of TB-related symptoms and yield of sputum microscopy and culture. DESIGN: Cross-sectional survey using interview, sputum smears and cultures and human immunodeficiency virus (HIV) testing. RESULTS: Of 496 participants, 29 (5.8%) had culture-confirmed PTB while 19 (65.5%) were acid-fast bacilli (AFB) smear-positive. PTB prevalence was higher (P < 0.001) in HIV-positives (20/124, 16.1%) than in HIV-negatives (9/372, 2.4%). On multivariable analysis, being HIV-positive, underweight (body mass index <18.5 kg/m(2)), rapid weight loss and age > or =35 years were predictors of PTB. Fever (93%) and hemoptysis (86%) had the highest sensitivity and specificity, respectively. The symptom complex of rapid weight loss, fever and hemoptysis detected all PTB cases (sensitivity 100%). Examination of three sputum smears with culture of the first sample detected 95% (19/20) of the HIV-associated PTB cases and 90% (26/29) overall. CONCLUSIONS: TB is common in the VCCT setting, regardless of HIV status. The high prevalence of HIV and PTB among the participants warrants consideration of TB screening for all HIV suspects. Such screening through VCCT is feasible. Adding a single culture test to the evaluation of an initial sputum sample set will substantially increase case detection.

Prospective randomized trial evaluating ketamine for advanced endoscopic procedures in difficult to sedate patients.

BACKGROUND: Adequate patient sedation is mandatory for advanced endoscopic procedures such as ERCP and EUS. AIM: To evaluate the effectiveness and safety of ketamine in difficult to sedate patients undergoing advanced endoscopic procedures. METHODS: This was a prospective, randomized trial of all patients undergoing ERCP or EUS who were not adequately sedated despite administration of meperidine 50 mg, midazolam 5 mg and diazepam 5 mg. Patients during endoscopy were then randomized to receive either intravenous ketamine (20 mg) every 5 min or continue to receive standard sedation using meperidine and diazepam. RESULTS: Of 175 patients, 82 were randomized to receive ketamine and 93 standard sedatives. Compared with standard sedation, qualitative physician rating (P < 0.0001) and depth of sedation (P < 0.001) were superior in the ketamine group with shorter recovery times (P < 0.0001). Both patient discomfort and sedation-related technical difficulty were significantly less among patients randomized to receive ketamine (P < 0.0001). More patients in the standard sedation group were crossed-over to the ketamine group due to sedation failure (35.5 vs. 3.7%, P < 0.0001). Nine patients who received ketamine, developed adverse events that were managed conservatively. CONCLUSIONS: Ketamine is a useful adjunct to conscious sedation in patients who are difficult to sedate. Its use Results in better quality and depth of sedation with shorter recovery times than patients sedated using benzodiazepines and meperidine alone. Further prospective studies evaluating the effectiveness and safety of ketamine for endoscopic sedation are needed.

Evaluation of dextrose 50 % as a medium for injection-assisted polypectomy.

BACKGROUND AND STUDY AIMS: Injection-assisted polypectomy (IAP) is traditionally carried out by using normal saline as the submucosal fluid cushion. However, normal saline, being isotonic, does not maintain the elevation of the mucosa for prolonged periods. It was hypothesized that dextrose 50 %, as a hypertonic solution, might be an ideal medium for IAP. This study evaluated the efficacy and safety of dextrose 50 % for performing IAP. PATIENTS AND METHODS: All patients undergoing IAP during gastroscopy or colonoscopy were randomly assigned on a prospective basis to receive either normal saline or dextrose 50 % as the submucosal fluid cushion. The endoscopist was blinded to the type of solution injected. The volume of solution and number of sites injected to elevate the lesion, the number of times IAP was interrupted to inject more fluid to maintain elevation, the rates of en bloc and complete resections, and the complication rates were compared in the two groups. The mean follow-up period was 10 months. RESULTS: Fifty-two sessile lesions were removed in 50 patients. In comparison with normal saline, smaller volumes (median 7 ml vs. 5 ml; P = 0.02) and fewer injections (median 2 vs. 1; P = 0.003) were required to perform IAP when dextrose 50 % was used. The en bloc resection rate was higher with dextrose 50 % than with normal saline (82 % vs. 44 %; P = 0.01). Elevation of the submucosal area persisted even after completion of IAP in 96 % of the patients randomly assigned to dextrose 50 %, compared with 20 % of those receiving normal saline ( P < 0.001). There were no significant differences in the rates of complete resection or complications between the two groups. CONCLUSIONS: Dextrose 50 % is superior to normal saline as a submucosal fluid cushion, as it allows better en bloc resection during injection-associated polypectomy.

Risk factor assessment in the management of patients with suspected deep venous thrombosis.

BACKGROUND: To evaluate the prevalence of thrombosis risk factors in a group of patients undergoing venous duplex scanning (VDS) and to design a risk factor stratification model with the ability to improve the diagnostic yield of VDS. METHODS: Risk factor assessment and VDS were performed on 1,000 patients with clinically suspected lower extremity deep vein thrombosis (DVT) and patients were divided into two groups based upon the outcome of their scan: those with and those without confirmed DVT. Univariate and multivariate logistic regression analyses were performed in order to determine the significance of each risk factor in relation to having a confirmed DVT. RESULTS: There were 181 patients (18.1%) with confirmed DVT. A prior history of DVT/pulmonary embolism, malignancy, prior immobilization, and age over 70 were the most important risk factors associated with having a DVT confirmed on VDS. A novel risk factor stratification model was created utilizing the odds ratios of those factors found to be significant and the prevalence of DVT was found to be 92.4% in the high risk category, 11.5% in the moderate risk category, and 3.2% in the low risk category using this model. CONCLUSIONS: Venous duplex scanning is established as the screening test of choice when one suspects the diagnosis of DVT despite the significant cost of performing and interpreting the test. We suggest that a better clinical model utilizing risk factor assessment may be the key to increasing the yield rate and cost-effectiveness of VDS by excluding low-risk patients from undergoing unnecessary testing.

Some new multiple-test procedures for dose finding.

In Tamhane, Hochberg, and Dunnett (1) we focused primarily on step-down test procedures based on contrasts among the sample means to find the minimum effective dose in a dose-response study. In the present article we use the global tests of Bartholomew (2,3) and Hayter (4) in these step-down procedures. We also propose a new step-down procedure that permits tests based on a class of contrasts [step and basin contrasts of Ruberg (5) are examples of such contrasts] that could not be used with the step-down procedures studied in our previous paper because of lack of control of the familywise error rate. A simulation study to compare the four procedures proposed in the present paper with the top four procedures from the previous article is carried out. It is found that the step-down procedure based on Bartholomew's test and the new step-down procedure based on step and modified basin contrasts generally perform better than the other procedures for a wide range of dose-response profiles.

Intraoperative radiofrequency microbipolar coagulation to replace incisions of maze III procedure for correcting atrial fibrillation in patients with rheumatic valvular disease.

OBJECTIVE: Radiofrequency catheter ablation of atrial tachycardias and flutter is an established technique. The same modality in the microbipolar mode is effective in producing full thickness coagulation injury. Cox's maze procedure is highly successful in curing atrial fibrillation (AF) surgically. However, it consumes relatively long cross clamp time and cardiopulmonary bypass time. In this study, radiofrequency microbipolar coagulation was used as an adjunct to corrective valve surgery, as an intraoperative ablative modality to replace Cox's maze III incisions, thus remarkably shortening the procedure. The results of this procedure are compared historically with those of 26 patients who underwent corrective valve surgery alone. METHODS: Radiofrequency microbipolar coagulation was used to produce conduction blocks along the Cox's maze III incision lines as an adjunct to valve surgery in 18 patients in atrial fibrillation undergoing surgery for rheumatic valvular disease. A bayonet type bipolar forceps with an active tip length of 7 mm drawing current from a microbipolar port of Valleylab Force 4 electrosurgical unit (Valleylab, Boulder, CO) was used for microbipolar coagulation. A 3-mm retinal handheld cryoprobe working on nitrous oxide gas was used for cryoablation. RESULTS: A total of 15 survivors in the coagulation maze group were followed from 43 to 224 days (149.7 +/- 73.1 mean +/- S.D.). Twelve of the 15 survivors (80%) converted to normal sinus rhythm (70% confidence limit: 64.7-90.6%). Atrial transport function studies with pulsed wave doppler, showed presence of a wave in all the 12 (100%) patients in tricuspid valve flow and in nine (75%) patients in mitral valve flow. The procedure took 11.62 +/- 3.86 min of elective cardioplegic arrest time for the left atrial portion and 18.71 +/- 4.25 min of cardiopulmonary bypass time during reperfusion for the right atrial portion. Of the 23 survivors out of 26 patients who underwent the valve procedure alone, only one patient (4.3%) converted to normal sinus rhythm (70% confidence limit: 0.6-14%). CONCLUSION: Thus, our modification considerably shortened the time taken for creating the maze in comparison to the Cox's maze procedure and was effective in restoring normal sinus rhythm in 80% of the patients.

Multiple testing to establish superiority/equivalence of a new treatment compared with kappa standard treatments.

In this paper we develop multiple hypotheses testing procedures to compare a new treatment with a set of standard treatments in a clinical trial. The aim is to classify the new treatment with respect to each of the standards, by specifying those to which the new treatment is superior, those to which the new treatment is equivalent and those to which one can establish neither superiority nor equivalence. We propose several stepwise procedures and compare them with respect to their familywise error rates and power. The step-down methods SD1 and SD2 test for superiority first, followed by tests for equivalence for those comparisons where we cannot establish superiority. The step-up methods SU1 and SU2 test for equivalence first, followed by tests for superiority for those comparisons where we can establish at least equivalence. The methods SD3 and SU3 apply the tests for superiority and equivalence in pairs. All the methods require that we specify a threshold value delta > 0 in advance for defining equivalence. In applications where it is not possible to specify a value delta, we can use the method SD1 by testing for superiority first, followed by one-sided confidence limits on the efficacy differences for those comparisons where we cannot establish superiority.

Multiple test procedures for dose finding.

The problem of identifying the lowest dose level for which the mean response differs from that at the zero dose level is considered. A general framework for stepwise testing procedures that use contrasts among the dose level means is proposed. Using this framework, several new procedures are derived. These and some existing procedures, including that of Williams (1971, Biometrics 27, 103-117; 1972, Biometrics 28, 519-531), are compared analytically and by an extensive simulation study for the normal theory balanced one-way layout case. It is pointed out that the procedures based on the so-called step and basin contrasts proposed by Ruberg (1989, Journal of American Statistical Association 84, 816-822) have excessively high type I familywise error rates (FWEs) and, hence, they should not be used. Some findings of the simulation study are as follows: For monotone dose mean configurations, Williams' procedure and two step-down test procedures based on Helmert and linear contrasts offer the best performance. For nonmonotone dose mean configurations, the performance of Williams' procedure does degrade somewhat, but the other two procedures are still the best. For more complex designs, a simple step-down test procedure that uses any alpha-level tests (not necessarily t-tests) to compare each dose level with the zero dose level controls the FWE and is the only alternative available, but its power is rather low, especially under nonmonotone configurations. Step-up procedures are generally dominated by step-down procedures when the same contrasts are used although the differences are not great.

Step-up multiple testing of parameters with unequally correlated estimates.

We consider the problem of simultaneously testing k > or = to 2 hypotheses on parameters theta(1), ..., theta(k) using test statistics t(1), ..., t(k) such that a specified familywise error rate alpha is achieved. Dunnett and Tamhane (1992a) proposed a step-up multiple test procedure, in which testing starts with the hypothesis corresponding to the least significant test statistic and proceeds towards the most significant, stopping the first time a significant test result is obtained (and rejecting the hypotheses corresponding to that and any remaining test statistics). The parameter estimates used in the t statistics were assumed to be normally distributed with a common variance, which was a known multiple of an unknown sigma(2), and known correlations which were equal. In the present article, we show how the procedure can be extended to include unequally correlated parameter estimates. Unequal correlations occur, for example, in experiments involving comparisons among treatment groups with unequal sample sizes. We also compare the step-up and step-down multiple testing approaches and discuss applications to some biopharmaceutical testing problems.

A model-based approach to estimate the AIDS-free time distribution in homosexual men using longitudinal data.

A model-based approach is developed to estimate the distribution of time from seroconversion to diagnosis with acquired immunodeficiency syndrome (AIDS) as a function of selected time-dependent covariates. The approach is applied to longitudinal data collected over 4 years of follow-up from 450 men seropositive for the human immunodeficiency virus (90 AIDS cases) and 62 seroconverters (nine AIDS cases) participating in the Chicago part of the Multicenter AIDS Cohort Study. Because of the periodic nature of monitoring, the seroconversion time is interval-censored for seroconverters and left-censored for seroprevalent cohort members; the end-point is right-censored for 413 individuals. Since serological monitoring is not continuous but only at regularly scheduled visit times, a model for the discrete hazard rate (DHR) is proposed that is a generalized linear model that relates the DHR to the covariate history through the complementary log-log link. Classification trees are used for preliminary screening of covariates to identify predictors of AIDS that should be incorporated into the DHR model. The missing seroconversion times for all men are imputed 100 times to obtain 100 completed datasets from which the parameters of the DHR are then estimated using the maximum-likelihood method. The final DHR model includes the following infection progression (marker) variables: CD4%, hemoglobin, p24 antigen, and CD4% x p24 antigen interaction. Using this DHR model, the discrete survival distribution of AIDS-free time is estimated for the given population. The jackknife procedure is used to assess the precision of the estimated survival distribution.

Exact repeated confidence intervals for Bernoulli parameters in a group sequential clinical trial.

This paper presents methods for constructing exact repeated confidence intervals (RCIs) for the success probability, p, of a single Bernoulli treatment and for the difference of success probabilities, delta = p1-p2, of two independent Bernoulli treatments in the context of a group sequential clinical trial. These RCIs calculated at each interim analysis are useful for evaluating the data in light of all the information available rather than relying on rigid stopping criteria used by repeated significance tests. Extensions to construction of RCIs for the relative risk p = p1/p2 and odds ratio psi = p1(1-p2)/p2(1-p1) are indicated.

Comparisons between a new drug and active and placebo controls in an efficacy clinical trial.

D'Agostino and Heeren (DH) discussed the multiple comparison issues that arise in evaluating both sensitivity and efficacy in over-the-counter drug trials. We propose a general definition of sensitivity that includes DH's definition as a special case. We also propose a test for sensitivity that coincides with the MIN test of Laska and Meisner at one extreme but has the advantage of identifying specific drugs satisfying the sensitivity criterion when some fail to do so. We suggest that the test of Dunnett as well as an extension of it may be useful for the efficacy comparisons.

Step-down multiple tests for comparing treatments with a control in unbalanced one-way layouts.

We show how a well-known multiple step-down significance testing procedure for comparing treatments with a control in balanced one-way layouts can be applied in unbalanced layouts (unequal sample sizes for the treatments). The method we describe has the advantage that it provides p-values, for each treatment versus control comparison, that take account of the multiple step-down testing nature of the procedure. These joint p-values can be used with any value of alpha, the fixed type I family wise error rate bound, that may be specified by the investigator. To determine the p-values, it is necessary to compute a multivariate Student t integral, for which a computer program is available. This procedure is more powerful than the step-down Bonferroni procedure of Holm and the single-step procedure of Dunnett. An example from the pharmaceutical literature is used to illustrate the procedure.

Comparison of the hamster sperm motility assay to the mouse one-cell and two-cell embryo bioassays as quality control tests for in vitro fertilization.

The hamster sperm motility assay, mouse one-cell embryo, and mouse two-cell embryo bioassays were used to test modified Tyrode's solution and modified Ham's F-10 (Gibco, Grand Island, NY) medium prepared in tap water versus ultrapure water. Factors influencing the ability of each assay to discriminate water quality were evaluated to characterize these assays for quality control use in the in vitro fertilization laboratory. The hamster sperm motility assay reproducibly detected differences in treatment without significant interanimal, interanalyst, or interassay variation. Interanalyst and interanimal variation significantly affected the ability to detect treatment differences using the mouse bioassays. Sample sizes needed to predict clinically significant treatment effects were calculated using varying assay conditions. Ham's F-10 medium can be tested with the hamster sperm motility assay.

Clinical assessment of venous thromboembolic risk in surgical patients.

Prophylaxis against postoperative venous thromboembolism should be tailored according to the patient's level of risk. However, risk assessment is not yet in widespread use in surgical practice. In this study, 538 general surgical patients were prospectively assessed based on a scoring system containing 20 risk factors. Depending on the total risk factor score, the patients were grouped into low (0 to 1, 34.5%), moderate (2 to 4, 48.5%), or high risk (more than 4, 17.2%) categories. Statistically significant (p less than 0.0001) correlation was found between our results and those of three existing risk assessment systems. Overall, of the 538 patients, 37.2% received prophylaxis; 10%, 42.1%, and 76% received prophylaxis in the low-, moderate-, and high-risk categories, respectively. Mechanical prophylactic modalities (graduated elastic compression and sequential intermittent compression) were preferred over pharmacologic modalities. These results suggest that implementation of prophylaxis remains underutilized despite published reports, including NIH guidelines. Our results indicate that the majority of surgical patients seen in this suburban hospital have two or more risk factors for developing venous thromboembolism.

Olivines: revelation of tracks of charged particles.

A one-step, three-component aqueous etchant was developed for revealing the tracks of charged particles in olivine. The etchant reveals tracks of small cone angle, which are equally well developed in all the crystallographic directions. The scope of fossil cosmic-ray track studies in extraterrestrial samples has thus been increased, because olivine is often an abundant constituent and because it has a higher threshold ionization for track registration and has lower uranium, thorium, and trace element concentrations as compared with pyroxenes and feldspars. The etchant does not attack any of the principal rock-forming minerals in normal etching time, which allows a nondestructive study of fossil tracks in thin-section mounts. The study of fossil cosmic-ray tracks in olivine is particularly valuable for investigations of very, very heavy cosmic-ray nuclei and for highly irradiated samples such as those found in the lunar regolith.