Search

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.

Objective This study compared the cost of an integrated primary-secondary care general practitioner (GP)-based Beacon model with usual care at hospital outpatient departments (OPDs) for patients with complex type 2 diabetes. Methods A costing analysis was completed alongside a non-inferiority randomised control trial. Costs were calculated using information from accounting data and interviews with clinic managers. Two OPDs and three GP-based Beacon practices participated. In the Beacon practices, GPs with a special interest in advanced diabetes care worked with an endocrinologist and diabetes nurse educator to care for referred patients. The main outcome was incremental cost saving per patient course of treatment from a health system perspective. Uncertainty was characterised with probabilistic sensitivity analysis using Monte Carlo simulation. Results The Beacon model is cost saving: the incremental cost saving per patient was A$365 (95% confidence interval -A$901, A$55) and was cost saving in 93.7% of simulations. The key contributors to the variance in the cost saving per patient course of treatment were the mean number of patients seen per site and the number of additional presentations per course of treatment associated with the Beacon model. Conclusions Beacon clinics were less costly per patient course of treatment than usual care in hospital OPDs for equivalent clinical outcomes. Local contractual arrangements and potential variation in the operational cost structure are of significant consideration in determining the cost-efficiency of Beacon models. What is known about this topic? Despite the growing importance of achieving care quality within constrained budgets, there are few costing studies comparing clinically-equivalent hospital and community-based care models. What does this paper add? Costing analyses comparing hospital-based to GP-based health services require considerable effort and are complex. We show that GP-based Beacon clinics for patients with complex chronic disease can be less costly per patient course of treatment than usual care offered in hospital OPDs. What are the implications for practitioners? In addition to improving access and convenience for patients, transferring care from hospital to the community can reduce health system costs.

Background: Diagnosis of primary ciliary dyskinesia (PCD) relies on a combination of tests. High-speed video microscopy analysis (HSVA) is widely used to contribute to the diagnosis. It can be analyzed on the day of diagnostic consultation, but the qualitative analyses are subjective. Diagnostic accuracy and reliability of assessing ciliary function have not been robustly evaluated. We aimed to establish the accuracy of HSVA to diagnose PCD compared with a combination of tests, and to assess the interobserver reliability of HSVA analysis., Methods: We randomly selected and anonymized archived videos from 120 patients seen at three UK PCD centers. Three experienced scientists independently reviewed six videos per patient, using a standardized proforma, blinded to diagnostic and clinical data. We compared study outcomes with two references: (1) a combination of diagnostic tests in accordance with the European Respiratory Society PCD diagnostic guidelines and (2) original clinical outcome determined by all available diagnostic tests., Results: HSVA had excellent sensitivity and specificity to diagnose PCD: (1) 100% and 96%, respectively, compared with ERS guidelines, and (2) 96% and 91% compared with diagnostic outcomes. There was high interobserver agreement for "PCD-positive" outcomes (κ = 0.7)., Conclusions: Specialist scientists accurately diagnosed PCD using HSVA, with high interobserver agreement. HSVA can be reliably used to counsel patients and commence treatment on the day of testing while awaiting confirmatory investigations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: The aim of the study was to determine if a Beacon model of integrated care utilising general practitioners (GPs) with special interests could achieve similar clinical outcomes to a hospital-based specialist diabetes outpatient clinic., Methods: This pragmatic non-inferiority multisite randomised controlled trial assigned individuals with complex type 2 diabetes to care delivered by a Beacon clinic or to usual care delivered by a hospital outpatient department, in a 3:1 ratio. Owing to the nature of the study, researchers were only blinded during the allocation process. Eligible participants were aged 18 or over, had been referred by their usual GP to the hospital central referral hub with type 2 diabetes and had been triaged to be seen within 30 or 90 days. The intervention consisted of diabetes management in primary care by GPs with a special interest who had been upskilled in complex diabetes under the supervision of an endocrinologist. The primary outcome was HbA 1c at 12 months post-recruitment. The non-inferiority margin was 4.4 mmol/mol (0.4%). Both per-protocol and intention-to-treat analyses are reported., Results: Between 27 November 2012 and 14 July 2015, 352 individuals were recruited and 305 comprised the intention-to-treat sample (71 in usual care group and 234 in the Beacon model group). The Beacon model was non-inferior to usual care for both the per-protocol (difference -0.38 mmol/mol [95% CI -4.72, 3.96]; -0.03% [95% CI -0.43, 0.36]) and the intention-to-treat (difference -1.28 mmol/mol [95% CI -5.96, 3.40]; -0.12% [95% CI -0.55, 0.31]) analyses. Non-inferiority was sustained in a sensitivity analysis at 12 months. There were no statistically or clinically significant differences in the secondary outcomes of BP, lipids or quality of life as measured by the 12 item short-form health survey (SF-12v2) and the diabetes-related quality of life (DQoL-Brief) survey. Safety indicators did not differ between groups. Participant satisfaction on the eight-item client satisfaction questionnaire (CSQ-8) was good in both groups, but scores were significantly higher in the Beacon model group than the usual care group (mean [SD] 28.4 [4.9] vs 25.6 [4.9], respectively, p < 0.001)., Conclusions/interpretation: In individuals with type 2 diabetes, a model of integrated care delivered in the community by GPs with a special interest can safely achieve clinical outcomes that are not inferior to those achieved with gold-standard hospital-based specialist outpatient clinics. Individuals receiving care in the community had greater satisfaction. Further studies will determine the cost of delivering this model of care., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12612000380897 FUNDING: The study was funded by the Australian National Health and Medical Research Council (GNT1001157).

Rationale: Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal., Objectives: To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive., Methods: Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay., Results: Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed., Conclusions: The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC 50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC 50 =28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Diagnosis of primary ciliary dyskinesia (PCD) lacks a "gold standard" test and is therefore based on combinations of tests including nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA), genotyping and transmission electron microscopy (TEM). There are few published data on the accuracy of this approach.Using prospectively collected data from 654 consecutive patients referred for PCD diagnostics we calculated sensitivity and specificity for individual and combination testing strategies. Not all patients underwent all tests.HSVMA had excellent sensitivity and specificity (100% and 93%, respectively). TEM was 100% specific, but 21% of PCD patients had normal ultrastructure. nNO (30 nL·min(-1) cut-off) had good sensitivity and specificity (91% and 96%, respectively). Simultaneous testing using HSVMA and TEM was 100% sensitive and 92% specific.In conclusion, combination testing was found to be a highly accurate approach for diagnosing PCD. HSVMA alone has excellent accuracy, but requires significant expertise, and repeated sampling or cell culture is often needed. TEM alone is specific but misses 21% of cases. nNO (≤30 nL·min(-1)) contributes well to the diagnostic process. In isolation nNO screening at this cut-off would miss ∼10% of cases, but in combination with HSVMA could reduce unnecessary further testing. Standardisation of testing between centres is a future priority., (Copyright ©ERS 2016.)

Primary health care in Australia has undergone 2 decades of change. Starting with a vision for a national health strategy with general practice at its core, Australia established local meso-level primary health care organizations--Divisions of General Practice--moving from focus on individual practitioners to a professional collective local voice. The article identifies how these meso-level organizations have helped the Australian primary health care system evolve by supporting the roll-out of initiatives including national practice accreditation, a focus on quality improvement, expansion of multidisciplinary teams into general practice, regional integration, information technology adoption, and improved access to care. Nevertheless, there are still challenges to ensuring equitable access and the supply and distribution of a primary care workforce, addressing the increasing rates of chronic disease and obesity, and overcoming the fragmentation of funding and accountability in the Australian system.

Studies in mice indicate that alpha-melanocyte-stimulating hormone (alphaMSH) is immunosuppressive, but it is not known whether alphaMSH suppresses human immune responses to exogenous Ags. Human PBMCs, including monocytes, express the melanocortin 1 receptor (MC1R), and it is thought that the ability of alphaMSH to alter monocyte-costimulatory molecule expression and IL-10 release is mediated by this receptor. However, the MC1R gene is polymorphic, and certain MC1R variants compromise receptor signaling via cAMP, resulting in red hair and fair skin. Here, we have investigated whether alphaMSH can suppress Ag-induced lymphocyte proliferation in humans and whether these effects are dependent on MC1R genotype. alphaMSH suppressed streptokinase-streptodornase-induced lymphocyte proliferation, with maximal inhibition at 10(-13)-10(-11) M alphaMSH. Anti-IL-10 Abs failed to prevent suppression by alphaMSH, indicating that it was not due to MC1R-mediated IL-10 release by monocytes. Despite variability in the degree of suppression between subjects, similar degrees of alphaMSH-induced immunosuppression were seen in individuals with wild-type, heterozygous variant, and homozygous/compound heterozygous variant MC1R alleles. RT-PCR of streptokinase-streptodornase-stimulated PBMCs for all five melanocortin receptors demonstrated MC1R expression by monocytes/macrophages, MC1R and MC3R expression by B lymphocytes, but no melanocortin receptor expression by T lymphocytes. In addition, alphaMSH did not significantly inhibit anti-CD3 Ab-induced lymphocyte proliferation, whereas alphaMSH and related analogs (SHU9119 and MTII) inhibited Ag-induced lymphocyte proliferation in monocyte-depleted and B lymphocyte-depleted assays. These findings demonstrate that alphaMSH, acting probably via MC1R on monocytes and B lymphocytes, and possibly also via MC3R on B lymphocytes, has immunosuppressive effects in humans but that suppression of Ag-induced lymphocyte proliferation by alphaMSH is independent of MC1R gene status.