The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study

Introduction

Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH.

Methods

We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).

Results

Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively.

Conclusions

The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.     

Equilibration of H labeling between body water and free amino acids: Enabling studies of proteome synthesis

Protein synthesis can be estimated by measuring the incorporation of a labeled amino acid into a proteolytic peptide. Although prelabeled amino acids are typically administered, recent studies have tested ²H₂O; the assumption is that there is rapid equilibration of ²H (in body water) with the carbon-bound hydrogens of amino acids before those amino acids are incorporated into a protein(s). We have determined the temporal changes in ²H labeling of body water and amino acids which should build confidence in ²H₂O-based studies of protein synthesis when one aims to measure the ²H labeling of proteolytic peptides.     

Equilibration of (2)H labeling between body water and free amino acids: enabling studies of proteome synthesis

Protein synthesis can be estimated by measuring the incorporation of a labeled amino acid into a proteolytic peptide. Although prelabeled amino acids are typically administered, recent studies have tested (2)H(2)O; the assumption is that there is rapid equilibration of (2)H (in body water) with the carbon-bound hydrogens of amino acids before those amino acids are incorporated into a protein(s). We have determined the temporal changes in (2)H labeling of body water and amino acids which should build confidence in (2)H(2)O-based studies of protein synthesis when one aims to measure the (2)H labeling of proteolytic peptides.     

An ultraperformance liquid chromatography method for the normal-phase separation of lipids

An ultraperformance liquid chromatography method using normal-phase solvents, a silica column, and evaporative light-scattering detection is presented. The method is based on a quaternary gradient profile and is capable of resolving the major neutral and polar lipids present in plasma and animal tissue in under 5 min, with a total cycle time of 11 min. Limits of quantitation for 7 different lipid classes were on the order of 200 ng of material on column which enables an accurate analysis from as little as 20 μL of plasma or 50 mg of tissue for typical samples. Intraday and interday precision for the determination of the major lipid classes in human plasma ranged from 3.6 to 10.5% CV with a variability in retention time of less than 6%. The utility of the method is demonstrated through the separation and quantitation of lipids in mouse plasma, liver, and heart tissue.     

Risk of vascular events in patients with polymyalgia rheumatica

Background:

Polymyalgia rheumatica is one of the most common inflammatory rheumatologic conditions in older adults. Other inflammatory rheumatologic disorders are associated with an excess risk of vascular disease. We investigated whether polymyalgia rheumatica is associated with an increased risk of vascular events.

Methods:

We used the General Practice Research Database to identify patients with a diagnosis of incident polymyalgia rheumatica between Jan. 1, 1987, and Dec. 31, 1999. Patients were matched by age, sex and practice with up to 5 patients without polymyalgia rheumatica. Patients were followed until their first vascular event (cardiovascular, cerebrovascular, peripheral vascular) or the end of available records (May 2011). All participants were free of vascular disease before the diagnosis of polymyalgia rheumatica (or matched date). We used Cox regression models to compare time to first vascular event in patients with and without polymyalgia rheumatica.

Results:

A total of 3249 patients with polymyalgia rheumatica and 12 735 patients without were included in the final sample. Over a median follow-up period of 7.8 (interquartile range 3.3–12.4) years, the rate of vascular events was higher among patients with polymyalgia rheumatica than among those without (36.1 v. 12.2 per 1000 person-years; adjusted hazard ratio 2.6, 95% confidence interval 2.4–2.9). The increased risk of a vascular event was similar for each vascular disease end point. The magnitude of risk was higher in early disease and in patients younger than 60 years at diagnosis.

Interpretation:

Patients with polymyalgia rheumatica have an increased risk of vascular events. This risk is greatest in the youngest age groups. As with other forms of inflammatory arthritis, patients with polymyalgia rheumatica should have their vascular risk factors identified and actively managed to reduce this excess risk.Inflammatory rheumatologic disorders such as rheumatoid arthritis,^1,2 systemic lupus erythematosus,^2,3 gout,⁴ psoriatic arthritis^2,5 and ankylosing spondylitis^2,6 are associated with an increased risk of vascular disease, especially cardiovascular disease, leading to substantial morbidity and premature death.^2–6 Recognition of this excess vascular risk has led to management guidelines advocating screening for and management of vascular risk factors.^7–9Polymyalgia rheumatica is one of the most common inflammatory rheumatologic conditions in older adults,¹⁰ with a lifetime risk of 2.4% for women and 1.7% for men.¹¹ To date, evidence regarding the risk of vascular disease in patients with polymyalgia rheumatica is unclear. There are a number of biologically plausible mechanisms between polymyalgia rheumatica and vascular disease. These include the inflammatory burden of the disease,^12,13 the association of the disease with giant cell arteritis (causing an inflammatory vasculopathy, which may lead to subclinical arteritis, stenosis or aneurysms),¹⁴ and the adverse effects of long-term corticosteroid treatment (e.g., diabetes, hypertension and dyslipidemia).^15,16 Paradoxically, however, use of corticosteroids in patients with polymyalgia rheumatica may actually decrease vascular risk by controlling inflammation.¹⁷ A recent systematic review concluded that although some evidence exists to support an association between vascular disease and polymyalgia rheumatica,¹⁸ the existing literature presents conflicting results, with some studies reporting an excess risk of vascular disease^19,20 and vascular death,^21,22 and others reporting no association.^23–26 Most current studies are limited by poor methodologic quality and small samples, and are based on secondary care cohorts, who may have more severe disease, yet most patients with polymyalgia rheumatica receive treatment exclusively in primary care.²⁷The General Practice Research Database (GPRD), based in the United Kingdom, is a large electronic system for primary care records. It has been used as a data source for previous studies,²⁸ including studies on the association of inflammatory conditions with vascular disease²⁹ and on the epidemiology of polymyalgia rheumatica in the UK.³⁰ The aim of the current study was to examine the association between polymyalgia rheumatica and vascular disease in a primary care population.     

Chlamydia Detection during the Menstrual Cycle: A Cross-Sectional Study of Women Attending a Sexual Health Service

Background

We investigated the detection of chlamydia at different stages of the menstrual cycle.

Methods

Electronic medical records for women attending Melbourne Sexual Health Centre between March 2011 and 31^st December 2012, who were tested for chlamydia by nucleic acid amplification of high vaginal, cervical, or urinary samples, and who recorded a date of last normal menstrual period (LNMP) between 0–28 days were included in the analysis. Logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence intervals (CI) for the association of chlamydia with menstrual cycle adjusted by demographics and behavioural variables. Chlamydia and beta globin load were determined on those with stored samples.

Results

Of the 10,017 consultations that included a test for chlamydia and a valid LNMP, there were 417 in which chlamydia was detected. The proportion of samples with chlamydia was greater in the luteal phase (4.8%, 184/3831) than in the follicular phase (3.4%, 233/6816) both in the crude (OR 1.29 95%CI 1.1–1.6, p = 0.01) and adjusted odds ratio (aOR) 1.4 (95%CI 1.1–1.8, p = 0.004). Among women using hormonal contraception, there was no significant association with the luteal phase of the menstrual cycle (aOR 1.3, 95%CI 0.9, 1.8, p = 0.18). Among women not using hormonal contraception, there was a significant association with the luteal phase (aOR 1.6, (95% CI 1.1–2.3, p = 0.007). The chlamydia load was not significantly different in the 329 positive stored samples in weeks 3 and 4 vs weeks 1 and 2 for any site (P>0.12).

Conclusions

The higher detection of chlamydia detection in the luteal phase of the menstrual cycle in only those not taking hormonal contraception suggest that hormonal factors influence chlamydia detection. The absence of a significantly highly chlamydia load in women during the luteal phase raises questions about the mechanism.     

Methodological Challenges in Collecting Social and Behavioural Data Regarding the HIV Epidemic among Gay and Other Men Who Have Sex with Men in Australia

Background

Behavioural surveillance and research among gay and other men who have sex with men (GMSM) commonly relies on non-random recruitment approaches. Methodological challenges limit their ability to accurately represent the population of adult GMSM. We compared the social and behavioural profiles of GMSM recruited via venue-based, online, and respondent-driven sampling (RDS) and discussed their utility for behavioural surveillance.

Methods

Data from four studies were selected to reflect each recruitment method. We compared demographic characteristics and the prevalence of key indicators including sexual and HIV testing practices obtained from samples recruited through different methods, and population estimates from respondent-driven sampling partition analysis.

Results

Overall, the socio-demographic profile of GMSM was similar across samples, with some differences observed in age and sexual identification. Men recruited through time-location sampling appeared more connected to the gay community, reported a greater number of sexual partners, but engaged in less unprotected anal intercourse with regular (UAIR) or casual partners (UAIC). The RDS sample overestimated the proportion of HIV-positive men and appeared to recruit men with an overall higher number of sexual partners. A single-website survey recruited a sample with characteristics which differed considerably from the population estimates with regards to age, ethnically diversity and behaviour. Data acquired through time-location sampling underestimated the rates of UAIR and UAIC, while RDS and online sampling both generated samples that underestimated UAIR. Simulated composite samples combining recruits from time-location and multi-website online sampling may produce characteristics more consistent with the population estimates, particularly with regards to sexual practices.

Conclusion

Respondent-driven sampling produced the sample that was most consistent to population estimates, but this methodology is complex and logistically demanding. Time-location and online recruitment are more cost-effective and easier to implement; using these approaches in combination may offer the potential to recruit a more representative sample of GMSM.     

Decreased Management of Genital Warts in Young Women in Australian General Practice Post Introduction of National HPV Vaccination Program: Results from a Nationally Representative Cross-Sectional General Practice Study

Objectives

Since the introduction of Australia''s human papillomavirus vaccination program, the management rate of genital warts in sexual health clinics and private hospitals has decreased in women of vaccine-eligible age. However, most genital warts in Australia are managed in general practice. This study examines whether a similar decrease occurred in Australian general practice after the introduction of the program.

Methods

Analysis of a nationally representative cross-sectional database of Australian general practice activity (1,175,879 patient encounters with 11,780 general practitioners). Genital warts management rates were estimated for the periods before and after introduction of the program (Pre-program, July 2002-June 2006; Post-program, July 2008-June 2012). Control conditions included genital herpes and gardnerella/bacterial vaginosis in female patients and genital herpes and urethritis in male patients. Trends in management rates by year, pre-vaccine (July 2000-June 2007) and post-vaccine (July 2007-June 2012) were also calculated.

Results

Management rate of genital warts among women potentially covered by program (aged 15–27 years) decreased by 61% from 4.33 per 1,000 encounters in the Pre-program period to 1.67 in the Post-program period. Trend analysis of the post-vaccine period showed, among women of vaccine eligible age, a significant year-on-year reduction in the rate of genital warts management (p<0.0001) and a significant increase in the management rate of control conditions per year (p<0.0001). For all other age-sex groups there was no significant change in the management rate of genital warts between the Pre- and Post-program periods.

Conclusion

The large decrease in general practice management of genital warts in women of vaccine-eligible age highlights the success of the program in the wider community.