Oral estrogen receptor PROTAC® vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.

PURPOSE: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR or PI3K inhibitors is now a central strategy for the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition. RESULTS: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth inhibition (TGI) (87-123%) in MCF7 orthotopic xenograft models, better than the ET agent fulvestrant (31-80% TGI). In the hormone-independent ER Y537S patient derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regressions and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the mTOR inhibitor everolimus, and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

World Federation for Interventional Stroke Treatment (WIST) multispecialty training guidelines for endovascular stroke intervention.

Introduction: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. Aim: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. Material and methods: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. Results: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. Conclusions: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted.

World Federation for Interventional Stroke Treatment (WIST) Multispecialty Training Guidelines for Endovascular Stroke Intervention.

INTRODUCTION: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. AIM: To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. MATERIAL AND METHODS: The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency - rather than time-based - guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. RESULTS: The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. CONCLUSIONS: WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SUMMARY: The World Federation for Interventional Stroke Treatment (WIST) establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in endovascular treatment (EVT). WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centers to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. SIMULTANEOUS PUBLICATION: The WIST 2023 Guidelines are published simultaneously in Europe (Adv Interv Cardiol 2023).

Social, health and economic impact of COVID-19: Healthy Ageing In Scotland (HAGIS) - a protocol for a mixed-methods study.

INTRODUCTION: Public health responses to the COVID-19 pandemic have reaped adverse physical, psychological, social and economic effects, with older adults disproportionally affected. Psychological consequences of the pandemic include fear, worry and anxiety. COVID-19 fear may impact individuals' mitigation behaviours, influencing their willingness to (re)engage in health, social and economic behaviours. This study seeks (1) to develop a robust and evidence-based questionnaire to measure the prevalence of COVID-19 fear among older adults (aged ≥50) in Scotland and (2) to examine the impact of COVID-19 fear on the willingness of older adults to (re)engage across health, social and economic domains as society adjusts to the 'new normal' and inform policy and practice. METHODS AND ANALYSIS: This mixed-method study includes a large-scale multimodal survey, focus groups and interviews with older adults (aged ≥50) living in Scotland, and an email-based 'e-Delphi' consultation with professionals working with older adults. The COVID-19 fear scale was developed and validated using exploratory and confirmatory factor analyses. Survey data will be analysed using descriptive and inferential statistics. Thematic analysis will be used to analyse qualitative data. Survey and qualitative findings will be triangulated and used as the starting point for an 'e-Delphi' consensus consultation with expert stakeholders. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the University of Stirling for multimodal survey development, fieldwork methodology and data management. Anonymised survey data will be deposited with the UK Data Service, with a link provided via the Gateway to Global Ageing. Qualitative data will be deposited with the University of Stirling online digital repository-DataSTORRE. A dedicated work package will oversee dissemination via a coproduced project website, conference presentations, rapid reports and national and international peer-reviewed journal articles. There is planned engagement with Scottish and UK policy makers to contribute to the UK government's COVID-19 recovery strategy.

High- and low-latitude forcings drive Atacama Desert rainfall variations over the past 16,000 years.

Late Quaternary precipitation dynamics in the central Andes have been linked to both high- and low-latitude atmospheric teleconnections. We use present-day relationships between fecal pellet diameters from ashy chinchilla rats (Abrocoma cinerea) and mean annual rainfall to reconstruct the timing and magnitude of pluvials (wet episodes) spanning the past 16,000 years in the Atacama Desert based on 81 14C-dated A. cinerea paleomiddens. A transient climate simulation shows that pluvials identified at 15.9 to 14.8, 13.0 to 8.6, and 8.1 to 7.6 ka B.P. can be linked to North Atlantic (high-latitude) forcing (e.g., Heinrich Stadial 1, Younger Dryas, and Bond cold events). Holocene pluvials at 5.0 to 4.6, 3.2 to 2.1, and 1.4 to 0.7 ka B.P. are not simulated, implying low-latitude internal variability forcing (i.e., ENSO regime shifts). These results help constrain future central Andean hydroclimatic variability and hold promise for reconstructing past climates from rodent middens in desert ecosystems worldwide.

Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis.

The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer's disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize the so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded ß-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose-dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.

Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis.

The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures  of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded ß-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.

The Bright and Dark Aspects of Grit in the Pursuit of Success.

Grit, defined as passion and perseverance for long-term goals, predicts success in a number of social domains. The present two studies examined grit and its subscales, and how these relate to both adaptive and maladaptive personality traits pertaining to success. For Study 1, based on data from 249 participants, results indicated that grit was correlated positively with proactive personality, personal growth initiative, and competitiveness, and the perseverance subscale also was correlated positively with self- and other-oriented perfectionism. The findings of Study 1 led us to further explore the dark aspects of grit in Study 2: based on data from 222 participants, results indicated that grit was correlated negatively with Machiavellianism, hypercompetitiveness, and most forms of narcissism but positively correlated with adaptive grandiose narcissism. Collectively, results reveal grit to be a positive, adaptive trait but raise questions regarding the perfectionistic tendencies of gritty individuals and the unitary nature of the construct.

A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial.

AIM: We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D). METHODS AND RESULTS: We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of -2.82g [95% confidence interval (CI): -5.13 to -0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change -2.92g; 95% CI: -5.45 to -0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049). CONCLUSION: Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin. CLINICALTRIALS.GOV IDENTIFIER: NCT02956811.

Assessment of brachial artery mechanics using velocity vector imaging does not predict arteriovenous fistula failure; a feasibility study.

Strain measurements by US have been suggested as a method of assessing arterial elasticity prior to arterio venous fistula creation. This pilot study sought to develop an imaging protocol to measure strain in the brachial artery via velocity vector imaging (VVI) and determine if differences in strain could be observed between a healthy group and a group with end-stage renal disease (ESRD), and if VVI measurements were associated with arterio-venous fistula malfunction. 40 healthy volunteers and 33 patients with ESRD were included in this study. All participants underwent US assessment of brachial artery strain via VVI. Peak velocity, strain, strain-rate and velocity were assessed. Patients with and without AVF failure at 3-months were assessed for differences in VVI measurement. Mean VVI measurements between the patient and volunteer groups were similar, and no significant differences were observed. Measurements were reproducible. No significant differences were observed in patients with or without AVF dysfunction. The results from this pilot study suggest VVI measurements of brachial artery mechanics are feasible and that VVI measurements may be used to assess age related changes of the brachial artery.

Increased Brachial Artery Compliance After Arteriovenous Fistula Creation as Measured by Shear Wave Elastography: Results From a Feasibility Study.

OBJECTIVES: Arterial stiffness has been proposed as a marker of arteriovenous fistula failure and can be measured locally by using ultrasound shear wave elastography (SWE). This preliminary study aimed to assess whether SWE measurements of the brachial artery were associated with arteriovenous fistula failure. METHODS: Data were collected on patients who were indicated for fistula creation. Preoperative and postoperative vessel diameters from B-mode ultrasound, brachial artery SWE maps, and demographic data were collected. Logistic and linear regression analyses were used to determine whether any of these variables were related to the outcome of the fistula 3 months after creation. RESULTS: Data were acquired for 33 patients. Shear wave velocity values decreased after fistula creation (mean ± SD, -1.2 ± 1 m/s; P < .05). No parameters were associated with failure of the fistula in the logistic regression analysis. CONCLUSIONS: No markers were related to fistula failure, but a decrease in the shear wave velocity was observed in the brachial arteries after fistula creation, indicating increased compliance.

A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial.

AIM: We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. METHODS AND RESULTS: We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference -1.37 (95% confidence interval: -2.63 to -0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. CONCLUSION: Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Aortic stiffness in aortic stenosis assessed by cardiovascular MRI: a comparison between bicuspid and tricuspid valves.

OBJECTIVES: To compare aortic size and stiffness parameters on MRI between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with aortic stenosis (AS). METHODS: MRI was performed in 174 patients with asymptomatic moderate-severe AS (mean AVAI 0.57 ± 0.14 cm2/m2) and 23 controls on 3T scanners. Valve morphology was available/analysable in 169 patients: 63 BAV (41 type-I, 22 type-II) and 106 TAV. Aortic cross-sectional areas were measured at the level of the pulmonary artery bifurcation. The ascending and descending aorta (AA, DA) distensibility, and pulse wave velocity (PWV) around the aortic arch were calculated. RESULTS: The AA and DA areas were lower in the controls, with no difference in DA distensibility or PWV, but slightly lower AA distensibility than in the patient group. With increasing age, there was a decrease in distensibility and an increase in PWV. After correcting for age, the AA maximum cross-sectional area was higher in bicuspid vs. tricuspid patients (12.97 [11.10, 15.59] vs. 10.06 [8.57, 12.04] cm2, p < 0.001), but there were no significant differences in AA distensibility (p = 0.099), DA distensibility (p = 0.498) or PWV (p = 0.235). Patients with BAV type-II valves demonstrated a significantly higher AA distensibility and lower PWV compared to type-I, despite a trend towards higher AA area. CONCLUSIONS: In patients with significant AS, BAV patients do not have increased aortic stiffness compared to those with TAV despite increased ascending aortic dimensions. Those with type-II BAV have less aortic stiffness despite greater dimensions. These results demonstrate a dissociation between aortic dilatation and stiffness and suggest that altered flow patterns may play a role. KEY POINTS: • Both cellular abnormalities secondary to genetic differences and abnormal flow patterns have been implicated in the pathophysiology of aortic dilatation and increased vascular complications associated with bicuspid aortic valves (BAV). • We demonstrate an increased ascending aortic size in patients with BAV and moderate to severe AS compared to TAV and controls, but no difference in aortic stiffness parameters, therefore suggesting a dissociation between dilatation and stiffness. • Sub-group analysis showed greater aortic size but lower stiffness parameters in those with BAV type-II AS compared to BAV type-I.

Non-contrast MRI methods as a tool for the pre-operative assessment and surveillance of the arterio-venous fistula for haemodialysis.

OBJECTIVE: To compare non-contrast enhanced MRI with ultrasound (US) for measurement of arm blood vessel geometries and flow velocities in volunteers and patients with end-stage renal disease. MATERIALS AND METHODS: Subjects were scanned using US (reference standard), and MRI 2D time-of-flight (ToF), 2D phase contrast (PC), and 3D multi-echo data image combination (MEDIC). Patients were also scanned after arteriovenous fistula (AVF) surgery. RESULTS: For mean vessel diameters (radial and brachial arteries; cephalic vein) MEDIC measurements were similar to US (p > 0.05). However, ToF underestimated the mean diameter of the cephalic vein relative to US (p < 0.05). For arterial velocity measurements, the mean values derived by PC-MR and US were similar (p > 0.05). Post-operatively, the intra-luminal signal intensity was hypo-intense at the anastomosis site using ToF and MEDIC. At the same site the outer boundary of the vessel was consistently lost on ToF, but remained clearly delineated on the MEDIC images. DISCUSSION: With the exception of ToF, the MRI data demonstrated excellent agreement with US for measurements of vessel geometry and flow velocity. Further, the ability to clearly delineate the post-surgery vessel edges with MEDIC MRI suggests that the technique may be useful for surveillance after AVF creation or for patient-specific modelling studies.

The Bacteroidetes Q-Rule: Pyroglutamate in Signal Peptidase I Substrates.

Bacteroidetes feature prominently in the human microbiome, as major colonizers of the gut and clinically relevant pathogens elsewhere. Here, we reveal a new Bacteroidetes specific feature in the otherwise widely conserved Sec/SPI (Sec translocase/signal peptidase I) pathway. In Bacteroidetes, but not the entire FCB group or related phyla, signal peptide cleavage exposes N-terminal glutamine residues in most SPI substrates. Reanalysis of published mass spectrometry data for five Bacteroidetes species shows that the newly exposed glutamines are cyclized to pyroglutamate (also termed 5-oxoproline) residues. Using the dental pathogen Porphyromonas gingivalis as a model, we identify the PG2157 (also called PG_RS09565, Q7MT37) as the glutaminyl cyclase in this species, and map the catalytic activity to the periplasmic face of the inner membrane. Genetic manipulations that alter the glutamine residue immediately after the signal peptide in the pre-pro-forms of the gingipains affect the extracellular proteolytic activity of RgpA, but not RgpB and Kgp. Glutamine statistics, mass spectrometry data and the mutagenesis results show that the N-terminal glutamine residues or their pyroglutamate cyclization products do not act as generic sorting signals.

Stiffness Matters: Part II-The Effects of Plate Stiffness on Load-Sharing and the Progression of Fusion Following Anterior Cervical Discectomy and Fusion In Vivo.

STUDY DESIGN: Real time in vivo measurement of forces in the cervical spine of goats following anterior cervical discectomy and fusion (ACDF). OBJECTIVE: To measure interbody forces in the cervical spine during the time course of fusion following ACDF with plates of different stiffnesses. SUMMARY OF BACKGROUND DATA: Following ACDF, the biomechanics of the arthrodesis is largely dictated by the plate. The properties of the plate prescribe the extent of load-sharing through the disc space versus the extent of stress-shielding. Load-sharing promotes interbody bone formation and stress-shielding can inhibit maturation of bone. However, these principles have never been validated in vivo. Measuring in vivo biomechanics of the cervical spine is critical to understanding the complex relationships between implant design, interbody loading, load-sharing, and the progression of fusion. METHODS: Anterior cervical plates of distinct bending stiffnesses were placed surgically following ACDF in goats. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads were measured in vivo in real time during the course of fusion for each plate. RESULTS: Interbody forces during flexion/extension were highly dynamic. In animals that received high stiffness plates, maximum forces were in extension whereas in animals that received lower stiffness plates, maximum forces were in flexion. As fusion progressed, interbody load magnitude decreased. CONCLUSION: The magnitude of interbody forces in the cervical spine is dynamic and correlates to activity and posture of the head and neck. The magnitude and consistency of forces in the interbody space correlates to plate stiffness with more compliant plates resulting in more consistent load-sharing. The magnitude of interbody forces decreases as fusion matures suggesting that smart interbody implants may be used as a diagnostic tool to indicate the progression of interbody fusion. LEVEL OF EVIDENCE: N/A.

Imaging in Vascular Access.

This review examines four imaging modalities; ultrasound (US), digital subtraction angiography (DSA), magnetic resonance imaging (MRI) and computed tomography (CT), that have common or potential applications in vascular access (VA). The four modalities are reviewed under their primary uses, techniques, advantages and disadvantages, and future directions that are specific to VA. Currently, US is the most commonly used modality in VA because it is cheaper (relative to other modalities), accessible, non-ionising, and does not require the use of contrast agents. DSA is predominantly only performed when an intervention is indicated. MRI is limited by its cost and the time required for image acquisition that mainly confines it to the realm of research where high resolution is required. CT's short acquisition times and high resolution make it useful as a problem-solving tool in complex cases, although accessibility can be an issue. All four imaging modalities have advantages and disadvantages that limit their use in this particular patient cohort. Current imaging in VA comprises an integrated approach with each modality providing particular uses dependent on their capabilities. MRI and CT, which currently have limited use, may have increasingly important future roles in complex cases where detailed analysis is required.

The outer-membrane export signal of Porphyromonas gingivalis type IX secretion system (T9SS) is a conserved C-terminal ß-sandwich domain.

In the recently characterized Type IX Secretion System (T9SS), the conserved C-terminal domain (CTD) in secreted proteins functions as an outer membrane translocation signal for export of virulence factors to the cell surface in the Gram-negative Bacteroidetes phylum. In the periodontal pathogen Porphyromonas gingivalis, the CTD is cleaved off by PorU sortase in a sequence-independent manner, and anionic lipopolysaccharide (A-LPS) is attached to many translocated proteins, thus anchoring them to the bacterial surface. Here, we solved the atomic structure of the CTD of gingipain B (RgpB) from P. gingivalis, alone and together with a preceding immunoglobulin-superfamily domain (IgSF). The CTD was found to possess a typical Ig-like fold encompassing seven antiparallel ß-strands organized in two ß-sheets, packed into a ß-sandwich structure that can spontaneously dimerise through C-terminal strand swapping. Small angle X-ray scattering (SAXS) revealed no fixed orientation of the CTD with respect to the IgSF. By introducing insertion or substitution of residues within the inter-domain linker in the native protein, we were able to show that despite the region being unstructured, it nevertheless is resistant to general proteolysis. These data suggest structural motifs located in the two adjacent Ig-like domains dictate the processing of CTDs by the T9SS secretion pathway.