Contract for UK consultants.
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Consultants↗
Biomedical subjects
Paul Miller
Publications and source records attributed to Paul Miller.
Non-standard grade (trust grade) doctors: the BMA seniors' view.
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Humans↗
Viagra use in a community-recruited sample of men who have sex with men, San Francisco.
The authors conducted a community-based anonymous survey of 837 men who have sex with men (MSM) to gauge the extent of Viagra (sildenafil citrate) use, its association with high-risk sexual behavior, and its combination with other drugs. Participants' mean age was 35 years, 67% were white, and 66% had a college degree. The majority (76%) reported anal sex in the past 6 months, with 49% reporting always using condoms. Overall, 32% had ever used Viagra (CI: 29%-36%). Significant independent predictors of Viagra use were white race, older age, HIV positivity, illicit drug use, and having had unprotected anal sex with potentially serodiscordant partners. Over one third of Viagra users had combined Viagra with other drugs, 18% with amyl nitrate. Only a minority (44%) obtained Viagra under the care of a physician. For some MSM, Viagra appears to be an emerging contributing factor to unsafe sex, potentially increasing HIV transmission. HIV care and prevention providers should target Viagra users for enhanced education on safer sex and potentially harmful drug interactions.
Adult↗
Surgical aortic valvotomy in infancy: impact of leaflet morphology on long-term outcomes.
BACKGROUND: Surgical valvotomy for critical aortic stenosis in children enables relatively accurate commissurotomies to be fashioned, resulting in the formation of two or three leaflets. We hypothesized that outcomes after surgery may be best in patients in whom three leaflets are produced. METHODS: A retrospective review of infants undergoing primary surgical valvotomy at our institution during a 12-year period was carried out. Patients who had additional intracardiac defects were excluded. Clinical and echocardiographic follow-up data were analyzed. RESULTS: Fifty-four patients fulfilled the study criteria. Median age at surgery was 3 weeks (range, 0 to 51 weeks). Commissurotomy resulted in bileaflet anatomy in 41 patients (group A) and trileaflet anatomy in 13 patients (group B). Operative mortality was 5% in group A and 0% in group B (p = 1.0). In group A, 18 patients required one or more aortic valve reinterventions, including valve replacement in 8 patients. In group B, there was only one reintervention (repeat valvotomy). Kaplan-Meier analysis showed that at 10 years, comparisons of group A versus group B were as follows: actuarial survival, 85% versus 100% (p = 0.15); freedom from reintervention, 33% versus 92% (p = 0.01); freedom from aortic reoperation, 45% versus 92% (p = 0.04); and freedom from aortic valve replacement, 57% versus 100% (p = 0.07). CONCLUSIONS: Long-term outcomes after aortic valvotomy are significantly better in infants in whom surgery results in trileaflet rather than bileaflet anatomy. Preoperative evaluation of valve morphology may enable selection of a group of patients in whom results of surgery are excellent.
Aortic Valve↗
Midterm results after restoration of the morphologically left ventricle to the systemic circulation in patients with congenitally corrected transposition of the great arteries.
OBJECTIVE: This study was undertaken to determine the outcomes of patients with congenitally corrected transposition of the great arteries after restoration of the morphologically left ventricle to the systemic circulation. METHODS: Between November 1991 and June 2001, a total of 54 patients (median age 3.2 years, range 7 weeks-40 years) with either congenitally corrected transposition of the great arteries (n = 51) or atrioventricular discordance with double-outlet right ventricle (n = 3) underwent anatomic repair. This comprised a Senning procedure in all cases plus arterial switch (double-switch group) in 29 cases (53.7%), plus a Rastelli procedure (Rastelli-Senning group) in 22 cases (40.7%), and plus intraventricular rerouting (Senning-tunnel group) in 3 cases (5.6%). Left ventricular training by PA banding was performed before the double-switch operation in 9 of 29 cases (31%). Follow-up is complete (median 4.4 years). RESULTS: Early mortality was 5.6% (n = 3), with 2 late deaths. Kaplan-Meier survivals (+/- SEM) were 94.4% +/- 3.1% at 1 year and 89.7% +/- 4.4% at 9 years. Survivals at 7 years were 84.9% +/- 7.1% in the double-switch group and 95.5% +/- 4.4% in the Rastelli-Senning group (P =.32). Of the 49 survivors, 46 (94%) were in New York Heart Association functional class I. Six have acquired new left ventricular dilatation or impaired systolic ventricular function. Four patients in the double-switch group had moderate aortic valve regurgitation develop, and 2 of them required valve replacement. Overall freedoms from reoperation at 1 and 9 years were 94.2% +/- 3.3% and 77.5% +/- 9.0%, with no significant difference between the groups (P =.60). CONCLUSIONS: Anatomic repair of congenitally corrected transposition of the great arteries can be carried out with low early mortality. Excellent functional status can be achieved, with good midterm survival. Continued surveillance is necessary for patents with valved conduits and to determine the longer-term function of the aortic valve and the morphologically left ventricle in the systemic circulation.
Adolescent↗
Photochemical smog effects in mixed conifer forests along a natural gradient of ozone and nitrogen deposition in the San Bernardino Mountains.
Toxic effects of photochemical smog on ponderosa and Jeffrey pines in the San Bernardino Mountains were discovered in the 1950s. It was revealed that ozone is the main cause of foliar injury manifested as chlorotic mottle and premature needle senescence. Various morphological, physiological and biochemical alterations in the affected plants have been reported over a period of about 40 years of multidisciplinary research. Recently, the focus of research has shifted from studying the effects of ozone to multiple pollutant effects. Recent studies have indicated that the combination of ozone and nitrogen may alter biomass allocation in pines towards that of deciduous trees, accelerate litter accumulation, and increase carbon sequestration rates in heavily polluted forests. Further study of the effects of multiple pollutants, and their long-term consequences on the mixed conifer ecosystem, cannot be adequately done using the original San Bernardino Mountains Air Pollution Gradient network. To correct deficiencies in the design, the new site network is being configured for long-term studies on multiple air pollutant concentrations and deposition, physiological and biochemical changes in trees, growth and composition of over-story species, biogeochemical cycling including carbon cycling and sequestration, water quality, and biodiversity of forest ecosystems. Eleven sites have been re-established. A comparison of 1974 stand composition with data from 2000 stand composition indicate that significant changes in species composition have occurred at some sites with less change at other sites. Moist, high-pollution sites have experienced the greatest amount of forest change, while dryer low-pollution sites have experienced the least amount of stand change. In general, ponderosa pine had the lowest basal area increases and the highest mortality across the San Bernardino Mountains.
Air Pollutants↗
Counseling versus antidepressant therapy for the treatment of mild to moderate depression in primary care: economic analysis.
OBJECTIVE: To compare the cost-effectiveness of generic psychological therapy (counseling) with routinely prescribed antidepressant drugs in a naturalistic general practice setting for a follow-up period of 12 months. METHODS: Economic analysis alongside a randomized clinical trial with patient preference arm. Comparison of depression-related health service costs at 12 months. Cost-effectiveness analysis of bootstrapped trial data using net monetary benefits and acceptability curves. RESULTS: No significant difference between the mean observed costs of patients randomized to antidepressants or to counseling (342 pounds sterling vs 302 pounds sterling , p = .56 [t test]). If decision makers are not willing to pay more for additional benefits (value placed on extra patient with good outcome, denoted by K, is zero), then we find little difference between the treatment modalities in terms of cost-effectiveness. If decision makers do place value on additional benefit (K > 0 pounds sterling), then the antidepressant group becomes more likely to be cost-effective. This likelihood is in excess of 90% where decision makers are prepared to pay an additional 2,000 pounds sterling or more per additional patient with a good global outcome. The mean values for incremental net monetary benefits (INMB) from antidepressants are substantial for higher values of K (INMB = 406 pounds sterling when K = 2,500 pounds sterling). CONCLUSION: For a small proportion of patients, the counseling intervention (as specified in this trial) is a dominant cost-effective strategy. For a larger proportion of patients, the antidepressant intervention (as specified in this trial) is the dominant cost-effective strategy. For the remaining group of patients, cost-effectiveness depends on the value of K. Since we cannot observe K, acceptability curves are a useful way to inform decision makers.
Antidepressive Agents↗
A recurrent network model of somatosensory parametric working memory in the prefrontal cortex.
A parametric working memory network stores the information of an analog stimulus in the form of persistent neural activity that is monotonically tuned to the stimulus. The family of persistent firing patterns with a continuous range of firing rates must all be realizable under exactly the same external conditions (during the delay when the transient stimulus is withdrawn). How this can be accomplished by neural mechanisms remains an unresolved question. Here we present a recurrent cortical network model of irregularly spiking neurons that was designed to simulate a somatosensory working memory experiment with behaving monkeys. Our model reproduces the observed positively and negatively monotonic persistent activity, and heterogeneous tuning curves of memory activity. We show that fine-tuning mathematically corresponds to a precise alignment of cusps in the bifurcation diagram of the network. Moreover, we show that the fine-tuned network can integrate stimulus inputs over several seconds. Assuming that such time integration occurs in neural populations downstream from a tonically persistent neural population, our model is able to account for the slow ramping-up and ramping-down behaviors of neurons observed in prefrontal cortex.
Action Potentials↗
Analysis of 1-year vertebral fracture risk reduction data in treatments for osteoporosis.
One-year vertebral fracture risk reduction from clinical trials in adults with postmenopausal or glucocorticoid-induced osteoporosis is reviewed. Data were obtained by conducting a literature search of osteoporosis medications using the MEDLINE database, bibliographies of selected citations, and recent meeting abstracts. The methodologic quality of the trials was assessed using recently published criteria for ranking evidence. In prospective analyses, the 1-year risk of new morphometric vertebral fractures was reduced by risedronate 5 mg/d in two 3-year studies in postmenopausal women with prevalent vertebral fracture, and in two 1-year studies in patients with or at risk for glucocorticoid-induced osteoporosis. The 1-year risk of clinical vertebral fractures was reduced by alendronate and raloxifene in post hoc analyses. Reduction of morphometrically identified vertebral fracture risk is a more stringent therapeutic goal than clinical vertebral fracture risk. Therefore, more weight should be given to data from studies that use the morphometry to assess vertebral fracture incidence.
Adult↗
Gene targeting by triple helix-forming oligonucleotides.
Effective gene targeting reagents would have widespread utility for genomic manipulation including transgenic cell and animal construction and for gene therapy. They would also be useful in basic research as probes of chromatin structure, and as tools for studying the repair and mutagenesis of targeted DNA damage. We are developing triple helix-forming oligonucleotides (TFOs) for gene targeting in living mammalian cells. Challenges to TFO bioactivity include the impediments to the biochemistry of triplex formation presented by the physiological environment and the charge repulsion between the duplex and the third strand. In addition, there are biological constraints to target access imposed by mammalian chromatin structure. Here we describe the oligonucleotide modification format that appears to support biological activity of TFOs. In addition we show that manipulation of the cell biology, specifically the cell cycle, has a dramatic influence on TFO bioactivity.
Animals↗
Cost-effectiveness of lumbar spine radiography in primary care patients with low back pain.
STUDY DESIGN: Fifty-two practices in the East Midlands, United Kingdom, were included. OBJECTIVES: To test the hypothesis that referral for lumbar spine radiography is cost-effective in primary care patients with low back pain of at least 6 weeks' duration compared with usual care in which referral is not routine. SUMMARY OF BACKGROUND DATA: Lumbar spine radiography is commonly used in the management of low back pain, although the yield of findings that alter clinical management is low. Evidence is needed on the cost-effectiveness of lumbar spine radiographs in patients with low back pain. METHODS: A prospective economic analysis alongside a randomized controlled trial was used. Outcomes included the Roland disability score, pain, health status scale, EuroQol, satisfaction, direct health care costs (primary, secondary, and community care; prescribed and over-the-counter medicines; special equipment), and indirect costs (informal care, extra expenses, welfare benefits, loss of earnings and productivity). RESULTS A total of 210 participants were randomly assigned to lumbar spine radiography, and 211, to usual care. At 9 months' postrandomization, no difference between the groups was found in any health outcomes other than satisfaction. The intervention group had a higher overall satisfaction score (21 19, < 0.01). The intervention group had higher direct costs (150 pounds sterling vs 109 pounds sterling, < 0.01). Cost-effectiveness analysis shows that patient satisfaction can be increased using lumbar radiography but at an additional cost (point estimate 20 pounds sterling per point on satisfaction scale). The simulated distribution based on trial data shows that only when a 1-point increase in satisfaction is valued at more than 50 pounds sterling can it be claimed that radiography is cost-effective in these terms (incremental net monetary benefit mean = 116 pounds sterling, 95% CI pound 7, 225 pounds sterling). CONCLUSIONS: Radiography is likely to be cost-effective only when satisfaction is valued relatively highly. Strategies to enhance satisfaction for patients with low back pain without using lumbar radiography should be pursued.
Adult↗
Real doctors, treating real patients.
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Holistic Health↗
Communication mode and the processing of printed words: evidence from readers with prelingually acquired deafness.
The aim of this study was to elucidate how the primary communication background of prelingual deafened readers affects the way they mediate the recognition of written words. A computer-controlled research paradigm (a semantic decision task) asking for the categorization of familiar Hebrew nouns was used to investigate the participants' sensibility to phonological and orthographic manipulations in the target stimuli. Two groups of readers with hearing impairments and a hearing control group participated in the study. Twenty-seven of the participants with deafness (mean grade 6.9) were raised by hearing parents advocating a strict oral approach at home and at school. For an additional 22 students who were deaf (mean grade 6.9), the majority of them children of deaf parents, Israeli Sign Language was the preferred means of communication. The mean grade of the 39 participants in the hearing control group was 6.5. Findings indicate that both the hearing participants and the participants with prelingual deafness who were trained to communicate orally recoded visually presented target words phonologically. No such evidence was found for participants with deafness who were native signers. Although participants from signing backgrounds seemed to generate nonphonological representations of written words, there was no evidence that for them, the absence of recoding to phonology detrimentally affected on their ability to process such representations flexibly. In all, findings suggest a causal link between an individual's processing strategy for some written words and the modal nature of his or her primary language.
Journal Article↗
Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents.
Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.
Adult↗
Another look at the STM capacity of prelingually deafened individuals and its relation to reading comprehension.
The study investigated the short-term recall of serially presented verbal(izable) information by prelingually deafened individuals and hearing individuals, and reconsidered how short-term memory (STM) is linked with their reading skills and their memory coding strategies. A computer-controlled paradigm calling for written ordered recall of 12 lists of 8 consecutively displayed Hebrew nouns was used to assess STM capacity. Forty-nine students with prelingual deafness (mean grade 6.9) and 39 hearing students (mean grade 6.5) participated in the experiment. Twenty-seven of the participants with deafness were raised according to an oral philosophy. The remaining 22 participants from the deaf group used sign language as their preferred communication code. In general, the findings suggest that neither discrepancy in the ordered short-term recall of verbal materials nor discrepancies in reading comprehension are directly assignable to differences in the memory coding strategies of prelingually deafened and hearing individuals. If such functional discrepancies develop, they reflect absent or insufficiently internalized knowledge.
Child, Preschool↗
Protamine-fragment peptides fused to an SV40 nuclear localization signal deliver oligonucleotides that produce antisense effects in prostate and bladder carcinoma cells.
The development of antisense technology has focused on improving methods for oligonucleotide delivery into cells. In the present work, we describe a novel strategy for oligonucleotide delivery based on a bifunctional peptide composed of a C-terminal protamine-fragment that contains a DNA-binding domain and an N-terminal nuclear localization signal sequence derived from the SV40 large-T antigen (The sequences of two of the peptides are R6WGR6-PKKKRKV [s-protamine-NLS] and R4SR6FGR6VWR4-PKKKRKV [l-protamine-NLS]). We demonstrated, by intrinsic fluorescence quenching, that peptides of this class form complexes with oligodeoxynucleotides. To evaluate delivery, we used a 20-mer phosphorothioate oligomer (Isis 3521) targeted to the 3'-untranslated region of the PKC-alpha mRNA and G3139, an 18-mer phosphorothioate targeted to the first six codons of the human bcl-2 open reading frame, and complexed them with either of two peptides (s- or l-protamine-NLS). These peptides bind to and deliver antisense oligonucleotides to the nucleus of T24 bladder and PC3 prostate cancer cells, as demonstrated by confocal microscopy. Furthermore, as shown by Western and Northern blotting, the peptide-oligonucleotide complexes produced excellent downregulation of the expression of the complementary mRNAs, which in turn resulted in downregulation of protein expression. However, under certain circumstances (predominantly in PC3 cells), incubation of the cells with chloroquine was required to produce antisense activity. Using this strategy, PKC-alpha protein and mRNA expression in T24 and PC3 cells and bcl-2 expression in PC3 cells was reduced by approximately 75 +/- 10% at a minimum concentration of oligomer of 0.25 microM, in combination with 12-15 microM peptide. On the basis of our results, we conclude that arginine-rich peptides of this class may be potentially useful delivery vehicles for the cellular delivery of antisense oligonucleotides. This new strategy may have several advantages over other methods of oligonucleotide delivery and may complement already existing lipid-based technologies.
Active Transport, Cell Nucleus↗
Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study.
OBJECTIVES: Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT. DESIGN: Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire. RESULTS: At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P < 0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement. CONCLUSIONS: We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.
Aged↗
Reading comprehension and its relation to the quality of functional hearing: evidence from readers with different functional hearing abilities.
Three groups of students--19 hard of hearing, 20 deaf, and a control group of 36 typically developing hearing readers--were compared on their ability to process written words at the lexical level and on their comprehension of words within the structure of a sentence. Findings generally suggested that severe prelingual hearing loss does not prevent the development of word processing strategies adequate for efficient processing of written words at the lexical level, although such hearing loss seems to put individuals at risk of failure in internalizing syntactic knowledge crucial for proper processing of words at the sentence level. Evidence further indicated that neither the amount of functional hearing (deaf vs. hard of hearing), the hearing status of their parents (hearing impaired vs. hearing), nor the use of sign language as a primary communication mode was a direct cause in this regard.
Audiometry, Pure-Tone↗