Zero-inflated negative binomial mixed model: an application to two microbial organisms important in oesophagitis.

Altered microbial communities are thought to play an important role in eosinophilic oesophagitis, an allergic inflammatory condition of the oesophagus. Identification of the majority of organisms present in human-associated microbial communities is feasible with the advent of high throughput sequencing technology. However, these data consist of non-negative, highly skewed sequence counts with a large proportion of zeros. In addition, hierarchical study designs are often performed with repeated measurements or multiple samples collected from the same subject, thus requiring approaches to account for within-subject variation, yet only a small number of microbiota studies have applied hierarchical regression models. In this paper, we describe and illustrate the use of a hierarchical regression-based approach to evaluate multiple factors for a small number of organisms individually. More specifically, the zero-inflated negative binomial mixed model with random effects in both the count and zero-inflated parts is applied to evaluate associations with disease state while adjusting for potential confounders for two organisms of interest from a study of human microbiota sequence data in oesophagitis.

Pulmonary diffusion and aerobic capacity: is there a relation? Does obesity matter?

AIM: We sought to determine whether pulmonary diffusing capacity for nitric oxide (DLNO), carbon monoxide (DLCO) and pulmonary capillary blood volume (Vc) at rest predict peak aerobic capacity (VO2peak), and if so, to discern which measure predicts better. METHODS: Thirty-five individuals with extreme obesity (body mass index or BMI = 50 +/- 8 kg m((-2)) and 26 fit, non-obese subjects (BMI = 23 +/- 2 kg m((-2)) participated. DLNO and DLCO at rest were first measured. Then, subjects performed a graded exercise test on a cycle ergometer to determine (VO2peak). Multivariate regression was used to assess relations in the data. RESULTS: Findings indicate that (i) pulmonary diffusion at rest predicts (VO2peak) in the fit and obese when measured with DLNO, but only in the fit when measured with DLCO; (ii) the observed relation between pulmonary diffusion at rest and (VO2peak) is different in the fit and obese; (iii) DLNO explains (VO2peak) better than DLCO or Vc. The findings imply the following reference equations for DLNO: (VO2peak) (mL kg(-1) min(-1)) = 6.81 + 0.27 x DLNO for fit individuals; (VO2peak) (mL kg(-1) min(-1)) = 6.81 + 0.06 x DLNO, for obese individuals (in both groups, adjusted R(2 )=( )0.92; RMSE = 5.58). CONCLUSION: Pulmonary diffusion at rest predicts (VO2peak), although a relation exists for obese subjects only when DLNO is used, and the magnitude of the relation depends on gender when either DLCO or Vc is used. We recommend DLNO as a measure of pulmonary diffusion, both for its ease of collection as well as its tighter relation with (VO2peak).

Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy.

BACKGROUND: CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once international normalized ratio (INR) values are available because INR response reflects warfarin sensitivity. METHODS: We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs. RESULTS: A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R(2)). The R(2) increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R(2) of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21. CONCLUSION: Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.

Factors associated with the technical performance of colonoscopy: An EPAGE Study.

BACKGROUND: Variations in colonoscopy practice exist, which may be related to healthcare quality. AIMS: To determine factors associated with three performance indicators of colonoscopy: complete colonoscopy, adenomatous polyp diagnosis, and duration. PATIENTS: Consecutive patients referred for colonoscopy from 21 centres in 11 countries. METHODS: This prospective observational study used multiple variable regression analyses to identify determinants of the quality indicators. RESULTS: Six thousand and four patients were included in the study. Patients from private, open-access centres (odds ratio: 3.17, 95% confidence interval: 1.87-5.38) were more likely to have a complete colonoscopy than patients from public, gatekeeper centres. Patients from centres where over 50% of the endoscopists were of senior rank were roughly twice as likely to have an adenoma diagnosed, and longer average withdrawal duration (odds ratio: 1.08, 95% confidence interval: 1.07-1.09) was associated with more frequent adenoma diagnoses. Patients who had difficulty during colonoscopy had longer durations to caecum (time ratio: 2.87, 95% confidence interval: 2.72-3.01) and withdrawal durations (time ratio: 1.26, 95% confidence interval: 1.18-1.33) than patients who had no difficulties. CONCLUSIONS: Multiple factors have been identified as being associated with key quality indicators. The non-modifiable factors permit the identification of patients who may be at greater risk of not having quality colonoscopy, while changes to the modifiable factors may help improve the quality of colonoscopy.

The appropriateness of colonoscopy: a multi-center, international, observational study.

OBJECTIVE: To examine the appropriateness and necessity of colonoscopy across Europe. DESIGN: Prospective observational study. SETTING: A total of 21 gastrointestinal centers from 11 countries. PARTICIPANTS: Consecutive patients referred for colonoscopy at each center. INTERVENTION: Appropriateness criteria developed by the European Panel on the Appropriateness of Gastrointestinal Endoscopy, using the RAND appropriateness method, were used to assess the appropriateness of colonoscopy. MAIN OUTCOME MEASURE: Appropriateness of colonoscopy. RESULTS: A total of 5213 of 6004 (86.8%) patients who underwent diagnostic colonoscopy and had an appropriateness rating were included in this study. According to the criteria, 20, 26, 27, or 27% of colonoscopies were judged to be necessary, appropriate, uncertain, or inappropriate, respectively. Older patients and those with a major illness were more likely to have an appropriate or necessary indication for colonoscopy as compared to healthy patients or patients who were 45-54 years old. As compared to screening patients, patients who underwent colonoscopy for iron-deficiency anemia [OR: 30.84, 95% CI: 19.79-48.06] or change in bowel habits [OR: 3.69, 95% CI: 2.74-4.96] were more likely to have an appropriate or necessary indication, whereas patients who underwent colonoscopy for abdominal pain [OR: 0.64, 95% CI: 0.49-0.83] or chronic diarrhea [OR: 0.54, 95% CI: 0.40-0.75] were less likely to have an appropriate or necessary indication. CONCLUSIONS: This study identified significant proportions of inappropriate colonoscopies. Prospective use of the criteria by physicians referring for or performing colonoscopies may improve appropriateness and quality of care, especially in younger patients and in patients with nonspecific symptoms.

Current sedation and monitoring practice for colonoscopy: an International Observational Study (EPAGE).

BACKGROUND AND STUDY AIMS: Sedation and monitoring practice during colonoscopy varies between centers and over time. Knowledge of current practice is needed to ensure quality of care and help focus future research. The objective of this study was to examine sedation and monitoring practice in endoscopy centers internationally. PATIENTS AND METHODS: This observational study included consecutive patients referred for colonoscopy at 21 centers in 11 countries. Endoscopists reported sedation and monitoring practice, using a standard questionnaire for each patient. RESULTS: 6004 patients were included in this study, of whom 53 % received conscious/moderate sedation during colonoscopy, 30 % received deep sedation, and 17 % received no sedation. Sedation agents most commonly used were midazolam (47 %) and opioids (33 %). Pulse oximetry was done during colonoscopy in 77 % of patients, blood pressure monitoring in 34 %, and electrocardiography in 24 %. Pulse oximetry was most commonly used for moderately sedated patients, while blood pressure monitoring and electrocardiography were used predominantly for deeply sedated patients. Sedation and monitoring use ranged from 0 % to 100 % between centers. Oxygen desaturation (

Gastroenterologists overestimate the appropriateness of colonoscopies they perform: an international observational study.

BACKGROUND AND STUDY AIM: Little is known about how gastroenterologists perceive the appropriateness of colonoscopies they perform. The objective of this study was to compare the appropriateness and necessity of colonoscopies as assessed by an expert panel and by the gastroenterologists performing the colonoscopies. METHODS: This observational study included 21 centers in 11 countries. Patients referred for colonoscopy were consecutively included. Appropriateness and necessity of colonoscopies were independently rated on a 9-point scale by the gastroenterologists performing them and by an expert panel using a validated method (RAND). The differences between the ratings from the two groups were examined. RESULTS: 6004 patients were included in the study. Comparisons of ratings were possible for 5381 (89.6 %) patients. The gastroenterologists' mean appropriateness rating was 7.2 +/- 1.7, and the panel's mean appropriateness rating was 5.4 +/- 2.3 ( P < 0.001). The percentages of indications rated inappropriate, uncertain, appropriate, and necessary were 4.1 %, 23.8 %, 14.2 %, and 58.0 % for the gastroenterologists and 27.2 %, 26.7 %, 25.0 %, and 21.1 % for the panel, respectively. Agreement between the two groups' ratings was poor (28.8 %, kappa = 0.11). Differences between the two groups' ratings decreased with increasing patient age, decreasing health status, and decreasing expertise level of the referring physician. However, the gastroenterologists produced consistently higher ratings. CONCLUSIONS: Compared with an expert panel, gastroenterologists tend to overestimate the appropriateness of colonoscopies they perform. Except for well-delineated reasons, participating gastroenterologists weighed patient characteristics differently from the panel when judging appropriateness. Ways to increase the prospective use of appropriateness criteria in order to improve appropriateness and reduce overuse of colonoscopies should be examined further.

Evaluation and refinement of tmRNA structure using gene sequences from natural microbial communities.

DNA harvested directly from complex natural microbial communities by PCR has been successfully used to predict RNase P RNA structure, and can potentially provide an abundant source of information for structural predictions of other RNAs. In this study, we utilized genetic variation in natural communities to test and refine the secondary and tertiary structural model for the bacterial tmRNA. The variability of proposed tmRNA secondary structures in different organisms and the lack of any predicted tertiary structure suggested that further refinement of the tmRNA could be useful. To increase the phylogenetic representation of tmRNA sequences, and thereby provide additional data for statistical comparative analysis, we amplified, sequenced, and compared tmRNA sequences from natural microbial communities. Using primers designed from gamma proteobacterial sequences, we determined 44 new tmRNA sequences from a variety of environmental DNA samples. Covariation analyses of these sequences, along with sequences from cultured organisms, confirmed most of the proposed tmRNA model but also provided evidence for a new tertiary interaction. This approach of gathering sequence information from natural microbial communities seems generally applicable in RNA structural analysis.

Utility of a demographic equation in detecting impaired NART performance after TBI.

OBJECTIVES: This study applies a demographic regression equation devised by Crawford, Allan, Cochrane, and Parker (1990) to determine its utility in New Zealand, and to determine the proportion of persons with traumatic brain injury (TBI) with impaired performance on the National Adult Reading Test (NART). METHOD: The NART was administered to 80 community participants, 65 people with traumatic brain injury (TBI), and 27 orthopaedic controls. The Crawford et al. (1990) equation was applied to all three samples. RESULTS: The Crawford et al. (1990) equation was applicable in the New Zealand community sample. It was found that 30% of the TBI sample had impaired performance on the NART. Using corrected NART scores, a significantly larger proportion of the TBI sample was detected as intellectually impaired than in the control sample. CONCLUSION: Nearly one-third of the TBI sample evidenced impaired performance on the NART. Consequently, clinicians that use the NART in assessing people with TBI should use the demographic equation to check the accuracy of NART performances, and correct the NART scores if this is indicated.

Caregiver depression following traumatic brain injury (TBI): a consequence of adverse effects on family members?

Many studies have demonstrated that the behaviour of individuals with traumatic brain injury (TBI) predicts the emotional adjustment of their caregivers. The primary objective of the present study was to obtain an understanding of potential moderating and mediating variables between carer depression and analogous stressors. Seven sets of predictor variables (demographic variables, concurrent stressful life events, behavioural problems, social role problems, extent of adverse effects on family members, appraisal, and support) and the criterion variable of depression in caregivers were examined. Fifty-eight carers participated in the study at 6 months, 1 year, 2 years, or 3 years following injury. The number of adverse effects on family members (other than the informant) was the only stressor significantly related to carer depression. However, carer appraisal of adverse family effects was found to mediate the relationship between stressor and depression, and carer perception of support effectiveness was found to moderate the effect of adverse family effects on depression. Forty-six per cent of the variance in caregiver depression was accounted for by carers appraisal of adverse family effects and the interaction of adverse family effects and support effectiveness. These findings highlight the importance of supporting families as a whole in the rehabilitation of persons with TBI.

New insight into RNase P RNA structure from comparative analysis of the archaeal RNA.

A detailed comparative analysis of archaeal RNase P RNA structure and a comparison of the resulting structural information with that of the bacterial RNA reveals that the archaeal RNase P RNAs are strikingly similar to those of Bacteria. The differences between the secondary structure models of archaeal and bacterial RNase P RNA have largely disappeared, and even variation in the sequence and structure of the RNAs are similar in extent and type. The structure of the cruciform (P7-11) has been reevaluated on the basis of a total of 321 bacterial and archaeal sequences, leading to a model for the structure of this region of the RNA that includes an extension to P11 that consistently organizes the cruciform and adjacent highly-conserved sequences.

Stereotactic proton beam therapy of skull base meningiomas.

PURPOSE: To review outcomes for patients with skull base meningiomas treated using the stereotactic proton beam at the National Accelerator Center (NAC), Republic of South Africa. METHODS AND MATERIALS: Since 1993, 27 patients with intracranial meningiomas have been treated stereotactically with protons at NAC. Of those, 23 were located on the skull base, were large or had complex shapes, and were treated with radical intent. Both stereotactic radiotherapy (SRT, 16 or more fractions) and hypofractionated stereotactic radiotherapy (HSRT, 3 fractions) were used. Eighteen patients underwent proton HSRT, while 5 patients were treated with SRT. The mean target volume for the HSRT group was 15.6 cm(3) (range 2.6-63 cm(3)). The mean ICRU reference dose was 20.3 cobalt Gray equivalent (CGyE), and the mean minimum planning target dose was 16.3 CGyE. The mean clinical and radiologic follow-up periods were 40 and 31 months respectively. The mean volume in the SRT group was 43.7 cm(3), with ICRU reference doses ranging from 54 CGyE in 27 fractions to 61.6 CGyE in 16 fractions. RESULTS: In the HSRT group, 16/18 (89%) of patients remained clinically stable or improved, while 2/18 (11%) deteriorated. Radiologic control was achieved in 88% of patients, while 2 patients had a marginal failure. Among the 5 SRT patients, 2 were clinically better, and 3 remained stable. All SRT patients achieved radiologic control. Three patients (13%), 2 of them in the HSRT group, suffered permanent neurologic deficits. Analyzing different dose/fractionation schedules, an alpha/beta value of 3.7 Gy for meningiomas is estimated. CONCLUSION: Proton irradiation is effective and safe in controlling large and complex-shaped skull base meningiomas.

Spontaneous pneumothorax: is it under tension?

A diagnosis of tension pneumothorax is usually only considered within the context of trauma, incorrect chest drain insertion or positive pressure ventilation. Four patients are presented who developed spontaneous tension pneumothorax with no precipitating factors. In three of these instances, the diagnosis was only made radiologically and in every case the treating physician was unaware that a spontaneous tension pneumothorax could occur. Previously, emphasis has been placed on tracheal deviation in a tension pneumothorax. However, this is an inconsistent finding as one of the cases highlights. Patients may appear surprisingly clinically well until they decompensate. These cases are highlighted to raise awareness of this potentially life threatening condition.

Expanding the known diversity and environmental distribution of an uncultured phylogenetic division of bacteria.

Culture-independent molecular phylogenetic methods were used to explore the breadth of diversity and environmental distribution of members of the division-level "candidate" phylogenetic group WS6, recently discovered in a contaminated aquifer and with no cultivated representatives. A broad diversity of WS6-affiliated sequences were cloned from 7 of 12 environments investigated: mainly from anaerobic sediment environments. The number of sequences representing the WS6 candidate division was increased from 3 to 60 in this study. The extent of phylogenetic divergence (sequence difference) in this candidate division was found to be among the largest of any known bacterial division. This indicates that organisms representing the WS6 phylogenetic division offer a broad diversity of undiscovered biochemical and metabolic novelty. These results provide a framework for the further study of these evidently important kinds of organisms and tools, the sequences, with which to do so.

RNase P RNAs from some Archaea are catalytically active.

The RNA subunits of RNase Ps of Archaea and eukaryotes have been thought to depend fundamentally on protein for activity, unlike those of Bacteria that are capable of efficient catalysis in the absence of protein. Although the eukaryotic RNase P RNAs are quite different than those of Bacteria in both sequence and structure, the archaeal RNAs generally contain the sequences and structures of the bacterial, phylogenetically conserved catalytic core. A spectrum of archaeal RNase P RNAs were therefore tested for activity in a wide range of conditions. Many remain inactive in ionically extreme conditions, but catalytic activity could be detected from those of the methanobacteria, thermococci, and halobacteria. Chimeric holoenzymes, reconstituted from the Methanobacterium RNase P RNA and the Bacillus subtilis RNase P protein subunits, were functional at low ionic strength. The properties of the archaeal RNase P RNAs (high ionic-strength requirement, low affinity for substrate, and catalytic reconstitution by bacterial RNase P protein) are similar to synthetic RNase P RNAs that contain all of the catalytic core of the bacterial RNA but lack phylogenetically variable, stabilizing elements.

Structure and evolution of ribonuclease P RNA in Gram-positive bacteria.

The sequences and structures of RNase P RNAs of some Gram-positive bacteria, e.g. Bacillus subtilis, are very different than those of other bacteria. In order to expand our understanding of the structure and evolution of RNase P RNA in Gram-positive bacteria, gene sequences encoding RNase P RNAs from 10 additional species from this evolutionary group have been determined, doubling the number of sequences available for comparative analysis. The enlarged data set allows refinement of the secondary structure model of these unusual RNase P RNAs and the identification of potential tertiary interactions between P10.1 and L12, and between L5.1 and L15.1. The newly-obtained sequences suggest that RNase P RNA underwent an abrupt, dramatic restructuring in the ancestry of the low-G+C Gram-positive bacteria after the divergence of the branches leading to the 'Clostridia and relatives' and the remaining low-G+C Gram-positive species. The unusual structures of the RNase P RNAs of Mycoplasma hyopneumoniae and M.floccularre are apparently derived from RNAs with Bacillus-like structure rather than from intermediate, partially restructured ancestral RNAs. The structure of the RNase P RNA from the photosynthetic Heliobacillus mobilis supports the relationship of this specie with Bacillus and Staphylococcus rather than the 'Clostridia and relatives' as suggested by the sequences of their small-subunit ribosomal RNAs.

The role of emergency surgery in malignant spinal extradural compression: assessment of functional outcome.

The role of emergency surgery for spinal cord or cauda equina compression secondary to extradural metastases is assessed in terms of functional outcome in 84 cases. The records of patients with proven malignant extradural spinal compression were reviewed retrospectively to determine the influence of emergency versus elective decompressive surgery on functional outcome. A greater proportion undergoing emergency surgery, rather than electively (within 24 h) on the next list showed functional improvement, with recovered mobility (61.5% vs 25%). Overall, 70% of patients were mobile postoperatively. The findings suggest that despite initial delays in referral, and even if the patient is incontinent and immobile, emergency spinal decompression is justified.

A perinatal continuing education program: its effects on the knowledge and practices of health professionals.

OBJECTIVES: To determine whether there was an increase in knowledge when an interdisciplinary group of health care providers participated in the same comprehensive perinatal continuing education program and to determine whether care practices followed before the program differed from those followed 1 year after its completion. DESIGN: Administration of a 100-item comprehensive pretest and a similar posttest measuring knowledge before the continuing education program and 1 year after taking it, as well as an ex post facto audit of medical records of newborns who were sick and at risk. SETTING: Hospitals throughout the state of Oklahoma that provide perinatal care. Test data were derived from health care providers in 24 hospitals; data on care practices were obtained from 12 hospitals. INTERVENTION: A comprehensive program of perinatal continuing education. PARTICIPANTS: Physicians, nurses, and other providers of perinatal health care. MAIN OUTCOME MEASURES: Scores on a 100-item test measuring knowledge of perinatal care and newborn care practices taught in the educational program. RESULTS: Pretest and posttest scores demonstrated an increase in scores at the p < 0.001 level for each group of providers studied. There was a statistically significant increase in use of two care practices and a definite trend toward an increase in the use of three others. CONCLUSION: A continuing education program delivered to a multidisciplinary group of health care providers can increase knowledge and improve perinatal care to newborns who are sick and at risk.

Mottled cyan opacification of the posterior cornea in contact lens wearers.

PURPOSE: We studied patients who had mottled cyan-colored opacities of the cornea to better understand the cause and prognosis of this entity. METHODS: We reviewed examinations of patients who had a mottled cyan opacification of the cornea. Risk factors, including contact lens wear and exposure to heavy metals, were analyzed. Clinical findings, pachymetry specular microscopy, and progression of the abnormality were noted. RESULTS: Six patients who had a mottled cyan opacification at the level of Descemet's membrane were identified. These opacities were located in the peripheral and midperipheral cornea. All patients had bilateral findings, had visual acuities of 20/20 or better, and were asymptomatic. All patients had worn soft contact lenses bilaterally for periods ranging from seven to 14 years. CONCLUSION: All patients had the similar clinical appearance of a mottled cyan opacification at the level of Descemet's membrane in the peripheral cornea. Long-term contact lens wear appears to be associated; however, the exact cause is unclear.

Dietary and physical activity correlates of long-term weight loss.

Covariations in body mass index (BMI), physical activity, macronutrient intake, and the frequency of consumption of specific foods were examined among 82 men and 75 women participating in a behavioral weight loss program over a period of 18 months. Results of repeated measures analyses of covariance showed that BMI change was inversely related to change in physical activity and change in frequency of vegetable consumption. BMI change was positively related to change in calorie intake from fat and change in frequency of consumption of beef, hot dogs, and sweets. Change in fat calories predicted BMI change better than change in total calories. In addition, change in the frequency of consumption of specific foods accounted for a larger percentage of the variance in BMI change than did change in macronutrients (10.4% vs. 5.2%). No differences were found between predictors of weight loss vs. weight maintenance.