Modular Synthesis of Anti-HER2 Dual-Drug Antibody-Drug Conjugates Demonstrating Improved Toxicity.

Antibodies have gained clinical success in the last two decades for the targeted delivery of highly toxic small molecule chemotherapeutics. Yet antibody-drug conjugates (ADCs) often fail in the clinic due to the development of resistance. The delivery of two mechanistically distinct small molecule drugs on one antibody is of increasing interest to overcome these challenges with single-drug ADCs.

Factors associated with anxiety and depression one year after trauma critical care admission: A multi-centre study.

Background: Recovery after severe injury may be impacted by a range of psychological factors. This multi-site study investigated the prevalence and impact of anxiety and depression at one year after trauma critical care admission.

Methods: Adult trauma patients admitted to four Level 1 Critical Care Units were prospectively enrolled over 18 months.

Digital empowerment in long-term condition management: A systematic review and narrative synthesis of the experiences and perceptions of home-based digital health coaching interventions.

Objectives: Globally, the prevalence of long-term conditions (LTCs) continues to rise. The impact of LTCs presents significant challenges for international health and social care systems and continues to be a leading cause of mortality. Despite this, digital health coaching interventions (DHCIs) appear to be a promising strategy for managing chronic disease.

The Physiome Project and Digital Twins.

Interest in the concept of a virtual human model that can encompass human physiology and anatomy on a biophysical (mechanistic) basis, and can assist with the clinical diagnosis and treatment of disease, appears to be growing rapidly around the globe. When such models are personalised and coupled with continual diagnostic measurements, they are called 'digital twins'. We argue here that the most useful form of virtual human model will be one that is constrained by the laws of physics, contains a comprehensive knowledge graph of all human physiology and anatomy, is multiscale in the sense of linking systems physiology down to protein function, and can to some extent be personalized and linked directly with clinical records.

A comparative study of influenza surveillance systems and administrative data in England during the 2022-2023 season.

Accurate and representative surveillance is essential for understanding the impact of influenza on healthcare systems. During the 2022-2023 influenza season, the Northern Hemisphere experienced its most significant epidemic wave since the onset of the COVID-19 pandemic in 2020. Concurrently, new surveillance systems, developed in response to the pandemic, became available within health services.

Acceptability of an automated directly observed therapy (DOT) application for PrEP adherence support among young men who have sex with men: a qualitative exploration.

Pre-exposure prophylaxis (PrEP) adherence remains a challenge among young men who have sex with men (MSM). We developed and tested a smartphone application ("app"), "DOT Diary", which combines automated directly observed therapy (DOT) with information about PrEP protection levels, pill-taking reminders, a sexual behavior diary, and a PrEP dosing calendar. To contextualize trial results, we qualitatively explored participants' app experiences.

A high-throughput lysosome trafficking assay guides ligand selection and elucidates differences in CD22-targeted nanodelivery.

Targeted nanoparticles offer potential to selectively deliver therapeutics to cells; however, their subcellular fate following endocytosis must be understood to properly design mechanisms of drug release. Here we describe a nanoparticle platform and associated cell-based assay to observe lysosome trafficking of targeted nanoparticles in live cells. The nanoparticle platform utilizes two fluorescent dyes loaded onto PEG-poly(glutamic acid) and PEG-poly(Lysine) block co-polymers that also comprise azide reactive handles on PEG termini to attach antibody-based targeting ligands.

Identifying Unmet Needs in Major Depressive Disorder Using a Computer-Assisted Alternative to Conventional Thematic Analysis: Qualitative Interview Study With Psychiatrists.

Background: The development of digital health tools that are clinically relevant requires a deep understanding of the unmet needs of stakeholders, such as clinicians and patients. One way to reveal unforeseen stakeholder needs is through qualitative research, including stakeholder interviews. However, conventional qualitative data analytical approaches are time-consuming and resource-intensive, rendering them untenable in many industry settings where digital tools are conceived of and developed.

EMCDDA framework and practical guidance for naming cathinones.

Cathinones are often sold as "legal" alternatives to controlled stimulants such as amphetamine, MDMA and cocaine. Cathinones are the second largest group of new psychoactive substances (NPS), with close to 170 monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Although all cathinones are related to the parent compound cathinone, one of the psychoactive principles in khat, assigning consistent, informative and user-friendly common names to these substances is challenging.

Identifying employee, workplace and population characteristics associated with COVID-19 outbreaks in the workplace: a population-based study.

Objectives: To identify risk factors that contribute to outbreaks of COVID-19 in the workplace and quantify their effect on outbreak risk.

Methods: We identified outbreaks of COVID-19 cases in the workplace and investigated the characteristics of the individuals, the workplaces, the areas they work and the mode of commute to work, through data linkages based on Middle Layer Super Output Areas in England between 20 June 2021 and 20 February 2022. We estimated population-level associations between potential risk factors and workplace outbreaks, adjusting for plausible confounders identified using a directed acyclic graph.

Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria.

Chronic intermittent hypoxia (CIH, a model for sleep apnoea) is a major risk factor for several cardiovascular diseases. Autonomic imbalance (sympathetic overactivity and parasympathetic withdrawal) has emerged as a causal contributor of CIH-induced cardiovascular disease. Previously, we showed that CIH remodels the parasympathetic pathway.

Forecasting influenza hospital admissions within English sub-regions using hierarchical generalised additive models.

Background: Seasonal influenza places a substantial burden annually on healthcare services. Policies during the COVID-19 pandemic limited the transmission of seasonal influenza, making the timing and magnitude of a potential resurgence difficult to ascertain and its impact important to forecast.

Methods: We have developed a hierarchical generalised additive model (GAM) for the short-term forecasting of hospital admissions with a positive test for the influenza virus sub-regionally across England.

Opportunities for digital health technology: identifying unmet needs for bipolar misdiagnosis and depression care management.

Introduction: Digital health technologies (DHTs) driven by artificial intelligence applications, particularly those including predictive models derived with machine learning methods, have garnered substantial attention and financial investment in recent years. Yet, there is little evidence of widespread adoption and scant proof of gains in patient health outcomes. One factor of this paradox is the disconnect between DHT developers and digital health ecosystem stakeholders, which can result in developing technologies that are highly sophisticated but clinically irrelevant.

Nowcasting the 2022 mpox outbreak in England.

In May 2022, a cluster of mpox cases were detected in the UK that could not be traced to recent travel history from an endemic region. Over the coming months, the outbreak grew, with over 3000 total cases reported in the UK, and similar outbreaks occurring worldwide. These outbreaks appeared linked to sexual contact networks between gay, bisexual and other men who have sex with men.

Organization and morphology of calcitonin gene-related peptide-immunoreactive axons in the whole mouse stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g.

Mapping the Organization and Morphology of Calcitonin Gene-Related Peptide (CGRP)-IR Axons in the Whole Mouse Stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers [e.g.

Engineered Ultrasmall Nanoparticle Drug-Immune Conjugates with "Hit and Run" Tumor Delivery to Eradicate Gastric Cancer.

Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core-shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties.

From JWH-018 to OXIZIDS: Structural evolution of synthetic cannabinoids in the European Union from 2008 to present day.

With new synthetic cannabinoids (SCs) appearing on the European drug market every year, early warning systems are key to detect, monitor, and respond to threats posed by them. The European Union Early Warning System (EU EWS) implemented by the European Monitoring Centre for Drugs and Drug Addiction has monitored these substances since their first European detection in 2008. Since then, national and international responses have been implemented, aimed at tackling risks posed by SCs.

Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

Purpose: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models.

Experimental Design: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies.

EMCDDA framework and practical guidance for naming synthetic cannabinoids.

Synthetic cannabinoids (SCs), often sold as "legal" replacements for cannabis, are the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Currently, close to 240 structurally heterogeneous SCs are monitored through the European Union (EU) Early Warning System, and attributing consistent, informative, and user-friendly names to SCs has been a challenge in the past. Over time, several naming conventions have been employed with the aim of making SCs more easily recognizable by non-chemists, including regulators.

Transmission dynamics of monkeypox in the United Kingdom: contact tracing study.

Objective: To analyse the transmission dynamics of the monkeypox outbreak in the UK, declared a Public Health Emergency of International Concern in July 2022.

Design: Contact tracing study, linking data on case-contact pairs and on probable exposure dates.

Setting: Case questionnaires from the UK Health Security Agency (UKHSA), United Kingdom.