Author Correction: Structural insights into the activation of metabotropic glutamate receptors.

The surname of author Toon Laeremans was misspelled 'Laermans'. This error has been corrected online.

Structural insights into the activation of metabotropic glutamate receptors.

Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich domains to their 7-transmembrane domains. Spectroscopic studies show that signalling is a dynamic process, in which large-scale conformational changes underlie the transmission of signals from the extracellular Venus flytraps to the G protein-coupling domains-the 7-transmembrane domains-in the membrane. Here, using a combination of X-ray crystallography, cryo-electron microscopy and signalling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the Venus flytraps leads to a compaction of the intersubunit dimer interface, thereby bringing the cysteine-rich domains into close proximity. Interactions between the cysteine-rich domains and the second extracellular loops of the receptor enable the rigid-body repositioning of the 7-transmembrane domains, which come into contact with each other to initiate signalling.

Comparing the resource implications of old and new colorectal adenoma surveillance guidelines in Australia.

BACKGROUND: The latest update to the Australian adenoma surveillance guideline in 2018 introduced a novel risk stratification system with updated surveillance recommendations. The resource implications of adopting this new system are unclear. AIMS: To quanitfy the resource demands of adopting new over old adenoma surveillance guidelines. METHODS: We studied data from 2443 patients undergoing colonoscopies, in which a clinically significant lesion was identified in their latest, or previous procedure(s) across five Australian hospitals. We excluded procedures with inflammatory bowel disease, new or prior history of colorectal cancer or resection, inadequate bowel preparation and incomplete procedures. Old and new Australian surveillance intervals were calculated according to the number, size and histological characteristics of lesions identified. We used these data to compare the rate of procedures according to each guideline. RESULTS: Based on the procedures for 766 patients, the new surveillance guidelines significantly increased the number of procedures allocated an interval of 1 year (relative risk (RR): 1.57, P = 0.009) and 10 years (RR: 3.83, P < 0.00001) and reduced those allocated to half a year (RR: 0.08, P = 0.00219), 3 years (RR: 0.51, P < 0.00001) and 5 years (RR: 0.59, P < 0.00001). Overall, this reduced the relative number of surveillance procedures by 21% over 10 years (25.92 vs 32.78 procedures/100 patient-years), which increased to 22% after excluding patients 75 or older at the time of surveillance (19.9 vs 25.65 procedures/100 patient-years). CONCLUSION: The adoption of the latest Australian adenoma surveillance guidelines can reduce demand for surveillance colonoscopy by more than a fifth (21-22%) over 10 years.

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein.

Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R-Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.

Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket.

The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson's disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A2A receptor with a cytochrome b562-RIL (BRIL) fusion (A2AR-BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A2AR-BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1-bound A2AR-BRIL prevented formation of the lattice observed with the ZM241385-bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35 and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson's disease.

Inappropriate noise detection in Tendril family pacing leads.

INTRODUCTION: Noise oversensing encountered in patients with Abbott Tendril leads in our hospital triggered an internal investigation. METHODS: We retrospectively analyzed patients with a Tendril lead model 1688, 1788, 1888, and 2088. Most leads were connected to Abbott generators. To exclude a primary generator issue as the cause of noise oversensing, we enrolled a cohort of patients in whom Medtronic CapSureFix leads model 4076 and 5076 were prospectively connected to similar Abbott generators. RESULTS: A total of 1063 Tendril leads were implanted in 869 patients. Noise was encountered in 66 leads (6.2%) during a follow-up of 3.9 years. Most affected leads had normal impedance and only a few of these patients were symptomatic. Reprogramming was attempted in 44 of 66 (67%), and reduced oversensing in 34 of 44 (77%) of these patients. Seventeen malfunctioning leads (1.5%) were replaced, including 16 of 66 (24%) of those with noise. Of the four leads with noise extracted and returned to the manufacturer, lead to device abrasion was identified in two and inner insulation breach in one. None of the 145 Medtronic CapSureFix leads connected to Abbott generators had noise during a follow-up of 3.6 years. CONCLUSION: Noise oversensing was relatively common in Tendril leads, but was not detected in Medtronic leads despite connecting to Abbott generators. Although the majority of the affected leads did not show abnormal impedance, outer or inner insulation breach was identified in three of the four returned leads. As patients with affected leads are generally asymptomatic, most of them can be managed conservatively.

Management of functional Sprint Fidelis leads at cardiac resynchronization therapy-defibrillator generator replacement: a novel option for preventing inappropriate shocks from lead failure in fragile patients with high risk of sudden death.

AIMS: In patients with a functional Sprint Fidelis lead at generator replacement, the manufacturer recommended to either continue to use the existing lead or replace it with a new lead. For those patients who continue to use a functional Fidelis lead, the risk of inappropriate shocks remains present if the lead fails in the future. We evaluated the feasibility of an alternative approach at the time of cardiac resynchronization therapy-defibrillator (CRT-D) generator replacement in patients with a functional bipolar left ventricular (LV) lead for prevention of inappropriate shocks from future Fidelis lead failure. METHODS AND RESULTS: During the procedure, the pace/sense IS-1 connection pin of the functional Fidelis lead was intentionally inserted into the LV port of the new CRT-D generator, while the existing bipolar LV lead IS-1 connection pin was inserted into the right ventricular (RV) pace/sense port. After such switching, the existing bipolar LV lead was used for functional LV pacing/sensing, while the Fidelis lead was used for functional RV pacing and high voltage shock only and could no longer be used for the purpose of sensing and detecting. This approach precluded oversensing and inappropriate shocks should the functional Fidelis lead fail in the future. Six fragile patients, who were not considered suitable candidates for lead replacement, underwent the alternative approach. During a follow-up of 35 ± 23 months, the CRT-D system functioned normally in five patients. The Fidelis lead fractured in one patient 7 months after generator replacement. The malfunction was detected promptly and the defected lead was replaced. No inappropriate detections or shock was triggered. CONCLUSIONS: In CRT-D patients with a functional Fidelis lead and a bipolar LV lead, switching of the Fidelis lead pace/sense IS-1 pin with the bipolar LV lead IS-1 pin at generator replacement did not affect normal system function. This novel approach may be valuable in fragile patients with high risk of sudden death for prevention of inappropriate shocks triggered by oversensing from a malfunctioning Fidelis lead.

A cost utility analysis for the management of acute exacerbations of chronic rhinosinusitis.

BACKGROUND: The management of acute exacerbations of chronic rhinosinusitis (AECRS) is understudied and the most cost-effective management of AECRS has not been previously investigated. The aim of this study is to determine the most cost-effective strategy for the initial management of AECRS. METHODS: The study design consisted of a decision-tree economic model comparing three different initial strategies for managing a patient perceived AECRS: observation, upfront rescue medications, or clinic visit with diagnostic nasal endoscopy (DNE). The primary study outcome was the disease burden of a single AECRS, which was determined by the health utility value and the duration of symptoms. Strategies with an incremental cost-effectiveness ratio < $50,000/quality-adjusted life year (QALY) or equivalently < $137/quality-adjusted life day (QALD) were considered cost-effective. RESULTS: Observation was the most cost-effective strategy at a willingness to pay of $137 per QALD. One-way sensitivity analysis demonstrated that observation was more effective than upfront rescue medications when the probability of bacterial infection as the cause of AECRS was <24.0%. Upfront rescue medications wer more cost effective than observation when the probability of bacterial infection exceeded 49.0%. Clinic visit with DNE was the most effective strategy to manage an AECRS, but it was not considered cost-effective. CONCLUSION: Observation is the most cost-effective strategy for the initial management of AECRS when there is a low likelihood of bacterial infection. When the probability of bacterial etiology of AECRS exceeds 49.0%, upfront rescue medications proved to be the most cost-effective strategy.

Patient-reported disease control versus overall symptom severity as global metrics of chronic rhinosinusitis disease status.

BACKGROUND: Overall symptom severity (OSS) and patient-reported chronic rhinosinusitis (CRS) control are global measures of CRS identified as consensus, essential criteria for CRS disease control assessment. We sought to determine the functional relationship between these two metrics. METHODS: Using an international multicenter mixed-methods design, 260 CRS patients were recruited. OSS score was measured using a visual analog scale. Patient-reported CRS control was measured as "controlled," "partly controlled," and "uncontrolled." Twelve participants underwent semi-structured interviews to discuss OSS and patient-reported CRS control. RESULTS: The majority of interviewed participants felt OSS and patient-reported CRS control measured different constructs-while OSS only measured symptoms, patient-reported CRS control was more global, including not only symptom severity but also concepts such as medication usage, activity impairment, and exacerbations. Nevertheless, OSS score was strongly correlated with (ρ = 0.67, p < 0.001) and highly predictive of patient-reported CRS control. OSS score of >4 (95% confidence interval [CI]: 1.8-4.2) had 74.7% sensitivity and 93.2% specificity in identifying patients reporting their CRS as not controlled. OSS score of >6.6 (95% CI: 4.1-7.1) had 77.0% sensitivity and 75.9% specificity in identifying patients reporting their CRS as uncontrolled. The 22-item Sinonasal Outcome Test score was also predictive of patient-reported CRS disease control but OSS was significantly more predictive. CONCLUSIONS: Patients conceptually view patient-reported CRS control as a more global measure that subsumes OSS. Quantitatively, however, OSS is highly correlated with patient-reported CRS control, possibly reflecting their redundancy. For ease of use, we recommend patient-reported CRS control be reflected by OSS <4 for controlled, 4 ≤ OSS < 7 for partly controlled, and OSS ≥7 for uncontrolled CRS.

Design, Construction, and Test of Compact, Distributed-Charge, X-Band Accelerator Systems that Enable Image-Guided, VHEE FLASH Radiotherapy.

The design and optimization of laser-Compton x-ray systems based on compact distributed charge accelerator structures can enable micron-scale imaging of disease and the concomitant production of beams of Very High Energy Electrons (VHEEs) capable of producing FLASH-relevant dose rates. The physics of laser-Compton x-ray scattering ensures that the scattered x-rays follow exactly the trajectory of the incident electrons, thus providing a route to image-guided, VHEE FLASH radiotherapy. The keys to a compact architecture capable of producing both laser-Compton x-rays and VHEEs are the use of X-band RF accelerator structures which have been demonstrated to operate with over 100 MeV/m acceleration gradients. The operation of these structures in a distributed charge mode in which each radiofrequency (RF) cycle of the drive RF pulse is filled with a low-charge, high-brightness electron bunch is enabled by the illumination of a high-brightness photogun with a train of UV laser pulses synchronized to the frequency of the underlying accelerator system. The UV pulse trains are created by a patented pulse synthesis approach which utilizes the RF clock of the accelerator to phase and amplitude modulate a narrow band continuous wave (CW) seed laser. In this way it is possible to produce up to 10 µA of average beam current from the accelerator. Such high current from a compact accelerator enables production of sufficient x-rays via laser-Compton scattering for clinical imaging and does so from a machine of "clinical" footprint. At the same time, the production of 1000 or greater individual micro-bunches per RF pulse enables > 10 nC of charge to be produced in a macrobunch of < 100 ns. The design, construction, and test of the 100-MeV class prototype system in Irvine, CA is also presented.

Determinants of patient satisfaction in an Australian emergency department fast-track setting.

OBJECTIVES: To describe the relationship between waiting time and patient satisfaction, and to determine predictors of overall care rating in an emergency department (ED) fast-track setting. METHODS: A convenience sample of patients triaged to a fast-track unit were surveyed. Patient satisfaction was scored using a validated survey instrument, as well as a single overall care rating (poor to excellent). Median satisfaction scores were compared between each incremental hour of waiting time. Bivariate analysis was conducted between those who waited 1 h or less, and those who waited longer. Ordered logistic regression was used to determine predictors of improved overall care rating. RESULTS: 236 patients completed surveys (response rate of 74%). Of these, 84% rated their care as either very good or excellent. There was a linear decrease in median satisfaction scores for each incremental hour of waiting time associated with half the odds of higher overall care rating after adjusting for presenting problem type, triage category, and treating clinician type (OR 0.53 95% CI 0.37 to 0.75 p<0.001). English language (OR 2.43 95% CI 1.33 to 4.42 p=0.004) and initial consultation by a nurse practitioner (NP) (OR 1.81 95% CI 1.03 to 3.31 p=0.038) were also found to be significant predictors of improved overall care rating. CONCLUSIONS: Waiting time was found to be highly predictive of patient satisfaction in an emergency fast-track unit with English language and NPs also associated with improved overall care rating. Future measures to improve patient satisfaction in fast-track units should focus on these factors.

Pleomorphic Hyalinizing Angiectatic Tumor of the Larynx.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, benign soft tissue tumor with uncertain pathogenesis and lineage most commonly found in the lower and upper extremities. No reports exist of this tumor metastasizing, though local recurrence is common. To date, only approximately 100 cases have been reported. We present the case of a patient presenting with hoarseness and dyspnea found to have PHAT of the larynx, a location previously unreported in the literature and requiring unique management considerations.

Association of Circulating Plasma Secreted Frizzled-Related Protein 5 (Sfrp5) Levels with Cardiac Function.

Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that may play a role in cardiovascular development and disease. However, there is yet to be a comprehensive investigation into whether circulating SFRP5 can be a biomarker for cardiac function. Plasma SFRP5 levels were measured via ELISA in 262 patients admitted to a cardiology unit. Plasma SFRP5 levels were significantly lower in patients with a history of heart failure (HF), coronary artery disease (CAD), and atrial fibrillation (AF; p = 0.001). In univariate analyses, SFRP5 levels were also significantly positively correlated with left ventricular ejection fraction (LVEF) (r = 0.52, p < 0.001) and negatively correlated with E/E' (r = -0.30, p < 0.001). Patients with HF, CAD, low LVEF, low triglycerides, high CRP, and high eGFR were associated with lower SFRP5 levels independent of age, BMI, or diabetes after multivariate analysis (overall model r = 0.729, SE = 0.638). Our results show that low plasma SFRP5 levels are independently associated with the presence of HF, CAD, and, importantly, impaired LV function. These results suggest a potential role of SFRP5 as a biomarker, as well as a mediator of cardiac dysfunction independent of obesity and metabolic regulation.

Potentially avoidable mortality after endoscopic retrograde cholangiopancreatography in Australia: an 8-year qualitative analysis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a commonly performed procedure worldwide. The aim of this study was to examine cases of mortality after ERCP to identify clinical incidents that are potentially preventable, to improve patient safety. METHODS: The Australian and New Zealand Audit of Surgical Mortality provides an independent and externally peer-reviewed audit of surgical mortality pertaining to potentially avoidable issues. A retrospective review of prospectively collected data within this database was performed for the 8-year audit period from 1 January 2009 to 31 December 2016. Clinical incidents were identified by assessors through first- or second-line review, and thematically coded into periprocedural stages. These themes were then qualitatively analysed. RESULTS: There were 58 potentially avoidable deaths following ERCP, with 85 clinical incidents. Preprocedural incidents were most common (n = 37), followed by postprocedural (n = 32) and then intraprocedural (n = 8). Communication issues occurred across the periprocedural period (n = 8). Preprocedural incidents included delay to procedure, inadequate resuscitative management, decision to perform procedure and inadequate assessment. Intraprocedural incidents comprised technical factors and inadequate support. Postprocedural incidents involved inappropriate treatment, delay in definitive surgical treatment or in recognizing complications, inappropriate second-line intervention and inadequate assessment. Communication incidents comprised inadequate documentation, failure to escalate care and poor inter-clinician communication. CONCLUSION: Causes of mortality following ERCP are wide-ranging, and reviewing clinical incidents associated with potentially avoidable mortality can serve to inform and educate practitioners. In collating a subset of cases in which procedure-related mortality was deemed avoidable, a series of cautionary tales about ERCP is presented that may provide cues to practitioners on improving patient safety and inform future surgical practice.

The impact of sleep events on weight gain following early adenotonsillectomy compared to supportive care for pediatric OSA.

OBJECTIVES: Children with obstructive sleep apnea (OSA) who undergo adenotonsillectomy (AT) often experience post-operative weight gain, although the mechanism remains unclear. Our aim is to understand how changes in sleep events impact changes in weight in children with OSA following adenotonsillectomy compared to watchful waiting with supportive care. METHODS: We performed a secondary analysis of the Childhood adenotonsillectomy trial (CHAT) dataset in which children with OSA were randomized to undergo early adenotonsillectomy (eAT) or watchful waiting with supportive care (WWSC). The primary outcome measures included changes in body mass index (BMI) percentile, apnea-hypopnea index (AHI) and arousal index (AI) during rapid eye movement (REM) sleep. The change in BMI percentile attributable to changes in AHI and AI during REM sleep was determined using causal mediation analysis. RESULTS: Of the 453 children with OSA randomized to eAT or WWSC, 397 children were included in the analysis. Children in the eAT arm experienced a greater increase in their weight as measured by BMI percentile, compared to children who received WWSC (WWSC 4.12 (2.70, 5.55) vs. eAT 6.62 (4.87, 8.38), Cohen's d = 0.22 (0.02, 0.42), p = 0.02). A significant proportion of the weight gain was attributable to decreases in apneic events (proportion mediated 19% (2-97%), p = 0.03) and arousals (proportion mediated 20% (5-78%), p = 0.01) during REM sleep. CONCLUSION: A significant proportion of post-adenotonsillectomy weight gain in children with OSA is attributable to polysomnographic changes during REM sleep, potentially due to the mitigation of REM-related sleep fragmentation and subsequent reduction in metabolic expenditure.

Intraocular pressure improvement in patients receiving teprotumumab for the treatment of thyroid eye disease: a case series.

BACKGROUND: Teprotumumab is a novel treatment that reduces inflammation and symptoms caused by thyroid eye disease. There are limited data on teprotumumab's effect on intraocular pressure. CASE PRESENTATION: We report nine patients diagnosed with thyroid eye disease whose intraocular pressure decreased during teprotumumab treatment for 8 weeks: patient 1, a 67-year-old Hispanic woman; patient 2, an 86-year-old African-American man; patient 3, a 71-year-old Caucasian woman; patient 4, a 72-year-old Hispanic woman; patient 5, a 65-year-old Caucasian woman; patient 6, a 54-year-old Caucasian man; patient 7, a 54-year-old Asian man; patient 8, a 31-year-old Asian woman; patient 9, a 60-year-old Caucasian woman. The diagnosis of thyroid eye disease was based on increased redness, swelling, and excessive tearing; abnormal proptosis, lid retraction, and diplopia measurements were also taken during physical examination. Intraocular pressure in primary, lateral gaze, and upgaze was documented. There was significant (p = 0.0397) improvement of primary gaze eye pressure from pre-teprotumumab infusions (baseline) to completion of the treatment course. CONCLUSIONS: Teprotumumab significantly decreased the intraocular pressure for patients during the duration of the study. Teprotumumab is a novel medication that is approved for the primary treatment of thyroid eye disease in both acute and chronic thyroid eye disease. Previous treatments used to treat thyroid eye disease include glucocorticoids, radiotherapy, or orbital decompression surgery; however, these treatments all have significant limitations. Teprotumumab is an effective noninvasive alternative for decreasing symptoms of thyroid eye disease and, as shown, also lowers intraocular pressure. However, teprotumumab should not be used as a substitute for glaucoma medications; its ability to lower intraocular pressure may be in addition to lowering periorbital pressure and retro-orbital pressure.

Quality of colonoscopy performed by medical or surgical specialists and trainees in five Australian hospitals.

BACKGROUND: Ensuring colonoscopy procedure quality is vital to the success of screening and surveillance programmes for bowel cancer in Australia. However, the data on the performance of quality metrics, through adequate adenoma detection, bowel preparation, and procedure completion rates, in the Australian public sector is limited. Understanding these can inform quality improvement to further strengthen our capacity for prevention and early detection of colorectal cancer. AIM: To determine the quality of colonoscopy in Australian teaching hospitals and their association with proceduralist specialty, trainee involvement, and location. METHODS: We retrospectively evaluated 2443 consecutive colonoscopy procedure reports from 1 January to 1 April, 2018 from five public teaching tertiary hospitals in Australia (median 60 years old, 49% male). Data for bowel preparation quality, procedure completion rates, and detection rates of clinically significant adenomas, conventional adenomas, and serrated lesions was collected and compared to national criteria for quality in colonoscopy. Participating hospital, proceduralist specialty, and trainee involvement indicators were used for stratification. Data was analysed using Chi-squared tests of independence, Mann-Whitney U, One-way ANOVA, and multivariate binary logistic regression. RESULTS: Fifty-two point two percent (n = 1276) and 43.3% (n = 1057) were performed by medical and surgical proceduralists respectively, whilst 29.8% (n = 728) involved a trainee. Inadequate bowel preparation affected 7.3% of all procedures. The procedure completion rate was 95.1%, which increased to 97.5% after adjustment for bowel preparation quality. The pooled cancer, adenoma, and serrated lesion detection rates for all five hospitals were 3.5%, 40%, and 5.9% respectively. Assessed hospitals varied significantly by patient age (P < 0.001), work-force composition (P < 0.001), adequacy of bowel preparation (P < 0.001), and adenoma detection rate (P < 0.001). Two hospitals (40%) did not meet all national criteria for quality, due to a procedure completion rate of 94.5% or serrated lesion detection rate of 2.6%. Although lower than the other hospitals, the difference was not significant. Compared with surgical specialists, procedures performed by medical specialists involved older patients [65 years (inter-quartile range, IQR 58-73) vs 64 years (IQR 56-71); P = 0.04] and were associated with a higher adenoma detection rate [odds ratio (OR) 1.53; confidence interval: 1.21-1.94; P < 0.001]. Procedures involving trainee proceduralists were not associated with differences in the detection of cancer, adenoma, or serrated lesions, compared with specialists, or according to their medical or surgical background. On multivariate analysis, cancer detection was positively associated with patient age (OR 1.04; P < 0.001) and negatively associated with medical compared to surgical proceduralists (OR 0.54; P = 0.04). Conventional adenoma detection rates were independently associated with increasing patient age (OR 1.04; P < 0.001), positively associated with medical compared to surgical proceduralists (OR 1.41; P = 0.002) and negatively associated with male gender (OR 0.53; P < 0.001). CONCLUSION: Significant differences in the quality of colonoscopy in Australia exist, even when national benchmarks are achieved. The role of possible contributing factors, like procedural specialty and patient gender need further evaluation.

Rhopressa-induced corneal edema: a case report.

BACKGROUND: Rhopressa (netarsudil) has recently been added to the arsenal of treatment for open-angle glaucoma. It is an effective norepinephrine transporter and Rho-associated protein kinase (ROCK) inhibitor used to decrease intraocular pressure (IOP), with the most common side effect being conjunctival hyperemia. CASE PRESENTATION: We report a unique case of Rhopressa-induced corneal edema in a 79-year-old African-American woman, which resolved after discontinuation. She had a history of smoking one cigarette per day and did not consume alcohol. She had no history of corneal edema or uveitis. CONCLUSIONS: Previous case reports have documented patients with Rhopressa-induced corneal edema; however, they have all had a preexisting history of corneal edema or uveitis. We believe that this is a unique case of Rhopressa-induced corneal edema in a relatively healthy eye. While Rhopressa is effective in managing glaucoma, there may be effects of treatment that are still unknown. We will discuss clinical findings of our case, along with a review of previous literature on Rhopressa and novel ROCK inhibitors. We hope that we can add to the existing body of literature and invite further investigation of Rhopressa and ROCK inhibitors and their effects on the cornea.

Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist.

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.