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BACKGROUND AND PURPOSE:The safety and efficacy of the PulseRider for the treatment of wide-neck, bifurcation aneurysms at the basilar and carotid terminus locations were studied in a prospective trial, the Adjunctive Neurovascular Support of Wide-Neck Aneurysm Embolization and Reconstruction (ANSWER) trial, reporting on initial 6-month angiographic and clinical results. This report provides insight into the longer term durability and safety with 12-month data. MATERIALS AND METHODS:Aneurysms treated with the PulseRider among enrolled sites were prospectively studied. Updated 12-month data on clinical and imaging end points are included. RESULTS:Thirty-four patients were enrolled (29 women, 5 men) with a mean age of 60.9 years. The mean aneurysm height ranged from 2.4 to 15.9 mm with a mean neck size of 5.2 mm (range, 2.3-11.6 mm). At 1 year, there were no device migrations or symptomatic in-stent stenoses. Raymond-Roy I occlusion was achieved in 53% of cases at the time of treatment and progressed to 61% and 67% at 6 and 12 months, respectively. Adequate occlusion (Raymond-Roy I/II) progressed from 88% at 6 months to 90% at 12 months. No recanalizations were observed. There was 1 delayed ischemic event. Good outcome (mRS 0-2) was achieved in 90% of patients. CONCLUSIONS:The updated 1-year results from the ANSWER trial demonstrate aneurysm stability and an acceptable safety profile for aneurysms treated at the basilar apex and carotid terminus. Prospective data from a larger set of aneurysms treated at other locations are required to assess how treatment with PulseRider compares with alternatives for treating wide-neck bifurcation aneurysms.

Chronic cough (CC; ≥8 weeks in duration) is a common and burdensome feature of respiratory diseases. The understanding of cough has progressed significantly in recent years, albeit largely in refractory (unexplained) chronic cough (RCC) in the absence of other respiratory conditions. The prevalence of CC in respiratory diseases is poorly described, but estimates have been reported: asthma (8-58%), chronic obstructive pulmonary disease (COPD; 10-74%), bronchiectasis (82-98%), interstitial lung disease (ILD; 50-89%) and sarcoidosis (3-64%). CC in respiratory conditions generally predicts impaired health status and more severe disease. It is associated with increased symptom burden and disease severity in asthma, COPD, bronchiectasis and ILD, higher exacerbation frequency in asthma and bronchiectasis, and increased mortality and lung transplantation in idiopathic pulmonary fibrosis (IPF). Physiologically, heightened cough reflex sensitivity (CRS) has been reported and postulated to be mechanistic in isolated RCC. Cough reflex hypersensitivity (CRH) has also been reported in asthma, COPD, bronchiectasis, ILD and sarcoidosis. Unlike recent advances in isolated RCC, there are limited studies and understanding of central cough neuropathways in other respiratory conditions. Of note, dysfunctional central voluntary cough suppression neuropathways and physiology were observed in isolation in RCC; cough suppression is preserved in COPD. Understanding in the mechanism of RCC cannot be simply extrapolated to other respiratory conditions. The restricted understanding of cough mechanisms in these conditions has limited cough-specific therapeutic options in this context. There is currently an unmet need to expand our understanding of cough in chronic respiratory conditions, both in order to improve the quality of life of patients, and to improve knowledge of cough in general. This review aims to describe the prevalence, impact, pathophysiology and management of CC in asthma, COPD, bronchiectasis, ILD and sarcoidosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1776/coif). The series “Novel Insights into Chronic Cough” was commissioned by the editorial office without any funding or sponsorship. SSB has received personal fees for consultancy from Merck, Bellus, Trevi, Genentech, Nerre, Kinevant, Boehringer Ingelheim and Bayer. PSPC reports two ongoing grants: EPSRC and MERCK, outside of the submitted work. The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: The antiplatelet management in acute ischemic stroke requiring carotid artery stenting is heterogenous, with no clear guidelines to direct management., Objective: To evaluate the safety and efficacy of an intravenous eptifibatide protocol in the management of acute ischemic stroke requiring emergent carotid artery stenting., Methods: We performed a retrospective analysis of consecutive patients who underwent carotid artery stenting for acute ischemic stroke at a high-volume tertiary neuroscience center, who were managed with an intravenous eptifibatide protocol. The protocol consists of an intravenous loading eptifibatide bolus (180 mcg/kg) at the time of stenting, followed by a maintenance infusion of 1 mcg/kg/min, then oral or nasogastric loading of dual antiplatelet agents., Results: 80 patients were included for analysis. Median presenting NIHSS was 17. Sixty-six patients (83%) had a tandem intracranial occlusion. Six (7.5%) patients developed symptomatic intracranial hemorrhage (sICH). Those who received intravenous thrombolysis were not more likely to develop sICH (10% vs 5%, p = 0.40). Those patients with a presenting ASPECTS <8 were significantly more likely to develop sICH than those with ASPECTS 8-10 (25% vs 3%, p = 0.004)., Conclusions: Eptifibatide may have a role in the management of acute stroke requiring carotid stenting. Caution may be required in those with established infarct on presentation imaging.

The clinical and research discipline of cough has grown substantially over the last two decades as methods to measure cough have developed and evolved. Cough can be thought of both as a symptom and an objectively observable pathophysiological phenomenon, two aspects whose interrelationship is complicated. The following review explores the varied methods to measuring cough, both subjective, patient-reported measures and objective approaches. Specifically, symptom scores, questionnaires of cough-related quality of life, and associated mental health impacts of chronic cough are addressed, as are developments in measuring cough frequency, cough intensity, cough reflex sensitivity, and cough suppressibility. Measuring patient reported cough-severity with a simple visual analogue scale increasingly appears to be justified, but has limitations. The Leicester Cough Questionnaire has been widely used for twenty years, within varied settings and diseases, in research and routine clinical practice, and captures cough-related quality of life. Objective cough frequency has become the primary outcome measure for clinical trials of antitussives, and technology is now enabling the wider application of cough counting. Inhaled tussive challenge testing still has a role, including in the assessment of cough hypersensitivity, and in the identification of failure to supress cough. Ultimately, many measures have a contributory and complementary role, with differing merits in quantifying the multiple facets of cough, the complexity of which is being increasingly recognised., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-230/coif). The series “Novel Insights Into Chronic Cough” was commissioned by the editorial office without any funding or sponsorship. SSB has received personal fees from Merck, Bayer, Shionogi, Bellus, Nerre, Gala and Trevi, research grants from Merck, fees for LCM cough monitoring analysis and LCQ. The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Control of cell size and morphology is of paramount importance for bacterial fitness. In the opportunistic pathogen Enterococcus faecalis, the formation of diplococci and short cell chains facilitates innate immune evasion and dissemination in the host. Minimisation of cell chain size relies on the activity of a peptidoglycan hydrolase called AtlA, dedicated to septum cleavage. To prevent autolysis, AtlA activity is tightly controlled, both temporally and spatially. Here, we show that the restricted localization of AtlA at the septum occurs via an unexpected mechanism. We demonstrate that the C-terminal LysM domain that allows the enzyme to bind peptidoglycan is essential to target this enzyme to the septum inside the cell before its translocation across the membrane. We identify a membrane-bound cytoplasmic protein partner (called AdmA) involved in the recruitment of AtlA via its LysM domains. This work reveals a moonlighting role for LysM domains, and a mechanism evolved to restrict the subcellular localization of a potentially lethal autolysin to its site of action., (© 2023. The Author(s).)

Background: There is a clinical need for a guide catheter with combined stability and navigability, which can be used in a biaxial system for neuroendovascular procedures in place of triaxial systems., Objective: To assess the safety and feasibility of the Q'Apel Medical Wahoo Hybrid Access System, a dual-mode 0.072″ internal diameter guide catheter, in a range of neuroendovascular procedures., Methods: We performed a retrospective analysis of consecutive cases from a high-volume tertiary center in which the Wahoo Hybrid Access System was used as the guide catheter. Characteristics of the patients, vascular lesions, procedure, and procedural complications were assessed., Results: A total of 102 patients were included for analysis. Vascular lesions were in the anterior circulation in 90 of 102 (88%), and posterior circulation in 12 of 102 (12%). Eighty-four cases were ruptured or unruptured aneurysm embolization procedures, the majority being balloon-assisted coiling (42%) and flow diversion (42%). All cases, including flow diversion, were performed as a biaxial system. There were no instances of prolapse of the catheter beyond the arterial segment in which it was initially placed. The procedure was able to be performed to completion in 101 of 102 (99%) cases. Thromboembolic complications occurred in 5 of 102 (5%); causality in two cases was unrelated to the guide catheter, and three were indeterminate., Conclusions: The Wahoo guide catheter is safe and feasible when used in a variety of neuroendovascular procedures. It can accommodate a range of devices, can be safely navigated into distal vasculature, and provides support for a range of procedures, including those which traditionally require triaxial support.

Background: Radiomics allows information not readily available to the naked eye to be extracted from high resolution imaging modalities such as CT. Identifying that a cancer has already metastasised at the time of presentation through a radiomic signature will affect the treatment pathway. The ability to recognise the existence of metastases earlier will have a significant impact on the survival outcomes., Aim: To create a novel radiomic signature using textural analysis in the evaluation of synchronous liver metastases in colorectal cancer., Methods: CT images at baseline and subsequent surveillance over a 5-year period of patients with colorectal cancer were processed using textural analysis software. Comparison was made between those patients who developed liver metastases and those that remained disease free to detect differences in the 'texture' of the liver., Results: A total of 24 patients were divided into two matched groups for comparison. Significant differences between the two groups scores when using the textural analysis programme were found on coarse filtration (p = 0.044). Patients that went on to develop metastases an average of 18 months after presentation had higher levels of hepatic heterogeneity on CT., Conclusion: This initial study demonstrates the potential of using a textural analysis programme to build a radiomic signature to predict the development of hepatic metastases in rectal cancer patients otherwise thought to have clear staging CT scans at time of presentation., (© 2022 The Authors.)

Many software solutions are available for proteomics and glycomics studies, but none are ideal for the structural analysis of peptidoglycan (PG), the essential and major component of bacterial cell envelopes. It icomprises glycan chains and peptide stems, both containing unusual amino acids and sugars. This has forced the field to rely on manual analysis approaches, which are time-consuming, labour-intensive, and prone to error. The lack of automated tools has hampered the ability to perform high-throughput analyses and prevented the adoption of a standard methodology. Here, we describe a novel tool called PGFinder for the analysis of PG structure and demonstrate that it represents a powerful tool to quantify PG fragments and discover novel structural features. Our analysis workflow, which relies on open-access tools, is a breakthrough towards a consistent and reproducible analysis of bacterial PGs. It represents a significant advance towards peptidoglycomics as a full-fledged discipline., Competing Interests: AP, RT, AR, MA, DL, IG, MC, SM none, AA None, AN Andrew Nichols is affiliated with Protein Metrics Inc. The author has no other competing interests to declare, MB Marshall Bern is affiliated with Protein Metrics Inc. The author has no other competing interests to declare, (© 2021, Patel et al.)

Cough reflex hypersensitivity and impaired cough suppression are features of chronic refractory cough (CRC). Little is known about cough suppression and cough reflex hypersensitivity in cough associated with chronic obstructive pulmonary disease (COPD). This study investigated the ability of patients with COPD to suppress cough during a cough challenge test in comparison to patients with CRC and healthy subjects. This study also investigated whether cough reflex hypersensitivity is associated with chronic cough in COPD.Participants with COPD (n=27) and CRC (n=11) and healthy subjects (n=13) underwent capsaicin challenge tests with and without attempts to self-suppress cough in a randomised order over two visits, 5 days apart. For patients with COPD, the presence of self-reported chronic cough was documented, and objective 24-h cough frequency was measured.Amongst patients with COPD, those with chronic cough (n=16) demonstrated heightened cough reflex sensitivity compared to those without chronic cough (n=11): geometric mean±sd capsaicin dose thresholds for five coughs (C5) 3.36±6.88 µmol·L -1 versus 44.50±5.90 µmol·L -1 , respectively (p=0.003). Participants with CRC also had heightened cough reflex sensitivity compared to healthy participants: geometric mean±sd C5 3.86±5.13 µmol·L -1 versus 45.89±3.95 µmol·L -1 , respectively (p<0.001). Participants with COPD were able to suppress capsaicin-evoked cough, regardless of the presence or absence of chronic cough: geometric mean±sd capsaicin dose thresholds for 5 coughs without self-suppression attempts (C5) and with (CS5) were 3.36±6.88 µmol·L -1 versus 12.80±8.33 µmol·L -1 (p<0.001) and 44.50±5.90 µmol·L -1 versus 183.2±6.37 µmol·L -1 (p=0.006), respectively. This was also the case for healthy participants (C5 versus CS5: 45.89±3.95 µmol·L -1 versus 254.40±3.78 µmol·L -1 , p=0.033), but not those with CRC, who were unable to suppress capsaicin-evoked cough (C5 versus CS5: 3.86±5.13 µmol·L -1 versus 3.34±5.04 µmol·L -1 , p=0.922). C5 and CS5 were associated with objective 24-h cough frequency in patients with COPD: ρ= -0.430, p=0.036 and ρ= -0.420, p=0.041, respectively.Patients with COPD-chronic cough and CRC both had heightened cough reflex sensitivity but only patients with CRC were unable to suppress capsaicin-evoked cough. This suggests differing mechanisms of cough between patients with COPD and CRC, and the need for disease-specific approaches to its management., Competing Interests: Conflict of interest: P.S.P. Cho reports a grant from Merck, outside the submitted work. Conflict of interest: H.V. Fletcher has nothing to disclose. Conflict of interest: I.S. Patel has nothing to disclose. Conflict of interest: R.D. Turner has nothing to disclose. Conflict of interest: C.J. Jolley has nothing to disclose. Conflict of interest: S.S. Birring reports grants from Merck, and personal fees from Merck, Bayer, Shionogi, Bellus, Nerre, Nocion and Boehringer Ingelheim, outside the submitted work., (Copyright ©ERS 2021.)

The primary structural component of the bacterial cell wall is peptidoglycan, which is essential for viability and the synthesis of which is the target for crucial antibiotics 1,2 . Peptidoglycan is a single macromolecule made of glycan chains crosslinked by peptide side branches that surrounds the cell, acting as a constraint to internal turgor 1,3 . In Gram-positive bacteria, peptidoglycan is tens of nanometres thick, generally portrayed as a homogeneous structure that provides mechanical strength 4-6 . Here we applied atomic force microscopy 7-12 to interrogate the morphologically distinct Staphylococcus aureus and Bacillus subtilis species, using live cells and purified peptidoglycan. The mature surface of live cells is characterized by a landscape of large (up to 60 nm in diameter), deep (up to 23 nm) pores constituting a disordered gel of peptidoglycan. The inner peptidoglycan surface, consisting of more nascent material, is much denser, with glycan strand spacing typically less than 7 nm. The inner surface architecture is location dependent; the cylinder of B. subtilis has dense circumferential orientation, while in S. aureus and division septa for both species, peptidoglycan is dense but randomly oriented. Revealing the molecular architecture of the cell envelope frames our understanding of its mechanical properties and role as the environmental interface 13,14 , providing information complementary to traditional structural biology approaches.

Infectious diseases (exacerbated by antimicrobial resistance) cause death, loss of quality of life and economic burden globally. Materials with inherent antimicrobial properties offer the potential to reduce the spread of infection through transfer via surfaces or solutions, or to directly reduce microbial numbers in a host if used as implants. Additive Manufacturing (AM) techniques offer shorter supply chains, faster delivery, mass customisation and reduced unit costs, as well as highly complicated part geometries which are potentially harder to clean and sterilise. Here, we present a new approach to introducing antibacterial properties into AM, using Laser Sintering, by combining antimicrobial and base polymer powders prior to processing. We demonstrate that the mechanical properties of the resultant composite parts are similar to standard polymer parts and reveal the mode of the antibacterial activity. We show that antibacterial activity is modulated by the presence of obstructing compounds in different experimental media, which will inform appropriate use cases. We show that the material is not toxic to mammalian cells. This material could be quickly used for commercial products, and our approach could be adopted more generally to add new functionality to Laser Sintered parts.

Background and Purpose: The impact of increased aneurysm packing density on angiographic outcomes has not been studied in a randomized trial. We sought to determine the potential for larger caliber coils to achieve higher packing densities and to improve the angiographic results of embolization of intracranial aneurysms at 1 year., Materials and Methods: Does Embolization with Larger Coils Lead to Better Treatment of Aneurysms (DELTA) was an investigator-initiated multicenter prospective, parallel, randomized, controlled clinical trial. Patients had 4- to 12-mm unruptured aneurysms. Treatment allocation to either 15- (experimental) or 10-caliber coils (control group) was randomized 1:1 using a Web-based platform. The primary efficacy outcome was a major recurrence or a residual aneurysm at follow-up angiography at 12 ± 2 months adjudicated by an independent core lab blinded to the treatment allocation. Secondary outcomes included indices of treatment success and standard safety outcomes. Recruitment of 564 patients was judged necessary to show a decrease in poor outcomes from 33% to 20% with 15-caliber coils., Results: Funding was interrupted and the trial was stopped after 210 patients were recruited between November 2013 and June 2017. On an intent-to-treat analysis, the primary outcome was reached in 37 patients allocated to 15-caliber coils and 36 patients allocated to 10-caliber coils (OR = 0.931; 95% CI, 0.528-1.644; P  = .885). Safety and other clinical outcomes were similar. The 15-caliber coil group had a higher mean packing density (37.0% versus 26.9%, P  = .0001). Packing density had no effect on the primary outcome when adjusted for initial angiographic results (OR = 1.001; 95% CI, 0.981-1.022; P  = .879)., Conclusions: Coiling of aneurysms randomized to 15-caliber coils achieved higher packing densities compared with 10-caliber coils, but this had no impact on the angiographic outcomes at 1 year, which were primarily driven by aneurysm size and initial angiographic results., (© 2020 by American Journal of Neuroradiology.)

Functional brain imaging in individuals with chronic cough demonstrates reduced activation in cortical regions associated with voluntary cough suppression. Little is known about the ability of patients with chronic cough to suppress cough. This study aimed to compare the ability to voluntarily suppress cough during inhaled capsaicin challenge in participants with chronic refractory cough with that in healthy controls. In addition, this study aimed to assess the repeatability of capsaicin challenge test with voluntary cough suppression.Participants with chronic refractory cough and healthy controls underwent inhaled capsaicin challenge tests while attempting to suppress their cough responses. After 5 days, either a conventional capsaicin challenge test with no cough suppression attempt, or a repeat test with an attempt at cough suppression was performed. Threshold capsaicin concentrations required to elicit one, two and five coughs were calculated by interpolation. Objective 24-h cough frequency was measured in individuals with chronic refractory cough.Healthy controls were able to suppress capsaicin-evoked cough while participants with chronic refractory cough were not. Geometric mean±sd capsaicin dose thresholds for five coughs with (CS5) and without (C5) suppression attempts were 254.40±3.78 versus 45.89±3.95 µmol·L -1 , respectively, in healthy controls (p=0.033) and 3.34±5.04 versus 3.86±5.13 µmol·L -1 , respectively, in participants with chronic refractory cough (p=0.922). Capsaicin dose thresholds for triggering five coughs with self-attempted cough suppression were significantly lower in participants with chronic refractory cough than in healthy controls; geometric mean±sd 4.94±4.43 versus 261.10±4.34 µmol·L -1 , respectively; mean difference (95% CI) 5.72 (4.54-6.91) doubling doses (p<0.001). Repeatability of cough suppression test in both patients and healthy controls was high; intraclass correlation coefficients of log(CS5) values 0.81 and 0.87, respectively. CS5 was associated with objective cough frequency (ρ=-0.514, p=0.029).Participants with chronic refractory cough were less able to voluntarily suppress capsaicin-evoked cough compared to healthy controls. This may have important implications for the pathophysiology and treatment of chronic cough., Competing Interests: Conflict of interest: P.S.P. Cho reports a grant from Merck outside the submitted work. Conflict of interest: H.V. Fletcher has nothing to disclose. Conflict of interest: R.D. Turner has nothing to disclose. Conflict of interest: C.J. Jolley has nothing to disclose. Conflict of interest: S.S. Birring reports grants and personal fees for advisory board work from Merck, personal fees for advisory board work from Bayer, GSK, Menlo and Sanofi, and conference travel expenses from Boehringer Ingelheim, outside the submitted work., (Copyright ©ERS 2019.)

Setting: Although cough in tuberculosis (TB) is presumed to be important for transmission, there is little objective supporting evidence., Objective: To describe 24-h cough frequency in a group with TB, and investigate associations with household rates of infection., Design: Patients with a new diagnosis of pulmonary TB underwent 24-h cough frequency measurement at or just before initiation of anti-tuberculosis treatment. A group with latent Mycobacterium tuberculosis infection (LTBI) acted as controls. Rates of infection among household contacts of sputum smear-positive TB were measured using the interferon-gamma release assay and the tuberculin skin test, and compared with variables relating to the contacts themselves, and to the index case, including cough frequency., Results: Daily cough frequency in TB patients (n = 44) was variable (geometric mean [GM] 174, interquartile range [IQR] 68-475 coughs/24 h), higher than in LTBI (n = 17; GM 19 coughs/24 h, IQR 8-53; P < 0.001), and higher during the day than overnight (GM 8.9 coughs/h, IQR 4.1-19.0 vs. GM 2.9 coughs/h, IQR 0.7-13.4; P < 0.0001). Also, 24-h cough frequency in TB was associated with sputum smear status (P = 0.040), but not smoking (P = 0.475). Multivariable logistic regression confirmed that infection in contacts was independently associated with index case sputum smear grade (P = 0.014) and cough frequency (P = 0.022)., Conclusion: Measurement of 24-h cough frequency in pulmonary TB helps predict infectiousness and transmission patterns.

Biopolymer composite cell walls maintain cell shape and resist forces in plants, fungi and bacteria. Peptidoglycan, a crucial antibiotic target and immunomodulator, performs this role in bacteria. The textbook structural model of peptidoglycan is a highly ordered, crystalline material. Here we use atomic force microscopy (AFM) to image individual glycan chains in peptidoglycan from Escherichia coli in unprecedented detail. We quantify and map the extent to which chains are oriented in a similar direction (orientational order), showing it is much less ordered than previously depicted. Combining AFM with size exclusion chromatography, we reveal glycan chains up to 200 nm long. We show that altered cell shape is associated with substantial changes in peptidoglycan biophysical properties. Glycans from E. coli in its normal rod shape are long and circumferentially oriented, but when a spheroid shape is induced (chemically or genetically) glycans become short and disordered.

Background: Facet joint pain contributes significantly to lower back pain. Image intensifier x-ray guidance is used to locate the facet joints. This can either be in the oblique "Scotty dog" or antero-posterior views. The aim is to investigate whether improved visualisation of facet joints using the oblique method would increase the accuracy of the injection and hence lead to enhanced pain relief effect when compared to AP views in Lumbar facet joints., Methods: Single centre, single blinded. A total of 42 consecutive patients were recruited between December 2014 and March 2015 at Colchester General Hospital. Patients randomly allocated into facet joint injections using the oblique or AP projection. Pre-operatively the patients were asked to rate their back pain using a numerical 11 point pain rating scale in the questionnaire. Post-operatively patients were seen at 6 weeks and once again were asked to fill out the afore mentioned questionnaire. The results were collated and statistical analysis performed using Microsoft Excel., Results: 29 patients returned their post-op questionnaire at approximately 6 weeks post-op. 12 patients had oblique view and 17 patients had AP view. There was a statistically significant difference in the pain scores comparing pre and post op scores for both the Oblique and AP groups. However, there was no significant difference when comparing the post-op pain scores or the absolute changes in pain scores between the two groups., Discussion: Spinal facet joint injections provide significant relief at the 6 week post-op follow up with no difference between the oblique and AP techniques.

The bacterial cytoplasmic membrane is the interface between the cell and its environment, with multiple membrane proteins serving its many functions. However, how these proteins are organised to permit optimal physiological processes is largely unknown. Based on our initial findings that 2 phospholipid biosynthetic enzymes (PlsY and CdsA) localise heterogeneously in the membrane of the bacterium Staphylococcus aureus, we have analysed the localisation of other key membrane proteins. A range of protein fusions were constructed and used in conjunction with quantitative image analysis. Enzymes involved in phospholipid biosynthesis as well as the lipid raft marker FloT exhibited a heterogeneous localisation pattern. However, the secretion associated SecY protein, was more homogeneously distributed in the membrane. A FRET-based system also identified novel colocalisation between phospholipid biosynthesis enzymes and the respiratory protein CydB revealing a likely larger network of partners. PlsY localisation was found to be dose dependent but not to be affected by membrane lipid composition. Disruption of the activity of the essential cell division organiser FtsZ, using the inhibitor PC190723 led to loss of PlsY localisation, revealing a link to cell division and a possible role for FtsZ in functions not strictly associated with septum formation.

The bacterial cell wall is essential for viability, but despite its ability to withstand internal turgor must remain dynamic to permit growth and division. Peptidoglycan is the major cell wall structural polymer, whose synthesis requires multiple interacting components. The human pathogen Staphylococcus aureus is a prolate spheroid that divides in three orthogonal planes. Here, we have integrated cellular morphology during division with molecular level resolution imaging of peptidoglycan synthesis and the components responsible. Synthesis occurs across the developing septal surface in a diffuse pattern, a necessity of the observed septal geometry, that is matched by variegated division component distribution. Synthesis continues after septal annulus completion, where the core division component FtsZ remains. The novel molecular level information requires re-evaluation of the growth and division processes leading to a new conceptual model, whereby the cell cycle is expedited by a set of functionally connected but not regularly distributed components., Competing Interests: VL, KW, RT, BC, CW, SF, FG, AW, ML, NO, AC, SM, SJ, SF No competing interests declared, (© 2018, Lund et al.)

Background and Purpose: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils., Materials and Methods: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2)., Results: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%-53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%-61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838-2.295; P = .20) and in 49.0% (95% CI, 38.8%-59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%-52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428-1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011)., Conclusions: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum., (© 2017 by American Journal of Neuroradiology.)

Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAP r ]) reported in MRSA is frequently accompanied by a paradoxical decrease in β-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and β-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAP r MRSA strains. However, the mechanisms underlying the interactions between DAP and β-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in β-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of β-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and β-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a., (Copyright © 2016 American Society for Microbiology.)

Acute ischemic stroke (AIS) in the pediatric population is rare. Furthermore, it is common for physicians to take significantly longer diagnosing a posterior circulation stroke in a child than in an adult. There are increasing case reports in the literature of treating AIS in children with intravenous tissue plasminogen activator, intra-arterial thrombolysis, and/or mechanical thrombectomy. We present the first case of pediatric AIS treated using a direct aspiration first pass technique (ADAPT) as a means of mechanical thrombectomy., (2016 BMJ Publishing Group Ltd.)

Chronic cough is common in the community and can cause significant morbidity. It is not clear how closely treatment guidelines are used in general practice, or how often specialist referral is indicated. We aimed to assess the management of chronic cough in primary care before referral to a cough clinic, and to assess the outcome of managing chronic cough with an approach of simple investigation and empirical treatment trials. Data were extracted from the records of all patients attending a district general hospital respiratory clinic over a two-year period with isolated chronic cough lasting ⩾8 weeks. The clinic assessed symptoms with a cough-severity visual analogue scale and the Leicester Cough Questionnaire. Among 266 patients, the most frequent diagnoses were asthma (29%), gastro-oesophageal reflux (22%) and angiotensin-converting enzyme inhibitor use (14%). In all, 12% had unexplained chronic cough. Common diagnoses had often not been excluded in primary care: only 21% had undergone spirometry, 86% had undergone chest radiography and attempts to exclude asthma with corticosteroids had been made only in 39%. In the clinic few investigations were conducted that were not available in primary care. Substantial improvements in symptoms occurred with a median (interquartile range) total of 2 (2-3) clinic visits. We estimated that 87% of patients could have been managed solely in primary care; we did not identify distinguishing characteristics among this group. Most cases of chronic cough referred to secondary care could be managed with a simple and systematic approach, which is potentially transferrable to a community setting.

Background and Purpose: Patients with posterior circulation strokes have been excluded from recent randomized endovascular stroke trials. We reviewed the recent multicenter experience with endovascular treatment of posterior circulation strokes to identify the clinical, radiographic, and procedural predictors of successful recanalization and good neurological outcomes., Methods: We performed a multicenter retrospective analysis of consecutive patients with posterior circulation strokes, who underwent thrombectomy with stent retrievers or primary aspiration thrombectomy (including A Direct Aspiration First Pass Technique [ADAPT] approach). We correlated clinical and radiographic outcomes with demographic, clinical, and technical characteristics., Results: A total of 100 patients were included in the final analysis (mean age, 63.5±14.2 years; mean admission National Institutes of Health Stroke Scale score, 19.2±8.2). Favorable clinical outcome at 3 months (modified Rankin Scale score ≤2) was achieved in 35% of patients. Successful recanalization and shorter time from stroke onset to the start of the procedure were significant predictors of favorable clinical outcome at 90 days. Stent retriever and aspiration thrombectomy as primary treatment approaches showed comparable procedural and clinical outcomes. None of the baseline advanced imaging modalities (magnetic resonance imaging, computed tomographic perfusion, or computed tomography angiography assessment of collaterals) showed superiority in selecting patients for thrombectomy., Conclusions: Time to the start of the procedure is an important predictor of clinical success after thrombectomy in patients with posterior circulation strokes. Both stent retriever and aspiration thrombectomy as primary treatment approaches are effective in achieving successful recanalization., (© 2016 American Heart Association, Inc.)

Unlabelled: Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of Staphylococcus aureus, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan., Importance: Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using Staphylococcus aureus, we have identified a set of enzymes that are critical for cellular enlargement. We show that these enzymes are required for normal growth and define the mechanism through which cellular enlargement is accomplished, i.e., by breaking bonds in the peptidoglycan, which reduces the stiffness of the cell wall, enabling it to stretch and expand, a process that is likely to be fundamental to many bacteria., (Copyright © 2015 Wheeler et al.)

The polyphenol (-)-epicatechin gallate (ECg) inserts into the cytoplasmic membrane (CM) of methicillin-resistant Staphylococcus aureus (MRSA) and reversibly abrogates resistance to β-lactam antibiotics. ECg elicits an increase in MRSA cell size and induces thickened cell walls. As ECg partially delocalizes penicillin-binding protein PBP2 from the septal division site, reduces PBP2 and PBP2a complexation and induces CM remodelling, we examined the impact of ECg membrane intercalation on phospholipid distribution across the CM and determined if ECg affects the equatorial, orthogonal mode of division. The major phospholipids of the staphylococcal CM, lysylphosphatidylglycerol (LPG), phosphatidylglycerol (PG), and cardiolipin (CL), were distributed in highly asymmetric fashion; 95%-97% of LPG was associated with the inner leaflet whereas PG (~90%) and CL (~80%) were found predominantly in the outer leaflet. ECg elicited small, significant changes in LPG distribution. Atomic force microscopy established that ECg-exposed cells divided in similar fashion to control bacteria, with a thickened band of encircling peptidoglycan representing the most recent plane of cell division, less distinct ribs indicative of previous sites of orthogonal division and concentric rings and "knobbles" representing stages of peptidoglycan remodelling during the cell cycle. Preservation of staphylococcal membrane lipid asymmetry and mode of division in sequential orthogonal planes appear key features of ECg-induced stress.

The nanoscale mechanical properties of live Staphylococcus aureus cells during different phases of growth were studied by atomic force microscopy. Indentation to different depths provided access to both local cell wall mechanical properties and whole-cell properties, including a component related to cell turgor pressure. Local cell wall properties were found to change in a characteristic manner throughout the division cycle. Splitting of the cell into two daughter cells followed a local softening of the cell wall along the division circumference, with the cell wall on either side of the division circumference becoming stiffer. Once exposed, the newly formed septum was found to be stiffer than the surrounding, older cell wall. Deeper indentations, which were affected by cell turgor pressure, did not show a change in stiffness throughout the division cycle, implying that enzymatic cell wall remodeling and local variations in wall properties are responsible for the evolution of cell shape through division., (Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Cough causes morbidity and transmits disease yet has been under-researched. The best method for recognising and counting coughs remains unclear. We tested the accuracy of the human ear and measured the influence of visual data on cough counting. We also evaluated PulmoTrack®, a potentially fully-automated cough monitor., Methods: Consistency amongst listeners and the effect of visual data: Three 14–22-min sequences containing 45–79 coughs were played to 15 respiratory physicians on at least two occasions. Only sound was played on the first occasions but on the final occasion a simultaneous display of audio activity was included. Counts of cough sounds across methods and listeners were compared. Evaluation of PulmoTrack®: 20-h recordings were made from 10 patients with cough. Automated counts were compared with assessment by one investigator., Results: Agreement among listeners was high. The intraclass correlation coefficient (ICC) for cough counts by ear alone was 0.89 (95% CI, 0.65–1.00). With a concurrent visual display of sound amplitude it was 0.94 (0.80–1.00). 4.8% (0.6–9.5) fewer coughs were counted using visual data than by listening alone (mean [SD] total coughs: 190.2 [3.4] vs 200.7 [14.6]; p = 0.04). Cough frequencies reported by PulmoTrack® and the researcher differed substantially (ICC 0.23, −0.51 to 0.34, p = 0.87); PulmoTrack® had a sensitivity of 26% for detecting coughs identified by ear., Conclusion: Coughs are well recognised by different listeners. The method used to count coughs should be clearly described as visual information has a significant influence. Non-automated cough counting remains the gold standard method of quantifying cough.

Bacterial cell division is a fundamental process that requires the coordinated actions of a number of proteins which form a complex macromolecular machine known as the divisome. The membrane-spanning proteins DivIB and its orthologue FtsQ are crucial divisome components in Gram-positive and Gram-negative bacteria respectively. However, the role of almost all of the integral division proteins, including DivIB, still remains largely unknown. Here we show that the extracellular domain of DivIB is able to bind peptidoglycan and have mapped the binding to its β subdomain. Conditional mutational studies show that divIB is essential for Staphylococcus aureus growth, while phenotypic analyses following depletion of DivIB results in a block in the completion, but not initiation, of septum formation. Localisation studies suggest that DivIB only transiently localises to the division site and may mark previous sites of septation. We propose that DivIB is required for a molecular checkpoint during division to ensure the correct assembly of the divisome at midcell and to prevent hydrolytic growth of the cell in the absence of a completed septum., (© 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Background and Purpose: Some patients with large or recurrent aneurysms may be at increased risk of recurrence postcoiling. The Patients Prone to Recurrence after Endovascular Treatment (PRET) trial was designed to assess whether hydrogel coils were superior to platinum coils in these high-risk patients. This article reports periprocedural safety and operator-assessed angiographic results from the PRET trial., Materials and Methods: PRET was a pragmatic, multicenter, randomized controlled trial. Patients had ≥10-mm aneurysms (PRET-1) or a major recurrence after coiling of an aneurysm of any size (PRET-2). Patients were randomly allocated to hydrogel or control arms (any platinum coil) by using concealed allocation with minimization. Assist devices could be used as clinically required. Aneurysms could be unruptured or recently ruptured. Analyses were on an intent-to-treat basis., Results: Four hundred forty-seven patients were recruited (250 PRET-1; 197 PRET-2). Aneurysms were recently ruptured in 29% of PRET-1 and 4% of PRET-2 patients. Aneurysms were ≥10 mm in all PRET-1 and in 50% of PRET-2 patients. They were wide-neck (≥4 mm) in 70% and in the posterior circulation in 24% of patients. Stents were used in 28% of patients (35% in PRET-2). Coiling was successful in 98%. Adverse events occurred in 28 patients with hydrogel and 23 with platinum coils. Mortality (n=2, unrelated to treatment) and morbidity (defined as mRS>2 at 1 month) occurred in 25 patients (5.6%; 12 hydrogel, 13 platinum), related to treatment in 10 (4 hydrogel; 6 platinum) (or 2.3% of 444 treated patients). No difference was seen between hydrogel and platinum for any of the indices used to assess safety up to at least 30 days after treatment. At 1 month, 95% of patients were home with a good outcome (mRS≤2 or unchanged). Operator-assessed angiographic outcomes were satisfactory (complete occlusion or residual neck) in 339 of 447 or 76.4% of patients, with no significant difference between groups., Conclusions: Endovascular treatment of large and recurrent aneurysms can be performed safely with platinum or hydrogel coils., (© 2014 by American Journal of Neuroradiology.)

A patient presented with headaches and was found to have a colloid cyst in the third ventricle and ventriculomegaly. The patient underwent endoscopic colloid cyst resection and third ventriculostomy without incidence. Prior to emergence, a blown right pupil was acutely noted, and bright red blood emanated from the ventricular drain that was routinely placed in the endoscopy tract at the conclusion of the procedure. CTangiography demonstrated active extravasation from the pre-pontine cistern into the third ventricle and subarachnoid space. Emergency DSA confirmed active extravasation from an avulsed thalamoperforator arising from the proximal right P1 posterior cerebral artery, which was immediately embolized without incident., (2014 BMJ Publishing Group Ltd.)

Peptidoglycan performs the essential role of resisting turgor in the cell walls of most bacteria. It determines cell shape, and its biosynthesis is the target for many important antibiotics. The fundamental chemical building blocks of peptidoglycan are conserved: repeating disaccharides cross-linked by peptides. However, these blocks come in many varieties and can be assembled in different ways. So beyond the fundamental similarity, prodigious chemical, organizational and architectural diversity is revealed. Here, we track the evolution of our current understanding of peptidoglycan and underpinning technical and methodological developments. The origin and function of chemical diversity is discussed with respect to some well-studied example species. We then explore how this chemistry is manifested in elegant and complex peptidoglycan organization and how this is interpreted in different and sometimes controversial architectural models. We contend that emerging technology brings about the possibility of achieving a complete understanding of peptidoglycan chemistry, through architecture, to the way in which diverse species and populations of cells meet the challenges of maintaining viability and growth within their environmental niches, by exploiting the bioengineering versatility of peptidoglycan., (© 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

The use of two stents in a "Y" configuration (Y-stenting) to assist with coil embolization of complex bifurcation aneurysms has been accepted as an alternative to clip reconstruction of a select subset of challenging aneurysms. We review the risks associated with Y-stenting, including its procedural complication rates, angiographic occlusion rates, rerupture, and retreatment rates.

Cellular integrity and morphology of most bacteria is maintained by cell wall peptidoglycan, the target of antibiotics essential in modern healthcare. It consists of glycan strands, cross-linked by peptides, whose arrangement determines cell shape, prevents lysis due to turgor pressure and yet remains dynamic to allow insertion of new material, and hence growth. The cellular architecture and insertion pattern of peptidoglycan have remained elusive. Here we determine the peptidoglycan architecture and dynamics during growth in rod-shaped Gram-negative bacteria. Peptidoglycan is made up of circumferentially oriented bands of material interspersed with a more porous network. Super-resolution fluorescence microscopy reveals an unexpected discontinuous, patchy synthesis pattern. We present a consolidated model of growth via architecture-regulated insertion, where we propose only the more porous regions of the peptidoglycan network that are permissive for synthesis.

Nitrofurantoin has well-described associations with a range of adverse pulmonary effects. We report the case of a 72-year old woman with relapsing pneumonitis secondary to the intermittent use of nitrofurantoin, a pattern of disease not well-represented in the literature. The case is also noteworthy as the diagnosis was initially overlooked due to the circumstances of the patient's medication use. Lung biopsy was avoided by detailed history taking.

A 43-year-old patient with a basilar apex aneurysm had a 4.5-mm x 14-mm Enterprise stent placed from the midbasilar artery to the left P1 segment of the posterior cerebral artery. The patient experienced vertigo 4 months after stent placement and 1 week after stopping clopidogrel. At 5 months postembolization, angiography showed stent migration into the proximal basilar artery. This is the first described case of the spontaneous delayed migration of a self-expanding intracranial microstent.

Marginal sinus fistulas (MSFs) are uncommon vascular anomalies. Occasionally, the dominant venous drainage is forced retrograde up the inferior petrosal sinus and into the cavernous sinus, causing chemosis, proptosis, and ocular hypertension, mimicking a carotid cavernous fistula. This atypical clinical presentation may lead to misdiagnosis and inappropriate hazardous treatment of an MSF. Identifying the site of the fistula and understanding the anatomy of the venous drainage are critical in providing appropriate, safe, and efficacious endovascular treatment.

Case Description: A cohort of 35,200, 13-week-old, female rainbow trout at a fish farm was evaluated because of a 2-week history of anorexia and lethargy and a mortality rate of approximately 100 fish/d., Clinical Findings: Affected fish were lethargic and thin and had disequilibrium, bilateral exophthalmia, pale red gills and kidneys, red-tinged coelomic fluid, and pale brown livers. Some fish were differentially pigmented bilaterally. The presumptive diagnosis was bacterial or viral septicemia. The definitive diagnosis was rainbow trout fry syndrome caused by infection with Flavobacterium psychrophilum., Treatment and Outcome: A strategy for controlling the outbreak based on reducing pathogen numbers in affected tanks and reducing pathogen spread among tanks was developed. The option of treating with antimicrobial-medicated feed was discussed with the farmer, but was declined. After changes were made, mortality rate declined quickly, with no more deaths within 10 days after the initial farm visit., Clinical Relevance: Bacterial coldwater disease is the most common manifestation of infection with F psychrophilum in fingerling and adult rainbow trout. However, the organism can also cause rainbow trout fry syndrome. This condition should be included on a list of differential diagnoses for septicemia in hatchery-reared rainbow trout fry.

Scientists often develop techniques that have obvious benefits for patients but then find great difficulty in introducing them into the National Health Service-usually because the necessary finance does not seem to be available. This article provides a practical guide.

A single-ended, all-fiber polarimetric strain sensor with wide dynamic range and linearized response is described. Linear response is achieved by using a dual-wavelength technique, with modified pseudoheterodyne signal recovery. Single-valued, multiple-fringe phase tracking is obtained by using a binary signal division technique. An average strain sensitivity of 0.050 +/- 0.02 deg microepsilon(-1) cm(-1) is found for sensors that are surface adhered to cantilever beams. The sensor system is applied successfully to the measurement of the local orientation of a 1-m structural beam, with an accuracy of +/-0.02 deg of beam slope. Limitations on the applicability of this sensing technique are discussed.