Risk of Bias Assessments and Evidence Syntheses for Observational Epidemiologic Studies of Environmental and Occupational Exposures: Strengths and Limitations.

BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis. https://doi.org/10.1289/EHP6980.

Translocation of a gut pathobiont drives autoimmunity in mice and humans.

Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and T cells. Hepatocyte-E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum-specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.

A systematic review of distal interphalangeal joint arthrodesis.

Arthrodesis of the distal interphalangeal joint of the hand is a reliable procedure for creating a painless stable joint. Numerous techniques are described within the literature for varying indications. We undertook a systematic review of all studies published within the English literature to provide a comparison of the different techniques. The published studies were predominantly of Level IV evidence. The most commonly employed techniques were Kirschner wire, headless compression screw and cerclage wires. There was no difference in infection rates. Headless compression screws appear to have increased union rates but are associated with complications not seen with other well-established and cheaper techniques. The screw diameter is often similar to or larger than the joint itself, which can result in penetration. Furthermore, they limit the available angle for achieving fusion. Other than in terms of union, there is insufficient evidence to show the headless compression screw is superior to other techniques.

Comparative outcome of arthroscopic release for frozen shoulder in patients with and without diabetes.

Our aim was to compare the outcome of arthroscopic release for frozen shoulder in patients with and without diabetes. We prospectively compared the outcome in 21 patients with and 21 patients without diabetes, two years post-operatively. The modified Constant score was used as the outcome measure. The mean age of the patients was 54.5 years (48 to 65; male:female ratio: 18:24), the mean pre-operative duration of symptoms was 8.3 months (6 to 13) and the mean pre-operative modified Constant scores were 36.6 (standard deviation (sd) 4.6) and 38.4 (sd 5.7) in the diabetic and non-diabetic groups, respectively. The mean modified Constant scores at six weeks, six months and two years post-operatively in the diabetics were 55. 6 (sd 4.7), 67. 4 (sd 5.6) and 84. 4 (sd 6.8), respectively; and in the non-diabetics 66.8 (sd 4.5), 79.6 (sd 3.8) and 88.6 (sd 4.2), respectively. A total of 15 (71%) of diabetic patients recovered a full range of movement as opposed to 19 (90%) in the non-diabetics. There was significant improvement (p < 0.01) in the modified Constant scores following arthroscopic release for frozen shoulder in both groups. The results in diabetics were significantly worse than those in non-diabetics six months post-operatively (p < 0.01) with a tendency towards persistent limitation of movement two years after operation. These results may be used when counselling diabetic patients for the outcome after arthroscopic treatment of frozen shoulder.

Application of support vector machine for the detection of P- and T-waves in 12-lead electrocardiogram.

Electrocardiogram (ECG) is characterized by a recurrent wave sequence of P, QRS and T-wave associated with each beat. The performance of the computer-aided ECG analysis systems depends heavily upon the accurate and reliable detection of these component waves. This paper presents an efficient method for the detection of P- and T-waves in 12-lead ECG using support vector machine (SVM). Digital filtering techniques are used to remove power line interference and base line wander. SVM is used as a classifier for the detection of P- and T-waves. The algorithm is validated using original simultaneously recorded 12-lead ECG recordings from the standard CSE ECG database. Significant detection rate of 95.43% is achieved for P-wave detection and 96.89% for T-wave detection. The method successfully detects all kind of morphologies of P- and T-waves. The on-sets and off-sets of the detected P- and T-waves are found to be within the tolerance limits given in CSE library.

Detection of QRS complexes in electrocardiogram using support vector machine.

This paper presents the application of a support vector machine (SVM) for the detection of QRS complexes in the electrocardiogram (ECG). The ECG signal is filtered using digital filtering techniques to remove noise and baseline wander. The support vector machine is used as a classifier to delineate QRS and non-QRS regions. Two different algorithms are presented for the detection of QRS complexes. The first uses a single-lead ECG at a time for the detection of QRS complexes, while the second uses 12-lead simultaneously recorded ECG. Both algorithms have been tested on the standard CSE ECG database. A detection rate of 99.3% is achieved when tested using a single-lead ECG. This improves to 99.75% for the simultaneously recorded 12-lead ECG signal. The percentage of false negative detection is 0.7% and the percentage of false positive detection is 12.4% in the single-lead QRS detection and it reduces to 0.26% and 1.61% respectively for QRS detection in simultaneously recorded 12-lead ECG signals. The performance of the algorithms depends strongly on the selection and the variety of the ECGs included in the training set, data representation and the mathematical basis of the classifier.

Combined entropy based method for detection of QRS complexes in 12-lead electrocardiogram using SVM.

A method based on signal entropy is proposed for the detection of QRS complexes in the 12-lead electrocardiogram (ECG) using support vector machine (SVM). Digital filtering techniques are used to remove power line interference and base line wander in the ECG signal. Combined Entropy criterion was used to enhance the QRS complexes. SVM is used as a classifier to delineate QRS and non-QRS regions. The performance of the proposed algorithm was tested using 12-lead real ECG recordings from the standard CSE ECG database. The numerical results indicated that the algorithm achieved 99.93% of detection rate. The percentage of false positive and false negative is 0.54% and 0.06%, respectively. The proposed algorithm performs better as compared with published results of other QRS detectors tested on the same database.

Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: a prospective study.

BACKGROUND: Adverse drug reactions (ADRs) are now recognized as an important cause of hospital admissions, with a proportion ranging from 0.9-7.9%. They also constitute a significant economic burden. We thus aimed at determining the prevalence and the economic burden of ADRs presenting to Medical Emergency Department (ED) of a tertiary referral center in India METHODS: A prospective, observational study of adult patients carried out over a 6 week period in 2005. The prevalence of ADRs, their economic burden from the hospital perspective, severity, and preventability were assessed using standard criteria. RESULTS: A total 6899 patients presented during the study period. Of these, 2046 were admitted for various reasons. A total of 265/6899 patients had ADRs (3.84 %). A total of 141/265 was admitted due to ADsR, and thus ADRs as a cause of admissions were 6.89% of total admissions. A majority (74.71%) were found to be of moderate severity. The most common ADRs were anti-tubercular drug induced hepatotoxicity, warfarin toxicity and chloroquine induced gastritis. The median duration of hospitalization was 5 days [95% CI 5.37, 7.11], and the average hospitalization cost incurred per patient was INR 6197/- (USD 150). Of total ADRs, 59.62% (158/265) were found to be either definitely or potentially avoidable. CONCLUSION: The study shows that ADRs leading to hospitalization are frequent and constitute a significant economic burden. Training of patients and prescribers may lead to a reduction in hospitalization due to avoidable ADRs and thus lessen their economic burden.

A randomized, parallel study of the safety and efficacy of 45 mg primaquine versus 75 mg bulaquine as gametocytocidal agents in adults with blood schizonticide-responsive uncomplicated falciparum malaria [ISCRTN50134587].

BACKGROUND: The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine (PQ) 45 mg as a gametocytocidal agent. An earlier pilot study suggested that 75 mg of bulaquine (BQ), of which PQ is a major metabolite, may be a useful alternate to PQ. METHODS: In a randomized, partial blind study, 90 hospitalized adults with Plasmodium falciparum malaria that was blood schizonticide-responsive and a gametocytemia of > 55/microl within 3 days of diagnosis were randomized to receive single doses of either PQ 45 mg or BQ 75 mg on day 4. We assessed gametocytemia on days 8, 15, 22 and 29 and gametocyte viability as determined by exflagellation (2 degrees end point) on day 8. RESULTS: On day 8, 20/31 (65%) primaquine recipients versus 19/59 (32%) bulaquine recipients showed persistence of gametocytes (P = 0.002). At day 15 and beyond, all patients were gametocyte free. On day 8, 16/31 PQ and 7/59 BQ volunteers showed gametocyte viability (p = 0.000065). CONCLUSION: BQ is a safe, useful alternate to PQ as a Plasmodium falciparum gametocytocidal agent and may clear gametocytemia faster than PQ.

Memokath stents for the treatment of detrusor sphincter dyssynergia (DSD) in men with spinal cord injury: the Princess Royal Spinal Injuries Unit 10-year experience.

STUDY DESIGN: Medical records review. OBJECTIVE: To assess the effectiveness of the Memokath (Engineers and Doctors A/S, Denmark) thermosensitive stent as a 'nondestructive' means of reducing bladder outlet resistance by treating detrusor sphincter dyssynergia (DSD) of neurogenic bladder dysfunction associated with spinal cord injury. SETTING: Spinal Injuries Unit, Sheffield, England. METHODS: A medical records review was performed to examine our experience of Memokaths over the last 10 years. During this time, 29 patients with spinal cord injury (17 tetraplegic and 12 paraplegic) underwent stenting of the external urethral sphincter either for prevention of dysreflexic symptoms, high residual urine volumes and subsequent urinary tract infection (UTI) or for protection of the upper tracts. RESULTS: A total of 33 stents were inserted into 29 men (25-77 years) with suprasacral spinal cord injury. Initial results showed that the Memokath was effective in almost all for relief of dysreflexic symptoms and elimination of DSD on pressure flow urodynamics. However, to date, 30 of the 33 stents have been removed. The overall mean working life of the Memokath was 21 months. Four stents were removed electively and 23 for complications, which included stent migration (seven) and blockage (14). Single-ended stents were more prone to migration, which was rare after 1 year (1-13 months, median 3 months, mean 5.5 months). Stent blockage by encrustation or prostatic ingrowth did not occur before 12 months (12-45 months, median 30, mean 27.9 months). CONCLUSIONS: In selected patients, temporary, thermo-expandable (Memokath) stents are effective in the treatment of DSD. The 'working life' of a Memokath stent is 21 months; however, complications do occur which may necessitate removal. Our overall experience with Memokath stents was disappointing. In future, Memokath stents will only be inserted after careful consideration in patients with prior 'failed' transurethral sphincterotomy or with caution in patients suitable for reconstructive surgery.

Three dimensional ultrasound and prostate cancer.

Three-dimensional ultrasound (3-D US) is a non-invasive method of producing whole volume images of solid structures. Early work on prostate imaging identified several advantages over 2-D imaging with a good ability to detect intraprostatic lesions. Several 3-D transrectal ultrasound (3-D TRUS) systems are now available for prostate imaging. Initial work using gray scale ultrasound appears promising with reported overall staging accuracies of up to 94%. These results were favourable when compared to other modalities for local staging of prostate cancer. Several adjuncts to 3-D gray scale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents. Further clinical applications for 3-D TRUS include assessing placement of brachytherapy seeds and for cyroablation techniques. Computer enhancement with image registration has shown that 3-D US images can be manipulated to derive more information. Although the results of gray scale imaging alone or with adjuncts and post processing appear promising, these techniques remain largely experimental.

Bone material ultrasound velocity is predictive of whole bone strength.

In humans, bone strength is assessed indirectly by the noninvasive measurement of structure or mass. Recent clinical application of an ultrasonic critical-angle reflectometry technique (UCR) has demonstrated the measurement of the regional and directional distribution of mechanical stiffness. This study investigates the specific question: are these measurements of a local material level property predictive of the strength of whole bone? Maximum values of pressure wave velocity and breaking strength were recorded at two locations (midshaft and base of neck) on rat femurs from growing rats. The results demonstrate a strong empirical relationship between material-level ultrasound (US) velocity and whole bone mechanical strength. However, the US velocity at a specific bone site can be used to assess bone strength at that site only, explaining discrepancies in other published studies that negate a relationship between strength and US velocity. The results indicate an important role for US velocity measurement in clinical evaluation of bone health.

Bioreductive metabolism of mitomycin C in EMT6 mouse mammary tumor cells: cytotoxic and non-cytotoxic pathways, leading to different types of DNA adducts. The effect of dicumarol.

The six DNA adducts formed in EMT6 mouse mammary tumor cells upon treatment with mitomycin C (MC) fall into two groups: (1) four guanine adducts of MC and (2) two guanine adducts derived from 2,7-diaminomitosene (2,7-DAM), the major reductive metabolite of MC. The two groups of adducts were proposed to originate from two pathways arising from reductive activation of MC: (a) direct alkylation of DNA and (b) formation of 2,7-DAM, which then alkylates DNA. The aim of this study was to test the validity of this proposal and to evaluate the significance of alkylation of DNA by 2,7-DAM. Treatment of the cells with 2,7-DAM itself yielded the same 2,7-DAM-guanine adducts as treatment with MC; however, 2,7-DAM was approximately 100-fold less cytotoxic than MC. The uptake and efflux of 2,7-DAM by EMT6 cells was comparable to that of MC, but 2,7-DAM alkylated DNA with higher efficiency than MC. These results validate the two proposed pathways and show that formation of 2,7-DAM-DNA adducts in MC-treated cells represents a relatively non-toxic pathway of reductive metabolism of MC. A selective stimulatory effect of dicumarol (DIC) on 2,7-DAM-DNA adduct formation in EMT6 cells treated with MC was also investigated. DIC had no effect on alkylation by MC in cell-free systems, nor did it have significant effects on adduct formation or cell survival for cells treated with 2,7-DAM. It is proposed that in the cell DIC stimulates a reductase enzyme located at subcellular sites where the activated MC species has no direct access to DNA and therefore is diverted into the non-cytotoxic pathway, which leads to the formation of 2,7-DAM and its adducts.

Determining an episode of care using claims data. Diabetic foot ulcer.

OBJECTIVE: Amid changes in the organization and financing of health care, health care decision makers are increasingly interested in episodes of care. We sought to determine an episode of care for diabetic foot ulcer using an administrative claims database. RESEARCH DESIGN AND METHODS: We used 1993-1995 claims data to assess resource utilization for privately insured patients with diabetic foot ulcers. Over a 26-week period, we determined the episode length by comparing differences in average daily charges and proportion of patients with charges before and after foot ulcer diagnosis. All 13 weeks before diagnosis were used to calculate baseline values. Significance was determined by CIs, which were calculated by a nonparametric bootstrap technique. Costs associated with the episode were also calculated. A sensitivity analysis using weeks with highest and lowest values as baseline was also conducted. RESULTS: Based on average daily charges, the episode of care for diabetic foot ulcer was 5 weeks. Using proportion of patients with charges, the episode was longer than 13 weeks. The cost for an episode of care ranged from $900 to $2,600. In the sensitivity analyses, episodes of care ranged from 1 to 13 weeks. CONCLUSIONS: Episodes of care can be defined by the period beginning with increased resource consumption and ending when resource consumption returns to baseline levels. With the growth of managed care and disease management programs, episode-of-care analysis may have an increasingly important role in health care provision and delivery.

Treatment of hypertension in patients with comorbidities: results from the study of hypertensive prescribing practices (SHyPP).

Approximately 50 million people have hypertension. Many agents with differing efficacy, side effects, dosing schedules, and costs are available to treat hypertension. Joint National Committee (JNC) guidelines attempt to simplify this decision by recommending specific agents based on special considerations such as comorbidities. The objective of this study was to survey primary care physicians' antihypertensive prescribing practices and their treatment recommendations for patients with comorbidities. A direct mail survey was sent to a national random sample of 500 office-based primary care internists, family practitioners, and general practitioners. There were no significant differences between initial treatment recommendations at the time of the survey and those recommended before the survey. However, there were several therapeutic classes whose reported utilization for specific comorbidities significantly changed over 18 months. Angiotensin converting enzyme (ACE) inhibitors reportedly increased in patients with congestive heart failure and diabetes. In addition, the reported use of selective beta-blockers increased for patients with a history of myocardial infarction. Physicians did not follow JNC recommendations when initiating treatment in black patients, older patients, or those with mild renal failure. Younger physicians were more likely than older physicians to select agents consistent with guideline recommendations. Physicians did not adhere to JNC guidelines when initiating treatment in patients with comorbidities; however, more physicians are prescribing recommended agents today as compared to 18 months ago. Younger physicians were more likely to prescribe agents consistent with the guidelines. More direct efforts are needed to ensure awareness and compliance with these guidelines.

Bone material elasticity in a murine model of osteogenesis imperfecta.

To investigate the source of bone brittleness in the disease osteogenesis imperfecta (OI), biomechanical properties have been measured in the femurs from a homozygous (oim/oim) mutant mouse model of OI, its heterozygous littermates, and wild-type animals. The novel technique of ultrasound critical-angle reflectometry (UCR) was used to determine bone material elasticity matrix from measurements of the pressure and shear wave velocity at different orientations about selected points of the bone specimens. This nondestructive method is the only available means for obtaining measurements of this nature from a single surface. The ultrasound pressure wave velocity showed an increased isotropy in the homozygous compared to the wild-type specimens. This was reflected in a significant decrease in the principal elastic modulus measured along the length of the oim/oim bones (E33) while the modulus along the width (E11) did not change significantly, compared to wild-type specimens. The Poisson's ratio, v12, also had a significantly increased value in oim/oim bones. Measurements of these parameters in heterozygous animals generally fell between those from homozygous and control mice. The differences in the elasticity components in oim/oim bones indicate an altered stress distribution and a modified elastic response to loads, compared to normal bone.

Prescription medication use in older Americans: a national report card on prescribing.

BACKGROUND AND OBJECTIVES: Due to their high prevalence of disease, older Americans receive more prescription medication than any other age group. We evaluated prescription medication use in patients age 50 or older; categorized and reported medication use by age group, drug class, and therapeutic class; and examined differences in prescribing patterns for older patients. METHODS: All prescription medications reported in the 1995 National Ambulatory Medical Care Survey, a nationally representative sample of ambulatory care visits in the United States for patients age 50 and older (n = 16,289), were evaluated in a cross-sectional analysis. We evaluated the number of prescription medications reported for each patient visit and ranked use of drug and therapeutic classes. RESULTS: Most patients seeing physicians (61%) had a prescription for at least one medication, ranging from a mean of 1.27 medications in patients ages 50-64 to 1.58 in patients over 85. Calcium channel blockers and angiotensin-converting enzyme inhibitors were prescribed more than beta blockers in all patients. Data also indicated a significant decrease in estrogen/progestin and antidepressant medication use in older patients. CONCLUSIONS: Our findings indicate prescribing patterns inconsistent with national guidelines and decreased medication use, suggesting underprescription. Active intervention may be needed to improve the pharmacological treatment of older patients.