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Biomedical subjects

David Bennett

Publications and source records attributed to David Bennett.

At least 19 recordsLinked to original sources
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2006

Mild cognitive impairment.

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

Aged↗
PubMed2005

Vitamin E and donepezil for the treatment of mild cognitive impairment.

BACKGROUND: Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. METHODS: In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. RESULTS: A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers. CONCLUSIONS: Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Alzheimer Disease↗
PubMed2005

Aggression at age 5 as a function of prenatal exposure to cocaine, gender, and environmental risk.

OBJECTIVE: To examine childhood aggression at age 5 in a multiple risk model that includes cocaine exposure, environmental risk, and gender as predictors. METHODS: Aggression was assessed in 206 children by using multiple methods including teacher report, parent report, child's response to hypothetical provocations, and child's observed behavior. Also examined was a composite score that reflected high aggression across contexts. RESULTS: Multiple regression analyses indicated that a significant amount of variance in each of the aggression measures and the composite was explained by the predictors. The variables that were independently related differed depending on the outcome. Cocaine exposure, gender, and environmental risk were all related to the composite aggression score. CONCLUSIONS: Cocaine exposure, being male, and a high-risk environment were all predictive of aggressive behavior at 5 years. It is this group of exposed boys at high environmental risk that is most likely to show continued aggression over time.

Aggression↗
PubMed2004

Replacing positivism in medical geography.

Revisiting debates about philosophical approaches in medical geography suggests that logical positivism may have been prematurely discarded. An analysis of authoritative texts in medical geography and their sources in human geography shows that logical positivism has been conflated with Comtean positivism, science, empiricism, quantification, science politics, scientism and so on, to produce the "standard version" of the all-purpose pejorative "positivism", which it is easy to dismiss as an evil. It is argued that the standard version fails to do justice to logical positivism, being constructed on sources which are at some distance from the logical positivist movement itself. An alternative approach is then developed, an historically and geographically situated interpretation of logical positivism as a deliberately and knowingly constructed oppositional epistemology within an oppressive and anti-scientific culture predicated on idealist intuitionism. Contrasting the standard version with this alternative reading of logical positivism suggests that much may have been lost in human, and thus, medical geography, by throwing out the logical positivist baby with the "positivism" bath water. It is concluded that continuing to unpack the standard version of logical positivism may identify benefits from a more nuanced appreciation of logical positivism, but it is premature to take these to the level of detailed impacts on the kinds of medical geographies that could be done or the ways of doing them.

Geography↗
PubMed2004

Type I immune-mediated polyarthritis in dogs: 39 cases (1997-2002).

OBJECTIVE: To determine clinical signs, laboratory findings, relationship to vaccination, and response to treatment for type I immune-mediated polyarthritis (IMPA) in dogs. DESIGN: Retrospective study. ANIMALS: 39 dogs PROCEDURE: Clinical records and radiographic reports from 3 university referral hospitals were reviewed. Clinical signs, laboratory and investigative findings, relationship to vaccination, and response to treatment were evaluated. RESULTS: Clinical signs and initial laboratory and clinical investigative findings were frequently abnormal but were nonspecific and not associated with likelihood of recovery. Time of vaccination was not associated with onset of disease. Chemotherapeutic immunosuppression resulted in complete cure in 56% of dogs. Continuous medication was required in 18% (7/39) of dogs, relapses were treated successfully in 13% (5/39) of dogs, and 15% (6/39) of dogs died or were euthanatized as a result of disease. CONCLUSIONS AND CLINICAL RELEVANCE: The possible involvement of vaccination in type I IMPA was not made clear from this study because of the small population size. Signalment, clinical signs, and results of diagnostic tests other than multiple synovial fluid analyses were generally nonspecific. Most dogs with type I IMPA responded to initial immunosuppressive treatment, but 31% (12/39) of dogs relapsed, required further treatment, or both.

Animals↗
PubMed2004

Microscale fractionation facilitates detection of differentially expressed proteins in Alzheimer's disease brain samples.

Fractionation enhances the resolution of proteins with similar characteristics by reducing the number of proteins that comigrate in gels, thus facilitating the detection of lower-abundance proteins and the accurate determination of quantitative and qualitative differences in disease and normal samples. An efficient, reproducible microscale fractionation protocol for complex protein mixtures using novel ion-exchange membrane chromatographic substrates (PerkinElmer, Boston, MA, USA; Vivascience, Carlsbad, CA, USA) is described. The fractionation techniques were used in combination with two-dimensional (2-D) gels and orthogonal matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry to identify differentially expressed proteins in brain samples from persons with and without Alzheimer's disease.

Alzheimer Disease↗
PubMed2004

A european, multicenter, observational study to assess the value of gastric-to-end tidal PCO2 difference in predicting postoperative complications.

Automated online tonometry displays a rapid, semicontinuous measurement of gastric-to-endtidal carbon dioxide (Pr-etCO2) as an index of gastrointestinal perfusion during surgery. Its use to predict postoperative outcome has not been studied in general surgery patients. We, therefore, studied ASA physical status III-IV patients operated on for elective surgery under general anesthesia and a planned duration of >2 h in a European, multicenter study. As each center was equipped with only 1 tonometric monitor, a randomization was performed if more than one patient was eligible the same day. Patients not monitored with tonometry were assessed only for follow-up. The main outcome measure was the assessment of postoperative functional recovery delay (FRD) on day 8. Among the 290 patients studied, 34% had FRD associated with a longer hospital stay. The most common FRDs were gastrointestinal (45%), infection (39%), and respiratory (35%). In those monitored with tonometry (n = 179), maximum Pr-etCO2 proved to be the best predictor increasing the probability of FRD from 34% for all patients to 65% at a cut-off of 21 mm Hg (2.8kPa) (sensitivity 0.27, specificity 0.92, positive predictive value 64%, negative predictive value 70%). We conclude that intraoperative Pr-etCO2 measurement may be a useful prognostic index of postoperative morbidity.

Adult↗
PubMed2004

Access to primary health care for Australian adolescents: how congruent are the perspectives of health service providers and young people, and does it matter?

OBJECTIVE: To explore the extent of congruence between the views of service providers and young people (on adolescents' health concerns, barriers to accessing health services and ideal service model) in order to improve and increase the appropriateness, quality and usage of primary health care services. METHODS: A qualitative data collection technique was used. During 2001/02, focus groups were conducted in urban and rural locations with adolescents (in and out of mainstream education), general practitioners, community health staff and youth health workers. RESULTS: Service providers and young people identified a similar range of health concerns for young people, with young people adding additional issues of great importance to them that service providers felt were not in their 'domain of treatment'. There was reasonable congruence in regard to 'ideal service model' with some differences relating to methods of information delivery. However, for 'barriers to accessing services' there were major discrepancies. CONCLUSIONS: While there is some common understanding between young people and service providers on certain aspects of health services, there are clearly areas where perceptions differ. This discrepancy matters because it may adversely affect the quality of provider-adolescent interaction and the willingness of adolescents to access services. IMPLICATIONS: To deliver optimal health services to young people, the differences in understanding regarding services need to be addressed. Strategies could include promotion to, and encouragement of, young people to seek help, continuing professional education of providers and changes in remuneration policies.

Adolescent↗
PubMed2003

Genetic characterization of a novel metallo-beta-lactamase gene, blaIMP-13, harboured by a novel Tn5051-type transposon disseminating carbapenemase genes in Europe: report from the SENTRY worldwide antimicrobial surveillance programme.

OBJECTIVE: In 2001, as part of the SENTRY worldwide antimicrobial surveillance programme, Pseudomonas aeruginosa 86-14571A was isolated at a hospital in Rome from a cancer patient with a bloodstream infection. The isolate was resistant to all antibiotics except amikacin, and displayed an imipenem MIC of 64 mg/L that decreased to 8 mg/L in the presence of EDTA. The resistance determinant was investigated. METHODS: The resistant determinant was cloned in Escherichia coli using a shotgun cloning approach. RESULTS: Sequence analysis revealed the presence of a novel IMP-type metallo-beta-lactamase (MBL) gene, blaIMP-13. This encoded a protein displaying most identity to IMP variants: 93% and 92.3% identity, respectively, to IMP-8 and IMP-2 (previously identified in Italy). The protein had 19 amino acid changes from IMP-2 and 17 amino acid changes from IMP-8. The blaIMP-13 gene was found as a gene cassette in the first position of a class 1 integron. A 25 bp inverted repeat sequence IRi was identified 174 bp upstream of the class I integrase, which suggests that the integron is found on a Tn402-like transposon, or defective transposon derivative. This element, in turn, is located in the transposition locus (tnp region) of a Tn21 subfamily transposon that showed most identity to Tn5051, a transposon recently identified from a strain of Pseudomonas putida isolated in New York. Interestingly, the insertion point of the Tn402-like transposon and the sequence of the Tn5051-like genes were identical to those of the genetic element harbouring blaVIM-2 recently identified in Poland. CONCLUSIONS: The resistance determinant of P. aeruginosa 86-14571A is a novel IMP-type MBL carried on a composite transposon responsible for wide geographical dissemination of MBL genes in Europe.

Amino Acid Sequence↗
PubMed2003

Calcium-binding proteins MRP 8 and 14 in a Staphylococcus aureus infection model: role of therapy, inflammation, and infection persistence.

Concentrations of the calcium-binding proteins of the S100 family, myeloid-related proteins 8 and MRP 14 (MRP8/14), are elevated in chronic infections, yet the role of these proteins is not clearly defined. Using commercial and developed enzyme immunoassays, we assayed for MRP8/14 in sterile-filtered abscess fluid from tissue-cage-implanted rats and rabbits. Staphylococcus aureus abscesses were created 6 weeks after the intraperitoneal implantation of tissue cages. Leukocytes, bacteria, and non-protein-bound calcium and zinc were measured in the infection exudate at day 3 or 5 of infection and after 8 days of treatment with antimicrobials beta-lactams (18 rabbits, 35 rats) and fluoroquinolone-rifampin (6 rabbits). Half of the infected rats were depleted of neutrophils; these rats exhibited significantly lower MRP 8/14 concentrations on all days sampled, regardless of the level of infection. The level of abscess MRP 8/14 is high early in the course of infection but decreases with effective antimicrobial treatment by as much as 100-fold. Thirty-day-old abscesses with log 6 bacterial counts and low neutrophil counts showed low concentrations of MRP 8/14 in these models. In abscess fluid, interleukin-6, as a representative marker of inflammation, correlated with MRP8/14, whereas ionized calcium and zinc did not. Our data suggest that infection and inflammation are not equal stimuli for MRP 8/14. The neutrophil appears to be the main source of MRP8/14 in this model.

Abscess↗
PubMed2003

Assessment of lifetime participation in cognitively stimulating activities.

Cognitively stimulating experience is thought to contribute to cognitive reserve. We constructed a questionnaire consisting of 25 items about frequency of participation in cognitive activities across the life span and administered it to two groups of older persons. The total score on the scale had high internal consistency (coefficient alpha = 0.88) and temporal stability over a 4-week re-test interval (r = 0.79), and it was positively correlated with education. In analyses controlling for age, sex, and education, more frequent cognitive activity was related to better perceptual speed, visuospatial ability, and semantic memory but not to episodic memory or working memory. The results suggest that the scale provides a psychometrically sound measure of frequency of cognitive activity across the life span.

Aged↗
PubMed2003

Cancer Battles and the Sleep of Reason policy and science need not be related.

Cancer Battles and the Sleep of Reason is an inquiry into the role of scientific experts in environmental health policy-making. The article first establishes two propositions: that there is no necessary relationship between science and environmental health policy; and that risk assessment is not the only science of environmental health. It then asks the question: why should policy-makers consult the scientific experts? If experts are to be consulted, there will have to be some way of grading experts as to the quality of their advice and their usefulness to policy-makers. A mode of grading experts is provided in Environmental Cancer--A Political Disease? by S. Robert Lichter and Stanley Rothman. But the arguments in this book are shown to be worthless; the book fails to address the underlying issue of why the experts should be consulted at all. The article concludes that experts are to be consulted whenever policy-makers consider their advice to be essential or useful. There is nothing in the scientific disciplines that entrenches them in the policymaking process; the opinions of scientific experts have no special place in environmental health policy.

Journal Article↗
PubMed2003

Evaluation of ground reaction forces produced by chickens walking on a force plate.

OBJECTIVE: To evaluate the use of a force plate as a method for objective gait analysis in adult poultry, to characterize ground reaction forces (GRFs) produced in adult chickens during normal walking, and to assess the variability of GRFs. ANIMALS: 18 clinically normal 5-month-old Brown Leghorn hens. PROCEDURE: Vertical, craniocaudal, and mediolateral GRFs were measured as hens walked across a standard force plate embedded in the middle of a runway. RESULTS: All GRFs were significantly affected by speed, and variability was high. With increasing speed, overall stance time decreased, but the percentage of stance time spent in braking or propulsion remained approximately equal. There was an overall increase in maximum propulsion force, which was produced at a greater rate over a shorter time; thus, propulsion integral decreased. Maximum braking forces and braking integrals were variable, but the rate at which the forces were generated increased. Mediolateral forces were 2 to 3 times greater in hens than values that have been reported for other species. CONCLUSIONS AND CLINICAL RELEVANCE: A standard force plate can be used to objectively measure GRFs in walking adult hens; however, the large variation in the data suggests that the technique in its current form would be of limited clinical use. Overall, vertical and craniocaudal forces had similar characteristics to those of other species, whereas mediolateral forces were found to be much greater in chickens than for other species.

Animals↗
PubMed2003

Access to primary health care for Australian young people: service provider perspectives.

BACKGROUND: To adequately address the complex health needs of young people, their access to services, and the quality of services received, must be improved. AIMS: To explore the barriers to service provision for young people and to identify the training needs of primary healthcare service providers in New South Wales (NSW), Australia. DESIGN OF STUDY: A cross-sectional, qualitative study of the perspectives of a range of health service providers. SETTING: A range of primary healthcare organisations across NSW. METHODS: Samples of general practitioners (GPs), youth health workers, youth health coordinators, and community health centre staff were drawn from urban and rural clusters across NSW. Focus groups and interviews were used to identify barriers to service provision and the training needs of service providers. Data were tape recorded, transcribed, and analysed. RESULTS: Barriers to service provision among GPs and community health centre staff included inadequate time, flexibility, skills, and confidence in working with young people, and poor linkages with other relevant services. Training needs included better knowledge of and skills in adolescent health requirements, working with adolescents, and working with other services. Barriers to service provision for youth health workers and coordinators included lack of financial resources and infrastructure. There were few linkages between groups of service providers. CONCLUSION: Models of service provision that allow stronger linkages between service providers, sufficient time for consultation with young people, adequate training and support of health professionals, and flexibility of service provision, including outreach, should be explored and evaluated.

Adolescent↗