A Novel Approach to Targeted Oncologic Therapy - Co-culture Viability of Polymer Prodrug Conjugation to Mesenchymal Stem Cells

Background/Purpose: Conjugation of polymer prodrugs to tumor homing cells, such as Mesenchymal Stem Cells (MSCs), could provide a vehicle for actively targeted delivery of polymer prodrugs. Methods: Human Bone Marrow MSCs were conjugated to either a doxorubicin polymer prodrug or free doxorubicin and were co-cultured with T-cells. Viability was assessed through the use of a Vi-cell counter. In Vivo Migration Analysis was performed NOD SCID mice implanted with subcutaneous MDA MB-231 breast cancer xenografts. Following tumor establishment, mice were injected via lateral tail vein injection with either saline or polymer loaded MSCs. Five days following stem cell injection, mice were euthanized, tumors were harvested and sections were analyzed using fluorescent microscopy and immuno-histochemical staining for cd105. Results: T-cell viability was reduced when co-cultured with MSCs conjugated to free doxorubicin although cells co-cultured with MSCs conjugated to doxorubicin polymer did not exhibit reduced viability. Polymer loaded MSCs displayed intact tumor homing migratory ability in vivo (Figure 1). Conclusion: MSCs conjugated to doxorubicin released the drug, resulting in reduced neighboring T-cells viability. MSCs loaded with polymer maintained their migratory capacity were able to migrate to tumors in vivo. MSCs therefore represent a potential vehicle for targeted drug delivery. Future work will focus on developing methods for releasing the drug upon successful delivery to the target in vivo

Assessing international alcohol consumption patterns during isolation from the COVID-19 pandemic using an online survey: highlighting negative emotionality mechanisms

Objectives: The COVID-19 pandemic has required drastic safety measures to control virus spread, including an extended self-isolation period. Stressful situations increase alcohol craving and consumption in alcohol use disorder (AUD) and non-AUD drinkers. Thus, we assessed how COVID-19 related stress may have affected drinking behaviours in the general population. Design: We developed an online cross-sectional survey, Habit Tracker (HabiT), which measured changes in drinking behaviours before and during COVID-19 quarantine. We also assessed psychiatric factors such as anxiety, depression (Hospital Anxiety and Depression Scale) and impulsivity (Short-Impulsive Behavior Scale). Lastly, we related drinking behaviours to COVID-19 specific stress factors. Setting: HabiT was released internationally, with individuals from 83 countries participating. Participants: Participants were included if they were 18 years of age or older and confirmed they were proficient in English. The survey was completed by 2873 adults with 1346 usable data (46.9% accurately completed). Primary outcome measures: Primary outcome measures were change in amount and severity of drinking behaviours before and during quarantine, and current drinking severity during quarantine. Results: Although drinking behaviours decreased overall during quarantine, 36% reported an increase in alcohol use. Those who increased alcohol use during quarantine were older individuals (95% CI 0.04 to 0.1, p<0.0001), essential workers (95% CI −0.58 to −0.1, p=0.01), individuals with children (95% CI −12.46 to 0.0, p=0.003), those with a personal relationship with someone severely ill from COVID-19 (95% CI −2 to −0.38, p=0.01) and those with higher depression (95% CI 0.67 to 1.45, p<0.0001), anxiety (95% CI 0.61 to 1.5, p=0.0002), and positive urgency impulsivity (95% CI 0.16 to 0.72, p=0.009). Furthermore, country-level subsample analyses indicated that drinking amount (95% CI 9.36 to 13.13, p=0.003) increased in the UK during quarantine. Conclusions: Our findings highlight a role for identifying those vulnerable for alcohol misuse during periods of self-isolation and underscore the theoretical mechanism of negative emotionality underlying drinking behaviours driven by stress. Limitations include a large degree of study dropout (n=1515). Future studies should assess the long-term effects of isolation on drinking behaviours

In Vivo Evaluation of a Biomimetic Polymer-Doxorubicin Conjugate for Cancer Therapy

This poster will describe a novel polymer pro-drug platform designed for conjugation and delivery of chemotherapeutics. Specifically, polymer pro-drugs were prepared from functional polymer zwitterions and doxorubicin (DOX), and evaluated in vivo to assess toxicological, pharmacokinetic and therapeutic properties. The biocompatible polymer scaffold (PolyMPC) consists of zwitterionic phosphorylcholine pendent groups, which mimic the natural hydrophilic moieties of phospholipids in cell membranes, and hydrazone linkages that allow for pH-triggered release of DOX. PolyMPC-DOX pro-drugs were isolated as dry solids using a facile strategy that allows for precise control of molecular weight and DOX incorporation. In vivo toxicity of PolyMPC and PolyMPC-DOX was assessed in a murine model. The maximum tolerated dose of the pro-drug was five times greater than that of free DOX, while PolyMPC alone exhibited no toxicity even at a dose of 800 mg/kg. A pharmacokinetic study in tumor-bearing mice demonstrated a significant increase in circulation half-life of conjugated DOX (t1/2=2 hours) compared to free DOX (t1/2=15 minutes), with conjugated DOX detectable in blood serum for longer than 24 hours. This pronounced enhancement in circulation time was attributed to the macromolecular scaffold, which precludes rapid renal clearance compared to native DOX. Examination of mice given PolyMPC-DOX five days after injection in the PK study showed a three-fold increase of drug accumulated in tumor tissue compared to that of mice treated with free DOX and drug accumulation in off-target organs was reduced for mice given DOX conjugate. The therapeutic efficacy of the PolyMPC-DOX conjugates was then assessed in an orthotopic murine breast cancer model. The treatment group given PolyMPC-DOX exhibited a two-fold increase in overall survival and a significant reduction in average tumor volume compared to the free DOX and saline control groups. A study evaluating the therapeutic efficacy of PolyMPC-DOX in a human ovarian xenograft tumor model is ongoing

RAISE study protocol: a cross-sectional, multilevel, neurobiological study of resilience after individual stress exposure.

INTRODUCTION: This paper describes the protocol for an ongoing project funded by the Royal Society, the Resilience After Individual Stress Exposure (RAISE) study; which aims to examine the factors and mechanisms that facilitate resilient functioning after childhood adversity (CA). METHODS AND ANALYSIS: We aim to recruit up to 200 participants. We will use dimension reduction techniques (principal component analysis) on standard-normally transformed individual parameters of mental health, social functioning and CA to calculate a composite measure of adaptive (ie, 'resilient') psychosocial functioning. To examine the neuroimmune responses to stress and their relationship with the brain and social environment, we will use a well validated functional MRI task; the Montreal imaging stress task and venepuncture. We will run group or dimensional comparisons in multiple levels of biological and psychological outcomes, as well as mediation and moderation analyses to study how key biological systems (ie, the hypothalamic-pituitary-adrenal axis and the immune system) interrelate and interact with brain function and social influences in order to facilitate resilient functioning after CA. We hypothesise that resilient functioning will be facilitated by reduced morning cortisol and cytokine levels before and after the stressor and improved neural responses to such stress, as well as increased gray matter volume in the hippocampus and prefrontal cortex, enhanced inhibitory control and emotion regulation, and more friendship and family support. ETHICS AND DISSEMINATION: This study has been reviewed and given favourable opinion by the National Research Ethics Service, NRES Committee East of England-Cambridge Central and external reviewers from the Royal Society (RGF\R1\180064 and RGF\EA\180029). The results of the RAISE study will be disseminated through (1) publications in scientific peer reviewed journals, (2) presentations on relevant scientific conferences and meetings, (3) publications and presentations for the general public and (4) through social media

Aerobic and strength training exercise programme for cognitive impairment in people with mild to moderate dementia : the DAPA RCT

Background Approximately 670,000 people in the UK have dementia. Previous literature suggests that physical exercise could slow dementia symptom progression. Objectives To estimate the clinical effectiveness and cost-effectiveness of a bespoke exercise programme, in addition to usual care, on the cognitive impairment (primary outcome), function and health-related quality of life (HRQoL) of people with mild to moderate dementia (MMD) and carer burden and HRQoL. Design Intervention development, systematic review, multicentred, randomised controlled trial (RCT) with a parallel economic evaluation and qualitative study. Setting 15 English regions. Participants People with MMD living in the community. Intervention A 4-month moderate- to high-intensity, structured exercise programme designed specifically for people with MMD, with support to continue unsupervised physical activity thereafter. Exercises were individually prescribed and progressed, and participants were supervised in groups. The comparator was usual practice. Main outcome measures The primary outcome was the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog). The secondary outcomes were function [as measured using the Bristol Activities of Daily Living Scale (BADLS)], generic HRQoL [as measured using the EuroQol-5 Dimensions, three-level version (EQ-5D-3L)], dementia-related QoL [as measured using the Quality of Life in Alzheimer’s Disease (QoL-AD) scale], behavioural symptoms [as measured using the Neuropsychiatric Inventory (NPI)], falls and fractures, physical fitness (as measured using the 6-minute walk test) and muscle strength. Carer outcomes were HRQoL (Quality of Life in Alzheimer’s Disease) (as measured using the EQ-5D-3L) and carer burden (as measured using the Zarit Burden Interview). The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year (QALY) gained from a NHS and Personal Social Services perspective. We measured health and social care use with the Client Services Receipt Inventory. Participants were followed up for 12 months. Results Between February 2013 and June 2015, 494 participants were randomised with an intentional unequal allocation ratio: 165 to usual care and 329 to the intervention. The mean age of participants was 77 years [standard deviation (SD) 7.9 years], 39% (193/494) were female and the mean baseline ADAS-Cog score was 21.5 (SD 9.0). Participants in the intervention arm achieved high compliance rates, with 65% (214/329) attending between 75% and 100% of sessions. Outcome data were obtained for 85% (418/494) of participants at 12 months, at which point a small, statistically significant negative treatment effect was found in the primary outcome, ADAS-Cog (patient reported), with a mean difference of –1.4 [95% confidence interval (CI) –2.62 to –0.17]. There were no treatment effects for any of the other secondary outcome measures for participants or carers: for the BADLS there was a mean difference of –0.6 (95% CI –2.05 to 0.78), for the EQ-5D-3L a mean difference of –0.002 (95% CI –0.04 to 0.04), for the QoL-AD scale a mean difference of 0.7 (95% CI –0.21 to 1.65) and for the NPI a mean difference of –2.1 (95% CI –4.83 to 0.65). Four serious adverse events were reported. The exercise intervention was dominated in health economic terms. Limitations In the absence of definitive guidance and rationale, we used a mixed exercise programme. Neither intervention providers nor participants could be masked to treatment allocation. Conclusions This is a large well-conducted RCT, with good compliance to exercise and research procedures. A structured exercise programme did not produce any clinically meaningful benefit in function or HRQoL in people with dementia or on carer burden

Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity

Childhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N = 2406, aged 14–24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N = 275) using a sliding window approach. We found that higher resilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z > 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodeling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning

Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity

© The Author(s), 2023. Published by Cambridge University Press. This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided that no alterations are made and the original article is properly cited. The written permission of Cambridge University Press must be obtained prior to any commercial use and/or adaptation of the article.Childhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N = 2406, aged 14–24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N = 275) using a sliding window approach. We found that higher resilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z > 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodeling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning.This work was supported by the Neuroscience in Psychiatry Network (NSPN) Consortium, a strategic award from the Wellcome Trust to the University of Cambridge and University College London (095844/Z/11/Z); the Leiden Social Resilience and Security program, the Cambridge NIHR Biomedical Research Center and by the Max Planck–UCL Center for Computational Psychiatry and Ageing, a joint initiative of the Max Planck Society and University College London; a Royal Society Dorothy Hodgkin Fellowship for Prof. Anne-Laura van Harmelen (DH150176); an NIHR Senior Investigator award for Prof. Ed Bullmore and a Wolfe Health Fellowship for Dr Laura Moreno-López. Dr František Váša was supported by the Gates Cambridge Trusts, the Data to Early Diagnosis and Precision Medicine Industrial Strategy Challenge Fund, UK Research and Innovation, and the Bill & Melinda Gates Foundation.Peer reviewe

RAISE study protocol: a cross-sectional, multilevel, neurobiological study of resilience after individual stress exposure

Introduction: This paper describes the protocol for an ongoing project funded by the Royal Society, the Resilience After Individual Stress Exposure (RAISE) study; which aims to examine the factors and mechanisms that facilitate resilient functioning after childhood adversity (CA). Methods and analysis: We aim to recruit up to 200 participants. We will use dimension reduction techniques (principal component analysis) on standard-normally transformed individual parameters of mental health, social functioning and CA to calculate a composite measure of adaptive (ie, ‘resilient’) psychosocial functioning. To examine the neuroimmune responses to stress and their relationship with the brain and social environment, we will use a well validated functional MRI task; the Montreal imaging stress task and venepuncture. We will run group or dimensional comparisons in multiple levels of biological and psychological outcomes, as well as mediation and moderation analyses to study how key biological systems (ie, the hypothalamic–pituitary–adrenal axis and the immune system) interrelate and interact with brain function and social influences in order to facilitate resilient functioning after CA. We hypothesise that resilient functioning will be facilitated by reduced morning cortisol and cytokine levels before and after the stressor and improved neural responses to such stress, as well as increased gray matter volume in the hippocampus and prefrontal cortex, enhanced inhibitory control and emotion regulation, and more friendship and family support. Ethics and dissemination: This study has been reviewed and given favourable opinion by the National Research Ethics Service, NRES Committee East of England-Cambridge Central and external reviewers from the Royal Society (RGF\R1\180064 and RGF\EA\180029). The results of the RAISE study will be disseminated through (1) publications in scientific peer reviewed journals, (2) presentations on relevant scientific conferences and meetings, (3) publications and presentations for the general public and (4) through social media

The Neurocognitive Dynamics Underlying Loss of Control in Alcohol Misuse and Addiction

“That’s the problem with drinking, I thought, as I poured myself a drink. If something bad happens you drink in an attempt to forget; if something good happens you drink in order to celebrate; and if nothing happens you drink to make something happen.” Charles Bukowski, Women Diverse motivations may underlie our alcohol consumption, yet what are the driving factors that sustain drinking behaviour even when confronted with unfavourable repercussions? Furthermore, how do we discern the boundary between moderate and problematic drinking, and why is this distinction often unnoticed until unhealthy patterns emerge? Alcohol consumption which detrimentally impacts one’s health, interpersonal dynamics, or ability to work- termed alcohol misuse- can, in its extremity, evolve into an addiction. This advanced stage is characterised by an overwhelming urge to seek and consume alcohol, a diminished ability to regulate intake, and persistent drinking despite recognition of the associated adverse consequences. Repeated, yet unsuccessful, attempts to abstain can lead to significant and potentially catastrophic functional impairment (United States Office of the Surgeon General, 2016). Alcohol misuse and addiction present as complex pathologies, broadly conceptualised as dynamic dysregulation of neural circuitry, subject to modulation by socio-environmental and genetic determinants (Koob & Volkow, 2016). Given the ubiquity of alcohol use and societal impact, a paramount task in cognitive neuroscience is the elucidation of the neuroadaptive variations distinguishing controlled and uncontrolled alcohol consumption, with the aim to discern clinical biomarkers pertinent to risk prediction and therapeutic prognosis (Heilig et al., 2010). This investigation gains urgency in light of the observed surge in alcohol consumption and associated morbidity and mortality during the COVID-19 pandemic and the concomitant isolation period (Office for National Statistics, 2020)- a trend which, alarmingly, has persisted post-pandemic (Angus et al., 2022). The prevailing adherence to traditional nosologies, which classify disorders based on the description and enumeration of heterogenous symptoms within arbitrary clinical boundaries- often overlapping with other disorders, is notably devoid of a biological basis (Morris & Cuthbert, 2012). While clinically invaluable, this approach has obfuscated a mechanistic understanding of aetiopathogenesis of addiction. Alternatively, emergent dimensional psychiatric frameworks underscore the conceptual application of endophenotypes (Gottesman & Gould, 2003)- or “intermediate phenotypes” that express tractable and causally relevant neurocognitive signatures (Kendler & Neale, 2010)- transcending traditional psychiatric categorisation, which may elucidate the aetiology and risk factors intrinsic not only to alcohol-related disorders but to a broader spectrum of psychopathologies (Robbins et al., 2012). Ultimately, these endophenotypes may present potential targets for neuromodulation interventions, via pharmacological or neurostimulation methods (Yee et al., 2015). Central to this thesis is a detailed examination of two intimately connected endophenotypes emblematic of the “loss of control” inherent to the addiction cycle (Robbins et al., 2012): impulsivity (i.e., “actions which are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation and that often result in undesirable consequences” [Daruna & Barnes, 1993]) and compulsivity (i.e., “actions which persist inappropriate to the situation, have no obvious relationship to the overall goal and which often result in undesirable consequences” [Dalley et al., 2011]). These constructs are delineated by unique motoric, cognitive, and neurobiological profiles (Voon & Dalley, 2016), and are theorised to play cardinal roles at different stages in the evolution of addiction (Koob & Le Moal, 1997). While incipient stages are typified by impulsivity, in which alcohol use is driven by immediate gratification, later stages are dominated by compulsivity, facilitated by neuroadaptations from escalated alcohol intake and ensuing psycho-emotional and physiological dependency (Koob & Le Moal, 2008; Everitt & Robbins, 2005). Neuro-functionally, this cycle reflects a shift from systems involved in reward anticipation to those involved in habit formation and stress (Koob & Volkow, 2010)- anchored by perturbations of fronto-striatal brain circuitry (Goldstein & Volkow, 2002)- culminating in observable impairments in incentive salience, negative emotionality, and executive function domains (Kwako et al., 2016; Voon et al., 2020). Critically, these neurocognitive deficits extend beyond alcohol addiction, indicating a shared pathophysiological basis integral to a range of disorders, including various substance and behavioural addictions (Grant & Chamberlain, 2014), and other disorder types, such as obsessive-compulsive disorder (OCD) (Voon et al., 2015), irrespective of their apparent phenotypic differences. Despite the extensive corpus of existing neuropsychiatric research delving into these areas, this thesis uniquely prioritises the pivotal transitional phase from impulsive to compulsive alcohol use and its associated biomarkers across both clinical and non-clinical cohorts (Everitt & Robbins, 2005). Accordingly, this thesis acknowledges the multifaceted natures of impulsivity (e.g., motor, decisional, trait) and compulsivity (e.g., attentional set-shifting vs. habitual learning) endophenotypes (Voon & Dalley, 2016), drawing from foundational research conducted using rodent models (Dalley et al., 2011). This understanding has been extrapolated to human subjects through a series of experiments tied to distinct stages of the addiction trajectory- and its corresponding neurofunctional impairments- leveraging three interrelated methodologies: Cognitive Task Development: Fundamental to this research is the development, optimisation, and validation of novel cognitive paradigms designed to quantify cognitive control in relation to impulsivity and compulsivity dimensions and their respective subtypes. The aim is dual-pronged: to refine neuropsychological evaluation of these constructs in humans, and to elucidate their interactions with other cognitive-emotional domains intrinsic to addiction psychopathology. Within the domain of impulsivity, emphasis is placed on waiting impulsivity, a motor impulsivity subtype characterised by a lack of internal restraint toward anticipated reward (Chapter 1). This feature is further operationalised in the context of alcohol cue reactivity, or the measurement of the conditioned response elicited by alcohol-related stimuli (Chapter 2). Concurrently, specific facets of compulsivity are delineated, chiefly habit formation mechanisms that signify an automatic response pattern bypassing deliberative decision-making processes. These mechanisms, tied to both reward/approach- and threat/avoidance-oriented dynamics, were operationalised for online empirical assessment (Chapter 3). The interplay among waiting impulsivity, previous exposure to alcohol, and habit is examined- emphasising a central aim of this thesis. Neurostimulation Intervention: Repetitive Transcranial Magnetic Stimulation (rTMS): Neuromodulatory techniques, such as repetitive transcranial magnetic stimulation (rTMS), are employed in this research to target salient brain regions and networks to identify and validate biomarkers associated with operationalised components of impulsivity and compulsivity, thereby elucidating their mechanistic contributions within the addiction spectrum. Insights from this approach not only augments our understanding of the neural circuitry underpinning alcohol addiction and related disorders, but also may inform neural substrates for therapeutic intervention. Using this methodology, attention is again accorded to motoric subtypes of impulsivity, specifically differentiating neural mechanisms governing the capacity to withhold an action (i.e., waiting impulsivity) versus those dictating the cessation of an already initiated action (i.e., response inhibition). To this end, two distinct rTMS protocols are employed, both tailored to specific neuromodulatory objectives. First, a neural region previously identified by functional magnetic resonance imaging (fMRI) is targeted utilising an inhibitory TMS protocol, termed continuous theta burst stimulation (cTBS), with the objective to discern a causal nexus between the activity of this region and waiting impulsivity, positioning it as a potential neuromodulation target for addiction disorders (Chapter 1). Second, a cortical paired associative stimulation (cPAS) protocol is applied to interrogate cortical excitability within the hyperdirect fronto-striatal response inhibition network in AUD patients to identify a potential neural mechanism giving rise to the observed cognitive deficit in this population, with implications for clinical course and treatment outcomes (Chapter 4). Epidemiological Analysis: Envisioned on a broader scale, this research further aimed to assess global health trends by analysing consumption patterns of alcohol and specific internet-based modalities- namely online gaming and pornography viewing- pre- to intra-COVID-19 to gauge the pandemic’s acute impact on addiction trajectories. This entailed the development and international distribution of an online survey tracking not only changes in quantity and frequency of consumption, but probes deeper into usage severity, highlighting potential amplification of addictive behaviours within the pandemic’s milieu. Furthermore, this instrument assesses the effects of psychiatric symptoms- primarily within the spheres of impulsivity and negative emotionality- and specific contextual stressors- such as occupational displacement and isolation- on these behavioural patterns (Chapter 5)

Assessing international alcohol consumption patterns during isolation from the COVID-19 pandemic using an online survey: highlighting negative emotionality mechanisms

Objectives: The COVID-19 pandemic has required drastic safety measures to control virus spread, including an extended self-isolation period. Stressful situations increase alcohol craving and consumption in alcohol use disorder (AUD) and non-AUD drinkers. Thus, we assessed how COVID-19 related stress may have affected drinking behaviours in the general population. Design: We developed an online cross-sectional survey, Habit Tracker (HabiT), which measured changes in drinking behaviours before and during COVID-19 quarantine. We also assessed psychiatric factors such as anxiety, depression (Hospital Anxiety and Depression Scale) and impulsivity (Short-Impulsive Behavior Scale). Lastly, we related drinking behaviours to COVID-19 specific stress factors. Setting: HabiT was released internationally, with individuals from 83 countries participating. Participants: Participants were included if they were 18 years of age or older and confirmed they were proficient in English. The survey was completed by 2873 adults with 1346 usable data (46.9% accurately completed). Primary outcome measures: Primary outcome measures were change in amount and severity of drinking behaviours before and during quarantine, and current drinking severity during quarantine. Results: Although drinking behaviours decreased overall during quarantine, 36% reported an increase in alcohol use. Those who increased alcohol use during quarantine were older individuals (95% CI 0.04 to 0.1, p<0.0001), essential workers (95% CI −0.58 to −0.1, p=0.01), individuals with children (95% CI −12.46 to 0.0, p=0.003), those with a personal relationship with someone severely ill from COVID-19 (95% CI −2 to −0.38, p=0.01) and those with higher depression (95% CI 0.67 to 1.45, p<0.0001), anxiety (95% CI 0.61 to 1.5, p=0.0002), and positive urgency impulsivity (95% CI 0.16 to 0.72, p=0.009). Furthermore, country-level subsample analyses indicated that drinking amount (95% CI 9.36 to 13.13, p=0.003) increased in the UK during quarantine. Conclusions: Our findings highlight a role for identifying those vulnerable for alcohol misuse during periods of self-isolation and underscore the theoretical mechanism of negative emotionality underlying drinking behaviours driven by stress. Limitations include a large degree of study dropout (n=1515). Future studies should assess the long-term effects of isolation on drinking behaviours