Post-COVID care delivery: The experience from an Irish tertiary centre's post-COVID clinic.

BACKGROUND: The long-term effects of SARS-CoV-2 infection and optimal follow-up approach are not well-recognised. Here we describe the implementation of a post-COVID clinic in an Irish tertiary centre after the first wave of the pandemic. This study describes the characteristics of our patient cohort and the operations and outcomes of the clinic, exploring some of the risk factors for developing post-COVID syndrome and the appropriateness of the triage system employed. METHODS: All SARS-CoV-2 positive patients from March 10th to June 14th 2020 were telephone-triaged as red, amber or green based on ongoing symptoms with clinic appointments scheduled accordingly. All clinic visits were face-to-face with the infectious diseases medical team and a proforma for each patient was completed. Data were collected retrospectively by reviewing the proformas and the electronic medical record (EMR). RESULTS: 311 patients attended the clinic. Median time from illness to clinic appointment was 95 days (IQR 77-105.5). 204 patients (66%) were female, 192 (62%) were hospital staff, and the median age was 43 years (IQR 31-53). 138 patients (44%) had required hospital admission. At their first clinic visit 219 patients (70%) had ongoing symptoms. A further appointment was made for 62 patients (20%). 34 patients (11%) were discussed at an MDT meeting, and 55 (18%) were referred onward to a specialist service. 85% of those triaged green, 73% of those triaged amber, and 39% of those triaged red did not receive further follow up after one clinic visit. Patients were more likely to require follow up with reported dyspnoea (OR 5.6; 95% CI 2.8-11.3; p <0.001), cough (OR 3.0; 95% CI 1.1-8.4, p = 0.04), and palpitations (OR 3.6; 95% CI 1.0-12.3; p = 0.04). Female sex was associated with increased odds of a higher triage category (OR 1.8; 95% CI 1.08 to 3.20; p = 0.02), as was requiring admission to hospital (OR 4.0; 95% CI 2.34 to 6.90; p < 0.001). CONCLUSION: The long-term effects of COVID-19 are significant with 70% of our cohort experiencing persistent symptoms. Persistent dyspnoea, cough and palpitations were associated with increased need for follow up. This study also suggests that a traffic light telephone-triage service followed by a face-to-face medical-led clinic could be an effective way of identifying patients who require further management.

MET-PREVENT: metformin to improve physical performance in older people with sarcopenia and physical prefrailty/frailty - protocol for a double-blind, randomised controlled proof-of-concept trial.

INTRODUCTION: Skeletal muscle dysfunction is central to both sarcopenia and physical frailty, which are associated with a wide range of adverse outcomes including falls and fractures, longer hospital stays, dependency and the need for care. Resistance training may prevent and treat sarcopenia and physical frailty, but not everyone can or wants to exercise. Finding alternatives is critical to alleviate the burden of adverse outcomes associated with sarcopenia and physical frailty. This trial will provide proof-of-concept evidence as to whether metformin can improve physical performance in older people with sarcopenia and physical prefrailty or frailty. METHODS AND ANALYSIS: MET-PREVENT is a parallel group, double-blind, placebo-controlled proof-of-concept trial. Trial participants can participate from their own homes, including completing informed consent and screening assessments. Eligible participants with low grip strength or prolonged sit-to-stand time together with slow walk speed will be randomised to either oral metformin hydrochloride 500 mg tablets or matched placebo, taken three times a day for 4 months. The recruitment target is 80 participants from two secondary care hospitals in Newcastle and Gateshead, UK. Local primary care practices will act as participant identification centres. Randomisation will be performed using a web-based minimisation system with a random element, balancing on sex and baseline walk speed. Participants will be followed up for 4 months post-randomisation, with outcomes collected at baseline and 4 months. The primary outcome measure is the four metre walk speed at the 4-month follow-up visit. ETHICS AND DISSEMINATION: The trial has been approved by the Liverpool NHS Research Ethics Committee (20/NW/0470), the Medicines and Healthcare Regulatory Authority (EudraCT 2020-004023-16) and the UK Health Research Authority (IRAS 275219). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. TRIAL REGISTRATION NUMBER: ISRCTN29932357.

Assessing the impact of COVID-19 at 1-year using the SF-12 questionnaire: Data from the Anticipate longitudinal cohort study.

BACKGROUND: Few studies to date have explored the health-related quality of life (HRQoL) in patients with long COVID. METHODS: The Anticipate Study is a prospective single-centre observational cohort study. Hospitalised and nonhospitalised patients were seen at a dedicated post-COVID clinic at a 2-4 month (Timepoint 1) and 7-14 month follow-up (Timepoint 2). The main objectives of this study are to assess the longitudinal impact of COVID-19 in patients using the 12-item Short Form Survey (SF-12) score, a health-related quality of life tool, and to identify predictors of developing post-COVID-19 syndrome (PoCS). In addition, we aimed to describe symptomatology and identify predictors of PoCS at 1-year. RESULTS: A total of 155 patients were enrolled, 105 (68%) were female aged 43.3 (31-52) years. In total 149 (96%) and 94 (61%) patients completed follow-up at median 96 (76-118) days and 364 (303-398) days. The overall cohort had significantly reduced physical composite score (PCS) of the SF-12 (45.39 [10.58] vs 50 [10], p = 0.02). Participants with PoCS had significantly lower scores than those without symptoms at 1-year follow-up (37.2 [10.4] v 46.1 [10.9] p <0.001), and scores for these patients did not improve over the 2 Timepoints (PCS 34.95 [10.5] - 37.2 [10.4], p = 0.22). Fatigue was the most common symptom. Those with 5 or more symptoms at initial diagnosis had lower PCS and mental composite score (MCS) at 1-year. Predictors of PoCS at 1-year were lower PCS and higher baseline heart rate (HR) at clinic review median 3 months after COVID-19. CONCLUSION: Patients with PoCS have lower PCS scores during follow-up, which did not significantly improve up to a 1-year follow-up. Lower PCS scores and higher HR at rest can be used in the weeks after COVID-19 can help predict those at risk of PoCS at 1 year.

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.

Rare, disseminated Kaposi sarcoma in advanced HIV with high-burden pulmonary and skeletal involvement.

We describe the case of a 30-year-old man who presented to our institution with hypoxia and widespread pulmonary infiltrates managed initially as COVID-19 before receiving a new diagnosis of HIV-associated Kaposi sarcoma (KS) with widespread pulmonary and skeletal involvement. Initial differential diagnoses included Pneumocystis jirovecii pneumonia, disseminated mycobacterial infection and bacillary angiomatosis. A bone marrow biopsy showed heavy infiltration by spindle cells, staining strongly positive for human herpes virus-8 (HHV-8) and CD34, suggesting symptomatic, disseminated KS as the unifying diagnosis. The patient commenced cytotoxic therapy with weekly paclitaxel, with a clinical and radiological response. To our knowledge, this case is among the most severe described in the literature, which we discuss, along with how COVID-19 initially hindered developing a therapeutic allegiance with the patient.

Management of Urological Malignancy in Heart and Lung Transplant Recipients: An Irish National Cohort Study.

OBJECTIVES: Following the first hearttransplantin Ireland in 1985, there have been almost 700 deceased donor heart and lung transplants carried out in Ireland at a single institution. In this retrospective study, our aim was to assess the incidence and management of urological malignancies arising in this national cohort. MATERIALS AND METHODS: Our retrospective analysis included all heart and lung transplant recipients identified as having a urological malignancy. Primary outcome variables included incidence, management, and clinical outcomes following cancer diagnosis. RESULTS: A total of 28 patients (4.1%) had radiologically or histologically confirmed urological malignancies. Fourteen patientswere diagnosedwith prostate cancer, with 13 who underwent radical treatment. Eight renal cell carcinomas were diagnosed in heart transplant recipients, with 5 who underwent nephrectomies. Two bladder cancers and 1 uppertract urothelial carcinoma were diagnosed and managed with endoscopic resection, radiotherapy, and nephroureterectomy, respectively. Two patients were diagnosed with penile squamous cell carcinoma and managed with radical surgery and lymph node dissection/sampling, with 1 patient receiving adjuvant chemoradiotherapy. CONCLUSIONS: Urological malignancies are not common in heart and lung transplant recipients; however, standard management options can be safely used, including radical surgery. Prospective monitoring of these patients and potential considerations for screening should be maintained.

Antibiotic prescribing patterns in patients hospitalized with COVID-19: lessons from the first wave.

BACKGROUND: A high proportion of hospitalized patients with COVID-19 receive antibiotics despite evidence to show low levels of true bacterial coinfection. METHODS: A retrospective cohort study examining antibiotic prescribing patterns of 300 patients sequentially diagnosed with COVID-19. Patients were grouped into 3 sub-cohorts: Group 1 received no antibiotics, Group 2 received antibiotics for microbiologically confirmed infections and Group 3 was empirically treated with antibiotics for pneumonia. The primary aim was to identify factors that influenced prescription and continuation of antibiotics in Group 3. Secondary aims were to examine differences in outcomes between groups. RESULTS: In total, 292 patients were included (63 Group 1, 35 Group 2, 194 Group 3), median age was 60 years (IQR 44-76) and the majority were ethnically Irish (62%). The median duration of antibiotics was 7 days (IQR 5-10). In Group 3, factors associated with prescription IV antibiotics on admission were raised C-reactive protein (CRP) (P = 0.024), increased age (P = 0.023), higher quick SOFA (P = 0.016) score and fever >37.5 °C (P = 0.011). Factors associated with duration of antibiotic course were duration of hypoxia (P < 0.001) and maximum respiratory support requirement (P = 0.013). Twenty-one patients in Group 3 had one or more antibiotic escalation events, most (n = 139) had no escalation or de-escalation of therapy. CONCLUSIONS: Duration of hypoxia and need for respiratory support may have acted as surrogate measures of improvement where usual response measures (CRP, neutrophilia, culture clearance) were absent. Continuous review of antibiotic prescriptions should be at the forefront of clinical management of hospitalized patients with COVID-19.

Partial N Gene Sequencing for SARS-CoV-2 Verification and Pathway Tracing.

When SARS-CoV-2 prevalence is low, many RT-qPCR-positive test results are false positives. Sequencing of a 398-bp cDNA PCR amplicon derived from a highly conserved segment with single nucleotide polymorphisms of the nucleocapsid (N) gene in presumptive positive samples can verify true positives and differentiate at least 27 phylogenetically distinct strains of SARS-CoV-2 for helping track virus strain movement between individuals and across geographical areas. We report using this partial N gene sequencing method to confirm a case of mild COVID-19 disease. The patient was first seen on March 15, 2020, in the emergency department of the university hospital in Dublin, Ireland. RT-qPCR test on a nasopharyngeal swab sample was positive for SARS-CoV-2. Partial sequencing of the N gene in the residue of the tested RNA extract showed a characteristic set of 3-consecutive GGG-to-AAC mutations at positions 28881, 28882, 28883, which is known to first appear in samples collected in Continental Europe in February 2020. Using this sequencing-based method to re-test 9 reference nasopharyngeal swab samples supplied by the Connecticut State Department of Public Health Microbiology Laboratory revealed that 2 of the 9 positive samples had a single nucleotide mutation in the 398-base segment of the SARS-CoV-2 N gene. One of the 2 mutant samples showed a mutation at position 28821, which was first reported in a sample recently collected in the neighboring New York state. The other sample showed a novel frameshift nucleotide "A" insertion between position 29051 and position 29057, which co-existed with its wildtype parental virus in one sample. Routine sequencing of RT-qPCR-positive samples can minimize or eliminate false-positive SARS-CoV-2 test results that may cause unnecessary anxiety among the population and prevent false-positive tests from shutting down schools and workplaces unnecessarily as businesses try to resume normal operations in the community.

HepCare Ireland-a service innovation project.

Hepatitis C virus (HCV) remains a major cause of morbidity and death worldwide, with prevalence highest among people who inject drugs (PWID), homeless populations and prisoners. The World Health Organization has published targets to be achieved by 2030 as part of its global health sector strategy to eliminate viral hepatitis. Recent innovations in testing and treatment of HCV mean such goals are achievable with effective infrastructure, political will and funding. 'HepCare Europe' was a 3-year, EU-funded project involving four member states. It sought to develop, implement and evaluate interventions to improve HCV outcomes through multiple-level interventions, running between 2016 and 2019. This paper aims to summarize the methods and present the aggregate cascade of care figures for the Irish components of HepCare. 'HepCare Ireland' contained five integrated work packages: HepCheck, HepLink, HepFriend, HepEd and HepCost. Interventions included intensified screening, community-based assessment, linkage to specialist care, peer training and support, multidisciplinary educational resources and cost-effectiveness analysis. A total of 812 participants were recruited across the three clinical work packages in Ireland. Two hundred and fifty-seven (31.7%) of the tested participants had an HCV antibody-positive result, with 162 (63.0%) testing positive for HCV RNA. At the time of writing (6th of November 2019), 57 (54.8%) of participants put on treatment had achieved SVR12, with 44 (42.3%) still undergoing treatment. In HepCheck, HepLink. HepEd and HepFriend, we demonstrate a series of interventions to improve Irish HCV outcomes. Our findings highlight the benefits of multilevel interventions in HCV care.

Anticipate study protocol: Baseline profile and care outcomes of patients attending Mater Misericordiae University Hospital with COVID-19 infection.

Background: While the COVID-19 pandemic is currently impacting on health and social care in Ireland, this impact is most marked in metropolitan Dublin. This is especially the case for the Mater Misericordiae University Hospital (MMUH) in Dublin's North Inner, which is situated in an area where local socially deprived communities are at high risk of infection and of experiencing adverse outcomes. Aims: To determine baseline characteristics and longer-term care outcomes of COVID-19 patients presenting to / attending the Infectious Diseases Department at MMUH, including the virtual clinic. Methods: Retrospective study: we will retrospectively examine clinical records and extract anonymised data on patient demographics, baseline morbidity and outcomes. Prospective study: we will prospectively examine healthcare outcomes among patients who consent to follow up at two time points (three months, and six months to 12 months after discharge/onset of disease). Two patient groups will be assessed for morbid complications: those hospitalised with COVID infection and those followed-up remotely with confirmed COVID infection. Deliverables: The project will involve collaboration with Ireland's Health Service Executive (HSE) Clinical Programmes and Ireland East Hospital Group to inform health service policies that will attenuate the adverse impacts of the COVID pandemic on population health. This research protocol will evaluate morbid complications of COVID depending on the severity of the disease.

Leydig Cell Hyperplasia Mimicking a Testicular Tumour in a Patient with Klinefelter Syndrome.

BACKGROUND: Klinefelter syndrome (KS) is the most common sex-chromosomal disorder in males. Frequently under-recognized, it occurs in 1 in 500-600 male births. It is caused by the inheritance of at least one additional X chromosome from either parent. Patients often have uncommon or atypical malignancies. PATIENT: We describe the case of a 35-year-old man with 47XXY KS and previous cryptorchidism, presenting with a painful testicular mass. Histology confirmed Leydig cell hyperplasia. DISCUSSION: Cryptorchidism is an established risk factor for testicular tumours and occurs six times more commonly in KS than in the general population. Despite this, large epidemiological studies have shown a reduced burden of testicular cancer in these patients. The presentation of a hypoechoic lesion on ultrasound will prompt consideration of testicular tumours, however orchalgia represents an atypical presentation. In patients with KS, Leydig cell hyperplasia is a much more common entity and should be considered early in the differential diagnosis. LEARNING POINTS: The differential diagnosis of a testicular mass in Klinefelter syndrome includes malignancy and nodular Leydig cell hyperplasia.Diagnosis can be challenging, both radiologically and histologically.Orchalgia is atypical in Leydig cell hyperplasia.

Predicted carcass meat yield and primal cut yields in cattle divergent in genetic merit for a terminal index.

Several studies have clearly demonstrated the favorable impact of genetic selection on increasing beef cattle performance within the farm gate. Few studies, however, have attempted to quantify the value of genetic selection to downstream sectors of the beef industry, such as the meat processing sector. The objective of the current study was to characterize detailed carcass attributes of animals divergent in genetic merit for a terminal index as well as individual measures of genetic merit for carcass weight, conformation, and fat. The data used consisted of 53,674 young bulls and steers slaughtered between the years 2010 and 2013 in multiple Irish processing plants. All animals had a genetic evaluation as well as phenotypic measures of carcass characteristics. A terminal index, based on pedigree index for calving performance, feed intake, and carcass traits, calculated from the Irish national genetic evaluations, was obtained for each animal. Animals were categorized into four terminal index groups based on genetic merit estimates derived prior to the expression of the carcass phenotype by the animal. The association between genetic merit for terminal index with predicted phenotypic carcass red meat yield, carcass fat, carcass bone, and carcass composition, as well as between genetic merit for carcass weight, conformation, and fat with predicted phenotypic carcass red meat yield and composition were all quantified using linear mixed models. A greater terminal index value was associated with, on average, heavier phenotypic weights of each wholesale cut category. A greater terminal index value was also associated with a greater weight of meat and bone, but reduced carcass fat. Relative to animals in the lowest 25% genetic merit group, animals in the highest 25% genetic merit group had, on average, a greater predicted yield of very high value cuts (4.52 kg), high value cuts (13.13 kg), medium value cuts (6.06 kg), low value cuts (13.25 kg) as well as more total meat yield (37 kg). The results from the present study clearly signify a benefit to meat processers from breeding programs for terminal characteristics; coupled with the previously documented benefits to the producer, the benefits of breeding programs across the entire food production chain are obvious.

Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986).

A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986) as a highly potent, reversible, and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.

Asymptomatic Renal Pseudoaneurysm Following Laparoscopic Partial Nephrectomy.

A 66-year-old-woman underwent a laparoscopic left partial nephrectomy for a 3 cm partially exophytic tumor arising from the posterior interpolar region of the left kidney. Follow-up surveillance computed tomography 6 months following the surgery found an incidental 4 cm lesion in the left kidney that is avidly enhanced in the arterial phase, consistent with a renal pseudoaneurysm. She was completely asymptomatic. Renal pseudoaneurysm is a rare complication following minimally invasive nephron-sparing surgery and typically presents in the early postoperative period with gross hematuria. However, a large renal pseudoaneurysm may also present as an asymptomatic incidental finding and is amenable to angioembolization.

Diagnostic accuracy of preoperative computed tomography used alone to detect lymph-node involvement at radical nephrectomy.

OBJECTIVE: The aim of this study was to compare preoperative computed tomography (CT) with pathological findings in patients undergoing lymphadenectomy at the time of nephrectomy for renal cancer-associated lymphadenopathy. MATERIALS AND METHODS: Data from 515 consecutive nephrectomy surgeries (2004-2012) in a single university-affiliated centre were analysed to identify patients who had undergone lymph-node dissection concomitant with nephrectomy. Preoperative CT imaging was subjected to multiple repeated independent blinded reviews (two radiologists and one surgeon, each individually and on two separate occasions). Retroperitoneal lymph-node status was subjectively categorized (in a manner not based purely on size criteria) at each review as: 1 = unequivocally positive, 2 = equivocally positive, 3 = equivocally negative, or 4 = unequivocally negative. These findings were compared with pathological analysis, and interobserver and intraobserver agreement was assessed using non-weighted kappa () statistics. RESULTS: In total, 71 patients were stratified as category 1 (n = 18), 2 (n = 14), 3 (n = 31) and 4 (n = 8); pathological lymph-node metastasis was present in 14 (78%), four (28%), four (13%) and zero patients, respectively. Sensitivity, specificity, positive and negative predictive values for preoperative CT were 82%, 71%, 56% and 90%, respectively. Intraobserver agreement was greater for the radiologists (values 0.490, 0.540) than for the surgeon (value 0.393). Interobserver agreement was strongest for radiological category 1 (unequivocally positive; value 0.75). Receiver operating characteristics curves did not reveal significant differences in any observer accuracy. CONCLUSION: Contrary to concerns about a high false-positive rate, metastasis within regional lymph nodes can be predicted with reasonable accuracy by preoperative CT imaging alone.

Nephroureterectomy surgery in the UK in 2012: British Association of Urological Surgeons (BAUS) Registry data.

OBJECTIVE: To report registry data obtained by the British Association of Urological Surgeons (BAUS) for nephroureterectomy (NU) surgery in the UK performed between 1 January and 31 December 2012. SUBJECTS/PATIENTS AND METHODS: Registry data entered by each individual surgeon's team (self-reported) on all 6042 nephrectomy surgeries reported to BAUS during 2012 were analysed to identify all NU surgery. Parameters for analysis included demographics, indication, type of surgery, histopathology and complications (Clavien system) of surgery. Data did not include tumour location or multiplicity, preoperative diagnostic evaluation or details of minimally invasive surgery (MIS) undertaken. Before analysis for this report a central process of 'data-cleansing' was undertaken by a BAUS group to address any discrepancy between the listed surgery and the preoperative indication. RESULTS: In all, 863 NU surgeries were included, performed by 220 consultant surgeons in 119 centres, and the median (range) number of NU per surgeon and unit was 3 (1-20) and 6 (1-29), respectively. The most common age group was 71-80 years (40%), most were male (64%), and haematuria was the most common presentation (74%). The dominant pathology was upper tract urothelial cancer (89%, 735), with final stage ≥pT2 in 47% (367), and the grade was 1, 2 or 3 in 6% (38), 36% (228) and 58% (362) respectively. Operative technique included MIS in 85% (720) and total reported operative complication rate (any Clavien) was 15% (128), of which Clavien ≥3 was reported in 4% (36), and perioperative death was reported in nine patients (1%). Advantages in favour of MIS included reduced hospital stay (median 5 vs 8 days), reduced major blood loss (3% vs 14%) and reduced transfusion requirement (6% vs 24%). In all, 76 cases (8%) were excluded from analysis based on benign pathology leading to reassignment to the 'simple nephrectomy' category. CONCLUSIONS: NU is currently a low-volume operation (median 3 cases/year) within the remit of the nephrectomy surgeon, but is a safe procedure with a relatively low complication rate. Most NU surgery in the UK is now performed with laparoscopic assistance, with advantages including reduced major blood loss, reduced transfusion requirement and shorter hospital stay.

Discovery of AZD3199, An Inhaled Ultralong Acting ß2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.

Orally bioavailable allosteric CCR8 antagonists inhibit dendritic cell, T cell and eosinophil migration.

The chemokine receptor CCR8 is associated with asthma. Herein, we describe that both mature and immature dendritic cells (DC) express CCR8, whereas only mature DC migrate towards CCL1. Moreover, transient LPS challenge significantly down-regulates CCR8 expression hence attenuating CCL1 chemotaxis. To inhibit CCR8 pathophysiology, we recently developed a novel series of small molecule CCR8 antagonists containing a diazaspiroundecane scaffold, which had micromolar potency. However, these first generation antagonists had high lipophilicity that endowed the compounds with poor physicochemical properties, and were thus not suitable for further development. By introducing polar bicyclic groups on the N-benzyl substituent and building in further polar interactions on the amide group we now show second generation diazospiroundecane antagonists with significantly improved overall properties. Potency is substantially improved from micromolar to nanomolar potency in CCR8 binding and inhibition of chemotaxis in human primary T cells, DC and in an eosinophil cell line. In addition to high potency, the most attractive antagonist, AZ084 showed excellent selectivity, high metabolic stability in vitro and an attractive in vivo PK profile with a long half-life in rat. Interestingly, in ligand saturation experiments and in wash-off experiments, CCL1 was shown to have two binding sites to CCR8 with K(d) at 1.2/68pM respectively, and on-off rates of 0.004 and 0.0035/0.02pMmin, respectively. The lead antagonist, AZ084, appears to act as an allosteric inhibitor with a K(i) at 0.9nM. Taken together, we herein report a novel oral allosteric CCR8 antagonist with predicted low once-daily dosing capable of potent inhibition of both human T cell and DC functions.