This document provides the general methodology and specific resource access points for performing a Freedom to Operate (FtO) analysis tailored to the needs of a drug repurposing project. It has been deliberately written to be performed with minimal technical resources: only web access is required, and no use is made of artificial intelligence tools. It can be performed by the inventors, up to the point where potentially critical findings (if any) are discussed with a patent attorney. When done properly, this method actually improves the relevance of the analysis, since no patent specialist can be expected to be fully familiar with all the scientific aspects of a repurposing project.While patent searches are the dominant motive, there is also discussion of how to recruit suitable suppliers, an issue that is particularly important when the compound is reformulated (as will be the case in most cases).

Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1-30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/μL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

This letter describes 13 patients with hypoparathyroidism caused by autosomal dominant hypocalcemia type 1 in whom the investigational oral calcilytic encaleret restored physiologic mineral homeostasis.

BackgroundA previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses. MethodsWe compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset. ResultsOS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p = 0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response. ConclusionCAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.

Medical communicators are tasked with delivering scientific information to numerous stakeholders, including patients, caregivers, providers, researchers, policymakers, and payors, around the world. In recent years, content offerings have expanded beyond traditional scientific publications deliverables, such as abstracts and articles, to include enhancements that are more easily digestible by patients or busy clinicians, such as plain language summaries, infographics, graphical abstracts, and other multimedia formats. Global medical communication is a burgeoning field that involves the delivery of cutting-edge scientific research to a broader global audience. However, medical and scientific articles have historically been published only in English and kept behind journal paywalls, limiting accessibility by the global scientific community. In this special issue of the AMWA Journal, we explore some of these issues and consider ways that medical communicators are improving access to scientific data and bridging the gaps between stakeholders around the world.

This article highlights the contributions of three pillars of an evidence-based practice approach (service providers, researchers, and families/clients) in the development of a framework to offer a way forward for professionals, families, and technology companies to support optimal visual and communication outcomes of individuals with cortical visual impairment (CVI) who use augmentative and alternative communication (AAC). By providing available research findings as well as practical information and lived experiences, the article offers clinical considerations and design features that can lead to addressing the unique needs of these individuals. This article reviews literature concerning what is known about CVI and describes in detail and from multiple viewpoints important features required in AAC systems to support individuals with CVI and enable them to communicate effectively. Components necessary for teams, communication partners, and AAC designers to optimize AAC system design in CVI are presented using external research evidence as internal evidence from lived experience to support their importance. An AAC system design that is tailored to the unique visual processing characteristics in CVI is likely to promote positive communication outcomes. The presentation of the lived experience of an individual who has CVI themselves illustrates the need for individualized assessments and interventions that incorporate and reflect the research presented here. https://doi.org/10.23641/asha.23902239.