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    Open Access
    Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: a multinational embedded cluster crossover randomized trial (the HIKO STEC trial)
    (2023-05-27) Freedman, Stephen B.; Schnadower, David; Estes, Myka; Casper, T. C.; Goldstein, Stuart L.; Grisaru, Silviu; Pavia, Andrew T.; Wilfond, Benjamin S.; Metheney, Melissa; Kimball, Kadyn; Tarr, Phillip I.
    Abstract Background Shiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15–20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis. Methods We will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction. Discussion HUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection. Trial registration ClinicalTrials.gov NCT05219110 . Registered on February 1, 2022.
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    Open Access
    Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels
    (2023-05-25) de Maria Gadotti, Vinicius; Antunes, Flavia T. T.; Zamponi, Gerald W.
    Abstract Delta-9-tetrahydrocannabinol (Δ9-THC) is known to produce systemic analgesia that involves CB1 and CB2 cannabinoid receptors. However, there is compelling evidence that Δ9-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ9-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ9-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund’s Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ9-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB1 and CB2 null animals. Hence, the analgesic effects of spinally delivered Δ9-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.
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    Open Access
    Towards effective restriction of unhealthy food marketing to children: unlocking the potential of artificial intelligence
    (2023-05-26) Olstad, Dana L.; Boyland, Emma
    Abstract The World Health Organization recommends that member states enact policies to limit unhealthy food marketing to children. Chile enacted relatively stringent laws that restrict unhealthy food marketing to children in two phases, beginning in 2016. Dillman-Carpentier and colleagues examined the incremental effectiveness of the first and second phases of Chile’s policy in limiting children’s exposure to unhealthy food marketing on television relative to pre-policy. Banning advertisements for all ‘high-in’ products (i.e., those that exceeded thresholds for energy, saturated fats, sugars and/or sodium) during the daytime (phase 2) was more effective in reducing children’s exposure to unhealthy food marketing on television than only banning ‘high-in’ marketing during programs with large child audiences (phase 1). These findings underscore the importance of implementing comprehensive policies that reduce children’s exposure to all marketing for unhealthy foods—not simply that which targets them directly—to better protect them from its negative impacts. However, although policies in Chile and other nations have reduced children’s exposure to unhealthy food marketing in broadcast media, it is not clear whether such policies have meaningfully reduced children’s overall food marketing exposures. This is partly due to the challenges of studying children’s digital food marketing exposures, which are an increasingly important source of unhealthy food marketing. To address these methodologic gaps, several research teams are developing artificial intelligence (AI)-enabled systems to assess food marketing to children on digital media and support efforts to monitor compliance with policies that restrict this marketing. These and other AI systems will be essential to comprehensively and systematically study and monitor food marketing to children on digital media internationally and at scale.
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    Open Access
    Development of the global inflammatory bowel disease visualization of epidemiology studies in the 21st century (GIVES-21)
    (2023-05-25) Mak, Joyce W. Y.; Sun, Yang; Limsrivilai, Julajak; Abdullah, Murdani; Kaibullayeva, Jamilya; Balderramo, Domingo; Vergara, Beatriz I.; Paudel, Mukesh S.; Banerjee, Rupa; Hilmi, Ida; Ali, Raja A. R.; Wei, Shu C.; Ng, Ka K.; Altuwaijri, Mansour; Kelly, Paul; Yamamoto-Furusho, Jesus K.; Kotze, Paulo G.; Ahuja, Vineet; Chong, Vui H.; Dao, Hang V.; Abbey, Yvonne; Ching, Jessica Y. L.; Ho, Agnes; Chan, Alicia K. W.; Bernstein, Charles N.; Gearry, Richard B.; Abreu, Maria; Rubin, David T.; Dotan, Iris; Hracs, Lindsay; Kaplan, Gilaad G.; Ng, Siew C.
    Abstract Background There is a rapid increase in the incidence of inflammatory bowel diseases (IBD) in newly industrialized countries, yet epidemiological data is incomplete. We herein report the methodology adopted to study the incidence of IBD in newly industrialized countries and to evaluate the effect of environmental factors including diet on IBD development. Methods Global IBD Visualization of Epidemiology Studies in the 21st Century (GIVES-21) is a population-based cohort of newly diagnosed persons with Crohn’s disease and ulcerative colitis in Asia, Africa, and Latin America to be followed prospectively for 12 months. New cases were ascertained from multiple sources and were entered into a secured online system. Cases were confirmed using standard diagnostic criteria. In addition, endoscopy, pathology and pharmacy records from each local site were searched to ensure completeness of case capture. Validated environmental and dietary questionnaires were used to determine exposure in incident cases prior to diagnosis. Results Through November 2022, 106 hospitals from 24 regions (16 Asia; 6 Latin America; 2 Africa) have joined the GIVES-21 Consortium. To date, over 290 incident cases have been reported. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, medication history and environmental and dietary exposures data collected. We have established a comprehensive platform and infrastructure required to examine disease incidence, risk factors and disease course of IBD in the real-world setting. Conclusions The GIVES-21 consortium offers a unique opportunity to investigate the epidemiology of IBD and explores new clinical research questions on the association between environmental and dietary factors and IBD development in newly industrialized countries.
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    Open Access
    The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care
    (2023-05-19) Saya, Sibel; Chondros, Patty; Abela, Anastasia; Mihalopolous, Cathrine; Chatterton, Mary L.; Gunn, Jane; Chen, Timothy F.; Polasek, Thomas M.; Dettmann, Elise; Brooks, Rachel; King, Michelle; Spencer, Luke; Alphonse, Pavithran; Milton, Shakira; Ramsay, Georgia; Siviour, Zoe; Liew, Jamie; Ly, Philip; Thoenig, Matthew; Seychell, Raushaan; La Rocca, Floriana; Hesson, Luke B.; Mejias, Nydia; Sivertsen, Terri; Galea, Melanie A.; Bousman, Chad; Emery, Jon
    Abstract Background The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13 antidepressants. Although previous randomised controlled trials of PGx testing for antidepressant prescribing have shown an association with remission of depression in clinical psychiatric settings, few trials have focused on the primary care setting, where most antidepressant prescribing occurs. Methods The PRESIDE Trial is a stratified double-blinded randomised controlled superiority trial that aims to evaluate the impact of a PGx-informed antidepressant prescribing report (compared with standard prescribing using the Australian Therapeutic Guidelines) on depressive symptoms after 12 weeks, when delivered in primary care. Six hundred seventy-two patients aged 18–65 years of general practitioners (GPs) in Victoria with moderate to severe depressive symptoms, measured using the Patient Health Questionnaire-9 (PHQ-9), will be randomly allocated 1:1 to each arm using a computer-generated sequence. Participants and GPs will be blinded to the study arm. The primary outcome is a difference between arms in the change of depressive symptoms, measured using the PHQ-9 after 12 weeks. Secondary outcomes include a difference between the arms in change in PHQ-9 score at 4, 8 and 26 weeks, proportion in remission at 12 weeks, a change in side effect profile of antidepressant medications, adherence to antidepressant medications, change in quality of life and cost-effectiveness of the intervention. Discussion This trial will provide evidence as to whether PGx-informed antidepressant prescribing is clinically efficacious and cost-effective. It will inform national and international policy and guidelines about the use of PGx to select antidepressants for people with moderate to severe depressive symptoms presenting in primary care. Trial registration Australian and New Zealand Clinical Trial Registry ACTRN12621000181808. Registered on 22 February 2021.