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.

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.

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.

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.

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.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.

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.

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.

One size does not fit all: navigating the multi-dimensional space to optimize T-cell engaging protein therapeutics.

T-cell engaging biologics is a class of novel and promising immune-oncology compounds that leverage the immune system to eradicate cancer. Here, we compared and contrasted a bispecific diabody-Fc format, which displays a relatively short antigen-binding arm distance, with our bispecific IgG platform. By generating diverse panels of antigen-expressing cells where B cell maturation antigen is either tethered to the cell membrane or located to the juxtamembrane region and masked by elongated structural spacer units, we presented a systematic approach to investigate the role of antigen epitope location and molecular formats in immunological synapse formation and cytotoxicity. We demonstrated that diabody-Fc is more potent for antigen epitopes located in the membrane distal region, while bispecific IgG is more efficient for membrane-proximal epitopes. Additionally, we explored other parameters, including receptor density, antigen-binding affinity, and kinetics. Our results show that molecular format and antigen epitope location, which jointly determine the intermembrane distance between target cells and T cells, allow decoupling of cytotoxicity and cytokine release, while antigen-binding affinities appear to be positively correlated with both readouts. Our work offers new insight that could potentially lead to a wider therapeutic window for T-cell engaging biologics in general.

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.

Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity.

Agonistic antibodies targeting the tumor necrosis factor (TNF) superfamily of co-stimulatory receptors (TNFRSF) are progressing through various stages of clinical development for cancer treatment, but the desired and defining features of these agents for optimal biological activity remain controversial. One idea, based on recent studies with CD40, is that non-ligand-blocking antibodies targeting membrane-distal cysteine-rich domain 1 (CRD1) have superior agonistic activities compared with ligand-blocking antibodies targeting more membrane-proximal CRDs. Here, we determined the binding and functional characteristics of a panel of antibodies targeting CRDs 1-4 of OX40 (also known as TNFRSF4 or CD134). In striking contrast to CD40, we found that ligand-blocking CRD2-binding and membrane-proximal CRD4-binding anti-OX40 antibodies have the strongest agonistic and anti-tumor activities. These findings have important translational implications and further highlight that the relationship between epitope specificity and agonistic activity will be an important issue to resolve on a case-by-case basis when optimizing antibodies targeting different co-stimulatory tumor necrosis factor receptors (TNFRs).

Outcomes at non-trauma centres within a trauma referral network: A five-year retrospective cohort study from Australia.

OBJECTIVE: Describe major trauma activity and mortality within non-trauma centres within a single trauma referral network in New South Wales, Australia over a five-year period. DESIGN: Multi-centre retrospective cohort study. METHODS: This was a retrospective cohort study of trauma patients presenting to non-trauma centres within a metropolitan major trauma referral network between January 2011 and June 2016. The outcome of interest examined was in-hospital mortality for major trauma (Injury Severity Score ISS>12), consistent with current state-wide trauma reporting guidelines. RESULTS: A total of 4827 trauma patients were identified from non-major trauma centres of which 352 (7.3%) had an ISS>12. The most common mechanisms were road trauma (54.6%) and falls (37.4%). The mortality with those ISS>12 was 9.3%. During the same period, the overall trauma mortality (ISS>12) at the Major Trauma Centre was similar at 10.2% (p=0.10). After adjusting for age and ISS differences between Major Trauma Centre and other facilities within the network, the odds of in-hospital mortality after major trauma (ISS>12) was higher in the Major Trauma Centre compared to other facilities within the same network (adjusted odds ratio 2.7; 95% CI 1.6, 4.7; p=0.0004). CONCLUSION: Across a single trauma referral network coordinated by a major trauma service, non-trauma centres account for around a quarter of total major trauma volume and adjusted mortality was lower in these centres compared to patients treated at major trauma centres.

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.

Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes.

Rapidly evolving pathogens such as HIV or influenza can quickly mutate their antigenic profiles, reducing the efficacy of conventional vaccines. Despite this challenge, functionally required epitopes are highly conserved among heterologous viral strains and represent a key vulnerability that could be targeted during vaccine development. As the antigenicity of these conserved epitopes is frequently subdominant, there is a critical need for innovative vaccination strategies designed to target these neutralizing epitopes. Here, we immunized mice with antigens containing discrete immunodominant and subdominant moieties and show that treatment with soluble heterologous antigen bearing only the immunodominant epitope selectively suppresses these germinal center (GC) B cells. By exploiting this intrinsic tolerance mechanism, we promote the expansion of subdominant B cells in the GC and the subsequent long-lived components of the humoral response. We propose that this strategy may be applied to elicit preferential expansion of subdominant B cells that recognize weakly immunogenic epitopes on microbial pathogens.

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.