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For poisoned patients, ambulance services may be the first point of contact for medical attention. With limited training in toxicology, ambulance services are encouraged to contact the Poisons Information Centre (PIC) for advice. This study aims to characterise referrals to a PIC from a state ambulance service with the purpose of improving information delivery and efficient use of these services. This was a retrospective observational series of referrals to an Australian state PIC from ambulance staff from 1 January 2020 to 31 December 2020. Referrals were identified through the PIC Pharmhos database where the call originated from either a paramedic or emergency dispatch officer. Call reports were reviewed to extract data on patient demographics, exposure details and advice provided by the PIC. There were 1537 calls regarding 1420 poisoning exposures over the 12-month period, with 117 (7.6%) follow-up calls, representing 4.1% (1537/37835) of total calls to the PIC. Initial calls originated from paramedics in 999/1420 (70.4%) referrals, with dispatch officers referring 421/1420 (29.6%). Paediatric patients aged <15 years were involved in 492/1420 (34.6%) exposures with the commonest age range being 1–4 years. Most referrals involved pharmaceuticals exposures (756/1420 [53.2%]) followed by chemicals (557/1420 [39.2%]) and drugs of abuse (69/1420 [4.9%]). The commonest agents involved were paracetamol followed by quetiapine and sertraline. The PIC advised no treatment following benign exposures in 617/1420 (43.5%) calls, first aid measures in 333/1420 (23.5%) calls, supportive measures in 339/1420 (23.9%) calls and specific treatment in 32/1420 (2.3%) calls. Referral to the hospital was advised in 761/1420 (53.6%) calls, the majority of these were following deliberate self-poisonings (428/1420 [30.1%]). Ambulance staff commonly contact the PIC following benign exposures where no treatment is required. Ambulance referral to a PIC following suspected poisonings may have a role in preventing unnecessary transfer to hospital in poisoned patients. [ABSTRACT FROM AUTHOR]

A social network perspective can bring important insight into the processes that shape human behavior. Longitudinal social network data, measuring relations between individuals over time, has become increasingly common—as have the methods available to analyze such data. A friendship duration model utilizing discrete-time multilevel survival analysis with a multiple membership random effect structure is developed and applied here to study the processes leading to undirected friendship dissolution within a larger social network. While the modeling framework is introduced in terms of understanding friendship dissolution, it can be used to understand microlevel dynamics of a social network more generally. These models can be fit with standard generalized linear mixed-model software, after transforming the data to a pair-period data set. An empirical example highlights how the model can be applied to understand the processes leading to friendship dissolution between high school students, and a simulation study is used to test the use of the modeling framework under representative conditions that would be found in social network data. Advantages of the modeling framework are highlighted, and potential limitations and future directions are discussed. [ABSTRACT FROM PUBLISHER]

Aims The purpose of this paper is to discover patterns of drug use initiations over time through a multiple event process survival mixture model (MEPSUM model), a novel approach for substance use and prevention research. Design The MEPSUM model combines survival analysis and mixture modeling-specifically latent class analysis-to examine individual differences in the timing of initiation and cumulative risk of substance use over time, and is applied to cross-sectional survey data on drug initiations. Setting Data are drawn from the 2009 National Survey on Drug Use and Health. Participants The survey includes responses from 55 772 individuals (52.05% female). Measurements The age of first use of nine different types of substances are examined, including alcohol, tobacco, cocaine and non-medical use of prescription drugs. Findings It is argued that six patterns parsimoniously describe the population's risk of initiating different substances over time, described colloquially as general abstainers; early, late and progressive soft drug users; and early and late hard drug users. Both gender and ethnicity significantly predict the patterns, with Caucasians and males having a higher risk for the hard drug-using patterns. The MEPSUM model produced stable results in this application, as the patterns are validated in a split-sample design. Conclusions The MEPSUM model provides a statistical framework from which to evaluate patterns of risk for drug initiations over time and predict substance use trajectories relevant to public health interventions. The patterns that result from the model can be used as outcomes for subsequent investigations of etiological and mediating mechanisms. [ABSTRACT FROM AUTHOR]

Context: There is little research examining clinician adherence to specialist toxicological phone advice. Efforts to improve adherence should be sought to optimise the management of poisoned patients. This study aimed to determine if contemporaneous documentation in the patient electronic medical record (EMR) improved adherence to Poisons Information Centre (PIC) advice. Methods: This was a prospective before and after observational study following the implementation of documented poisoning management advice by PIC staff into the patient's EMR. Advice adherence was assessed following a review of the patient medical records and designated to complete adherence, minor discrepancies not affecting patient care, major discrepancies affecting patient care and non-adherence. The primary outcome was the proportion of satisfactory (complete adherence/minor discrepancies) adherence. Secondary outcomes included the accuracy of documented telephone advice by the treating clinician, the number of case recalls and episodes of sub-optimal management. Results: A total of 980 cases (347 in the pre-intervention phase and 633 in the post-intervention phase) were included in the study, of which 350 had PIC EMR documentation performed. Documented call advice by the treating clinician was absent in 41 of 347 cases (11.8%) cases and inaccurate in 42 of 306 cases (13.7%). Following PIC documentation, satisfactory adherence improved from 304/347(87.6%) to 333/350(95.1%)(difference 7.5% [95% CI 3.1% to 11.9%]), with suboptimal management decreasing from 48/347(13.8%) to 14/350(4%)(difference − 9.8% [95% CI −5.5% to −14.4%]). Recalls were similar in both periods. The median time to enter advice into the EMR was 26 min (IQR: 14–45 min). The main reason for not documenting advice was that the PIC staff member was working a solo shift with a prohibitively heavy workload. Discussion: EMRs enable PICs to supplement verbal advice with written documentation, offering an opportunity to improve communication and enable better handover of clinical information. Conclusion: Documentation of advice by PIC staff in the patient medical record was associated with improved advice adherence and reduced sub-optimal management. [ABSTRACT FROM AUTHOR]

Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance. [ABSTRACT FROM AUTHOR]

This paper examines associations among parental and adolescent health behaviors and pathways to adulthood. Using data from the National Longitudinal Study of Adolescent to Adult Health, we identify a set of latent classes describing pathways into adulthood and examine health-related predictors of these pathways. The identified pathways are consistent with prior research using other sources of data. Results also show that both adolescent and parental health behaviors differentiate pathways. Parental and adolescent smoking are associated with lowered probability of the higher education pathway and higher likelihood of the work and the work & family pathways (entry into the workforce soon after high school completion). Adolescent drinking is positively associated with the work pathway and the higher education pathway, but decreases the likelihood of the work & family pathway. Neither parental nor adolescent obesity are associated with any of the pathways to adulthood. When combined, parental/adolescent smoking and adolescent drinking are associated with displacement from the basic institutions of school, work, and family. [ABSTRACT FROM AUTHOR]

Interrupted glucagon signaling reduces hyperglycemia. However, interrupted glucagon signaling increases serum amino acid and glucagon levels and stimulates amino acid-dependent alpha cell proliferation as part of an endocrine feedback loop, the liver-alpha cell axis. Our previous studies showed that glutamine and SLC38A5, a transporter of glutamine and other amino acids, are required for amino acid-stimulated alpha cell proliferation. To understand the mechanism of glutamine-stimulated proliferation, we analyzed published transcriptomics data for enzymes involved in the glutamine metabolism pathway and found 3-fold greater gene expression of glutaminase (Gls/GLS) in mouse and human alpha cells than in other pancreatic endocrine cells, while Gls2/GLS2 expression was extremely low in islet cells. Immunohistochemical analyses of mouse and human pancreata showed greater protein expression of GLS in islets versus the surrounding exocrine tissue. Within islets, both human and mouse alpha cells had higher expression than beta cells, suggesting that alpha cells may have increased capacity for glutamine metabolism. This expression pattern was also observed in individuals with either type 1 or type 2 diabetes. To examine the role of GLS activity in alpha cell proliferation, we treated the αTC1-6 mouse glucagonoma cell line with a competitive GLS inhibitor CB-839. GLS inhibition resulted in a 1.6-fold decrease in cell count over an 8-day cell growth assay (DMSO: (9.7 ± 1.3)x105, 10 μM CB-839: (6.2 ± 1.4)x105; n=2-4). In isolated mouse islets cultured in high glutamine and amino acid containing media, GLS inhibition inhibited alpha cell proliferation (DMSO: 7.6 ± 2.2%, 0.1 μM CB-839: 0.11 ± 0.05%**, 1.0 μM: 0.04 ± 0.02**, 10 μM: 0.02 ± 0.01%**, n=3-4, p<0.01). These data indicate that glutamine metabolism through GLS is critical for amino acid-dependent alpha cell proliferation in mice and support that alpha cells are unique amino acid sensors playing a critical role in amino acid homeostasis. Disclosure: W. Siv: None. K. Sellick: None. A. Reuter: None. M. Shou: None. J. Stanley: None. E. Spears: None. W. Chen: None. D. Dean: None. Funding: National Institutes of Health (DK117969, DK117147, DK020593); JDRF (2-SRA-2016-149-Q-R) [ABSTRACT FROM AUTHOR]

Interrupting glucagon signaling (IGS) elicits robust alpha cell proliferation in an amino acid-dependent manner in mouse and human pancreatic islets. To determine whether IGS triggers beta cell proliferation in mouse and human islets in vivo, we quantified the percentage of Ki67-positive beta cells in adult mouse and human islets after IGS. Wild type (WT) mouse islets transplanted into liver-specific glucagon receptor (GCGR) knockout (LKO) mice exhibited a 4.1-fold increase in beta cell proliferation (WT to LKO: 0.98±0.34%, WT to WT: 0.24±0.19%, P=0.008, n=8). Likewise, treatment of C57BL6 mice with an anti-GCGR monoclonal antibody (GCGR-Ab) elicited a 3.6-fold increase in beta cell proliferation (GCGR-Ab: 1.09±0.21%, control (CTR): 0.30±0.14%, P=0.004, n=10). Given that the cationic amino acid transporter, Slc7a2, is one of the most highly expressed amino acid transporters in pancreatic islets and required for IGS-induced alpha cell proliferation, we assessed GCGR-Ab-induced beta cell proliferation in adult mice with inactivation of Slc7a2. There was a 3.2-fold increase in beta cell proliferation in WT mice treated with GCGR-Ab (GCGR-Ab: 1.45±0.46%, CTR: 0.46±0.15%, P=0.001, n=10). Notably, this effect was absent in Slc7a2 knockout mice (GCGR-Ab: 0.35±0.35%, CTR: 0.41±0.28%, n=10), suggesting that GCGR antagonism induces beta cell proliferation in an amino acid-dependent manner in mice. Furthermore, transplanted human islets from normal donors (ages 10-55, n=8) into immunodeficient mice exhibited a 2.8-fold increase in beta cell proliferation (GCGR-Ab: 0.61±0.60%, CTR: 0.22±0.21%, P=0.05, n=8) following GCGR-Ab treatment. These data indicate that IGS stimulates beta cell proliferation in mouse and human islets and that in mouse islets, this is Slc7a2-dependent. Disclosure: K.C. Coate: None. E. Spears: None. C. Dai: None. S. Wisniewski: None. G. Poffenberger: None. L.D. Shultz: None. D.L. Greiner: None. D.J. Drucker: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics. Research Support; Self; Novo Nordisk Inc. H. Yan: Stock/Shareholder; Self; REMD Biotherapeutics Inc. K. Sloop: None. A.C. Powers: None. D. Dean: None. Funding: National Institutes of Health (DK117147) [ABSTRACT FROM AUTHOR]

Interruption of glucagon signaling by glucagon receptor gene inactivation or treatment with a glucagon receptor blocking monoclonal antibody (GCGR-Ab) stimulates alpha cell proliferation and expansion. Surprisingly, pancreas weight is also increased in mice with GCG gene inactivation. To investigate mechanisms linking glucagon signaling and pancreas size, we treated C57BL/6J mice with GCGR-Ab or a control IgG. Eight weeks of treatment (N=4-15 mice/treatment) increased absolute pancreas weight (0.42±0.013 vs. 0.32±0.008; p<0.0001), pancreas weight normalized to body weight (1.39±0.03% vs. 1.11±0.02%; p<0.0001), and serum levels of 15 amino acids (AA), including glutamine (1.7-4.67 fold, p<0.0001). GCGR-Ab treatment promoted acinar cell proliferation (Ki67+, 0.65±0.14% vs. 0.20±0.03%; p=0.0058), increased acinar cell size (peri-islet region: 438.4±12.77 vs. 341.7±22.05μm2; p=0.0045; peripheral region: 431.1±9.34 vs. 334.2±25μm2, p=0.0055; central region: 437.0±10.45 vs. 338.7±13.6 μm2, p=0.0006), and increased pancreas protein content (248.3±9.84 vs. 194±8.67μg/mg tissue; p=0.0003). By electron microscopy, GCGR-Ab treatment increased acinar cell zymogen granule number (129±9 vs. 49±6; p<0.0001; n=28-37 cells/treatment) and led to acinar cell ER dilatation, but did not induce pancreatitis or alter acinar cell apoptosis or pancreatic macrophage number. Serum cholecystokinin and total glucagon-like peptide-1, trophic hormones linked to exocrine growth, were not changed by GCGR-Ab treatment. GCGR-Ab treatment upregulated mRNA and protein levels of the glutamine transporter, Slc38a3, and increased mTOR-related ribosomal protein S6 phosphorylation in acinar cells. Together, these data indicate that interruption of glucagon signaling increases pancreas mass by inducing acinar cell hyperplasia and hypertrophy and activates protein synthesis and mTOR signaling; whether this is mediated by elevated glutamine or AA levels is not known. Disclosure: C. Dai: None. A. Bradley: None. K.C. Coate: None. G. Poffenberger: None. E. Spears: None. J.J. Wright: None. S. Shrestha: None. D. Dean: None. M. Brissova: None. A.C. Powers: None. Funding: National Institutes of Health (DK117147) [ABSTRACT FROM AUTHOR]

Interrupting glucagon receptor signaling results in hyperaminoacidemia, which stimulates alpha cell hyperplasia. Arginine, a potent secretagogue for both insulin and glucagon, is required for hyperaminoacidemia-stimulated alpha cell proliferation. To investigate the role of arginine transport, we compared the expression of amino acid transporters in published datasets of sorted mouse and human islet cells and found that Slc7a2, cationic amino acid transporter, is the most highly expressed amino acid transporter in both mouse and human alpha cells and that its expression is three-fold higher in alpha cells than in beta cells. Following glucose/arginine injection, global Slc7a2 knockout mice (Slc7a2-/-) had 20% higher blood glucose (+/+ vs. -/-: 412±23 vs. 517±25mg/dL, n=11-12, p=0.004), 80% lower serum insulin (3.7±0.6 vs. 0.7±0.4nM, p=0.0008) and 59% lower serum glucagon (64.3±23.1pM vs. 26.3±11.4pM, p=0.009) than Slc7a2+/+ animals. Slc7a2+/- mice had 55% decreased insulin levels (+/+ vs. +/-: 3.7±0.6 vs. 1.7±0.3nM, n=8, p=0.012), but showed no difference in serum glucose or glucagon levels, indicating that Slc7a2 expression may be rate limiting for beta cell, but not alpha cell, function. Isolated islets from Slc7a2-/- mice had normal morphology, but reduced high amino acid-stimulated alpha cell proliferation by 90% and 58% in Slc7a2-/- and Slc7a2+/- islets, respectively (+/+ vs.-/-: 3.7±1.7 vs. 0.4±0.2%, p=0.007, n=4; +/+ vs. +/-: 3.7±1.7 vs. 1.5±0.6%, p=0.038, n=4). Knockdown with Slc7a2 shRNA in the aTC1-6 mouse alpha cell line also decreased proliferation. Taken together, these data indicate a central role for Slc7a2 in amino acid-stimulated alpha cell proliferation and glucagon and insulin secretion. Disclosure: E. Spears: None. M. Shou: None. W.A. Siv: None. C. Dai: None. W. Chen: None. A.C. Powers: None. D. Dean: None. [ABSTRACT FROM AUTHOR]