Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Structure of the MRAS-SHOC2-PP1C phosphatase complex.

RAS-MAPK signalling is fundamental for cell proliferation and is altered in most human cancers1-3. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. Although studies revealed snapshots for autoinhibited and active RAF-MEK1-14-3-3 complexes4, the intermediate steps that lead to RAF activation remain unclear. The MRAS-SHOC2-PP1C holophosphatase dephosphorylates RAF at serine 259, resulting in the partial displacement of 14-3-3 and RAF-RAS association3,5,6. MRAS, SHOC2 and PP1C are mutated in rasopathies-developmental syndromes caused by aberrant MAPK pathway activation6-14-and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)-RAS-driven tumours15-18. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we determine, using X-ray crystallography, the structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS through its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation that is extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS-GTP molecules recruit RAF-14-3-3 and SHOC2-PP1C to produce downstream pathway activation. Importantly, we find that rasopathy and cancer mutations reside at protein-protein interfaces within the holophosphatase, resulting in enhanced affinities and function. Collectively, our findings shed light on a fundamental mechanism of RAS biology and on mechanisms of clinically observed enhanced RAS-MAPK signalling, therefore providing the structural basis for therapeutic interventions.

CHARR efficiently estimates contamination from DNA sequencing data.

DNA sample contamination is a major issue in clinical and research applications of whole-genome and -exome sequencing. Even modest levels of contamination can substantially affect the overall quality of variant calls and lead to widespread genotyping errors. Currently, popular tools for estimating the contamination level use short-read data (BAM/CRAM files), which are expensive to store and manipulate and often not retained or shared widely. We propose a metric to estimate DNA sample contamination from variant-level whole-genome and -exome sequence data called CHARR, contamination from homozygous alternate reference reads, which leverages the infiltration of reference reads within homozygous alternate variant calls. CHARR uses a small proportion of variant-level genotype information and thus can be computed from single-sample gVCFs or callsets in VCF or BCF formats, as well as efficiently stored variant calls in Hail VariantDataset format. Our results demonstrate that CHARR accurately recapitulates results from existing tools with substantially reduced costs, improving the accuracy and efficiency of downstream analyses of ultra-large whole-genome and exome sequencing datasets.

Divergent Bimetallic Mechanisms in Copper(II)-Mediated C-C, N-N, and O-O Oxidative Coupling Reactions.

Copper-catalyzed aerobic oxidative coupling of diaryl imines provides a route for conversion of ammonia to hydrazine. The present study uses experimental and density functional theory computational methods to investigate the mechanism of N-N bond formation, and the data support a mechanism involving bimolecular coupling of Cu-coordinated iminyl radicals. Computational analysis is extended to CuII-mediated C-C, N-N, and O-O coupling reactions involved in the formation of cyanogen (NC-CN) from HCN, 1,3-butadiyne from ethyne (i.e., Glaser coupling), hydrazine from ammonia, and hydrogen peroxide from water. The results reveal two different mechanistic pathways. Heteroatom ligands with an uncoordinated lone pair (iminyl, NH2, OH) undergo charge transfer to CuII, generating ligand-centered radicals that undergo facile bimolecular radical-radical coupling. Ligands lacking a lone pair (CN and CCH) form bridged binuclear diamond-core structures that undergo C-C coupling. This mechanistic bifurcation is rationalized by analysis of spin densities in key intermediates and transition states, as well as multiconfigurational calculations. Radical-radical coupling is especially favorable for N-N coupling owing to energetically favorable charge transfer in the intermediate and thermodynamically favorable product formation.

Minorities Face Delays to Pancreatic Cancer Treatment Regardless of Diagnosis Setting.

INTRODUCTION: Our analysis was designed to characterize the demographics and disparities between the diagnosis of pancreas cancer during emergency presentation (EP) and the outpatient setting (OP) and to see the impact of our institutions pancreatic multidisciplinary clinic (PMDC) on these disparities. METHODS: Institutional review board-approved retrospective review of our institutional cancer registry and PMDC databases identified patients diagnosed/treated for pancreatic ductal adenocarcinoma between 2014 and 2022. Chi-square tests were used for categorical variables, and one-way ANOVA with a Bonferroni correction was used for continuous variables. Statistical significance was set at p < 0.05. RESULTS: A total of 286 patients met inclusion criteria. Eighty-nine patients (31.1%) were underrepresented minorities (URM). Fifty-seven (64.0%) URMs presented during an EP versus 100 (50.8%) non-URMs (p = 0.037). Forty-one (46.1%) URMs were reviewed at PMDC versus 71 (36.0%) non-URMs (p = 0.10). No differences in clinical and pathologic stage between the cohorts (p = 0.28) were present. URMs took 22 days longer on average to receive treatment (66.5 days vs. 44.8 days, p = 0.003) in the EP cohort and 18 days longer in OP cohort (58.0 days vs. 40.5 days, p < 0.001) compared with non-URMs. Pancreatic Multidisciplinary Clinic enrollment in EP cohort eliminated the difference in time to treatment between cohorts (48.3 days vs. 37.0 days; p = 0.151). RESULTS: Underrepresented minorities were more likely to be diagnosed via EP and showed delayed times to treatment compared with non-URM counterparts. Our PMDC alleviated some of these observed disparities. Future studies are required to elucidate the specific factors that resulted in these findings and to identify solutions.

Palliative Medicine and End of Life Care Between Races in an Academic Intensive Care Unit.

Background: Although palliative medicine (PM) is more commonly being integrated into the intensive care unit (ICU), research on racial disparities in this area is lacking. Our objectives were to (a) identify racial disparities in utilization of PM consultation for patients who received ICU care and (b) determine if there were differences in the use of code status or PM consultation over time based on race. Materials and Methods: Retrospective analysis of 571 patients, 18 years and above, at a tertiary care institution who received ICU care and died during their hospital stay. We analyzed two timeframes, 2008-2009 and 2018-2019. Univariate analysis was utilized to evaluate baseline characteristics. A multivariate logistic regression model and interaction P values were employed to assess for differential use of PM consultation, do not resuscitate (DNR) orders, and comfort care (CC) orders between races in aggregate and for changes over time. Results: There was a notable increase in Black/African-American (AA) (54% to 61%) and Hispanic/Latino (2% to 3%) patients over time in our population. Compared to White patients, we found no differences between PM consultation and CC orders. There was a lower probability of DNR orders for Black/AA (adjusted odds ratio [aOR] 0.569; P = .049; confidence interval [CI]: 0.324-0.997) and other/unknown/multiracial patients (aOR: 0.389; P = .273; CI: 0.169-0.900). Comparing our earlier time period to the later time period, we found an increased usage of PM for all patients. Interaction P values suggest there were no differences between races regarding PM, DNR, and CC orders. Conclusions: PM use has increased over time at our institution. Contrary to the previous literature, there were no differences in the frequency of utilization of PM consultation between races. Further analysis to evaluate the usage of PM in the ICU setting in varying populations and geographic locations is warranted.

High energy laser propagation through natural convection of air: a benchmark for validation of numerical simulation.

The study of propagation medium effects on lasers continues to be an active area of research. High energy laser (HEL) propagation through planetary atmosphere is particularly nuanced as the beam generates its own flow field and suffers from additional degrading effects. Herein, we construct experimental setups conducive to probing the physics of the laser-atmosphere interaction and generating validation datasets for high fidelity predictive software. Measured and derived parameters are presented, and predictive models are generated utilizing random forest regression.

PAGEANT: personal access to genome and analysis of natural traits.

GWASs have identified numerous genetic variants associated with a wide variety of diseases, yet despite the wide availability of genetic testing the insights that would enhance the interpretability of these results are not widely available to members of the public. As a proof of concept and demonstration of technological feasibility, we developed PAGEANT (Personal Access to Genome & Analysis of Natural Traits), usable through Graphical User Interface or command line-based version, aiming to serve as a protocol and prototype that guides the overarching design of genetic reporting tools. PAGEANT is structured across five core modules, summarized by five Qs: (i) quality assurance of the genetic data; (ii) qualitative assessment of genetic characteristics; (iii) quantitative assessment of health risk susceptibility based on polygenic risk scores and population reference; (iv) query of third-party variant databases (e.g. ClinVAR and PharmGKB) and (v) quick Response code of genetic variants of interest. Literature review was conducted to compare PAGEANT with academic and industry tools. For 2504 genomes made publicly available through the 1000 Genomes Project, we derived their genomic characteristics for a suite of qualitative and quantitative traits. One exemplary trait is susceptibility to COVID-19, based on the most up-to-date scientific findings reported.

The role of stigma in cannabis use disclosure: an exploratory study.

BACKGROUND: Although cannabis use incidence, societal acceptance, and legislation all trend positively, cannabis remains federally illegal in the USA. Prior studies have revealed that patients are reluctant to disclose their cannabis use history in the healthcare system, which can negatively impact patient care. This study reports the frequency of cannabis use disclosure with special considerations for stigmatization. To better understand the limitations, providers face in providing collaborative, comprehensive, and informed care, this study evaluated four domains of stigma: perceived, anticipated, enacted, and internalized. METHODS: This study used a descriptive exploratory design. Data collection occurred using an anonymous, online national survey with a convenience sample in the USA. Recruitment relied on electronic media and occurred between July and December 2022. Participants were adults older than 21 years and self-identified as having used cannabis and accessed the healthcare system within the last five years. The survey measured demographic characteristics, cannabis use, and disclosure patterns. Stigma was measured using the Stigma Use Stigma Mechanism Scale (SU-SMS) and Substance Abuse Use Self-Stigma Scale (SASSS) with language modifications for cannabis. Ordinal logistic regression models were performed to evaluate associations between the frequency of cannabis use disclosure patterns and each stigma category. Associations were assessed using Chi-squared or Fisher's exact tests. RESULTS: Data were available for 249 respondents. Most participants (57.1%) reported initiating a conversation about cannabis with their healthcare provider; 27.8% of the time, cannabis is never discussed, and healthcare providers initiate only 15.1% of related discussions. Anticipated stigma [95% CI 1.045-1.164] and total stigma [95% CI 1.001-1.039] had statistically significant associations with nondisclosure. Annual household income (p = .04), chronicity of cannabis use (p = .03), frequency of cannabis use (p = .02), and a known amount of CBD in products consumed (p = .01) had statistically significant associations with the frequency of cannabis use disclosure. CONCLUSIONS: Patients who use cannabis experience stigmatization in the healthcare setting that may limit disclosure of cannabis use history. Future studies would be well served to explore anticipated stigma more deeply. Healthcare providers should be knowledgeable to lead such conversations relating to cannabis while maintaining an unbiased perspective.

Mapping Youth Awareness of Sports Betting Advertising During the 2022 FIFA World Cup.

Young people are known to be highly engaged in sports betting and therefore may be particularly susceptible to the effects of gambling-related advertising. The purpose of the present study was to examine young people's recall of sports betting advertising during the 2022 FIFA World Cup. The sample consisted of 190 UK residents aged 18-24 who had watched at least one 2022 World Cup match. A cross-sectional survey was conducted to collect data on participants' recall of sports betting advertisements across several media types and for different bets and betting offers, as well as their problem gambling scores. The findings indicated that young people were able to recall a high amount of advertising for various types of bets (95.6%) and betting inducements (89.5%). A high proportion of young people recalled advertising for risky bet types and promotions, such as 64.2% for in-play betting and 68.1% for sign-up offers. Overall, higher-risk gamblers recalled encountering more advertising than lower-risk gamblers. Participants recalled encountering sports betting advertisements on social media the most (10-14 ads per week), then on internet banners and television (5-9 ads per week, respectively). Less than half (46.3%) of respondents were aware of advertising for responsible gambling tools. This study underscores the need for policy measures that limit young people's exposure to gambling advertising, particularly for products that may contribute to gambling-related harm, and that increase the promotion of responsible gambling tools.

Enhancing the Preanesthesia Evaluation: Consensus Development of the Cannabis Use and Behaviors Assessment Tool (CUBAT).

PURPOSE: This project aimed to develop an evidence-based preanesthesia cannabis use assessment tool to acquire complete and accurate patient history and develop a best-informed, individualized anesthesia and analgesia care plan. DESIGN: Modified Delphi. METHODS: Using an evidence synthesis and multistage, modified Delphi process, eight experts from across the United States developed a consensus-based tool to aid in developing a best-informed, individualized plan for anesthesia and analgesia care. FINDINGS: Two survey rounds integrated informed evidence-based tool revisions. The final tool included instructions for use, a glossary of terms, and seven key assessment items aimed at gathering the most influential information regarding cannabis use. CONCLUSIONS: The Cannabis Use and Behaviors Assessment Tool is a first-of-its-kind tool providing an essential framework for preanesthesia cannabis use assessment.

PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data.

The identification of rare haplotypes may greatly expand our knowledge in the genetic architecture of both complex and monogenic traits. To this aim, we developed PERHAPS (Paired-End short Reads-based HAPlotyping from next-generation Sequencing data), a new and simple approach to directly call haplotypes from short-read, paired-end Next Generation Sequencing (NGS) data. To benchmark this method, we considered the APOE classic polymorphism (*1/*2/*3/*4), since it represents one of the best examples of functional polymorphism arising from the haplotype combination of two Single Nucleotide Polymorphisms (SNPs). We leveraged the big Whole Exome Sequencing (WES) and SNP-array data obtained from the multi-ethnic UK BioBank (UKBB, N=48,855). By applying PERHAPS, based on piecing together the paired-end reads according to their FASTQ-labels, we extracted the haplotype data, along with their frequencies and the individual diplotype. Concordance rates between WES directly called diplotypes and the ones generated through statistical pre-phasing and imputation of SNP-array data are extremely high (>99%), either when stratifying the sample by SNP-array genotyping batch or self-reported ethnic group. Hardy-Weinberg Equilibrium tests and the comparison of obtained haplotype frequencies with the ones available from the 1000 Genome Project further supported the reliability of PERHAPS. Notably, we were able to determine the existence of the rare APOE*1 haplotype in two unrelated African subjects from UKBB, supporting its presence at appreciable frequency (approximatively 0.5%) in the African Yoruba population. Despite acknowledging some technical shortcomings, PERHAPS represents a novel and simple approach that will partly overcome the limitations in direct haplotype calling from short read-based sequencing.

Skin Gambling Contributes to Gambling Problems and Harm After Controlling for Other Forms of Traditional Gambling.

Esports betting and skin gambling involve betting on the outcomes of video game competitions and/or using virtual currencies for betting. The present study evaluated a conceptual model linking video game involvement, video-game related gambling, traditional gambling, and gambling problems and harm. Data were collected via a cross-sectional online survey with 737 participants aged 18 + who engaged in esports cash betting (n = 576), esports skin betting (n = 184), or skin gambling on games of chance (n = 330). The findings highlighted the distinctly different relationships esports cash betting versus skin gambling had with traditional gambling involvement and harmful gambling. Gambling with skins on games of chance was predictive of gambling problems and gambling harm after controlling for participation in traditional gambling (OR = 1.32 and 1.17 respectively). Whereas betting on esports with cash was associated with betting on a variety of other forms of gambling, and there was no unique contribution to problems and harm over and above participation on these other forms (e.g., EGMs, sports betting). Skin gambling is directly implicated in gambling problems and harm, whereas cash betting on esports is only indicative of interest in many forms of potentially harmful gambling. Greater research attention to skin gambling is warranted, and particularly with respect to its role as a virtual currency more easily accessible for gambling.

Motivations for Esports Betting and Skin Gambling and Their Association with Gambling Frequency, Problems, and Harm.

This study aimed to examine gambling motivations for esports betting and skin gambling and their association with gambling frequency, problems, and harm. Data were collected via a cross-sectional online survey with 736 participants aged 18 + who engaged in esports cash betting (n = 567), esports skin betting (n = 180), or skin gambling on games of chance (n = 325). Respondents were asked to rate their motivations for the three activities across seven domains: social, financial, positive feelings or enhancement, internal regulation, skill building, competition/challenge, and skin acquisition. The results highlight both similarities and differences in gambling motivations across products. Financial gain and enhancement (i.e., excitement) were the main motivations endorsed for all activities, whereas skin acquisition was an additional motivation for esports skin betting and skin gambling. Across all three products, gambling to escape or improve mood was associated with higher levels of problem gambling and harm. Financial gain motivation was associated with problem gambling only for esports skin betting and skin gambling on games of chance. These findings underscore the importance of considering motivational influences on engagement with emerging gambling activities, especially since some motivations may be a contributing factor in harmful gambling outcomes.

Pancreatic Cancer Patient-derived Organoids Can Predict Response to Neoadjuvant Chemotherapy.

OBJECTIVE: To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma. BACKGROUND: PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer. METHODS: During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing. RESULTS: One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection. CONCLUSION: Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.

YouTube to Teach Central Lines, The Expert vs Learner Perspective.

PURPOSE: Instructional videos of medical procedures can be a useful guide for learners, demonstrating proper and safe technique. Open publishing sites such as YouTube are readily accessible, however the content is not peer reviewed and quality of videos vary greatly. Our aim was to evaluate a learner's ability to interpret the quality of openly published content by comparing their rating of the most popular central line insertion videos on YouTube to expert evaluations. METHOD: YouTube search results for "central line placement" sorted by views or relevance compiled a list of the four most common videos. A fifth gold standard video, published by the New England Journal, was included, however was not found in the top results. Eleven expert practitioners from varying medical specialties (Critical Care, Surgery, Anesthesia, & Emergency Medicine) evaluated the 5 videos, utilizing a 22-item Likert scaled questionnaire emphasizing: preparation, sterility, anatomy, technique, & complications. Videos were compared as a composite average of the individual items on the survey. The highest, lowest, and 3rd ranked videos were evaluated by 45 residents ("learners") in varying specialties (Internal Medicine, Emergency Medicine, Surgery, Anesthesia) and post graduate year (PGY). Learners assessed the videos using the same scale. A Welch T-test assessed statistical significance between the two groups. Subgroup analysis compared experts against different PGY and specialty cohorts. RESULTS: The lowest scored video among the experts and learners was the most popular on YouTube, with 858,933 views at the time of inclusion. Though lowest in rank, this video was judged higher by learners than the experts (2.63/5 vs 2.18/5, P = 0.0029). The 3rd ranked video by experts with 249,746 views on YouTube, was also rated higher by learners (3.77/5 vs 3.45/5, P = 0.0084). The gold standard video by NEJM had 320,580 views and was rated highest by both the experts and learners (4.37/5 vs 4.28/5, P = 0.518). Subgroup analysis showed similar results with learners rating the videos overall better than experts, this was particularly true in the PGY-1 subgroup. CONCLUSION: The most popular central line insertion video was the worst rated by both experts and learners. Learners rated all the videos better than the expert. YouTube videos demonstrating medical procedures including central line insertion should come from peer reviewed sources if they are to be incorporated into educational curriculum.

The Growth of Palliative Practice and End of Life Care in an Academic Teaching Intensive Care Unit.

OBJECTIVE: Dying in the intensive care unit (ICU) has changed over the last twenty years due to increased utilization of palliative care. We sought to examine how palliative medicine (PM) integration into critical care medicine has changed outcomes in end of life including the utilization of do not resuscitate (no cardiopulmonary resuscitation but continue treatment) and comfort care orders (No resuscitation, only comfort medication). Design: Retrospective observational review of critical care patients who died during admission between two decades, 2008 to 09 and 2018 to 19. Setting: Single urban tertiary care academic medical center in Washington, D.C. Patients: Adult patients who were treated in any ICU during the admission which they died. INTERVENTIONS AND MEASUREMENTS: We sought to measure PM involvement across the two decades and its association with end of life care including do not resuscitate (DNR) and comfort care (CC) orders. Main Results: 571 cases were analyzed. Mean age was 65 ± 15, 46% were female. In univariate analysis significantly more patients received PM in 2018 to 19 (40% vs. 27%, p = .002). DNR status increased significantly over time (74% to 84%, p = .002) and was significantly more common in patients who were receiving PM (96% vs. 72%, p < 0.001). CC also increased over time (56% to 70%, p = <0.001), and was more common in PM patients (87% vs. 53%, p < 0.001). Death in the ICU decreased significantly over time (94% to 86%, p = .002) and was significantly lower in PM patients (76% vs. 96%, p < 0.001). The adjusted odds of getting CC for those receiving versus those not receiving PM were 14.51 (5.49-38.36, p < 0.001) in 2008 to 09 versus 3.89 (2.27-6.68, p < 0.001) in 2018 to 19. Conclusion: PM involvement increased significantly across a decade in our ICU and was significantly associated with incidence of DNR and CC orders as well as the decreased incidence of dying in the ICU. The increase in DNR and CC orders independent of PM over the past decade reflect intensivists delivering PM services.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders.