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1.  Management of High Blood Pressure in Those without Overt Cardiovascular Disease Utilising Absolute Risk Scores 
Increasing blood pressure has a continuum of adverse risk for cardiovascular events. Traditionally this single measure was used to determine who to treat and how vigorously. However, estimating absolute risk rather than measurement of a single risk factor such as blood pressure is a superior method to identify who is most at risk of having an adverse cardiovascular event such as stroke or myocardial infarction, and therefore who would most likely benefit from therapeutic intervention. Cardiovascular disease (CVD) risk calculators must be used to estimate absolute risk in those without overt CVD as physician estimation is unreliable. Incorporation into usual practice and limitations of the strategy are discussed.
PMCID: PMC3124675  PMID: 21747980
2.  Ankle-Brachial Index determination and peripheral arterial disease diagnosis by an oscillometric blood pressure device in primary care: validation and diagnostic accuracy study 
BMJ Open  2012;2(5):e001689.
To determine the level of agreement between a ‘conventional’ Ankle-Brachial Index (ABI) measurement (using Doppler and mercury sphygmomanometer taken by a research nurse) and a ‘pragmatic’ ABI measure (using an oscillometric device taken by a practice nurse) in primary care. To ascertain the utility of a pragmatic ABI measure for the diagnosis of peripheral arterial disease (PAD) in primary care.
Cross-sectional validation and diagnostic accuracy study. Descriptive analyses were used to investigate the agreement between the two procedures using the Bland and Altman method to determine whether the correlation between ABI readings varied systematically. Diagnostic accuracy was assessed via sensitivity, specificity, accuracy, likelihood ratios, positive and negative predictive values, with ABI readings dichotomised and Receiver Operating Curve analysis using both univariable and multivariable logistic regression.
Primary care in metropolitan and rural Victoria, Australia between October 2009 and November 2010.
250 persons with cardiovascular disease (CVD) or at high risk (three or more risk factors) of CVD.
Despite a strong association between the two method's measurements of ABI there was poor agreement with 95% of readings within ±0.4 of the 0.9 ABI cut point. The multivariable C statistic of diagnosis of PAD was 0.89. Other diagnostic measures were sensitivity 62%, specificity 92%, positive predictive value 67%, negative predictive value 90%, accuracy 85%, positive likelihood ratio 7.3 and the negative likelihood ratio 0.42.
Oscillometric ABI measures by primary care nurses on a population with a 22% prevalence of PAD lacked sufficient agreement with conventional measures to be recommended for routine diagnosis of PAD. This pragmatic method may however be used as a screening tool high-risk and overt CVD patients in primary care as it can reliably exclude the condition.
PMCID: PMC3488728  PMID: 23100446
Primary Care; Vascular Medicine; Public Health
3.  Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers 
PLoS ONE  2009;4(5):e5474.
HIV-1+ individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4+ T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.
Methodology/Principal Findings
CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-γ ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1+ individuals originally identified as “Long-term non-progressors” in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-γ producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-γ production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1+ patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-γ production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.
Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory.
PMCID: PMC2677159  PMID: 19434236
5.  A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy 
Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection.
Chronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination.
Thirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and neutralizing antibody titres.
Neither IL-2 nor Remune™ vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone.
Induction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses.
PMCID: PMC1864986  PMID: 17428345
7.  Managing conjunctivitis in general practice 
BMJ : British Medical Journal  2006;333(7565):446.
PMCID: PMC1553496  PMID: 16931848
8.  Interpretation of screening test results 
BMJ : British Medical Journal  2006;333(7564):397.
PMCID: PMC1550464  PMID: 16916838
9.  Epidemiological modelling of routine use of low dose aspirin for the primary prevention of coronary heart disease and stroke in those aged ≥70 
BMJ : British Medical Journal  2005;330(7503):1306.
Objective To investigate the routine use of low dose aspirin in people aged ≥ 70 without overt cardiovascular disease.
Design Epidemiological modelling in a hypothetical population.
Setting Reference populations of men and women in the year 2000 from the state of Victoria, Australia.
Subjects 10 000 men and 10 000 women aged 70-74 with no cardiovascular disease.
Main outcome measures First ever myocardial infarction or unstable angina, ischaemic or haemorrhagic stroke, and major gastrointestinal haemorrhage. Health adjusted years of life lived.
Results The proportional benefit gained from the use of low dose aspirin by the prevention of myocardial infarctions (-389 in men, -321 in women) and ischaemic stroke (-19 in men and -35 in women) is offset by excess gastrointestinal (499 in men, 572 in women) and intracranial (76 in men, 54 in women) bleeding. The results in health adjusted years of life lived (which take into account length and quality of life) are equivocal for aspirin causing net harm or net benefit.
Conclusion Epidemiological modelling suggests that any benefits of low dose aspirin on risk of cardiovascular disease in people aged ≥ 70 are offset by adverse events. These findings are tempered by wide confidence intervals, indicating that the overall outcome could be beneficial or adverse.
PMCID: PMC558207  PMID: 15908442
10.  The mummy's curse: historical cohort study 
BMJ : British Medical Journal  2002;325(7378):1482-1484.
To examine survival of individuals exposed to the “mummy's curse” reputedly associated with the opening of the tomb of Tutankhamen in Luxor, Egypt, between February 1923 and November 1926.
Retrospective cohort study.
44 Westerners identified by Howard Carter as present in Egypt at the specified dates, 25 of whom were potentially exposed to the curse.
Main outcome measures
Length of survival after date of potential exposure.
In the 25 people exposed to the curse the mean age at death was 70 years (SD 12) compared with 75 (13) in those not exposed (P=0.87 for difference). Survival after the date of exposure was 20.8 (15.2) v 28.9 (13.6) years respectively (P=0.95 for difference). Female sex was a predictor for survival (P=0.02).
There was no significant association between exposure to the mummy's curse and survival and thus no evidence to support the existence of a mummy's curse.
What is already known on this topicThe methods of evidence based medicine have not been used to investigate the reality of the “mummy's curse”The arguments against the curse have been as anecdotal as the contemporary newspapers that reported itWhat this study addsThere was no association between potential exposure to the mummy's curse during the excavation of Tutankamen's tomb and death within 10 yearsNo evidence was found for the existence of a mummy's curse
PMCID: PMC139048  PMID: 12493675
11.  Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort 
BMJ : British Medical Journal  2002;325(7368):815.
To identify simple long term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in elderly patients in general practice.
Prospective cohort study.
169 general practices in Victoria, Australia.
503 patients aged 65-84 with treated hypertension who were withdrawn from all antihypertensive drugs and remained drug free and normotensive for an initial two week period; all were followed for a further 12 months.
Main outcome measures
Relative likelihood of maintaining normotension 12 months after drug withdrawal; relative likelihood of early return to hypertension after drug withdrawal.
The likelihood of remaining normotensive at 12 months was greater among younger patients (65-74 years), patients with lower “on-treatment” systolic blood pressure, patients on single agent treatment, and patients with a greater waist:hip ratio. The likelihood of return to hypertension was greatest for patients with higher “on-treatment” systolic blood pressure.
Age, blood pressure control, and the number of antihypertensive drugs are important factors in the clinical decision to withdraw drug treatment. Because of consistent rates of return to antihypertensive treatment, all patients from whom such treatment is withdrawn should be monitored indefinitely to detect a recurrence of hypertension.
What is already known on this topicSystematic reviews have identified predictors of success of withdrawal of antihypertensive medicationThe reviewed studies have mainly been in a hospital or specialist clinic setting, and their recommendations may not be practical in general practiceWhat this paper addsThis study has identified simple predictors of success that are readily available to general practitionersOn-treatment systolic blood pressure, the number of blood pressure lowering drugs, and the age of the patient are reliable indicators of who may successfully stop taking their drugsGeneral practitioner practitioners should not be dissuaded from offering drug withdrawal to patients with greater waist:hip ratios
PMCID: PMC128950  PMID: 12376444
12.  Five-Year Safety Evaluation of Maraviroc in HIV-1–Infected Treatment-Experienced Patients 
Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc.
Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed.
A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up.
Maraviroc was generally safe in treatment-experienced participants for >5 years.
PMCID: PMC3893710  PMID: 24419064
maraviroc; CCR5 antagonist; HIV; antiretroviral therapy; safety; treatment-experienced patients
13.  Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study 
Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension.
Methods We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693).
Results Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group.
Conclusions Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.
PMCID: PMC2854890  PMID: 20392760

Results 1-13 (13)