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Larger effect sizes were associated with higher quality ratings in complementary and alternative medicine randomized controlled trials.

OBJECTIVE: To determine if the quality of complementary and alternative medicine (CAM) placebo controlled randomized controlled trials (RCTs) is related to the effect sizes they produce when the type of interventions and outcome variables are controlled. STUDY DESIGN AND SETTING: A sample of 25 CAM meta-analyses was identified from MEDLINE and hand searches containing published effect sizes for at least three efficacy trials employing placebo control groups. From these 25 reviews, 26 pairs of trials were selected: the one reporting the largest effect size and the matching trial reporting the smallest effect size. Quality and publication characteristics were then abstracted from each trial. RESULTS: Unlike the preponderance of past evidence examining the relationship between quality and effect size, the present study found that trials possessing the largest effect sizes within a meta-analysis were also associated with higher quality ratings than their counterparts possessing the lowest effect sizes (P=.019). CONCLUSIONS: Possible theoretical reasons for this unexpected positive relationship include (a) sampling error, (b) reduced within group variation, (c) fraudulent reporting, and (d) the restriction of the analyses to placebo controlled trial.

Complementary Therapies↗

Uncertainty method improved on best-worst case analysis in a binary meta-analysis.

BACKGROUND: Most systematic reviewers aim to perform an intention-to-treat meta-analysis, including all randomized participants from each trial. This is not straightforward in practice: reviewers must decide how to handle missing outcome data in the contributing trials. OBJECTIVE: To investigate methods of allowing for uncertainty due to missing data in a meta-analysis. STUDY DESIGN AND SETTING: The Cochrane Library was surveyed to assess current use of imputation methods. We developed a methodology for incorporating uncertainty, with weights assigned to trials based on uncertainty interval widths. The uncertainty interval for a trial incorporates both sampling error and the potential impact of missing data. We evaluated the performance of this method using simulated data. RESULTS: The survey showed that complete-case analysis is commonly considered alongside best-worst case analysis. Best-worst case analysis gives an interval for the treatment effect that includes all of the uncertainty due to missing data. Unless there are few missing data, this interval is very wide. Simulations show that the uncertainty method consistently has better power and narrower interval widths than best-worst case analysis. CONCLUSION: The uncertainty method performs consistently better than best-worst case imputation and should be considered along with complete-case analysis whenever missing data are a concern.

Antimalarials↗

Rapid assay for quantitative measurement of apoptosis in cultured cells and brain tissue.

Analysis of apoptosis in brain tissue following ischemia, hypoxia, or oxidative stress has technical limitations. The use of counting cells displaying apoptotic morphology is time intensive, vulnerable to sampling errors, and suffers from low numbers of total recorded events. Other cell death assays such as agarose gel analysis of DNA fragmentation, TUNEL, or ELISA are time intensive, limited to a single endpoint measure, and can be technically difficult to perform or reproduce. To overcome these limitations, we set out to develop a technique using flow cytometry to measure apoptosis based on the physical properties of light scatter produced from isolated nuclei. This dye/marker free approach would bypass many of the inherent encumbrances and reproducibility problems found in other apoptosis assays. Here we demonstrate that this new technique, using flow cytometry performed on isolated nuclei, allows rapid quantitation of apoptosis in a variety of brain tissues without the need for intercalating dyes or fluorescent markers. We conclude that this technique significantly improves currently available protocols to quantify apoptosis from tissue and offers the possibility to perform additional analysis on the same population of nuclei via downstream assays.

Animals↗

The attitude of gynecologists in São Paulo, Brazil 3 years after the Women's Health Initiative study.

OBJECTIVE: The objective of this study was to evaluate gynecologists' knowledge of the WHI study, and its repercussions on their attitudes and practice 3 years after publication. DESIGN: A self-administered, anonymous questionnaire containing 19 questions was sent to 6000 gynecologists, members of the São Paulo Society of Obstetrics and Gynecology. RESULTS: The response rate was 24.2% (1453 completed questionnaires) with a sample error of 2.23% and confidence level of 95%. Although 95.9% of the respondents were aware of the WHI study, only 24.4% knew of all the other studies mentioned (HERS I, HERS II and Million Women Study). Although 84.6% stated that the results of the WHI study could not be extrapolated to other forms of HT, 23.1% and 25.2%, respectively, stopped prescribing CEE or MPA, 63.7% decreased the dose, 55.2% opted for drugs such as bisphosphonates, tibolone and SERMS, and 46.3% began to prescribe tranquilizers, isoflavone and other natural medications. Moreover, 59.2% agreed that HT should be used for only 4-5 years. Prescriptions decreased significantly for all indications (p<0.0001). The principal reason for physicians to discontinue HT in a patient was increased risk of breast cancer (62.3%), whereas, according to the physicians, the most important factor for the patients was fear of HT (80.3%). CONCLUSION: A high percentage of gynecologists in this study knew of the WHI study and followed its recommendations concerning cardiovascular prevention; consequently they changed their management of the treatment of postmenopausal women by restricting indications for HT and decreasing its duration of use and dose.

Adult↗

High-definition and 3-dimensional imaging of macular pathologies with high-speed ultrahigh-resolution optical coherence tomography.

OBJECTIVE: To assess high-speed ultrahigh-resolution optical coherence tomography (OCT) image resolution, acquisition speed, image quality, and retinal coverage for the visualization of macular pathologies. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Five hundred eighty-eight eyes of 327 patients with various macular pathologies. METHODS: High-speed ultrahigh-resolution OCT images were obtained in 588 eyes of 327 patients with selected macular diseases. Ultrahigh-resolution OCT using Fourier/spectral domain detection achieves approximately 3-mum axial image resolutions, acquisition speeds of approximately 25 000 axial scans per second, and >3 times finer resolution and >50 times higher speed than standard OCT. Three scan protocols were investigated. The first acquires a small number of high-definition images through the fovea. The second acquires a raster series of high-transverse pixel density images. The third acquires 3-dimensional OCT data using a dense raster pattern. Three-dimensional OCT can generate OCT fundus images that enable precise registration of OCT images with the fundus. Using the OCT fundus images, OCT results were correlated with standard ophthalmoscopic examination techniques. MAIN OUTCOME MEASURES: High-definition macular pathologies. RESULTS: Macular holes, age-related macular degeneration, epiretinal membranes, diabetic retinopathy, retinal dystrophies, central serous chorioretinopathy, and other pathologies were imaged and correlated with ophthalmic examination, standard OCT, fundus photography, and fluorescein angiography, where applicable. High-speed ultrahigh-resolution OCT generates images of retinal pathologies with improved quality, more comprehensive retinal coverage, and more precise registration than standard OCT. The speed preserves retinal topography, thus enabling the visualization of subtle changes associated with disease. High-definition high-transverse pixel density OCT images improve visualization of photoreceptor and pigment epithelial morphology, as well as thin intraretinal and epiretinal structures. Three-dimensional OCT enables comprehensive retinal coverage, reduces sampling errors, and enables assessment of 3-dimensional pathology. CONCLUSIONS: High-definition 3-dimensional imaging using high-speed ultrahigh-resolution OCT improves image quality, retinal coverage, and registration. This new technology has the potential to become a useful tool for elucidating disease pathogenesis and improving disease diagnosis and management.

Adult↗

Histopathologic and cytopathologic diagnostic discrepancies in head and neck region: pitfalls, causes, and preventive strategies.

BACKGROUND: Clinicians commonly utilize fine needle aspiration biopsy (FNAB) for the primary investigation of head and neck masses. Correlation of these results with the surgical resection diagnosis is an essential part of quality control and assurance programs in all cytology laboratories. METHODS: Of 610 cases, 20 (3.3%) had corresponding surgical resections performed within 3 months of the FNAB, with a discrepant diagnosis identified through a search that involved all FNABs performed on the head and neck region, excluding the thyroid gland, at Wayne State University between 1999 and 2004. Sites of discrepant samples included the parotid or submandibular gland (n = 5), lymph nodes (n = 8), and paratracheal/paraesophageal neck masses (n = 7). RESULTS: The reasons of false-negative FNABs included sampling errors (n = 3), insufficient material for an adequate interpretation (n = 5), lack of triage necessary for ancillary studies (n = 4), and interpretation errors (n = 6). There were 2 false-positive FNABs, both reported as mucoepidermoid carcinoma and showed chronic sialadenitis in one and lymphoepithelial cyst in the other. CONCLUSIONS: FNAB is an effective tool for the diagnosis and triage of patients with head and neck masses that can be further improved with an onsite immediate adequacy evaluation and triage performed by a pathologist.

Biopsy, Fine-Needle↗

Ultrasonography for the endocrine surgeon: a valuable clinical tool that enhances diagnostic and therapeutic outcomes.

BACKGROUND: Surgeon-performed ultrasonography (U/S) has revolutionized many subspecialties by broadening the diagnostic and interventional scope of practice. We report our experience on the impact of surgeon-performed U/S in an endocrine surgery practice. METHODS: Prospectively maintained records of patients from November 1999 to November 2004 were reviewed to establish patterns and outcomes of U/S practice. Surgeon-performed neck U/S was done routinely at the initial clinic visit and incorporated into resident/fellow education. RESULTS: A total of 5703 U/S were performed on endocrine patients with thyroid 42%, parathyroid 57%, and adrenal 1% disorders. Diagnostic fine-needle aspiration biopsy (FNA) was achieved with low sampling errors (<7%). When U/S identified thyroid nodules coexisting with hyperparathyroidism, preoperative FNA correctly established benign thyroid diagnosis and minimized need for thyroidectomy. U/S successfully imaged abnormal parathyroid glands when (99)Tc-sestamibi scans were negative. U/S data significantly changed treatment plans in nearly two thirds of thyroid cancer patients. Surgical residents readily mastered essential U/S skills. CONCLUSIONS: Surgeon-performed U/S is a highly specific tool for identification of endocrine disease in the neck. It is learned readily and performed accurately, and functions as an informative extension of physical examination. Because it substantially benefits patient care and impacts surgical decision making, neck U/S is recommended highly as a valuable adjunct to endocrine surgical practice.

Ambulatory Care↗

Predictive models for protein crystallization.

Crystallization of proteins is a nontrivial task, and despite the substantial efforts in robotic automation, crystallization screening is still largely based on trial-and-error sampling of a limited subset of suitable reagents and experimental parameters. Funding of high throughput crystallography pilot projects through the NIH Protein Structure Initiative provides the opportunity to collect crystallization data in a comprehensive and statistically valid form. Data mining and machine learning algorithms thus have the potential to deliver predictive models for protein crystallization. However, the underlying complex physical reality of crystallization, combined with a generally ill-defined and sparsely populated sampling space, and inconsistent scoring and annotation make the development of predictive models non-trivial. We discuss the conceptual problems, and review strengths and limitations of current approaches towards crystallization prediction, emphasizing the importance of comprehensive and valid sampling protocols. In view of limited overlap in techniques and sampling parameters between the publicly funded high throughput crystallography initiatives, exchange of information and standardization should be encouraged, aiming to effectively integrate data mining and machine learning efforts into a comprehensive predictive framework for protein crystallization. Similar experimental design and knowledge discovery strategies should be applied to valid analysis and prediction of protein expression, solubilization, and purification, as well as crystal handling and cryo-protection.

Bayes Theorem↗

Sentinel node localization in breast cancer.

The status of the axillary nodes is the strongest known prognostic variable in patients with early breast cancer, and is routinely used in planning postoperative therapy. Conventional axillary lymph node dissection is limited by sampling error and potential morbidity. Sentinel node techniques have revolutionized the management of axillary nodes. Accurate identification and focused histologic evaluation of the sentinel node allow accurate prediction of the tumor status of other axillary nodes, thereby avoiding the morbidity and expense of a complete axillary dissection in node-negative patients. Radiotracer techniques play an important role in the preoperative and intraoperative localization of the sentinel nodes. Optimal localization of the sentinel node requires the use of both preoperative lymphoscintigraphy and intraoperative radiosensitive probes. Lymphoscintigraphy also identifies patients with lymphatic drainage to sites other than the axilla, thereby allowing more appropriate treatment and follow-up in this subset of patients. Procedures for localizing sentinel nodes require an understanding of the kinetics of the radiopharmaceuticals or other tracers used and the detection devices employed in each institution. Both surgical and nuclear medicine personnel should understand these principles, and close cooperation between surgeons, nuclear medicine physicians, and pathologists is essential for the application of sentinel node techniques.

Breast Neoplasms↗

Quantitative morphologic findings of the myocardium in idiopathic dilated cardiomyopathy.

This study assesses the relation between quantitative morphologic findings and left ventricular contractile function in patients with idiopathic dilated cardiomyopathy. Left ventricular endomyocardial catheter biopsy specimens were obtained from 73 patients during diagnostic heart catheterization. All patients had normal coronary arteriograms but abnormal electrocardiograms. Twenty-six patients had normal left ventricular function (ejection fraction greater than or equal to 55%), whereas 47 patients had contractile dysfunction (ejection fraction less than or equal to 54%). Myocardial fiber diameter, volume fraction of interstitial fibrosis, and intracellular volume fraction of myofibrils were determined by light microscopic morphometry. Results of light microscopic morphometry were confirmed by electron microscopic morphometry in 12 patients. The coefficient of variation (analysis of several biopsies from the same patient) was 6% for determination of fiber diameter, 43% for interstitial fibrosis, and 3% for volume fraction of myofibrils. Fiber diameter (r = -0.32, p less than 0.01) and fibrosis (r = -0.47, p less than 0.001) showed a negative correlation, the volume fraction of myofibrils (r = 0.55, p less than 0.001) and calculated myofibrillar mass per 100 g of myocardium (r = 0.64, p less than 0.001) a positive correlation with the ejection fraction. Thus, (1) sampling error is low for determination of fiber diameter and myofibrils but high for evaluation of fibrosis, and (2) a reduction in the volume fraction of myofibrils and an increase in fibrosis are morphologic correlates of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy.

Adult↗

Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence.

To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43% each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), HGD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN (22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.

Adenocarcinoma↗

Intraoperative analysis of sentinel lymph nodes by imprint cytology for cancer of the breast.

BACKGROUND: The utilization of lymphatic mapping techniques for breast carcinoma has made intraoperative evaluation of sentinel lymph nodes (SLN) attractive, because axillary lymph node dissection can be performed during the initial surgery if the SLN is positive. The optimal technique for rapid SLN assessment has not been determined. Both frozen sectioning and imprint cytology are used for rapid intraoperative SLN evaluation. METHODS: A retrospective review of the intraoperative imprint cytology results of 133 SLN mapping procedures from 132 breast carcinoma patients was performed. SLN were evaluated intraoperatively by bisecting the lymph node and making imprints of each cut surface. Imprints were stained with hematoxylin and eosin (H&E) and Diff-Quik. Permanent sections were evaluated with up to four H&E stained levels and cytokeratin immunohistochemistry. Imprint cytology results were compared with final histologic results. RESULTS: Sensitivity and specificity of imprint cytology were 56% and 100%, respectively, producing a 100% positive predictive value and 88% negative predictive value. Imprint cytology was significantly more sensitive for macrometastasis than micrometastasis 87% versus 22% (P = 0.00007). Of 13 total false negatives, 11 were found to be due to sampling error and 2 due to errors in intraoperative interpretation. Both intraoperative interpretation errors involved a diagnosis of lobular breast carcinoma. CONCLUSIONS: The sensitivity and specificity of imprint cytology are similar to that of frozen section evaluation. Imprint cytology is therefore a viable alternative to frozen sectioning when intraoperative evaluation is required. If SLN micrometastasis is used to determine the need for further lymphadenectomy, more sensitive intraoperative methods will be needed to avoid a second operation.

Adult↗

Pulmonary function and dyspnea/suffocation theory of panic.

This article presents a brief discussion of pulmonary function and panic attacks in the context of respiratory psychophysiology. Ley's (Behaviour Research and Therapy, 27, 549-554, 1989) earlier dyspnea/suffocation theory of panic is contrasted with Klein's (Archives of General Psychiatry, 50, 306-316, 1993) later false suffocation alarm theory. The distinction between "dyspnea" (the sensation of difficulty in breathing) and "suffocation" (a condition that sometimes gives rise to dyspnea) is emphasized. The brief discussion is followed by a critical comparison of two recent studies on pulmonary function and panic. Asmundson and Stein (Journal of Anxiety Disorders, 8, 63-69, 1994) reported an association between forced expiratory flow rate (a measure of pulmonary function) in panic disorder patients and the severity of panic-related symptoms. They interpreted their findings as support for the dyspnea/suffocation theory of panic since severity of dyspnea is a consequence of pulmonary function. Spinhoven et al. (Behaviour Research and Therapy, 33, 457-460, 1995) failed to replicate the findings of Asmundson and Stein. The present paper provides a critical analysis of the study by Spinhoven et al. and concludes that the failed attempt to replicate may have been a consequence of a flawed methodology (the subjects of the two studies are not comparable on a crucial pulmonary test) and a statistical anomaly (disproportionately small differences between means that exceed predictions based on sampling error). A recommendation is made that future attempts to replicate should pay special care to avoid the possibility of experimenter-demand effects.

Asphyxia↗

Radiologically-guided cutting needle biopsy for suspected malignancy in childhood.

Twenty-seven cutting needle biopsies were performed on 25 children with suspected malignancy using computed tomographic (CT, 22) or ultrasound (US, 5) guidance. Anatomical sites were: retroperitoneum 6, liver 4, kidney 4, abdomen/pelvis 4, thorax 4, bowel 2, neck 1. Sixteen patients (64%) underwent subsequent open biopsy (5), marrow biopsy (2) or resection (9). There was complete concordance between the histological findings from the open or marrow biopsy and the previous needle biopsy in 12 of these 16 patients; in two patients the needle biopsy was misleading, causing inappropriate initial treatment in one. In two other patients needle biopsy was correct but lacked specific diagnostic features. Needle biopsies were performed under general, local or Ketamine anaesthesia. There were no apparent complications related to these procedures. We believe that radiologically-guided cutting needle biopsy should replace open biopsy in most children with solid malignant lesions. It can easily be performed during a single anaesthetic episode which allows radiological evaluation, biopsy, bone marrow and cerebrospinal fluid sampling. However, the potential for sampling error and histological variation within these tumours needs to be borne in mind.

Adolescent↗

Ductal carcinoma in situ presenting as a stellate lesion on mammography.

Ductal carcinoma in situ (DCIS) usually manifests as microcalcification on mammography, but several other unusual forms of presentation on mammography are also described. One such atypical appearance is the stellate mass without calcification. This may occur with DCIS alone or when DCIS is associated with a complex sclerosing lesion (CSL). We retrospectively analysed the histopathological specimens and mammograms of women who were referred for biopsy from two large breast screening programmes, and were found to have DCIS as the dominant histological lesion. Of 677 women referred for surgical biopsy, 86 (13%) showed histological evidence of DCIS as the predominant lesion, and of these, seven (8%) showed a stellate appearance on mammography without associated calcification. In three cases the mammographic appearance was due to DCIS alone, and four were due to a CSL with associated DCIS. Only one case showed microinvasion (< 1 mm), and this was not large enough to account for the stellate lesion. We advocate biopsy of all radial lesions which are not surgical scars, as malignancy associated with benign lesions such as CSLs could be missed by cytological sampling errors.

Aged↗

Characterization of a computerized semen analysis system.

In the present studies we have evaluated the optimal operating conditions for the Hamilton-Thorn HTM-2000 computerized semen analyzer (Hamilton-Thorn, Danvers, MA). The best reproducibility in measurement of sperm concentration was obtained using 20 frames acquired at 19 frames/s. The measurement of sperm concentration was not adversely affected by the number of fields analyzed. The intrasample and intersample coefficients of variation for sperm concentration were 9.5% and 25.5%; sperm motility, 18.4% and 28.9%; lateral head displacement, 16.5% and 19.9%; path velocity, 6.8% and 13.9%; progressive velocity, 4.5% and 9.9%; and linear index, 2.5% and 4.2%; respectively. These differences suggest that sampling error has a significant influence on the reliability of sperm evaluation. The precision and rapidity of the HTM-2000 compares favorably with data previously reported from other systems available for clinical semen analysis.

Diagnosis, Computer-Assisted↗

An immuno-polymerase chain reaction assay for human interleukin-18.

Conventional enzyme-linked immunosorbent assays (ELISA) are sufficient to measure normal and elevated serum interleukin (IL)-18 concentrations, but have limited sensitivity when measuring low concentrations of IL-18 such as in patients with the acquired immunodeficiency syndrome. We have developed a highly sensitive method for detecting human (h) IL-18 using an immuno-polymerase chain reaction (PCR). A mouse monoclonal anti-hIL-18 antibody and rabbit polyclonal anti-hIL-18 antibody was used for an indirect sandwich ELISA with a detection limit of 40 ng/l and a very low background. For immuno-PCR, biotinylated DNA was produced from the plasmid Bluescript by PCR amplification with biotinylated M13-20 primer and nonbiotinylated M13 reverse primer. Immuno-PCR for hIL-18 was performed for 40 cycles using 1 ng/l of biotinylated DNA. This immuno-PCR has a detection limit of 2.5 pg/l, 1.6x10(4) times lower than that of the ELISA. In addition, our system avoids sampling error caused by heat transfer from the ELISA plate to the PCR tube because all procedures from immobilization of the antibody to PCR amplification can be performed in the same tube. This immuno-PCR for hIL-18 is the most sensitive method for detecting hIL-18 reported to date.

Animals↗

Dynamic trend monitoring of cerebral blood flow velocity in newborn infants.

A method for obtaining reproducible Doppler cerebral blood flow velocity (CBFV) measurements over several hours, utilizing a probe fixation technique and an on-line system for making beat-to-beat area under the curve (AUC) measurements, is described. Thirty heartbeat samples were collected at three time intervals over 3 hours in a group of 22 healthy preterm infants. The stability of the AUC measurements despite changes in behavioral state was demonstrated by randomized block ANOVA. The sampling error was +/- 6.92%, with 95% confidence intervals of +/- 13.1%. By facilitating reproducible serial measurements of CBFV, this trend monitoring technique encourages a dynamic view of cerebrovascular control, and may be used to probe central nervous system autoregulatory pathophysiology and to evaluate the effects of therapeutic interventions.

Blood Flow Velocity↗