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Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about ‘What are the topics you care about for making trials in lupus more effective?’. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs.

Background Transcatheter aortic valve replacement (TAVR) is becoming increasingly utilized for the treatment of severe aortic valvular heart disease. Infective endocarditis of TAVR is rare but associated with higher mortality and morbidity. The potential for leaflet thrombosis following TAVR is also becoming increasingly recognized. Diagnosis of these conditions on echocardiography can be challenging due to prosthesis artefact. Case summary An 84-year-old man with a previous transcatheter aortic valve replacement presented with a febrile illness and bacteraemia. Transthoracic and transoesophageal echocardiography demonstrated high transvalvular gradients with features of prosthesis endocarditis, though leaflet morphology could not be fully assessed due to prosthesis artefact. Four-dimensional computed tomography revealed hypo-attenuated leaflet thickening with reduced leaflet motion, consistent with prosthesis leaflet thrombosis. The patient was successfully treated with antibiotics and anticoagulation, with resolution of the infection and normalization of the transvalvular gradient after 6 weeks. Discussion Echocardiography should be the first-line investigation for assessing leaflet morphology in suspected prosthetic valve endocarditis or leaflet thrombosis but its accuracy may be limited by artefact. Our case highlights that fourdimensional computed tomography provides further evaluation of prosthesis leaflet morphology/motion, providing valuable diagnostic information.Copyright © The Author(s) 2020.

Background and Aim: Current guidelines recommend indefinite nucleot(-s)ide analog (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB) infection. However, sustained virological response (SVR) has been described in patients after discontinuation of long-term NA therapy, as well as HBsAg loss. The HBV-STOP study is a prospective multicenter study of NA discontinuation in patients who have achieved long-term virological suppression of hepatitis B virus (HBV) on treatment. The study describes clinical outcomes after treatment discontinuation, with the aim of identifying determinants of SVR. Method(s): We performed an interim narrative analysis of outcomes at Week 48 after NA discontinuation. Outcomes at Week 96 are the primary endpoint for the study. Inclusion criteria for the study were HBeAg-negative, non-cirrhotic, and virological suppression for > 18 months on NA therapy uninterrupted for > 2 years. Criteria for recommencing NA therapy were HBV DNA > 2000 IU/mL with either alanine aminotransferase (ALT) > 5x ULN for > 16 weeks or ALT > 10x ULN for > 8 weeks, international normalized ratio > 1.5, bilirubin level > 2x ULN, ascites, hepatic encephalopathy, and investigator discretion. Result(s): The cohort is fully enrolled, and data are currently available for 111 patients. At baseline, median patient age was 56 years, 64% were male, and 85% were Asian. The median HBsAg level was 705 IU/mL (214-2325). All patients were non-cirrhotic. Virological reactivation occurred in all, with a median time to detection of 8 weeks (4-12). Patients stopping tenofovir (TDF) experienced virological and biochemical relapse earlier than patients stopping entecavir (ETV) (Fig. 1; P < 0.001). Twenty-three patients (21%) have experienced an ALT flare > 10x ULN; there was no significant difference in the rate of ALT flare > 10x ULN after stopping TDF versus ETV. Two patterns of ALT flare were observed: beneficial flares that were associated with reductions in HBV DNA and

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Background: Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses. Objective(s): In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with >=6 months follow-up data from OCR initiation. Method(s): Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/ initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with >=6 months follow-up data from OCR initiation. Result(s): As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT's in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had >=6 months followup during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06- 0.10)

Background: In multiple sclerosis (MS), suboptimal medication adherence is associated with subsequent discontinuation, which occurs in ~30-50% of people within 2-years. Medication adherence is critical for realisation of pharmacotherapy benefits and reduced healthcare expenditure. Previous systematic reviews have not included oral DMTs, first introduced in 2010. Objective(s): To undertake a systematic review of adherence and persistence rates for self-administered oral and injectable disease modifying therapies (DMTs) in people with MS. Method(s): A literature search for publications examining DMT adherence and persistence rates in MS was conducted through databases including PubMed, Web of Science, Scopus and PsycINFO yielding 1,590 records, with 1,150 duplications removed, resulting in 440 abstracts screened. We included peerreviewed, English written studies for objectively measured selfadministered DMTs in samples aged 18+, published between July 1993, and December 2018. Studies reporting combined intravenous and self-administered DMT adherence results were excluded. Result(s): In total, 119 articles were extracted for quantitative synthesis. Preliminary results show 12-month mean adherence (medication possession ratio) for injectable compared to oral DMTs was 71.7% (n = 6) and 83.0% (n = 3), respectively. Mean discontinuation over 12- and 24-months for injectable DMTs were 30.4% (n = 9) and 29.7% (n = 8); and oral DMTs were 25.4% (n = 3) and 16.5% (n = 5), respectively. Conclusion(s): Medication adherence and persistence remains problematic despite the introduction of oral DMTs. Oral DMT improvements are noted for 12-month adherence and 24-month discontinuation. With limited oral DMT adherence and persistence data, studies are hampered by methodological issues, such as inconsistent adherence and persistence definitions.

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.Copyright © 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Background: Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited. Objective(s): We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with >=6 months follow-up data from cladribine initiation. Method(s): We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS). Result(s): As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow- up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%). Conclusion(s): This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setti

Background and Aims: Current guidelines recommend indefinite Nucleot(s)ide Analogue (NA) therapy for patients with HBeAg-negative CHB. However, sustained virological response (SVR) has been described in patients after discontinuation of long-term NA therapy, as well as HBsAg loss. The HBV-STOP study is a prospective multi-centre study of NA discontinuation in patients who have achieved long-term virological suppression on treatment. The study describes clinical outcomes post-treatment discontinuation, with the aim of identifying determinants of SVR. Method(s): An interim narrative analysis of outcomes at week 48 post-NA discontinuation was performed. The primary endpoint for the study is outcomes at week 96. Inclusion criteria for the study were HBeAg-negative, non-cirrhotic & virological suppression for >= 18 months on NA therapy uninterrupted for >= 2 years. Criteria for recommencing NA therapy were HBV DNA >2000 IU/mL with either ALT?>5x ULN for >= 16 weeks or ALT >10x ULN for >= 8 weeks, INR >= 1.5, Bilirubin?>2x ULN, ascites, hepatic encephalopathy and investigator discretion. Result(s): The cohort is fully enrolled and data are currently available for 90/111 patients. At baseline, median age was 55 yrs, 58% were male, 83% were Asian. Median HBsAg level was 699 (250-1819) IU/mL. All patients were non-cirrhotic. Virological reactivation occurred in all, with median time to detection 8 (4-12) weeks. At week 48, four (4%) patients have experienced HBsAg loss, 42 (47%) had DNA >,000 IU/mL, 13 (14%) had DNA >2,000 and ALT?>2x ULN, and 10 (11%) had restarted treatment. Patients who achieved HBsAg loss had low baseline HBsAg levels (HBsAg loss: median baseline HBsAg level = 3.1 IU/ml in HBsAg loss vs. 776 IU/mL in patients with no HBsAg loss). The overall median reduction in HBsAg was 68 IU/mL at week 48. 21 (23%) have experienced an ALT flare >10x ULN. ALT flare was associated with reduction in HBsAg level. Median reduction of HBsAg level from the flare time-point to

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenstrom macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients withWM who were either treatmentna ive (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per InternationalWorkshop onWaldenstromMacroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n 5 50) or 320 mg once daily (n 5 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0months for patientswith R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with singleagent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2020 by The American Society of Hematology.

Background: In multiple sclerosis (MS), suboptimal medication adherence is associated with subsequent discontinuation, which occurs in ~30-50% of people within 2-years. Medication adherence is critical for realisation of pharmacotherapy benefits and reduced healthcare expenditure. Previous systematic reviews have not included oral DMTs, first introduced in 2010. Objective(s): To undertake a systematic review of adherence and persistence rates for self-administered oral and injectable disease modifying therapies (DMTs) in people with MS. Method(s): A literature search for publications examining DMT adherence and persistence rates in MS was conducted through databases including PubMed, Web of Science, Scopus and PsycINFO yielding 1,590 records, with 1,150 duplications removed, resulting in 440 abstracts screened. We included peerreviewed, English written studies for objectively measured selfadministered DMTs in samples aged 18+, published between July 1993, and December 2018. Studies reporting combined intravenous and self-administered DMT adherence results were excluded. Result(s): In total, 119 articles were extracted for quantitative synthesis. Preliminary results show 12-month mean adherence (medication possession ratio) for injectable compared to oral DMTs was 71.7% (n = 6) and 83.0% (n = 3), respectively. Mean discontinuation over 12- and 24-months for injectable DMTs were 30.4% (n = 9) and 29.7% (n = 8); and oral DMTs were 25.4% (n = 3) and 16.5% (n = 5), respectively. Conclusion(s): Medication adherence and persistence remains problematic despite the introduction of oral DMTs. Oral DMT improvements are noted for 12-month adherence and 24-month discontinuation. With limited oral DMT adherence and persistence data, studies are hampered by methodological issues, such as inconsistent adherence and persistence definitions.

Background and Aim: Current guidelines recommend indefinite nucleot(-s)ide analog (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB) infection. However, sustained virological response (SVR) has been described in patients after discontinuation of long-term NA therapy, as well as HBsAg loss. The HBV-STOP study is a prospective multicenter study of NA discontinuation in patients who have achieved long-term virological suppression of hepatitis B virus (HBV) on treatment. The study describes clinical outcomes after treatment discontinuation, with the aim of identifying determinants of SVR. Method(s): We performed an interim narrative analysis of outcomes at Week 48 after NA discontinuation. Outcomes at Week 96 are the primary endpoint for the study. Inclusion criteria for the study were HBeAg-negative, non-cirrhotic, and virological suppression for > 18 months on NA therapy uninterrupted for > 2 years. Criteria for recommencing NA therapy were HBV DNA > 2000 IU/mL with either alanine aminotransferase (ALT) > 5x ULN for > 16 weeks or ALT > 10x ULN for > 8 weeks, international normalized ratio > 1.5, bilirubin level > 2x ULN, ascites, hepatic encephalopathy, and investigator discretion. Result(s): The cohort is fully enrolled, and data are currently available for 111 patients. At baseline, median patient age was 56 years, 64% were male, and 85% were Asian. The median HBsAg level was 705 IU/mL (214-2325). All patients were non-cirrhotic. Virological reactivation occurred in all, with a median time to detection of 8 weeks (4-12). Patients stopping tenofovir (TDF) experienced virological and biochemical relapse earlier than patients stopping entecavir (ETV) (Fig. 1; P < 0.001). Twenty-three patients (21%) have experienced an ALT flare > 10x ULN; there was no significant difference in the rate of ALT flare > 10x ULN after stopping TDF versus ETV. Two patterns of ALT flare were observed: beneficial flares that were associated with reductions in HBV DNA and

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Background Transcatheter aortic valve replacement (TAVR) is becoming increasingly utilized for the treatment of severe aortic valvular heart disease. Infective endocarditis of TAVR is rare but associated with higher mortality and morbidity. The potential for leaflet thrombosis following TAVR is also becoming increasingly recognized. Diagnosis of these conditions on echocardiography can be challenging due to prosthesis artefact. Case summary An 84-year-old man with a previous transcatheter aortic valve replacement presented with a febrile illness and bacteraemia. Transthoracic and transoesophageal echocardiography demonstrated high transvalvular gradients with features of prosthesis endocarditis, though leaflet morphology could not be fully assessed due to prosthesis artefact. Four-dimensional computed tomography revealed hypo-attenuated leaflet thickening with reduced leaflet motion, consistent with prosthesis leaflet thrombosis. The patient was successfully treated with antibiotics and anticoagulation, with resolution of the infection and normalization of the transvalvular gradient after 6 weeks. Discussion Echocardiography should be the first-line investigation for assessing leaflet morphology in suspected prosthetic valve endocarditis or leaflet thrombosis but its accuracy may be limited by artefact. Our case highlights that fourdimensional computed tomography provides further evaluation of prosthesis leaflet morphology/motion, providing valuable diagnostic information.Copyright © The Author(s) 2020.

Background: Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses. Objective(s): In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with >=6 months follow-up data from OCR initiation. Method(s): Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/ initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with >=6 months follow-up data from OCR initiation. Result(s): As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT's in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had >=6 months followup during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06- 0.10)

Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.Copyright © 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Background: Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited. Objective(s): We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with >=6 months follow-up data from cladribine initiation. Method(s): We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS). Result(s): As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow- up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%). Conclusion(s): This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setti

Background and Aims: Current guidelines recommend indefinite Nucleot(s)ide Analogue (NA) therapy for patients with HBeAg-negative CHB. However, sustained virological response (SVR) has been described in patients after discontinuation of long-term NA therapy, as well as HBsAg loss. The HBV-STOP study is a prospective multi-centre study of NA discontinuation in patients who have achieved long-term virological suppression on treatment. The study describes clinical outcomes post-treatment discontinuation, with the aim of identifying determinants of SVR. Method(s): An interim narrative analysis of outcomes at week 48 post-NA discontinuation was performed. The primary endpoint for the study is outcomes at week 96. Inclusion criteria for the study were HBeAg-negative, non-cirrhotic & virological suppression for >= 18 months on NA therapy uninterrupted for >= 2 years. Criteria for recommencing NA therapy were HBV DNA >2000 IU/mL with either ALT?>5x ULN for >= 16 weeks or ALT >10x ULN for >= 8 weeks, INR >= 1.5, Bilirubin?>2x ULN, ascites, hepatic encephalopathy and investigator discretion. Result(s): The cohort is fully enrolled and data are currently available for 90/111 patients. At baseline, median age was 55 yrs, 58% were male, 83% were Asian. Median HBsAg level was 699 (250-1819) IU/mL. All patients were non-cirrhotic. Virological reactivation occurred in all, with median time to detection 8 (4-12) weeks. At week 48, four (4%) patients have experienced HBsAg loss, 42 (47%) had DNA >,000 IU/mL, 13 (14%) had DNA >2,000 and ALT?>2x ULN, and 10 (11%) had restarted treatment. Patients who achieved HBsAg loss had low baseline HBsAg levels (HBsAg loss: median baseline HBsAg level = 3.1 IU/ml in HBsAg loss vs. 776 IU/mL in patients with no HBsAg loss). The overall median reduction in HBsAg was 68 IU/mL at week 48. 21 (23%) have experienced an ALT flare >10x ULN. ALT flare was associated with reduction in HBsAg level. Median reduction of HBsAg level from the flare time-point to

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenstrom macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients withWM who were either treatmentna ive (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per InternationalWorkshop onWaldenstromMacroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n 5 50) or 320 mg once daily (n 5 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0months for patientswith R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with singleagent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2020 by The American Society of Hematology.

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about ‘What are the topics you care about for making trials in lupus more effective?’. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs.

Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk–benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70–80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about ‘What are the topics you care about for making trials in lupus more effective?’. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs.

Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk–benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70–80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.

Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with Waldenstrom macroglobulinemia (WM) harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. The ASPEN trial evaluated ZANU, a potent and selective BTK inhibitor, in patients with WM. Aim(s): To evaluate the efficacy and safety of ZANU in patients who have WM with MYD88 wild-type (MYD88WT) mutation status. Method(s): In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics) using a wild-type-blocking polymerase chain reaction method. This MYD88 mutation assay detects all mutations in the region encompassing amino acid Ala260-Pro278, which includes the predominant mutation in WM (MYD88L265P), with enhanced sensitivity (Int J Lab Hematol. 2016;38:133). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 (MYD88 mutation) or cohort 2 (MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression. Result(s): In total, 28 patients (n = 26 MYD88WT; n = 2 MYD88 mutation status unknown) were enrolled into cohort 2. The median age was 72 years and 42.9% were > 75 years old; 5 patients were treatment-naive (TN), and 23 patients were relapsed/refractory (R/R; >=1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With a median follow- up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. In 26 confirmed MYD88WT patients, th

Background: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. Method(s): This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 x 104 IU/mL (HBeAg-positive) or 2 x 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. Finding(s): 48 [61%] of 79 healthy volunteers were enrolled in the sing

Background: Marginal zone lymphoma (MZL) is the third most common lymphoma and represents approximately 5% to 15% of all non-Hodgkin lymphomas. Improved understanding of the disease biology, including genetic and molecular characteristics, has changed the therapeutic landscape of MZL, and there is increasing evidence that targeted therapies, including Bruton tyrosine kinase inhibitors, have improved efficacy and have shown tolerable toxicity profiles over chemotherapy- based approaches. Zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor, has established therapeutic activity in B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in a phase 1/2 study of patients with relapsed/refractory MZL. Method(s): Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 17) or 320 mg once daily (n = 3) until disease progression or unacceptable toxicity. Efficacy end points included the proportion of patients achieving a complete or partial response in accordance with Lugano classification (J Clin Oncol. 2014;32:3059). Result(s): Between September 2014 and August 2018, 20 patients with relapsed/refractory MZL started treatment with zanubrutinib; 65% of patients were aged > 65, and 15% were aged > 75 years. Patient distribution across MZL subtypes was as follows: extranodal (mucosa-associated lymphoid tissue), 45%; splenic, 30%; and nodal, 25%. The median number of prior therapies was 2, with RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) being the most common type of therapy. At a median follow-up of 22.16 months, 60% of patients remained on treatment. Reasons for treatment discontinuation included disease progression (25%), adverse events (AEs) in 5% of patients (with 1 patient having treatment-related diarrhea), patient's withdrawal of consent (5%), and other (5%). Therapy was well-tole

Background: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. Method(s): Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. Result(s): Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (>= 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. Conclusion(s): The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.Copyright © 2020, Society of Surgical Oncology.

BACKGROUND: Very large cohorts that span an entire population raise new prospects for the conduct of multiple trials that speed up advances in prevention or treatment while reducing participant, financial and regulatory burden. However, a review of literature reveals no blueprint to guide this systematically in practice. This Statement of Intent proposes how diverse trials may be integrated within or alongside Generation Victoria (GenV), a whole-of-state Australian birth cohort in planning, and delineates potential processes and opportunities. METHOD(S): Parents of all newborns (estimated 160,000) in the state of Victoria, Australia, will be approached for two full years from 2021. The cohort design comprises four elements: (1) consent soon after birth to follow the child and parent/s until study end or withdrawal; retrospective and prospective (2) linkage to clinical and administrative datasets and (3) banking of universal and clinical biosamples; and (4) GenV-collected biosamples and data. GenV-collected data will focus on overarching outcome and phenotypic measures using low-burden, universal-capable electronic interfaces, with funding-dependent face-to-face assessments tailored to universal settings during the early childhood, school and/or adult years. RESULT(S): For population or registry-type trials within GenV, GenV will provide all outcomes data and consent via traditional, waiver, or Trials Within Cohorts models. Trials alongside GenV consent their own participants born within the GenV window; GenV may help identify potential participants via opt-in or opt-out expression of interest. Data sharing enriches trials with outcomes, prior data, and/or access to linked data contingent on custodian's agreements, and supports modeling of causal effects to the population and between-trials comparisons of costs, benefits and utility. Data access will operate under the Findability, Accessibility, Interoperability, and Reusability (FAIR) and Care and Five Safes Princip

Background: Sitravatinib is an investigational, orally bioavailable, receptor tyrosine-kinase inhibitor with immune modulatory and potential antitumor activity. Tislelizumab is an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death receptor-1 (PD-1). We assessed the safety and antitumor activity of sitravatinib plus tislelizumab in patients with advanced solid tumors. Method(s): This is an open-label, multicenter, non-randomized, phase Ib study (NCT03666143). This cohort evaluated anti-PD-(L)1 antibody-naive patients with recurrent, platinum-resistant, epithelial ovarian cancer who were treated with 120 mg of sitravatinib once daily in combination with 200 mg tislelizumab every 3 weeks until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination. The primary objective was to assess the safety and tolerability of this combination therapy. Overall response rate, duration of response (DOR), disease control rate, and progression-free survival (PFS) were assessed as secondary endpoints. Result(s): As of 17 July 2019, 20 patients (median age, 66.0 years) were enrolled; median number of prior regimens was 5 (range, 2-12). All 20 patients received study drugs and were included in the safety analysis. Common (frequency >=10%) grade >=3 treatment-emergent adverse events (TEAEs) assessed as related to sitravatinib by investigators were hypertension (25%) and fatigue (10%). Six patients had AEs that led to sitravatinib discontinuation. The common (frequency >=10%) grade >=3 TEAE assessed as related to tislelizumab by investigators was increased transaminases (10%). Three patients had AEs that led to tislelizumab discontinuation. Of 17 efficacy-evaluable patients, 4 achieved confirmed partial response, 11 had stable disease, and 2 had progressive disease per RECIST version 1.1. Median PFS was 18.0 weeks; median DOR was not reached (NR) (both ranges, 12.29 weeks-NR). Concl

Purpose: Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. Method(s): Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013. Result(s): GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs. Conclusion(s): GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.Copyright © 2020, American College of Medical Genetics and Genomics.

Background: EDP-305 is an oral FXR agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH) In the INTREPID study, EDP-305 was investigated in subjects with primary biliary cholangitis (PBC) Methods: Subjects with confirmed PBC diagnosis with or without an inadequate response to ursodeoxycholic acid (UDCA) were randomized to receive EDP-305 2 5mg or 1mg, or placebo (PBO), for 12 weeks Liver enzymes and safety/tolerability were assessed at baseline (BL) through week 12 The primary endpoint of the study was the proportion of subjects with at least 20% reduction in alkaline phosphatase (ALP) from pre-treatment value, or normalization of ALP, at week 12 (NCT03394924) Results: A total of 68 subjects were randomized: mean age of 56 years; 98% women; 95% on stable UDCA dose, and mean ALP at 300U/l In the intentto-treat (ITT) analysis, EDP-305 resulted in ALP response of 45% (n=14/31, p=0 106) and 46% (n=13/28, p=0 063) in the 1 mg and 2 5 mg treatment arms, respectively, compared to 11% (n=1/9) in the PBO arm Absolute changes from baseline in ALP were statistically significant at week 12 in both the EDP-305 1 mg arm (p=0 017) and the 2 5 mg arm (p= 0 021) compared to the change from baseline in the PBO arm There was also a statistically significant reduction from baseline in serum ALT, AST and GGT compared to PBO in both the EDP-305 1 mg arm and the 2 5 mg arm In addition to reduction in GGT, EDP-305 exhibited evidence of target engagement with reduction in C4 ranging from 18-60% Overall, EDP-305 was generally safe, with the most common (>=10% or >1 subject/arm) TEAEs including pruritus, GI-related symptoms, headache and insomnia Pruritus was present in 71% of the subjects in the 2 5mg arm, 47% in the 1mg arm and 33% in the PBO arm Pruritus led to treatment discontinuation in 3% of subjects with 1mg and 18% with 2 5mg Treatment with EDP-305 had no apparent effect on lipids Conclusion(s): The INTREPID study showed numerically higher response rates wi

Objective: The objective of this study was to evaluate the efficacy and tolerability of perampanel (PER) in late adjunctive treatment of focal epilepsy. We assessed outcomes 1) according to patients' clinical profiles and the broad mechanism of action (MoA) of concomitant antiepileptic drugs (AEDs) and 2) the effects of PER on adverse events, irritability, mood, and quality of life (QOL). Method(s): Consecutive patients commenced on PER at two epilepsy centers in Melbourne, Australia were identified. A nested cohort underwent detailed prospective assessment, while the remainder were retrospectively analyzed. Six- and 12-month efficacy endpoints were at least a 50% reduction in seizure frequency (responders) and complete seizure freedom. The prospective cohort underwent standardized validated questionnaires at 0, 1, 3, 6, and 12 months using the modified semi-structured seizure interview (SSI), Liverpool Adverse Events Profile (LAEP), Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P), Neurological Disorders Depression Inventory Epilepsy (NDDI-E), and an Irritability Questionnaire. Result(s): One hundred sixty patients were followed for a median of 6 months: the mean number of prior AEDs was 6, 99% had drug-resistant epilepsy, and 72% had never experienced a prior seizure-free period of at least 6 months (= continuously refractory epilepsy). Perampanel was associated with responder and seizure freedom rates of 30.6% and 9.4% at 6 months and 19.4% and 4.4% (5.6% adjusted for the titration period) at 12 months. Having "continuously refractory epilepsy" was associated with a reduced likelihood of seizure freedom at 6 months (5% vs. 30%; p = 0.001) and 12 months (3% vs. 13%; p = 0.058). Quality of Life in Epilepsy-Patient-Weighted, irritability, and NDDI-E showed mean improvement at 6 months from baseline. Significance: Even when used as late add-on adjunctive therapy in patients with highly refractory focal epilepsy, PER can result in 12-month seizure freedom of

Introduction: Implementation of rapid genomic testing in neonatal and paediatric intensive care units (NICUs/PICUs) is gathering momentum, and requires the development of systems capable of consistent delivery across multi-site networks. Method(s): We developed a rapid genomic diagnosis program involving 10 Australian hospitals and two laboratories with the aim of providing test results in <5 days for acutely unwell paediatric patients with suspected monogenic disorders. Rapid exome sequencing (rES) was performed as trios when possible, and analysis utilised multidisciplinary expertise. Experience was shared between clinical sites, laboratories, and professional groups to enable collective learning. Result(s): The program considered 123 patients for rES over 10 months, and approved 114 (93%). Five families declined testing (4.4%), and nine (7.9%) were withdrawn due to change in clinical circumstances. Of 100 patients tested, 51 received a diagnosis. Eleven of the diagnoses (21%) were made using approaches augmenting standard ES analysis: mitochondrial genome sequencing, ES-based copy number analysis, matchmaking of emerging genes, reverse phenotyping and RNA analysis. Median time from hospital admission to consent was 6 days (range 0-64 days); median time from sample receipt to clinical ES report was 3 days (range 2-7 days). The total cost of testing was AU$1,123,000/701,638 (AU$11,230/7,016 per case). Changes in management following a result occurred in 77% of diagnosed patients and 10% of undiagnosed patients. Conclusion(s): We demonstrate the feasibility of a national, highly integrated clinical-laboratory approach to rapid genomic diagnosis, which delivers results within a timeframe relevant to acute paediatrics, while optimising clinical utility and resource allocation.

Background: Fractured neck of femur (hip fracture) surgery is common and associated with high mortality and morbidity, principally due to prevalent heart disease that is often unrecognised and inadequately treated before surgery. Focused cardiac ultrasound (FCU) is a form of transthoracic echocardiography (TTE) used for non-invasive assessment of cardiac disease before surgery that frequently alters important perioperative cardiac diagnosis and management and may be associated with lower mortality(1). This pilot study aimed to assess feasibility, calibrate the primary composite outcome and determine group separation, prior to a multi-centre random control trial (RCT) (n=1900) of the impact of preoperative FCU on postoperative mortality and morbidity after hip fracture surgery. Method(s): Recruitment occurred between February 1 and December 21, 2016 at the Royal Melbourne Hospital, with other sites activated during the period (Western General Hospital, The Prince Charles Hospital and The Queen Elizabeth Hospital). Inclusion criteria included participants aged >18 years scheduled for unilateral repair of hip fracture. Exclusion criteria included additional or re-do surgery, known or suspected metastatic cancer or unlikely to survive>24 hours, or previous documented TTE within 30 days of admission. Participants were randomised to either receive (FCU group) or not (controls) before surgery. FCU was performed by independent operators proficient in FCU, and followed the iHeartScan protocol (University of Melbourne), which has been validated in the perioperative setting. The primary outcome was 30-day composite outcome of mortality, acute kidney injury, non-fatal myocardial infarction, stroke, pulmonary embolism and cardiac arrest. Secondary outcomes included impact of FCU on diagnosis and management by the anaesthetist and inpatient hospital costs. The feasibility aims included recruitment of >1 patient per week per site during active recruitment, a screening:recruitment

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to Fc 3R on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Methods Patients (aged >=18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab

Background: Using the MSBase registry, we characterised profiles of patients initiated on the recently approved treatment Cladribine. Objective(s): To describe baseline characteristics of patients with MS treated with cladribine, treatment pathway up to initiation of cladribine, and initial clinical experience in patients with >=6 months follow-up. Method(s): Using MSBase Registry data including patients with a confirmed diagnosis of MS and treated with cladribine after regulatory approval. Descriptive statistics were used to analyse baseline characteristics recorded within 3 months prior to or at time of cladribine initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analysed in patients with >=6 months follow-up data from cladribine initiation. Result(s): As of the 8th July 2019, MSBase included 317 patients treated with cladribine including 260 RRMS patients and 44 with SPMS. Median age at cladribine initiation was 44.98 years in RRMS and 57.28 years in SPMS. Median EDSS at cladribine start was 2.5 and 6.5 in RRMS and SPMS, respectively. Patientsswitched primarily from fingolimod or natalizumab and for 17%, Cladribine was their first treatment. 207 patients with RRMS had >=6 months follow-up after cladribine exposure. Of these, 10 (4.8%) experienced >=1 clinical relapse within the first 6 months on cladribine. Conclusion(s): This study characterizes patients with MS newly treated with cladribine in a real-world clinical setting. Median EDSS and disease duration were relatively high in this analysis. Rates of discontinuation were low in the first year and relapse rates similar to phase III studies.

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenstrom macroglobulinemia (WM). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. ASPEN is a randomized phase 3 study comparing ZANU, a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in patients with WM. Aim(s): To compare the efficacy and safety of ZANU versus IBR in patients with WM and MYD88 mutation. Method(s): Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutation were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary endpoint was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% versus 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at approximately 12 months after the last patient enrolled. Result(s): In total, 201 patients were randomized from January 2017 to July 2018. While the treatment groups were well balanced for important baseline factors, in the ZANU arm, there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more patients with anemia (hemoglobin <=110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P = 0.09). Landmark analysis at 12 months showed a trend toward longer progression-free survival and overall survival, particularly in the R/R population. Rates of adverse events leading to dose holds, dose reductions, drug discontinu

Aim: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. Method(s): Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 mug/L) were administered variable-dose tocilizumab. Result(s): At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. Conclusion(s): Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.Copyright © 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/ T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.Copyright © 2020 Wong et al.

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.Copyright © 2020, Springer Nature Switzerland AG.

Aim: A Delphi expert consensus panel proposed that fulfilling >=1 of the a 5-2-1 criteria' (>=five-times daily oral levodopa use, >=two daily hours with a Off' symptoms or >=one daily hour with troublesome dyskinesia) suggests advanced Parkinson's disease (PD). Patients & methods: DUOdopa/Duopa in Patients with Advanced PD-a GLobal OBservational Study Evaluating Long-Term Effectiveness (DUOGLOBE)-is a single-arm, postmarketing, observational, long-term effectiveness study of levodopa-carbidopa intestinal gel (LCIG) for advanced PD. Result(s): This 6-month interim analysis (n = 139) affirms that most (98%) enrolled patients fulfill >=1 of the 5-2-1 criteria. These patients responded favorably to LCIG treatment. Safety was consistent with other LCIG studies. Conclusion(s): In advanced PD patients, the 5-2-1 criteria generally aligns with clinician assessment.Copyright © 2020 AbbVie Inc., employer of authors L Bergmann, P Kukreja, K Onuk, W Robieson.

Context: Fedratinib is approved in the US for patients with Intermediate-2/High-risk myelofibrosis. Myelofibrosis can evolve from prior PV or essential thrombocythemia (ET). The ARD12042 study assessed fedratinib in patients with PV/ET. There was no response among 36 ET patients who received fedratinib 100-600 mg/day. Objective(s): Determine fedratinib clinical activity in patients with PV in ARD12042. Method(s): Phase II, open-label, dose-ranging and -expansion study. Patients were aged >=18 years with WHO-defined PV, ECOG-PS score <= 2, and were resistant/intolerant to hydroxyurea. Patients received once-daily fedratinib 100 mg, 200 mg, or 400 mg doses during the dose-ranging phase, and 400 mg during dose-expansion, in continuous 28-day cycles. All endpoints were prospectively defined. Response rate (RR) was the proportion of patients with hematocrit <45% lasting >=3 months through end-of-cycle (EOC) 8 (dose-ranging phase); or no required phlebotomy from Cycle 4/Day 1 (C4D1) through C6D1 (dose-expansion phase). Secondary endpoints included clinicohematologic RR (ELN criteria) from C6D1 through EOC8, spleen volume reductions (SVR) from baseline, and proportion of patients with >=35% SVR at EOC8. The modified ITT (mITT) population received >=8 fedratinib cycles and excluded response-ineligible patients (hematocrit <= 45% without phlebotomy in the previous 3 months). Result(s): 45 PV patients received fedratinib. Median age was 63 years (36-86) and 98% had ECOG-PS 0-1. The mITT population included 15 patients (13 dose-ranging, 2 dose-expansion): fedratinib 100 mg, n=2; 200 mg, n=5; 400 mg, n=8. RRs during dose-ranging were 0%, 40%, and 67% in the fedratinib 100 mg, 200 mg, and 400 mg groups. Both expansion phase patients responded. Clinicohematologic RRs were 20% and 63% with fedratinib 200 mg and 400 mg. Median SVRs from baseline at EOC8 were -16% and -39% in the 200-mg and 400-mg groups, respectively; 3 fedratinib 400 mg patients (38%) had >=35% SVR. Among all pati