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The clinical utility of the functional TSH receptor autoantibodies was prospectively evaluated in patients with thyroid-associated orbitopathy (TAO). Ophthalmic, endocrine, and serological investigations were performed in 101 consecutive patients with severe and active TAO. Serum thyroid stimulating (TSAb) and blocking (TBAb) antibody levels were measured with two bioassays using cells that express a chimeric TSH receptor and CRE-dependent luciferase. TSAb results are expressed as percentage of specimen-to-reference ratio (SRR %). Blocking activity is defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone. All 101 consecutively followed-up patients with severe and active TAO were TBAb negative. In contrast, 91 (90%) were TSAb positive of whom 90 had Graves’ disease. Serum TSAb levels correlated with the diplopia score (P=0.016), total severity eye score (P=0.009), proptosis (P=0.007), lid aperture (P=0.003), upper lid retraction (P=0.006), keratopathy (P=0.04), and thyroid binding inhibiting immunoglobulins (TBII, P

The most highly studied endocytic pathway, clathrin-dependent endocytosis, mediates a wide range of fundamental processes including nutrient internalization, receptor recycling, and signal transduction. In order to model tissue specific and developmental aspects of this process, CRISPR/Cas9 genomic editing was utilized to fluorescently label the C-terminus of clathrin light chain A (CLTA) within the phenotypically normal, parental CRMi001-A human induced pluripotent stem cell line. Successfully edited cells were isolated by fluorescently activated cell sorting, remained karyotypically normal, and maintained their differentiation potential. This cell line facilitates imaging of endogenous clathrin trafficking within varied cell types.

Of the Orthomyxoviridae family of viruses, only influenza A viruses are thought to exist as multiple subtypes and has non-human maintenance hosts. In April 2011, nasal swabs were collected for virus isolation from pigs exhibiting influenza-like illness. Subsequent electron microscopic, biochemical, and genetic studies identified an orthomyxovirus with seven RNA segments exhibiting approximately 50% overall amino acid identity to human influenza C virus. Based on its genetic organizational similarities to influenza C viruses this virus has been provisionally designated C/Oklahoma/1334/2011 (C/OK). Phylogenetic analysis of the predicted viral proteins found that the divergence between C/OK and human influenza C viruses was similar to that observed between influenza A and B viruses. No cross reactivity was observed between C/OK and human influenza C viruses using hemagglutination inhibition (HI) assays. Additionally, screening of pig and human serum samples found that 9.5% and 1.3%, respectively, of individuals had measurable HI antibody titers to C/OK virus. C/OK virus was able to infect both ferrets and pigs and transmit to naive animals by direct contact. Cell culture studies showed that C/OK virus displayed a broader cellular tropism than a human influenza C virus. The observed difference in cellular tropism was further supported by structural analysis showing that hemagglutinin esterase (HE) proteins between two viruses have conserved enzymatic but divergent receptor-binding sites. These results suggest that C/OK virus represents a new subtype of influenza C viruses that currently circulates in pigs that has not been recognized previously. The presence of multiple subtypes of co-circulating influenza C viruses raises the possibility of reassortment and antigenic shift as mechanisms of influenza C virus evolution.

Abstract Ezrin, an actin-binding protein, orchestrates the organization of the cortical cytoskeleton and plasma membrane during cell migration, adhesion, and proliferation. Its role in monocytes/macrophages (MΦs) is less understood. Here, we used a monocyte/MΦ-specific ezrin knock-out mouse model to investigate the contribution of ezrin to monocyte recruitment and adaptation to the lung extracellular matrix (ECM) in response to lipopolysaccharide (LPS). Our study revealed that LPS induces ezrin expression in monocytes/MΦs and is essential for monocytes to adhere to lung ECM, proliferate, and differentiate into tissue-resident interstitial MΦs. Mechanistically, the loss of ezrin in monocytes disrupts activation of focal adhesion kinase and AKT serine-threonine protein kinase signaling, essential for lung-recruited monocytes and monocyte-derived MΦs to adhere to the ECM, proliferate, and survive. In summary, our data show that ezrin plays a role beyond structural cellular support, influencing diverse monocytes/MΦ processes and signaling pathways during inflammation, facilitating their differentiation into tissue-resident macrophages.

This paper introduces the design of an ultra fast x-ray tomography scanner based on electron beam technology. The scanner has been developed for two-phase flow studies where frame rates of 1 kHz and higher are required. Its functional principle is similar to that of the electron beam x-ray CT scanners used in cardiac imaging. Thus, the scanner comprises an electron beam generator with a fast beam deflection unit, a semicircular x-ray production target made of tungsten alloy and a circular x-ray detector consisting of 240 CZT elements with 1.5 mm × 1.5 mm × 1.5 mm size each. The design is optimized with respect to ultra fast imaging of smaller flow vessels, such as pipes or laboratory-scale chemical reactors. In that way, the scanner is capable of scanning flow cross-sections at a speed of a few thousand frames per second which is sufficient to capture flows of a few meters per second velocity. [ABSTRACT FROM AUTHOR]

Macropinocytosis is a cellular process for the uptake of extracellular fluid. Here, the authors use lattice light sheet microscopy to examine the spatial dynamics of the plasma membrane, PI3K activity, and structural differences of various macrophage cell types during macropinocytosis.

Summary: Clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis in mammalian cells. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of human disorders of cholesterol metabolism. We report that inhibition of post-squalene cholesterol biosynthesis impairs CME. Imaging of membrane bending dynamics and the CME pit ultrastructure reveals prolonged clathrin pit lifetimes and shallow clathrin-coated structures, suggesting progressive impairment of curvature generation correlates with diminishing sterol abundance. Sterol structural requirements for efficient CME include 3′ polar head group and B-ring conformation, resembling the sterol structural prerequisites for tight lipid packing and polarity. Furthermore, Smith-Lemli-Opitz fibroblasts with low cholesterol abundance exhibit deficits in CME-mediated transferrin internalization. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest that reduced CME activity may contribute to cellular phenotypes observed within disorders of cholesterol metabolism.

Two distinct and opposing models for clathrin-mediated endocytosis have been inferred from EM and structural biology data. Here the authors develop an optical method to directly visualize membrane-bending dynamics and show that coat assembly accommodates membrane bending during or after the assembly of the clathrin lattice, which is not predicted by either model.

Fluorescence resonance energy transfer (FRET) microscopy is a powerful tool for imaging the interactions between fluorescently tagged proteins in two-dimensions. For FRET microscopy to reach its full potential, it must be able to image more than one pair of interacting molecules and image degradation from out-of-focus light must be reduced. Here we extend our previous work on the application of maximum likelihood methods to the 3-dimensional reconstruction of 3-way FRET interactions within cells. We validated the new method (3D-3Way FRET) by simulation and fluorescent protein test constructs expressed in cells. In addition, we improved the computational methods to create a 2-log reduction in computation time over our previous method (3DFSR). We applied 3D-3Way FRET to image the 3D subcellular distributions of HIV Gag assembly. Gag fused to three different FPs (CFP, YFP, and RFP), assembled into viral-like particles and created punctate FRET signals that become visible on the cell surface when 3D-3Way FRET was applied to the data. Control experiments in which YFP-Gag, RFP-Gag and free CFP were expressed, demonstrated localized FRET between YFP and RFP at sites of viral assembly that were not associated with CFP. 3D-3Way FRET provides the first approach for quantifying multiple FRET interactions while improving the 3D resolution of FRET microscopy data without introducing bias into the reconstructed estimates. This method should allow improvement of widefield, confocal and superresolution FRET microscopy data.

Fluorescence Resonance Energy Transfer (FRET) microscopy has emerged as a powerful tool to visualize nanoscale protein-protein interactions while capturing their microscale organization and millisecond dynamics. Recently, FRET microscopy was extended to imaging of multiple donor-acceptor pairs, thereby enabling visualization of multiple biochemical events within a single living cell. These methods require numerous equations that must be defined on a case-by-case basis. Here, we present a universal multispectral microscopy method (N-Way FRET) to enable quantitative imaging for any number of interacting and non-interacting FRET pairs. This approach redefines linear unmixing to incorporate the excitation and emission couplings created by FRET, which cannot be accounted for in conventional linear unmixing. Experiments on a three-fluorophore system using blue, yellow and red fluorescent proteins validate the method in living cells. In addition, we propose a simple linear algebra scheme for error propagation from input data to estimate the uncertainty in the computed FRET images. We demonstrate the strength of this approach by monitoring the oligomerization of three FP-tagged HIV Gag proteins whose tight association in the viral capsid is readily observed. Replacement of one FP-Gag molecule with a lipid raft-targeted FP allowed direct observation of Gag oligomerization with no association between FP-Gag and raft-targeted FP. The N-Way FRET method provides a new toolbox for capturing multiple molecular processes with high spatial and temporal resolution in living cells.

Fcgamma receptor (FcgammaR)-mediated phagocytosis of IgG-coated particles is regulated by 3'-phosphoinositides (3'PIs) and several classes of small GTPases, including ARF6 from the ADP Ribosylation Factor subfamily. The insensitivity of phagocytosis to brefeldin A (BFA), an inhibitor of certain ARF guanine nucleotide exchange factors (GEFs), previously indicated that ARF1 did not participate in phagocytosis. In this study, we show that ARF1 was activated during FcgammaR-mediated phagocytosis and that blocking normal ARF1 cycling inhibited phagosome closure. We examined the distributions and activation patterns of ARF6 and ARF1 during FcgammaR-mediated phagocytosis using fluorescence resonance energy transfer (FRET) stoichiometric microscopy of macrophages expressing CFP- or YFP-chimeras of ARF1, ARF6, and a GTP-ARF-binding protein domain. Both GTPases were activated by BFA-insensitive factors at sites of phagocytosis. ARF6 activation was restricted to the leading edge of the phagocytic cup, while ARF1 activation was delayed and delocalized over the phagosome. Phagocytic cups formed after inhibition of PI 3-kinase (PI-3K) contained persistently activated ARF6 and minimally activated ARF1. This indicates that a PI-3K-dependent signal transition defines the sequence of ARF GTPase activation during phagocytosis and that ARF6 and ARF1 coordinate different functions at the forming phagosome.

This scoping review aims to identify and systematically review published mapping reviews to assess their commonality and heterogeneity and determine whether additional efforts should be made to standardise methodology and reporting. The following databases were searched; Ovid MEDLINE, Embase, CINAHL, PsycINFO, Campbell collaboration database, Social Science Abstracts, Library and Information Science Abstracts (LISA). Following a pilot-test on a random sample of 20 citations included within title and abstracts, two team members independently completed all screening. Ten articles were piloted at full-text screening, and then each citation was reviewed independently by two team members. Discrepancies at both stages were resolved through discussion. Following a pilot-test on a random sample of five relevant full-text articles, one team member abstracted all the relevant data. Uncertainties in the data abstraction were resolved by another team member. A total of 335 articles were eligible for this scoping review and subsequently included. There was an increasing growth in the number of published mapping reviews over the years from 5 in 2010 to 73 in 2021. Moreover, there was a significant variability in reporting the included mapping reviews including their research question, priori protocol, methodology, data synthesis and reporting. This work has further highlighted the gaps in evidence synthesis methodologies. Further guidance developed by evidence synthesis organisations, such as JBI and Campbell, has the potential to clarify challenges experienced by researchers, given the magnitude of mapping reviews published every year., (© 2024 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Introduction: Prescription drug monitoring programs (PDMP) are electronic databases used by prescribers and pharmacists to monitor the use of high-risk prescription medications subject to extramedical use. This study aimed to explore how Australian pharmacists and prescribers are using PDMPs in practice and to gain an understanding of barriers to tool use, as well as practitioner recommendations to increase tool usability and uptake., Methods: Semi-structured interviews were conducted with pharmacists and prescribers who use a PDMP (n = 21). The interviews were audio-recorded, transcribed and thematically analysed., Results: The four themes that emerged were: (i) PDMP notifications combined with practitioner clinical judgement guide PDMP usability; (ii) practitioners use PDMPs to facilitate patient and practitioner communication; (iii) workflow systems integration impacts tool usability; and (iv) optimising PDMP information and data access including practitioner-tool engagement to improve tool uptake and usability., Discussion and Conclusions: Practitioners appreciate the value of PDMP information support for clinical decisions and patient communication. However, they also acknowledge the challenges to tool use and recommend improvements including enhanced workflow, systems integration, optimisation of tool information and national data sharing. Practitioners provide an important perspective on PDMP use in clinical practice. The findings can be drawn on by PDMP administrators to improve tool usefulness. Consequently, this may lead to an increase in practitioner PDMP use and optimise the delivery of quality patient care., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Introduction: Real time prescription monitoring tools have been implemented in Australia to address the growing concerns of drug misuse, drug-related mortality and morbidity. The objective of this pilot study is to investigate the barriers and facilitators related to healthcare practitioner use of real time prescription monitoring tools., Methods: An online survey was distributed to Australian prescribers and pharmacists who use a real time prescription monitoring tool. Data analysis included descriptive statistics, chi-square tests and multivariate logistic regression analyses., Results: A total of 102 questionnaires were analyzed. Practitioners mainly agreed that the tool was easy to use ( n  = 64; 66.7%) and access ( n  = 56; 57.7%), and the data was easy to interpret ( n  = 77; 79.4%). Over half agreed that they wanted training to guide clinical actions ( n  = 52; 55.9%) and clinical guidelines or guidance on what to do with the RTPM findings ( n  = 51; 54.8%). Prescribers were more likely to report difficulties with workplace access to a computer or the internet ( n  = 7; 21.2%) compared with pharmacists ( n = 6; 9.2%; p = 0.037). Practitioners working in community settings ( n  = 59; 57.9%; p  = 0.022) and those with 1-10 years practice experience ( n  = 45; 44.2%; p  = 0.036) were more likely to want training to guide clinical actions in response to RTPM information., Conclusion: This is the first known study to investigate the barriers and facilitators related to practitioner use of RTPM tools in Australia. The results from this study can inform further research to gain an understanding of healthcare practitioners use of RTPM tools, and how to minimize barriers and optimize use for the essential delivery of quality healthcare., Competing Interests: DH is an AHPRA registered pharmacist. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hoppe, Liu and Khalil.)

Objective The aim of this study is to investigate how healthcare practitioners use real-time prescription monitoring tools in clinical practice. Methods An online survey was distributed to Australian prescribers and pharmacists who use a real-time prescription monitoring tool. Data were analysed and descriptive statistics summarised participant characteristics and responses. A Chi-squared test was conducted to test the difference between prescribers and pharmacists. Results The majority of participants agreed that real-time prescription monitoring (RTPM) information is useful (92.2%) and the tool is valuable for informing clinical decisions (90.2%); however, just over half reported that they had changed their prescribing or dispensing practices as a result of RTPM information (51.0%), and they employed evidence-based clinical interventions to varying degrees. No statistically significant differences were detected between pharmacists and prescribers and perceptions on tool use. Conclusions This is the first known study to investigate practitioner use of RTPM tools in Australia, and is a starting point for further research. What constitutes 'success' in the clinical application of RTPM tools is yet to be realised.

Objective The aim of this study is to investigate how healthcare practitioners use real-time prescription monitoring tools in clinical practice. Methods An online survey was distributed to Australian prescribers and pharmacists who use a real-time prescription monitoring tool. Data were analysed and descriptive statistics summarised participant characteristics and responses. A Chi-squared test was conducted to test the difference between prescribers and pharmacists. Results The majority of participants agreed that real-time prescription monitoring (RTPM) information is useful (92.2%) and the tool is valuable for informing clinical decisions (90.2%); however, just over half reported that they had changed their prescribing or dispensing practices as a result of RTPM information (51.0%), and they employed evidence-based clinical interventions to varying degrees. No statistically significant differences were detected between pharmacists and prescribers and perceptions on tool use. Conclusions This is the first known study to investigate practitioner use of RTPM tools in Australia, and is a starting point for further research. What constitutes 'success' in the clinical application of RTPM tools is yet to be realised.

1. Introduction: Pulmonary vein isolation (PVI) is an established procedure used to achieve rhythm control in atrial fibrillation (AF). In obese patients (pts), in whom AF occurs more frequently, a reduced effectiveness of PVI has been observed. Therefore, this study’s aim was to compare the long-term efficacy of PVI between obese and non-obese patients. 2. Methods: We enrolled 111 consecutive pts with a body mass index (BMI) of >30 kg/m2 undergoing PVI from our large registry. Procedural data and outcomes were compared with a matched group of 115 non-obese PVI pts and the long-term outcomes were analyzed. 3. Results: Overall follow-up duration was 314 patient-years in the obese and 378 patient-years in the non-obese group. The follow-up rate was 71% in the obese and 76% in the non-obese group. In both groups, their AF-characteristics did not differ significantly, while known risk factors were significantly more prevalent in the obese group. Procedural characteristics were similar in both groups. During follow-up, the obese pts demonstrated significant weight loss compared to the non-obese pts, while at the same time, the overall recurrence rate during follow-up did not differ significantly between both groups (obese: 39.2% and non-obese: 43.7%). PVI related and long-term complications were comparable between both groups. In the univariate analysis, obesity was not found to be associated with an increased AF recurrence risk. 4. Conclusion: These real-life data demonstrate that obese pts may not show higher AF recurrence rates after PVI compared to pts with normal body weight. Furthermore, PVI was found to be safe and effective in obese patients; thus, a BMI alone may not be a criterion for refusal of PVI.

Issues: Prescription drug monitoring programs are a harm minimisation intervention and clinical decision support tool that address the public health concern surrounding prescription drug misuse. Given the large number of studies published to date and the ongoing implementation of these programs, it is important to map the literature and identify areas for further research to improve practice., Approach: A scoping review was undertaken to identify the research on prescription drug monitoring programs published between January 2015 and April 2021., Key Findings: A total of 153 citations were included in this scoping review. The majority of the studies originated from the USA and were quantitative. Results on program effectiveness are mixed and mainly examine their association with opioid-related outcomes. Unintended consequences are revealed in the literature and this review also highlights barriers to program use., Implications: Overall, findings are mixed despite the large number of studies published to date. Mapping the literature identifies priority areas for further research that can advise policymakers and clinicians on practice improvement., Conclusion: Results on prescription drug monitoring program effectiveness are mixed and mainly examine their association with opioid-related outcomes. This review highlights barriers to prescription drug monitoring program effectiveness related to program use and system integration. Further research is needed in these areas to improve prescription drug monitoring program use and patient outcomes., (© 2022 Australasian Professional Society on Alcohol and other Drugs.)

Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication., (© 2021 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background: Retrospective analyses of large databases of treated patients can provide useful links to the presence of drug misuse or rare and infrequent adverse effects, such as agranulocytosis, diabetic ketoacidosis or neuroleptic malignant syndrome. The aim of this study is to describe the adverse effects to antipsychotics reported in the Australian Database of Adverse Event Notifications (DAEN)., Methods: Data were collected from the DAEN - a spontaneous reporting database. The database, which covered the period from January 2004 to December 2017, was obtained from the Therapeutic Goods Administration (TGA) website (www.TGA.gov). The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. All data were analysed descriptively. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5-19 years) was undertaken using chi squared test, where p  < 0.05 is significant., Results: A total of 7122 adverse events associated with the antipsychotics aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine and risperidone were reported to the TGA between January 2004 and December 2017. On average, there were 2.6 adverse events reported for each case. The most common adverse event reported for antipsychotics was neuroleptic malignant syndrome. There were no significant differences in the number of co-medications, formulations, indications, therapeutic dose, hospital admission and overdose among the antipsychotics between paediatric and adult populations. However, there were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5-19 years) ( p  < 0.05, chi squared test)., Conclusion: The antipsychotic drug associated with the highest adverse events in adults was clozapine, followed by olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine., Plain Language Summary: Adverse events reported of antipsychotics Background: Retrospective analyses of large databases of treated patients can provide useful clues to the presence of drug misuse or rare and infrequent adverse effects associated with antipsychotics. The drugs selected for this investigation are the following: aripiprazole, clozapine, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, haloperidol and pimozide. Methods: All data were analysed descriptively and investigated for any associations between the variables collected. Comparison of reporting and management of adverse events between adults (older than 20 years) and children (5-19 years) was undertaken using chi squared test, where p  < 0.05 is significant. Results: The antipsychotic drug associated with the highest adverse events was clozapine, followed by olanzapine. In children, the highest numbers of adverse events reported in the database were associated with risperidone, clozapine and olanzapine. The most common adverse event in adults, and reported with a number of antipsychotic drugs, was neuroleptic malignant syndrome. Conclusion: There were significant differences between causality, death and the management of adverse events between adult and paediatric populations (5-19 years).Keywords: Antipsychotics, adverse effects, adverse events, safety., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Objectives: To investigate the predictive factors for changes in the quality of life (GO-QoL) of patients with Graves' orbitopathy (GO) prior to and after specific treatment., Methods: A prospective follow-up study was conducted at an academic tertiary referral orbital center with a joint thyroid-eye clinic on 100 consecutive patients with GO. Before and after the standard 12-week course of weekly intravenous methylprednisolone (cumulative dose 4.5 g), the GO-QoL questionnaire provided by the European Group on Graves' Orbitopathy (EUGOGO) was completed. Endocrine and ophthalmic assessments were performed at each visit., Results: All patients were biochemically euthyroid and untreated for GO at baseline and presented with active and moderate-to-severe disease. Both GO-QoL subscales (visual functioning [VF] and appearance [AP]) significantly increased after immunosuppressive therapy and showed a sustained improvement for 6 months. At baseline, demographic variables (sex, age, and smoking) influenced QoL in the stepwise linear regression ( p < 0.01, adjusted R 2 = 0.24 for VF and p < 0.01, adjusted R 2 = 0.21 for AP). In contrast, 6 months after treatment, the improved QoL was now exclusively associated with ophthalmic parameters ( p < 0.01, adjusted R 2 = 0.47 for VF; p < 0.01, adjusted R 2 = 0.23 for AP)., Conclusions: Predictive factors for GO-QoL differed not only between the 2 subscales but also before and after the first treatment of GO., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by European Thyroid Association Published by S. Karger AG, Basel.)

Objective: The review presents a systematic analysis of literature investigating the association between migraine and suicidal behaviors. Introduction: Migraine is a common neurological disorder. The prevalence of migraines increases with age from adolescence to adulthood in both sexes, and results in a substantial loss of productivity due to missing days of school or work and need for bed rest. Literature prior to 2015 suggests that migraine is a predictor of suicide. Given the worldwide public health interest in suicide prevention, we examined the literature collected from diverse, predominantly non-European, populations post-2015. Methods: The databases used in this systematic review included: Medline, PsycINFO, EMBASE (Ovid), Science Direct (Elsevier), Cochrane, and PubMed for all available years of publication from January 2015 onwards. The review included participants aged 16 and over who had been diagnosed with migraines with the following outcome variables: any suicidality, both fatal and non-fatal; suicidal ideation; and suicidal behavior. Results: The database searches yielded a total of 542 citations. Following title and abstract screening, 460 articles were excluded and a total of 21 citations were evaluated. After full-text review and excluding a further 11 non-eligible studies, a total of 10 studies were eligible for inclusion in the systematic review. Conclusions: Current existing research highlights the important association between the increased risk of suicidal behaviors in the clinical and general population among chronic migraineurs with/without aura worldwide. Future studies are needed to facilitate the development of clinical guidelines for risk assessment, targeted interventions, and evidence-based treatment of migraine to reduce the risk of suicide among this vulnerable population., (Copyright © 2020 Karimi, Hoppe, Burdick, Buultjens, Wijeratne and Crewther.)

What Is Known and Objective: Community pharmacists have a key role to play in addressing drug misuse. The objective of this research was to systematically review the current evidence and investigate the attitudes and practice strategies of community pharmacists towards drug misuse management., Methods: Data were extracted from 19 studies retrieved via a three-step search strategy using the Arksey and O'Malley methodological framework for conducting scoping reviews., Results and Discussion: The attitudes and practice strategies of pharmacists towards drug misuse management and relevance to years of practice experience were discussed in seven of the 19 studies. Pharmacists reported gaps in knowledge and insufficient education and training on drug misuse-related topics. Barriers to the effective management of drug misuse included lack of time and staff training. The most commonly reported strategy to address drug misuse was referral back to the doctor. Eight of the studies identified the benefits of real-time prescription monitoring systems. Pharmacists have a key role to play in addressing drug misuse. Opportunities exist in the development of new and innovative approaches for harm minimization led by pharmacists, and in the examination and evaluation of the pharmacists' role in referral services, interventions and screening., What Is New and Conclusion: It is important to consider the role and contribution of early career pharmacists in the delivery of primary health care. They are the future of the pharmacy profession; therefore, it is critical that they are sufficiently trained and provided with the necessary resources to ensure high quality care in the management of drug misuse., (© 2019 John Wiley & Sons Ltd.)

Objective: To systematically evaluate the scientific literature examining the efficacy of nonoperative management for midshaft clavicular fractures, specifically looking at the effect of immobilization and/or functional rehabilitation. TYPE: Systematic review., Literature Survey: MEDLINE (PubMed), EMBASE, CINAHL databases were searched., Methodology: Inclusion criteria included adult patients enrolled in a controlled study evaluating bony healing, pain and/or function-related improvements after a strict nonoperative treatment plan for management of midshaft clavicle fractures., Synthesis: A total of 10 articles were included in the study. Only four studies contained level I evidence; four studies were prospective case series without a control, and one was a retrospective case series without a control. Half of studies used a strict immobilization period, and most utilized a period of functional rehabilitation. There were no direct comparisons between rehabilitation protocols. Studies without a strict immobilization period had a nonunion rate of 5% to 24% and residual pain in 35% to 83% of patients compared to studies with a strict immobilization period with a nonunion rate of 3% to 29% and residual pain in 14% to 49% of patients. Studies including functional rehabilitation protocol reported functional as measured by the Constant Shoulder Score of 87.8 to 96, out of a maximum of 100 representing no functional limitations, and nonunion rates of 12% to 25% compared to 81 to 85 and 3% to 29% in those without a rehabilitation protocol., Conclusions: No studies directly examine the effect of immobilization and functional rehabilitation on clinical outcomes for midshaft clavicular fractures. Future studies are needed to better elucidate the most effective treatment., Level of Evidence: I., (© 2019 American Academy of Physical Medicine and Rehabilitation.)

The capability of directing gaze to relevant parts in the environment is crucial for our survival. Computational models have proposed quantitative accounts of human gaze selection in a range of visual search tasks. Initially, models suggested that gaze is directed to the locations in a visual scene at which some criterion such as the probability of target location, the reduction of uncertainty or the maximization of reward appear to be maximal. But subsequent studies established, that in some tasks humans instead direct their gaze to locations, such that after the single next look the criterion is expected to become maximal. However, in tasks going beyond a single action, the entire action sequence may determine future rewards thereby necessitating planning beyond a single next gaze shift. While previous empirical studies have suggested that human gaze sequences are planned, quantitative evidence for whether the human visual system is capable of finding optimal eye movement sequences according to probabilistic planning is missing. Here we employ a series of computational models to investigate whether humans are capable of looking ahead more than the next single eye movement. We found clear evidence that subjects' behavior was better explained by the model of a planning observer compared to a myopic, greedy observer, which selects only a single saccade at a time. In particular, the location of our subjects' first fixation differed depending on the stimulus and the time available for the search, which was well predicted quantitatively by a probabilistic planning model. Overall, our results are the first evidence that the human visual system's gaze selection agrees with optimal planning under uncertainty.

Eye blinking is one of the most frequent human actions. The control of blinking is thought to reflect complex interactions between maintaining clear and healthy vision and influences tied to central dopaminergic functions including cognitive states, psychological factors, and medical conditions. The most imminent consequence of blinking is a temporary loss of vision. Minimizing this loss of information is a prominent explanation for changes in blink rates and temporarily suppressed blinks, but quantifying this loss is difficult, as environmental regularities are usually complex and unknown. Here we used a controlled detection experiment with parametrically generated event statistics to investigate human blinking control. Subjects were able to learn environmental regularities and adapted their blinking behavior strategically to better detect future events. Crucially, our design enabled us to develop a computational model that allows quantifying the consequence of blinking in terms of task performance. The model formalizes ideas from active perception by describing blinking in terms of optimal control in trading off intrinsic costs for blink suppression with task-related costs for missing an event under perceptual uncertainty. Remarkably, this model not only is sufficient to reproduce key characteristics of the observed blinking behavior such as blink suppression and blink compensation but also predicts without further assumptions the well-known and diverse distributions of time intervals between blinks, for which an explanation has long been elusive., Competing Interests: The authors declare no conflict of interest.