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Biomedical subjects

R Sheldon

Publications and source records attributed to R Sheldon.

At least 19 recordsLinked to original sources
PubMed2005

Sacral nerve stimulation reduces corticoanal excitability in patients with faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) can produce symptomatic relief in patients with faecal incontinence. Moreover, peripheral nerve stimulation has been shown to affect brain function. The aim of this study was to determine whether SNS might produce important changes in cortical activity linked to improved continence. METHODS: In an experimental study, ten women with intractable faecal incontinence (mean age 51.3 years) were serially mapped with transcranial magnetic stimulation before and immediately after 14 days of temporary SNS (15 Hz, pulse width 210 micros), and then 2 weeks later. Anal sphincter electromyographic responses were recorded to cortical stimulation of multiple points over a scalp grid covering the bilateral medial cortex. Continence scores, anorectal manometry and rectal sensitivity data were also collected. RESULTS: SNS improved global symptom scores in the majority of patients; mean(s.e.m.) continence scores fell from 16.9(1.6) to 10.6(1.8) (P = 0.042). Cortical mapping showed a consistent decrease in corticoanal representation and overall excitability immediately after SNS compared with baseline (mean(s.e.m.) 38,083(13,669) versus 42,507(13,297) microV s; P = 0.017), which was reversed 2 weeks after SNS wire removal. CONCLUSION: SNS produces symptom benefit in patients with faecal incontinence that is associated with a reversible reduction in corticoanal excitability. SNS therefore drives dynamic brain changes that may play a functional role in influencing anal continence.

Adult↗
PubMed2003

Patients' preferences for characteristics associated with treatments for osteoarthritis.

OBJECTIVE: The purpose of this study was to investigate patient preferences for attributes associated with the efficacy and side-effects of treatment for osteoarthritis. METHODS: A stated preference design questionnaire was administered to a sample of 412 individuals diagnosed with osteoarthritis (OA). RESULTS: Statistically significant attributes in influencing treatment preferences were the level of joint aches, the level of physical mobility and the risk of experiencing serious side-effects from treatment. Respondents were relatively more concerned about the risk of serious side-effects (even with a very low probability) than mild to moderate side-effects (at a much higher probability). Data segmentation revealed some variations in preferences according to respondent characteristics. The importance of joint aches increased according to the severity of the symptoms of osteoarthritis, indicating that this attribute is more troublesome to those respondents with more severe symptoms. Older respondents were more willing than younger respondents to accept an increased risk of experiencing serious side-effects for an improvement in the symptoms of OA. Individuals in lower income brackets appeared to attach greater importance to joint aches and the level of mobility experienced than those in higher income brackets. Respondents who had previously experienced gastrointestinal side-effects from treatment were, as expected, more tolerant of them than those who had not. CONCLUSION: The use of conjoint analysis to assess patient preferences provides a useful insight to the likely attitudes of patients to novel treatments for osteoarthritis.

Age Factors↗
PubMed2003

Prevention of Syncope Trial (POST): a randomized clinical trial of beta blockers in the prevention of vasovagal syncope; rationale and study design.

BACKGROUND: Few therapies for vasovagal syncope have been proven effective. A large, placebo-controlled clinical trial of beta-blockers is needed. STRUCTURE OF STUDY: The Prevention of Syncope Trial (POST) is a multicentre, randomized, placebo-controlled, study of metoprolol in the prevention of vasovagal syncope. The primary hypothesis is that beta-blockers will increase the time to the first recurrence of syncope when compared with placebo. Patients will be randomized 1:1 to receive metoprolol or placebo, and followed for 1 year. The primary endpoint is the time to first syncope recurrence, and secondary endpoints include syncope frequency, presyncope, and quality of life. INCLUSION AND EXCLUSION CRITERIA: Patients are eligible if they have a positive tilt test and 3 syncopal spells preceding the tilt test. They are excluded if they have seizures or other causes of syncope; important heart disease; a contraindication to or need for beta blockers; a permanent pacemaker; a major noncardiovascular disease; or previous use of beta blockers at a dose greater than the equivalent of metoprolol 25mg twice daily for the purpose of suppressing vasovagal syncope. POWER CALCULATIONS: We assume a 40% risk of syncope in the control arm, an absolute reduction of 20% by metoprolol, and a dropout of 20%. Entry of 220 patients will result in an 80% chance of reaching a positive conclusion about beta-blocker therapy with 2p=0.05.

Adrenergic beta-Antagonists↗
PubMed2001

Catalytic reactions in ionic liquids.

The chemical industry is under considerable pressure to replace many of the volatile organic compounds (VOCs) that are currently used as solvents in organic synthesis. The toxic and/or hazardous properties of many solvents, notably chlorinated hydrocarbons, combined with serious environmental issues, such as atmospheric emissions and contamination of aqueous effluents is making their use prohibitive. This is an important driving force in the quest for novel reaction media. Curzons and coworkers, for example, recently noted that rigorous management of solvent use is likely to result in the greatest improvement towards greener processes for the manufacture of pharmaceutical intermediates. The current emphasis on novel reaction media is also motivated by the need for efficient methods for recycling homogeneous catalysts. The key to waste minimisation in chemicals manufacture is the widespread substitution of classical 'stoichiometric' syntheses by atom efficient, catalytic alternatives. In the context of homogeneous catalysis, efficient recycling of the catalyst is a conditio sine qua non for economically and environmentally attractive processes. Motivated by one or both of the above issues much attention has been devoted to homogeneous catalysis in aqueous biphasic and fluorous biphasic systems as well as in supercritical carbon dioxide. Similarly, the use of ionic liquids as novel reaction media may offer a convenient solution to both the solvent emission and the catalyst recycling problem.

Journal Article↗
PubMed2001

Effect of clinical risk stratification on cost-effectiveness of the implantable cardioverter-defibrillator: the Canadian implantable defibrillator study.

BACKGROUND: Three randomized clinical trials showed that implantable cardioverter-defibrillators (ICDs) reduce the risk of death in survivors of ventricular tachyarrhythmias, but the cost per year of life gained is high. A substudy of the Canadian Implantable Defibrillator Study (CIDS) showed that 3 clinical factors, age >/=70 years, left ventricular ejection fraction </=35%, and New York Heart Association class III, predicted the risk of death and benefit from the ICD. We estimated the extent to which selecting patients for ICD therapy based on these risk factors makes ICD therapy more economically attractive. METHODS AND RESULTS: Patients in CIDS were grouped according to whether they had >/=2 of 3 risk factors. Incremental cost-effectiveness of ICD therapy was computed as the ratio of the difference in mean cost to the difference in life expectancy between the 2 groups. Over 6.3 years, the mean cost per patient in the ICD group was Canadian (C) $87 715 versus $38 600 in the amiodarone group (C$1 approximately US$0.67). Life expectancy for the ICD group was 4.58 years versus 4.35 years for amiodarone, for an incremental cost-effectiveness of ICD therapy of C$213 543 per life-year gained. The cost per life-year gained in patients with >/=2 factors was C$65 195, compared with C$916 659 with <2 risk factors. CONCLUSIONS: The cost-effectiveness of ICD therapy varies by patient risk factor status. The use of ICD therapy in patients who have >/=2 risk factors of age >/=70 years, left ventricular ejection fraction </=35%, and NYHA class III is C$65 195 to gain a year of life.

Aged↗
PubMed2001

New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.

BACKGROUND: Although sex differences in coronary artery disease have received considerable attention, few studies have dealt with sex differences in the most common sustained cardiac arrhythmia, atrial fibrillation (AF). Differences in presentation and clinical course may dictate different approaches to detection and management. We sought to examine sex-related differences in presentation, treatment, and outcome in patients presenting with new-onset AF. METHODS AND RESULTS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled subjects at the time of first ECG-confirmed diagnosis of AF. Participants were followed at 3 months, at 1 year, and annually thereafter. Treatment was at the discretion of the patients' physicians and was not directed by CARAF investigators. Baseline and follow-up data collection included a detailed medical history, clinical, ECG, and echocardiographic measures, medication history, and therapeutic interventions. Three hundred thirty-nine women and 560 men were followed for 4.14+/-1.39 years. Compared with men, women were older at the time of presentation, more likely to seek medical advice because of symptoms, and experienced significantly higher heart rates during AF. Compared with older men, older women were half as likely to receive warfarin and twice as likely to receive acetylsalicylic acid. Compared with men on warfarin, women on warfarin were 3.35 times more likely to experience a major bleed. CONCLUSIONS: Anticoagulants are underused in older women with AF relative to older men with AF, despite comparable risk profiles. Women receiving warfarin have a significantly higher risk of major bleeding, suggesting the need for careful monitoring of anticoagulant intensity in women.

Anticoagulants↗
PubMed2001

Components of clinical trials for vasovagal syncope.

The time is ripe for adequately powered, randomized, placebo-controlled clinical trials in vasovagal syncope. Vasovagal syncope is a common syndrome, the symptoms of which can be troublesomely frequent. It is usually diagnosed by tilt-table testing, although this has persistent problems with both sensitivity and specificity. Patients with syncope and positive tilt tests have been the subjects of numerous studies of natural history, risk stratification, and treatment. This paper discusses studies of treatments for vasovagal syncope in the context of a classification of the levels of evidence that can be gleaned from clinical studies. The reasons for placebo-controlled trials are reviewed, as is the evidence for various methods of risk stratification. Data for power calculations are presented for the primary outcome, the time to the first syncope recurrence. Strengths and weakness of the four main types of outcomes for clinical trials are compared.

Clinical Trials as Topic↗
PubMed2001

Origins of heart rate variability: autonomic blockade of large magnitude, transient bradycardia in conscious rabbits.

BACKGROUND: Heart period sequences are composed of recurrent, similarly shaped, physiologically meaningful, transient heart period structures. One such structure is a large magnitude transient bradycardia (LMTB), which resembles published reports of responses to alerting stimuli. Alerting responses are sensitive to alpha1-adrenoceptor and cholinergic receptor blockade. OBJECTIVES: To determine whether LMTBs are related to alerting responses by assessing the response of rabbit LMTBs to autonomic inhibitors. ANIMALS AND METHODS: Using a Latin square, crossover design, six conscious, unsedated rabbits received placebo, intramuscular glycopyrrolate 0.05 mg/kg and intravenous prazosin 0.15 mg/kg, and six rabbits received placebo, intravenous metoprolol 0.15 mg/kg and intravenous ICI-118,551 0.1 mg/kg. Heart period and blood pressure were continuously recorded, digitized and analyzed off-line. RESULTS: LMTBs were suppressed by 93% and 95% by alpha1-adrenergic and muscarinic blockade, respectively, but not by beta1-adrenergic or beta2-adrenergic blockade. The drugs altered none of the morphological parameters of shape, magnitude or duration, or any of the hypotensive features. CONCLUSIONS: LMTBs are similar to alerting responses; they are both expressed as transient hypotensive and bradycardic events that are markedly reduced by muscarinic and alpha1-adrenoceptor blockade but not by beta-adrenoceptor blockade. The presence of LMTBs may indicate ongoing, subtle changes in the laboratory environment.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2001

A randomized study of tilt test angle in patients with undiagnosed syncope.

BACKGROUND: A widely used tilt test protocol involves passive head-up tilt followed by tilt with isoproterenol infusion if necessary. Little is known about the effects of passive tilt angle and duration, duration of isoproterenol infusion or hemodynamic diagnostic criteria. OBJECTIVES: To assess whether tilt angle and duration of isoproterenol infusion affected test outcomes in patients with undiagnosed syncope. PATIENTS AND METHODS: Two hundred one syncope patients (87 men, age 45+/-20 years, median five faints) were randomly assigned to undergo 60 degrees versus 80 degrees tilt for 45 min, then, if necessary, to receive isoproterenol 30 ng/kg/min for 20 min or less. Positive tests ended in presyncope or syncope. RESULTS: Overall, 49% and 71% of patients fainted at 60 degrees and 80 degrees, respectively (P=0.002). In the drug-free stage, 27% and 50% of patients fainted at 60 degrees and 80 degrees, respectively (P=0.0005). In the 119 patients who received isoproterenol, there was no significant difference in the probability of a positive isoproterenol test at 60 degrees and 80 degrees, respectively (31% compared with 43% of exposed patients, P=0.25). Symptoms developed in adults during drug-free tilt linearly with time at both 60 degrees and 80 degrees at 0.6% and 1.1%/min, respectively, while symptoms during isoproterenol tilt reached an asymptote after about 10 min. Rate-systolic pressure products of 7000 mmHg/min and 9000 mmHg/min best distinguished positive from negative passive and isoproterenol stages, respectively. CONCLUSIONS: The positive yield of passive tilt tests is higher at 80 degrees and increases linearly with the duration of tilt. A subsequent 10 min isoproterenol infusion maximizes positive yield. Evidence-based outcome criteria accurately distinguish negative from positive tilt tests.

Adult↗
PubMed2000

Identification of patients most likely to benefit from implantable cardioverter-defibrillator therapy: the Canadian Implantable Defibrillator Study.

BACKGROUND: Patients with resuscitated ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation) benefit from implantable cardioverter-defibrillators (ICDs) compared with medical therapy. We hypothesized that the patients who benefit most from an ICD are those at greatest risk of death. METHODS AND RESULTS: In the Canadian Implantable Defibrillator Study (CIDS), 659 patients with resuscitated ventricular tachyarrhythmias were randomly assigned to receive an ICD or amiodarone and were then followed for a mean of 3 years. There were 98 and 83 deaths in the amiodarone and ICD groups, respectively. We used multivariate Cox analysis to assess the impact of baseline parameters on the mortality in the amiodarone group. Reduced left ventricular ejection fraction, advanced age, and poor NYHA status identified high-risk patients (P=0.0001 to 0.0009). Quartiles of risk were constructed, and the mortality reduction associated with ICD treatment in each quartile was assessed. There was a significant interaction between risk quartile and the ICD treatment effect (P=0.011). In the highest risk quartile, there was a 50% relative risk reduction (95% CI 21% to 68%) of death in the ICD group, whereas in the 3 lower quartiles, there was no benefit. Patients who are most likely to benefit from an ICD can be identified with a simple risk score (>/=2 of the following factors: age >/=70 years, left ventricular ejection fraction </=35%, and NYHA class III or IV). Thirteen of 15 deaths that were prevented by the ICD occurred in patients with >/=2 risk factors. CONCLUSIONS: In CIDS, patients at highest risk of death benefited most from ICD therapy. These can be identified easily on the basis of age, poor ventricular function, and poor functional status.

Aged↗
PubMed2000

Usefulness of clinical factors in predicting outcomes of passive tilt tests in patients with syncope.

Pretest patient selection affects the outcome of many diagnostic tests; this may be true for tilt-table tests. We assessed the impact of patient age, sex, and symptom burden on the outcome of passive tilt tests. Two hundred one patients with idiopathic syncope (87 men, aged 45 +/- 20 years, median 5 fainting spells each) underwent passive, drug-free tilt tests for 45 minutes. Positive tests were defined as those ending in clinically reminiscent presyncope or syncope. Seventy-eight patients (39%) had a positive tilt test. Patients had a wide range of symptom burden, having a median 5 syncopal spells (interquartile range [IQR] 2.5 to 17.5) over a median 52.5 months (IQR 12 to 180) with a median frequency of 0.17 spells/month (IQR 0.042 to 0.67). None of these measures of symptom burden predicted tilt-test outcome (p = 0.33 to 0.46). In contrast, the age of the patient strongly predicted tilt-test outcome. The likelihood of a positive test was 75% in 36 patients < 25 years old and 31% in 165 patients > or = 25 years of age (p < 0.0001, chi-square for 2 x 5 table). Younger patients also fainted more quickly: patients < 25 years old fainted within 22 minutes of tilt and reached a clearly asymptotic value, whereas the likelihood of a positive tilt in patients > or = 25 years old increased linearly with time, and did not reach an asymptote. Measures of symptom burden do not predict test outcome, and younger patients are more likely to faint during passive tilt testing.

Adolescent↗
PubMed2000

Preference measurement using conjoint methods: an empirical investigation of reliability.

The application of conjoint measurement to the field of health economics is relatively new, although there is growing interest and there have been a number of studies undertaken recently. Wider acceptance of the technique requires methodological issues concerning both reliability and validity to be addressed. This paper reports an empirical investigation of the test-retest reliability of the discrete choice conjoint measurement approach in health care. This investigation of conjoint reliability was framed using the clinical context of investigation and treatment of knee injuries. A high level of reliability at both the input data and results levels was demonstrated.

Adolescent↗
PubMed2000

Pacing to prevent vasovagal syncope.

Patients with frequent vasovagal syncope have markedly poor quality of life and are often resistant to treatment with standard pharmacologic approaches. Vasovagal syncope is due to combinations of bradycardia and hypotension. There is accumulating evidence that many of these patients may respond to permanent cardiac pacing. Several controlled open-label studies suggest that about half of paced patients no longer faint, and most of the rest are improved. At this point, we do not know the role of placebo, and specific pacing modes in this improvement are not known. Ongoing trials will clarify how to select patients and how best to pace them.

Blood Pressure↗
PubMed2000

The relationship between health-related quality of life and frequency of spells in patients with syncope.

Chronic syncope has a wide range of symptom burden, and anecdotal data suggest substantial but variable physical and psychosocial morbidity. We hypothesized that health-related quality of life (HRQL) is impaired in syncope patients and the degree of impairment is proportional to syncope frequency. The EuroQol EQ-5D was completed by 136 patients (79 female and 57 male) with mean age 40 (SD = 17) prior to assessment. HRQL was substantially impaired in syncope patients compared to population norms in all five dimensions of health measured by the EQ-5D. In patients with six or more lifetime syncopal spells there was a significant (P < 0.001) negative relationship between the frequency of spells and overall perception of health, which was not evident in those who had a history of less than six lifetime spells. These relationships were maintained after controlling for comorbid conditions.

Adult↗
PubMed1999

Role of pacing in the treatment of vasovagal syncope.

Patients with frequent vasovagal syncope have a markedly poor quality of life and are often resistant to treatment by standard pharmacologic approaches. Although the evidence is not conclusive, clinical vasovagal syncope is probably associated with some degree of bradycardia. Studies of temporary pacing during tilt-table testing have shown that pacing prevents syncope in more than half of patients who develop a vasovagal response. Three open-label studies of permanent pacing showed that pacing was associated with substantial improvement, and the prospective randomized Vasovagal Pacemaker Study reported an 85% relative risk reduction in patients randomized to pacemaker therapy compared with medical therapy. The roles of specific pacemaker modes in vasovagal syncope have not been determined, although early evidence indicates that rate-drop responsiveness is useful. The second Vasovagal Pacemaker Study may clarify the role of rate-drop responsiveness.

Humans↗
PubMed1999

Putting it together: a new treatment algorithm for vasovagal syncope and related disorders.

The consensus process that culminated in this symposium established an algorithm to guide the diagnosis and treatment of patients with vasovagal syncope and related disorders. In some patients, the hemodynamic response to standing may identify an abnormality-postural orthostatic tachycardia syndrome or orthostatic hypotension-that can often be treated without further testing. When the response to standing is normal, tilt-table testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment. In some patients, however, the diagnosis is clear from the history, and tilt-table testing may not be necessary. Not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt. In evaluating the results of tilt-table testing, an important consideration is the distinction between vasovagal syncope and the dysautonomic response to tilt characterized by a gradual and progressive decrease in blood pressure that leads to syncope. Current practice patterns suggest that beta blockers, fludrocortisone, and midodrine, are commonly used to treat patients with vasovagal syncope, and patients with the dysautonomic response are generally treated with fludrocortisone and midodrine. Permanent pacing with specialized pacing algorithms should be considered for patients with frequent vasovagal syncope that is refractory to medical therapy. The guidelines proposed here are an amalgam of clinical experience, expert opinion, and research evidence; however, they do not suggest a standard of care for all patients.

Algorithms↗
PubMed1999

Enzymatic synthesis of beta-lactam antibiotics using penicillin-G acylase in frozen media.

Penicillin-G acylase (EC 3.5.1.11) from Escherichia coli catalyzed the synthesis of various beta-lactam antibiotics in ice at -20 degrees C with higher yields than obtained in solution at 20 degrees C. The initial ratio between aminolysis and hydrolysis of the acyl-enzyme complex in the synthesis of cephalexin increased from 1.3 at 20 degrees C to 25 at -20 degrees C. The effect on the other antibiotics studied was less, leading us to conclude that freezing of the reaction medium influences the hydrolysis of each nucleophile-acyl-enzyme complex to a different extent. Only free penicillin-G acylase could perform transformations in frozen media: immobilized preparations showed a low, predominantly hydrolytic activity under these conditions.

Amoxicillin↗
PubMed1999

Origins of heart rate variability. Inducibility and prevalence of a discrete, tachycardic event.

BACKGROUND: We propose that heart period sequences are linearly organized, like sentences, and that there is a lexicon of recurrent, similarly shaped transient structures like words. Each word (or lexon) has a characteristic physiological basis. One potential lexon is the transient, reversible tachycardia that is induced by exercise initiation under laboratory conditions. We hypothesized that this lexon was inducible and observable on ambulatory ECGs of most or all subjects, was morphologically similar in both induced and detected bursts, and shared a plausible origin in both circumstances. METHODS AND RESULTS: Ten healthy subjects (mean age, 36 years) underwent a protocol in which subjects rolled themselves from supine to lateral decubitus positions and back. Transient tachycardias ("bursts") were seen in 36 of 40 rollovers. Bursts were characterized by an initial monoexponential heart period decay (K=0.39+/-0.23 s-1), a maximum heart period decrease of 277+/-109 ms after 10.8+/-4.5 seconds, and a subsequent return to baseline 23.3+/-10.8 seconds after roll initiation. The roll-induced bursts were detected with 97% sensitivity and 99% specificity with a search algorithm that incorporated morphological parameters. In 24-hour ambulatory ECGs of 10 healthy subjects (mean age, 38 years; range, 17 to 69 years), 117+/-59 bursts were detected. Induced and detected bursts were similar in most morphological parameters. Finally, many bursts occurred at night, when rolling over also occurs. CONCLUSIONS: Bursts are inducible, transient tachycardias that occur clinically and constitute a lexon with an understandable physiology.

Adolescent↗