To Lose Both Would Look Like Carelessness: Tasmanian Devil Facial Tumour Disease

How can you manage an emerging disease threat--in this case, Tasmanian devil facial tumor disease--that poses a serious conservation threat, when so little is known about the disease

Strategies to improve control of sexually transmissible infections in remote Australian Aboriginal communities: a stepped-wedge, cluster-randomised trial

BACKGROUND: Remote Australian Aboriginal communities have among the highest diagnosed rates of sexually transmissible infections (STIs) in the world. We did a trial to assess whether continuous improvement strategies related to sexual health could reduce infection rates. METHODS: In this stepped-wedge, cluster-randomised trial (STIs in remote communities: improved and enhanced primary health care [STRIVE]), we recruited primary health-care centres serving Aboriginal communities in remote areas of Australia. Communities were eligible to participate if they were classified as very remote, had a population predominantly of Aboriginal people, and only had one primary health-care centre serving the population. The health-care centres were grouped into clusters on the basis of geographical proximity to each other, population size, and Aboriginal cultural ties including language connections. Clusters were randomly assigned into three blocks (year 1, year 2, and year 3 clusters) using a computer-generated randomisation algorithm, with minimisation to balance geographical region, population size, and baseline STI testing level. Each year for 3 years, one block of clusters was transitioned into the intervention phase, while those not transitioned continued usual care (control clusters). The intervention phase comprised cycles of reviewing clinical data and modifying systems to support improved STI clinical practice. All investigators and participants were unmasked to the intervention. Primary endpoints were community prevalence and testing coverage in residents aged 16–34 years for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis . We used Poisson regression analyses on the final dataset and compared STI prevalences and testing coverage between control and intervention clusters. All analyses were by intention to treat and models were adjusted for time as an independent covariate in overall analyses. This study was registered with the Australia and New Zealand Clinical Trials Registry, ACTRN12610000358044. FINDINGS: Between April, 2010, and April, 2011, we recruited 68 primary care centres and grouped them into 24 clusters, which were randomly assigned into year 1 clusters (estimated population aged 16–34 years, n=11 286), year 2 clusters (n=10 288), or year 3 clusters (n=13 304). One primary health-care centre withdrew from the study due to restricted capacity to participate. We detected no difference in the relative prevalence of STIs between intervention and control clusters (adjusted relative risk [RR] 0·97, 95% CI 0·84–1·12; p=0·66). However, testing coverage was substantially higher in intervention clusters (22%) than in control clusters (16%; RR 1·38; 95% CI 1·15–1·65; p=0·0006). INTERPRETATION: Our intervention increased STI testing coverage but did not have an effect on prevalence. Additional interventions that will provide increased access to both testing and treatment are required to reduce persistently high prevalences of STIs in remote communities.James Ward, Rebecca J Guy, Alice R Rumbold, Skye McGregor, Handan Wand, Hamish McManus, Amalie Dyda, Linda Garton, Belinda Hengel, Bronwyn J Silver, Debbie Taylor-Thomson, Janet Knox, Basil Donovan, Matthew Law, Lisa Maher, Christopher K Fairley, Steven Skov, Nathan Ryder, Elizabeth Moore, Jacqueline Mein, Carole Reeve, Donna Ah Chee, John Boffa and John M Kaldo

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study

Objectives To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population.Design Population based cohort study.Setting British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only).Participants 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019.Main outcome measures Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates.Results 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates.Conclusion Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals

Unilateral hydrocephalus from a gangliocytoma-somatotrophinoma:First reported case

SUMMARY: Although pituitary macroadenomas often cause mass effects on surrounding structures, it is extremely rare for pituitary lesions to disturb cerebrospinal fluid circulation. Sellar gangliocytoma-pituitary adenomas (SGPAs) are also extremely rare. Here we report the unique case of a man with the unusual combination of acromegaly from an SGPA, who presented with unilateral hydrocephalus. A 60-year-old man presented with rapid neurological deterioration, bitemporal hemianopia, and acromegalic features. Neuroimaging revealed a large sellar lesion extending superiorly into the left foramen of Monro, causing acute obstructive unilateral hydrocephalus. External ventricular drain placement improved consciousness immediately. Biochemical assessment confirmed acromegaly. Following trans-sphenoidal debulking, histology revealed a mixed gangliocytoma/sparsely-granulated somatotrophinoma. Despite the residual disease, his vision recovered remarkably, low-dose cabergoline controlled residual excess growth hormone (GH) secretion, and the residual tumour has remained extremely stable over 2 years. Hydrocephalus is an extremely rare complication of pituitary lesions, and unilateral hydrocephalus has never been reported previously. GH secretion in SGPAs is more common than for pituitary adenomas in general, raising questions regarding the aetiology and therapeutic approach to this rare combination tumour. LEARNING POINTS: Pituitary tumours most commonly present with symptoms related to endocrine disturbance or mass effects upon visual pathways (e.g. optic chiasm, nerves in the lateral cavernous sinus). However, extremely rarely, pituitary masses may disrupt cerebrospinal fluid (CSF) circulation resulting in hydrocephalus. Sellar gangliocytomas are very rare tumours and most of them are hybrid tumours with pituitary adenomas (SGPAs). SGPAs are typically indolent and may be functioning or non-functioning tumours. Growth hormone (GH)-producing SGPAs are less likely to respond to somatostatin agonists than classic somatotrophinomas. Primary surgical debulking via a trans-sphenoidal approach was effective in this individual, leading to the restoration of CSF circulation and improvement in visual disturbance, while also negating the need for permanent CSF diversion despite the residual tumour burden

Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides: First phosphodiesterase 7 inhibitors

The synthesis of a new family of benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]-thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell- dependent disorders. The IC50 values or percent inhibition values of the compounds against PDE 7 were calculated by testing them against human recombinant PDE 7 expressed in S. cerevisiae. In this expression system the only cyclic nucleotide hydrolyzing activity present in cell extracts corresponded to human PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also measured. Considering simultaneously inhibition of the three different isoenzymes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (around 10 μM); although not statistically significant, a trend toward selectivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, although less potent at PDE 7 (IC50 = 25 μM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.Peer Reviewe

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK.

Funder: Cancer Research UK; Id: http://dx.doi.org/10.13039/501100000289Funder: Medical Research CouncilFunder: Medical Research FoundationBACKGROUND: Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK. METHODS: Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time. RESULTS: A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4-4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12-2,09; p = .007). CONCLUSIONS: This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK

BackgroundPrevious studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK.MethodsHepatitis C cirrhosis patients achieving a sustained-viral-response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses; and (iii) HCC curative treatment, were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time.Results1,908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR:3.4-4.9) years. 10,396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR:1.53;95%CI: 1.12-2,09; P=0.007).ConclusionsThis study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients

Discovery of potent inhibitors of the lysophospholipase autotaxin

The autotaxin–lysophosphatidic acid (ATX–LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA ‘exit’ channel