<div><h4>Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.</h4><i>Krystal JH, Kane JM, Correll CU, Walling DP, ... Sanchez R, Renger J</i><br /><b>Background</b><br />Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia.<br /><b>Methods</b><br />We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873.<br /><b>Findings</b><br />Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6.<br /><b>Interpretation</b><br />These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile.<br /><b>Funding</b><br />Cerevel Therapeutics.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Dec 2023; 400:2210-2220</small></div>

<div><h4>Innovation for infection prevention and control-revisiting Pasteur\'s vision.</h4><i>Birgand G, Ahmad R, Bulabula ANH, Singh S, ... Sánchez EC, Holmes A</i><br /><AbstractText>Louis Pasteur has long been heralded as one of the fathers of microbiology and immunology. Less known is Pasteur\'s vision on infection prevention and control (IPC) that drove current infection control, public health, and much of modern medicine and surgery. In this Review, we revisited Pasteur\'s pioneering works to assess progress and challenges in the process and technological innovation of IPC. We focused on Pasteur\'s far-sighted conceptualisation of the hospital as a reservoir of microorganisms and amplifier of transmission, aseptic technique in surgery, public health education, interdisciplinary working, and the protection of health services and patients. Examples from across the globe help inform future thinking for IPC innovation, adoption, scale up and sustained use.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Dec 2023; 400:2250-2260</small></div>

<div><h4>Hepatitis C.</h4><i>Martinello M, Solomon SS, Terrault NA, Dore GJ</i><br /><AbstractText>Hepatitis C virus (HCV) is a hepatotropic RNA virus that can cause acute and chronic hepatitis, with progressive liver damage resulting in cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In 2016, WHO called for the elimination of HCV infection as a public health threat by 2030. Despite some progress, an estimated 57 million people were living with HCV infection in 2020, and 300 000 HCV-related deaths occur per year. The development of direct-acting antiviral therapy has revolutionised clinical care and generated impetus for elimination, but simplified and broadened HCV screening, enhanced linkage to care, and higher coverage of treatment and primary prevention strategies are urgently required.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 23 Sep 2023; 402:1085-1096</small></div>

<div><h4>CAR T-cell therapy in autoimmune diseases.</h4><i>Schett G, Mackensen A, Mougiakakos D</i><br /><AbstractText>Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 22 Sep 2023; epub ahead of print</small></div>

<div><h4>Glaucoma: now and beyond.</h4><i>Jayaram H, Kolko M, Friedman DS, Gazzard G</i><br /><AbstractText>The glaucomas are a group of conditions leading to irreversible sight loss and characterised by progressive loss of retinal ganglion cells. Although not always elevated, intraocular pressure is the only modifiable risk factor demonstrated by large clinical trials. It remains the leading cause of irreversible blindness, but timely treatment to lower intraocular pressure is effective at slowing the rate of vision loss from glaucoma. Methods for lowering intraocular pressure include laser treatments, topical medications, and surgery. Although modern surgical innovations aim to be less invasive, many have been introduced with little supporting evidence from randomised controlled trials. Many cases remain undiagnosed until the advanced stages of disease due to the limitations of screening and poor access to opportunistic case finding. Future research aims to generate evidence for intraocular pressure-independent neuroprotective treatments, personalised treatment through genetic risk profiling, and exploration of potential advanced cellular and gene therapies.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 21 Sep 2023; epub ahead of print</small></div>