Older women testing positive for HPV16/18 on cervical screening and risk of high-grade cervical abnormality

In Australia's HPV-based cervical screening program, we previously showed that risk of histological high-grade abnormality at 1 year post screening decreased with age in women with oncogenic HPV. In this study, we followed 878 HPV16/18 positive women aged 55 years and over for up to 3 years post screening test, to determine the proportion with histological high-grade abnormality (HGA, incorporating high-grade squamous intraepithelial abnormality (HSIL), adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma) and to correlate risk of HGA with liquid-based cytology result and with prior screening history. HGA was detected in 7.8% at 1 year and 10.0% at 3 years, with no significant difference (P = .136), despite the number of women with follow-up information significantly increasing from 82.9% to 91.0% (P < .0001). The proportion of HPV16/18 positive women with HGA at 3 years was highest in those with an HSIL cytology result (79.0%) and lowest in those with negative cytology (6.2%). Women with an adequate screening history had fewer HGA than such women with inadequate prior screening (6.6% vs 16.0%, P = .001) or with a history of an abnormality (6.6% vs 14.4%, P = .001). HPV16/18 infection in women over 55 years may have a different natural history from that in younger women, in whom HGA are more common after HPV16/18 detection. In HPV-based cervical screening programs, management algorithms for screen-detected abnormalities based on risk stratification should include factors such as age, screening history and index cytology result, so that women receive appropriate investigation and follow-up.     

The use of intermittent pneumatic compression of the thigh to affect arterial and venous blood flow proximal to a chronic wound site

Intermittent pneumatic compression of the lower limbs has been shown to have beneficial effects in patients with chronic ulceration. However, the intermittent compression cuff will normally be applied over the wound, which may produce discomfort or interfere with other treatments. Thigh‐only approaches to intermittent pneumatic compression could solve this problem. This study aimed to demonstrate if such a system would have positive effects on venous and arterial blood flow distal to the compression site, but proximal to wound sites. The distal venous and arterial effects of a prototype thigh‐only 3‐chamber sequential intermittent pneumatic compression system were tested in 20 healthy volunteers, and 13 patients with ulcers of various aetiologies using Doppler ultrasound. The system produced hyperaemic responses in the arterial flow of both test groups. The peak venous velocity on deflation of the first and second chambers of the cuff was also greater in the patients with ulceration than in the healthy volunteers (11.6 cm/s vs 8.3 cm/s, P = .1). This work demonstrates that compression of the thigh alone can produce positive haemodynamic effects in the calves of patients with chronic wounds, and that this approach should be investigated as a therapy to improve blood flow to wound sites.     

The changing face of sympathetic overactivity in hypertension

Background. The precise pathophysiological processes underlying the prothrombotic or hypercoagulable state in atrial fibrillation (AF) remain uncertain. We hypothesized a relationship between abnormal endothelial damage/dysfunction, coagulation, and angiogenic factors, thereby contributing to increased thrombogenicity.

Methods. Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and tissue factor (TF, an index of coagulation), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2), were measured by enzyme‐linked immunosorbant assay (ELISA) in 59 chronic AF patients. Data were compared to 40 age‐ and sex‐matched healthy controls in sinus rhythm.

Results. Plasma vWF, VEGF and Ang‐2 were significantly higher in AF patients compared to healthy controls (P = 0.005, P = 0.0055 and P<0.0001 respectively) but there were no significant differences in plasma Ang‐1 or TF levels between the two groups (P = 0.925 and P = 0.121 respectively). Significant correlations were found between VEGF and vWF levels (Spearman, r = 0.262, P = 0.011) and between VEGF and Ang‐2 (r = 0.333, P = 0.001).

Conclusions. Raised VEGF in association with Ang‐2 and vWF may reflect a link between abnormal endothelial damage/dysfunction and angiogenic factors. These may act together to alter TF expression and endothelial integrity, thereby contributing to the prothrombotic state in AF.     

Identification and characterisation of ten microsatellite loci in the Noisy Scrub-bird Atrichornis clamosus using next-generation sequencing technology

The Noisy Scrub-bird is an endangered species of songbird endemic to the south coast of Western Australia that has undergone a major and prolonged population bottleneck. Using shotgun 454 next-generation DNA sequencing we have identified and characterised ten polymorphic microsatellite loci in this species. Observed allelic diversity was relatively low (2–5 alleles per locus) and significant deviations from Hardy–weinberg Equilibrium observed, although the presence of null alleles was only postulated for two loci. The microsatellite loci characterised in this study will be useful in a future population genetics studies in this endangered species.     

What is Hospital at Home? Could Hospital at Home be a feasible option for acutely unwell paediatric patients?

Hospital at Home (HAH) care, where acutely unwell patients are treated at home is widely accepted across the world as a cost effective alternative to inpatient care for specific adult groups. HAH is utilised for the paediatric population in many countries although it is not a service routinely offered in the UK. This review investigates whether HAH care could be an acceptable and cost effective option for acutely unwell paediatric patients in the UK.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.