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One of the main difficulties faced in treating gambling disorder is compliance with psychological treatment. Gambling takes many forms and can differ greatly in its features such as speed of play and skill requirements. The type of gambling a pathological gambler opts for may play a key role in treatment compliance. The aim of the present study was to determine whether within treatment seeking sample of gambling disorder clients, gambling activity has any correlation with their resultant treatment outcomes. The study incorporated 524 treatment-seeking individuals who are clients of the National Problem Gambling Clinic in London. All of the clients were assessed prior to treatment and fulfilled the Problem Gambling Severity Index criteria for problem gambling. Data concerning clients’ gambling behavior over the previous year was gathered using self-reports. Subsequently, the data was fitted to a multinomial logistic regression model, with the treatment outcome (i.e. pre-treatment dropouts, during treatment dropouts, and completed treatment) as the dependent variable and gambling behavior as the independent variable, whilst controlling for socio-demographic factors. The use of gaming machines was a significant predictor of dropping out pre-treatment (p < 0.05, RRR 1.616), whilst betting on sports events was a significant predictor of dropping out during treatment (p < 0.01, RRR 2.435). Treatment outcomes have been found to significantly differ based on participation in certain gambling activities. Further research into the salient features of these gambling activities may help to further explain pre-treatment and during treatment dropouts within this population.

Background: Paclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. Method(s): An international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Result(s): 44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed: [Table presented] Conclusion(s): Oraxol (oral paclitaxel + HM30181) given daily for 3 days can show bio-equivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 - 125%. Clinical trial identification: ACTRN 12615000894594. Legal entity responsible for the study: Athenex. Funding(s): Athenex. Disclosure: C.G.C.A. Jackson: Travel / Accommodation / Expenses: Athenex. N.A. Hung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zentech. D. Cutler: Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. D. Kramer: Full / Part-time employment: Athenex. J. Zhi: Full / Part-time employment: Athenex. W. Chan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. M.R. Kwan: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment: Athenex. C. Hung

Background: Paclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel andHM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. Method(s): An international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Result(s): 44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed: Conclusion(s): Oraxol (oral paclitaxel + HM30181) given daily for 3 days can show bioequivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 - 125%.

Background: Paclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. Method(s): An international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Result(s): 44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed: [Table presented] Conclusion(s): Oraxol (oral paclitaxel + HM30181) given daily for 3 days can show bio-equivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 - 125%. Clinical trial identification: ACTRN 12615000894594. Legal entity responsible for the study: Athenex. Funding(s): Athenex. Disclosure: C.G.C.A. Jackson: Travel / Accommodation / Expenses: Athenex. N.A. Hung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zentech. D. Cutler: Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. D. Kramer: Full / Part-time employment: Athenex. J. Zhi: Full / Part-time employment: Athenex. W. Chan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. M.R. Kwan: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment: Athenex. C. Hung

Background: Paclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel andHM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. Method(s): An international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80 mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Result(s): 44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed: Conclusion(s): Oraxol (oral paclitaxel + HM30181) given daily for 3 days can show bioequivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 - 125%.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these 'hit' materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions.

The Silyl-Modified Sakurai (SMS) reaction and its intramolecular variant, the ISMS cyclisation, are powerful methodologies that can provide easy access to a range of important subunits present in a variety of complex biologically active natural products.

The concise synthesis of the fully functionalised right-hand dihydropyran subunit of the antifungal antibiotic ambruticin (1), using the ISMS annulation as the key-step, is described.

The ISMS reaction has been used to efficiently construct the right-hand portion 3 of the antifungal antibiotic ambruticine 1.

Substituted tetrahydropyrans, spiroethers and spiroketals can be prepared in a single step using the ISMS reaction between the bis-silylated reagent 7b and aldehydes (acetals), ketones (ketals) and ortholactones respectively. This simple methodology was applied to the rapid synthesis of a pheromone containing a [4,5]-spiroketal unit.

The Long-Range Search Sonar Problem is aimed at providing answers to the many questions within the Navy regarding long-range-search possibilities using echo-ranging.

Bacterial attachment and subsequent biofilm formation are key challenges to the long term performance of many medical devices. Here, a high throughput approach coupled with the analysis of surface structure-property relationships using a chemometics approach has been developed to simultaneously investigate the interaction of bacteria with hundreds of polymeric materials on a microarray format. Using this system, a new group of materials comprising ester and hydrophobic moieties are identified that dramatically reduce the attachment of clinically relevant, pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and uropathogenic Escherichia coli). Hit materials coated on silicone catheters resulted in up to a 30 fold reduction in coverage compared to a commercial silver embedded catheter, which has been proven to half the incidence of clinically acquired infection. These polymers represent a new class of materials resistant to bacterial attachment that could not have been predicted from the current understanding of bacteria-surface interactions.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus.. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.

Prosthetic joint infection is usually caused by staphylococci. Among the coagulase-negative staphylococci, Staphylococcus lugdunensis is important because it behaves as a pathogen similar to S aureus. It also develops biofilms, and the biofilm phenotype can appear as small-colony variants. Although genetically indistinguishable, they differ in size and antibiotic susceptibility from the parent strain and are responsible for chronic persistent infection and failure of antibiotic treatment. They can also lead to misinterpretation of results. The patient reported here underwent total knee replacement and 2 years later presented with prosthetic joint infection. Tissue samples and prosthesis taken at revision grew S lugdunensis, the majority of which were small-colony variants. Recommendations are made for their detection and identification.

Objectives External Ventricular Drain (EVD) insertion is a common neurosurgical procedure. EVD- related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the United Kingdom (UK) and Ireland and determine key factors influencing the infection risk. Methods A prospective multi-centre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox Regression Model was used for multivariate analysis to calculate Hazard Ratios (HR). Results A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in-situ for 4700 days (median 8 days; interquartile range 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days [HR=2.47 (1.12-5.45); p=0.03], regular sampling (daily sampling [HR=4.73 (1.28-17.42), p=0.02] and alternate day sampling [HR=5.28 (2.25-12.38); p<0.01]). There was no association between catheter type or tunnelling distance and ERI. Conclusions In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.

Objectives To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Methods Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson’s Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Results Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. Conclusions JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections.

Catheter-associated urinary tract infection (CAUTI) is the commonest hospital-acquired infection, accounting for over 100,000 hospital admissions within the USA annually. Biomaterials and processes intended to reduce the risk of bacterial colonization of the catheters for long-term users have not been successful, mainly because of the need for long duration of activity in flow conditions. Here we report the results of impregnation of urinary catheters with a combination of rifampicin, sparfloxacin and triclosan. In flow experiments, the antimicrobial catheters were able to prevent colonization by common uropathogens Proteus mirabilis, Staphylococcus aureus and Escherichia coli for 7 to 12 weeks in vitro compared with 1–3 days for other, commercially available antimicrobial catheters currently used clinically. Resistance development was minimized by careful choice of antimicrobial combinations. Drug release profiles and distribution in the polymer, and surface analysis were also carried out and the process had no deleterious effect on the mechanical performance of the catheter or its balloon. The antimicrobial catheter therefore offers for the first time a means of reducing infection and its complications in long-term urinary catheter users.

OBJECT Recently concern has arisen over the effect of released antimicrobial agents from antibiotic-impregnated external ventricular drainage (EVD) catheters on the reliability of CSF culture for diagnosis of ventriculitis. The authors designed a laboratory study to investigate this possibility, and to determine whether there was also a risk of loss of bacterial viability when CSF samples were delayed in transport to the laboratory. METHODS Three types of commercially available antibiotic-impregnated EVD catheters were perfused with a suspension of bacteria (Staphylococcus epidermidis) over 21 days. Samples were analyzed for bacterial viability and for concentrations of antibiotics released from the catheters. The authors also investigated the effect on bacterial viability in samples stored at 18°C and 4°C to simulate delay in CSF samples reaching the laboratory for analysis. RESULTS Bacterial viability was significantly reduced in all 3 catheter types when sampled on Day 1, but this effect was not observed in later samples. The results were reflected in stored samples, with significant loss of viability in Day 1 samples but with little further loss of viable bacteria in samples obtained after this time point. All samples stored for 18 hours showed significant loss of viable bacteria. CONCLUSIONS While there were differences between the catheters, only samples taken on Day 1 showed a significant reduction in the numbers of viable bacteria after passing through the catheters. This reduction coincided with higher concentrations of antimicrobial agents in the first few hours after perfusion began. Similarly, bacterial viability declined significantly after storage of Day 1 samples, but only slightly in samples obtained thereafter. The results indicate that drugs released from these antimicrobial catheters are unlikely to affect the diagnosis of ventriculitis, as sampling for this purpose is not usually conducted in the first 24 hours of EVD.

Prosthetic joint infection is usually caused by staphylococci. Among the coagulase-negative staphylococci, Staphylococcus lugdunensis is important because it behaves as a pathogen similar to S aureus. It also develops biofilms, and the biofilm phenotype can appear as small-colony variants. Although genetically indistinguishable, they differ in size and antibiotic susceptibility from the parent strain and are responsible for chronic persistent infection and failure of antibiotic treatment. They can also lead to misinterpretation of results. The patient reported here underwent total knee replacement and 2 years later presented with prosthetic joint infection. Tissue samples and prosthesis taken at revision grew S lugdunensis, the majority of which were small-colony variants. Recommendations are made for their detection and identification.

Objectives External Ventricular Drain (EVD) insertion is a common neurosurgical procedure. EVD- related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the United Kingdom (UK) and Ireland and determine key factors influencing the infection risk. Methods A prospective multi-centre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox Regression Model was used for multivariate analysis to calculate Hazard Ratios (HR). Results A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in-situ for 4700 days (median 8 days; interquartile range 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days [HR=2.47 (1.12-5.45); p=0.03], regular sampling (daily sampling [HR=4.73 (1.28-17.42), p=0.02] and alternate day sampling [HR=5.28 (2.25-12.38); p<0.01]). There was no association between catheter type or tunnelling distance and ERI. Conclusions In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.

Bacterial attachment and subsequent biofilm formation are key challenges to the long term performance of many medical devices. Here, a high throughput approach coupled with the analysis of surface structure-property relationships using a chemometics approach has been developed to simultaneously investigate the interaction of bacteria with hundreds of polymeric materials on a microarray format. Using this system, a new group of materials comprising ester and hydrophobic moieties are identified that dramatically reduce the attachment of clinically relevant, pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and uropathogenic Escherichia coli). Hit materials coated on silicone catheters resulted in up to a 30 fold reduction in coverage compared to a commercial silver embedded catheter, which has been proven to half the incidence of clinically acquired infection. These polymers represent a new class of materials resistant to bacterial attachment that could not have been predicted from the current understanding of bacteria-surface interactions.

Objective Otitis media with effusion (OME), a common chronic childhood condition affecting hearing, is thought to be a result of bacterial infection, with biofilms recently implicated. Although bacterial DNA can be detected by polymerase chain reaction in 80% of patients, typically fewer than half of effusions are positive using standard culture techniques. We adopted an alternative approach to demonstrating bacteria in OME, using a bacterial viability stain and confocal laser scanning microscopy (CLSM): staining allows detection of live bacteria without requiring growth on culture, while CLSM allows demonstration of the three-dimensional structure typical of biofilms. Methods Effusion samples were collected at the time of ventilation tube insertion, analysed with CLSM and bacterial viability stain, and extended culture techniques performed with the intention of capturing all possible organisms. Results Sixty-two effusions (42 patients) were analysed: 28 (45.2%) were culture-positive, but 51 (82.3%) were CLSM-positive. Combining the two techniques demonstrated live bacteria in 57 (91.8%) samples. Using CLSM, bacteria exhibited biofilm morphology in 25 effusions and were planktonic in 26; the proportion of samples exhibiting biofilm morphology was similar in the culture-positive and culture-negative groups (50.0% and 48.3%, respectively). Biofilm samples contained an average of 1.7 different bacterial isolates and planktonic samples 2.0, with the commonest bacteria identified being coagulase-negative staphylococci. Conclusion Live bacteria are present in most effusions, strongly suggesting that bacteria and biofilms are important in the aetiopathogenesis of OME.

Cerebrospinal fluid (CSF) shunts used to treat hydrocephalus have an overall infection rate of about 10% of operations. The commonest causative bacteria are Staphylococcus epidermidis, followed by Staphylococcus aureus and enterococci. Major difficulties are encountered with nonsurgical treatment due to biofilm development in the shunt tubing and inability to achieve sufficiently high CSF drug levels by intravenous administration. Recently, three cases of S. epidermidis CSF shunt infection have been treated by intravenous linezolid without surgical shunt removal, and we therefore investigated vancomycin and linezolid against biofilms of these bacteria in vitro. A continuous-perfusion model of shunt catheter biofilms was used to establish mature (1-week) biofilms of Staphylococcus aureus, Staphylococcus epidermidis (both methicillin resistant [MRSA and MRSE]), Enterococcus faecalis, and Enterococcus faecium. They were then “treated” with either vancomycin or linezolid in concentrations achievable in CSF for 14 days. The biofilms were then monitored for 1 week for eradication and for regrowth. Enterococcal biofilms were not eradicated by either vancomycin or linezolid. Staphylococcal biofilms were eradicated by both antibiotics after 2 days and did not regrow. No resistance was seen. Linezolid at concentrations achievable by intravenous or oral administration was able to eradicate biofilms of both S. epidermidis (MRSE) and S. aureus (MRSA). Neither vancomycin at concentrations achievable by intrathecal administration nor linezolid was able to eradicate enterococcal biofilms. It is hoped that these in vitro results will stimulate further clinical trials with linezolid, avoiding surgical shunt removal.

A 38yr-old male with a ventriculoatrial shunt presented with nonspecific symptoms (headache, back pain, night sweats) and inconclusive laboratory results. He showed an extremely high titre of antibody to Staphylococcus epidermidis which proved diagnostic of shunt infection. This was confirmed on shunt removal and he was successfully treated.

Shunt infection is a major complication affecting approximately 10% of procedures. Propionibacterium acnes, an anaerobic skin bacterium, is increasingly recognized as a shunt pathogen, causing up to 14% of infections. Though susceptible to penicillin and cephalosporins, P. acnes shunt infections are not preventable by means of perioperative prophylaxis, due to poor cerebrospinal fluid penetration. Antimicrobial shunts with activity against staphylococci are available, but their activity against P. acnes is unknown, and the study was designed to determine this. Three methods of evaluation were used in order to determine the emergence of resistance when exposure is to high inocula for long periods, the time taken to kill 100% of the bacteria attached to the shunt, and the duration of activity under constant flow conditions with repeated bacterial challenge. Despite repeated exposure to high bacterial inocula over 70 days, no resistance was seen. The time taken to kill all attached bacteria, 96 h, was twice that taken to kill attached staphylococci. Nevertheless, under constant flow conditions with repeated challenges, the antimicrobial catheters resisted colonization by P. acnes for 56 days. Using tests that were designed to be clinically predictive when done together, the results suggest that the antimicrobial catheters will be able to prevent colonization of hydrocephalus shunts by P. acnes.

The relationship between Crime and gambling is well established, however few studies have examined offending specifically to finance gambling within a UK gambling treatment-seeking population. 1226 treatment-seeking gamblers completed the Problem Gambling Severity Index (PGSI), Patient Health Questionnaire, and the Generalized Anxiety Disorder 7 item scale, and were asked whether they had committed any illegal behaviours to finance gambling. 42.5 % reported offending behaviour. A greater proportion of the offending group were single or married/ cohabiting, had a lower-level qualifications, lower income, had experienced childhood abuse, family mental health problems and gambling related harms compared to the non-offending group. Offenders reported higher anxiety, depression and disordered gambling scores. Disordered gamblers who offend make up a discrete and complex subgroup with distinct vulnerabilities. Findings will be useful to clinicians involved in the assessment and management of problematic gambling. Gamblers who offend to finance gambling may have different treatment needs and treatment providers should administer appropriate clinical interventions to address vulnerabilities.

The paper describes a treatment pilot for gambling and compulsive addiction within an NHS problem gambling clinic. The pilot study used a brief relational psychodynamic treatment protocol specifically designed to meet the needs of a group of patients who had not responded to CBT and who had other addictions or co- morbidities. Seventy two (n= 72) patients were offered 12 sessions of therapy by four psychodynamic counsellors. Results were assessed using pre and post treatment PHQ- 9, GAD- 7 and PGSI scores. Weekly feedback and supervision from counsellors and patients was used to assess the treatment model. The results highlighted that the Psychodynamic Addiction Model (PAM) was associated with reduced depression (Mean=14.9; SD 6.7), anxiety (Mean=11.5; SD 5.9) and gambling severity (p < .001), suggesting that a relational psychodynamic treatment is needed for complex patients with compulsive addiction, where CBT had not been successful. These results also highlight the importance of the therapeutic relationship as a critical factor in the treatment of patients with compulsive addiction problems.

Prosthetic joint infection is usually caused by staphylococci. Among the coagulase-negative staphylococci, Staphylococcus lugdunensis is important because it behaves as a pathogen similar to S aureus. It also develops biofilms, and the biofilm phenotype can appear as small-colony variants. Although genetically indistinguishable, they differ in size and antibiotic susceptibility from the parent strain and are responsible for chronic persistent infection and failure of antibiotic treatment. They can also lead to misinterpretation of results. The patient reported here underwent total knee replacement and 2 years later presented with prosthetic joint infection. Tissue samples and prosthesis taken at revision grew S lugdunensis, the majority of which were small-colony variants. Recommendations are made for their detection and identification.

Objectives External Ventricular Drain (EVD) insertion is a common neurosurgical procedure. EVD- related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the United Kingdom (UK) and Ireland and determine key factors influencing the infection risk. Methods A prospective multi-centre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox Regression Model was used for multivariate analysis to calculate Hazard Ratios (HR). Results A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in-situ for 4700 days (median 8 days; interquartile range 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days [HR=2.47 (1.12-5.45); p=0.03], regular sampling (daily sampling [HR=4.73 (1.28-17.42), p=0.02] and alternate day sampling [HR=5.28 (2.25-12.38); p<0.01]). There was no association between catheter type or tunnelling distance and ERI. Conclusions In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.

OBJECT Recently concern has arisen over the effect of released antimicrobial agents from antibiotic-impregnated external ventricular drainage (EVD) catheters on the reliability of CSF culture for diagnosis of ventriculitis. The authors designed a laboratory study to investigate this possibility, and to determine whether there was also a risk of loss of bacterial viability when CSF samples were delayed in transport to the laboratory. METHODS Three types of commercially available antibiotic-impregnated EVD catheters were perfused with a suspension of bacteria (Staphylococcus epidermidis) over 21 days. Samples were analyzed for bacterial viability and for concentrations of antibiotics released from the catheters. The authors also investigated the effect on bacterial viability in samples stored at 18°C and 4°C to simulate delay in CSF samples reaching the laboratory for analysis. RESULTS Bacterial viability was significantly reduced in all 3 catheter types when sampled on Day 1, but this effect was not observed in later samples. The results were reflected in stored samples, with significant loss of viability in Day 1 samples but with little further loss of viable bacteria in samples obtained after this time point. All samples stored for 18 hours showed significant loss of viable bacteria. CONCLUSIONS While there were differences between the catheters, only samples taken on Day 1 showed a significant reduction in the numbers of viable bacteria after passing through the catheters. This reduction coincided with higher concentrations of antimicrobial agents in the first few hours after perfusion began. Similarly, bacterial viability declined significantly after storage of Day 1 samples, but only slightly in samples obtained thereafter. The results indicate that drugs released from these antimicrobial catheters are unlikely to affect the diagnosis of ventriculitis, as sampling for this purpose is not usually conducted in the first 24 hours of EVD.

Objectives To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Methods Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson’s Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Results Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. Conclusions JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections.

Catheter-associated urinary tract infection (CAUTI) is the commonest hospital-acquired infection, accounting for over 100,000 hospital admissions within the USA annually. Biomaterials and processes intended to reduce the risk of bacterial colonization of the catheters for long-term users have not been successful, mainly because of the need for long duration of activity in flow conditions. Here we report the results of impregnation of urinary catheters with a combination of rifampicin, sparfloxacin and triclosan. In flow experiments, the antimicrobial catheters were able to prevent colonization by common uropathogens Proteus mirabilis, Staphylococcus aureus and Escherichia coli for 7 to 12 weeks in vitro compared with 1–3 days for other, commercially available antimicrobial catheters currently used clinically. Resistance development was minimized by careful choice of antimicrobial combinations. Drug release profiles and distribution in the polymer, and surface analysis were also carried out and the process had no deleterious effect on the mechanical performance of the catheter or its balloon. The antimicrobial catheter therefore offers for the first time a means of reducing infection and its complications in long-term urinary catheter users.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.

Bacterial attachment and subsequent biofilm formation are key challenges to the long term performance of many medical devices. Here, a high throughput approach coupled with the analysis of surface structure-property relationships using a chemometics approach has been developed to simultaneously investigate the interaction of bacteria with hundreds of polymeric materials on a microarray format. Using this system, a new group of materials comprising ester and hydrophobic moieties are identified that dramatically reduce the attachment of clinically relevant, pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and uropathogenic Escherichia coli). Hit materials coated on silicone catheters resulted in up to a 30 fold reduction in coverage compared to a commercial silver embedded catheter, which has been proven to half the incidence of clinically acquired infection. These polymers represent a new class of materials resistant to bacterial attachment that could not have been predicted from the current understanding of bacteria-surface interactions.

Objective Otitis media with effusion (OME), a common chronic childhood condition affecting hearing, is thought to be a result of bacterial infection, with biofilms recently implicated. Although bacterial DNA can be detected by polymerase chain reaction in 80% of patients, typically fewer than half of effusions are positive using standard culture techniques. We adopted an alternative approach to demonstrating bacteria in OME, using a bacterial viability stain and confocal laser scanning microscopy (CLSM): staining allows detection of live bacteria without requiring growth on culture, while CLSM allows demonstration of the three-dimensional structure typical of biofilms. Methods Effusion samples were collected at the time of ventilation tube insertion, analysed with CLSM and bacterial viability stain, and extended culture techniques performed with the intention of capturing all possible organisms. Results Sixty-two effusions (42 patients) were analysed: 28 (45.2%) were culture-positive, but 51 (82.3%) were CLSM-positive. Combining the two techniques demonstrated live bacteria in 57 (91.8%) samples. Using CLSM, bacteria exhibited biofilm morphology in 25 effusions and were planktonic in 26; the proportion of samples exhibiting biofilm morphology was similar in the culture-positive and culture-negative groups (50.0% and 48.3%, respectively). Biofilm samples contained an average of 1.7 different bacterial isolates and planktonic samples 2.0, with the commonest bacteria identified being coagulase-negative staphylococci. Conclusion Live bacteria are present in most effusions, strongly suggesting that bacteria and biofilms are important in the aetiopathogenesis of OME.

Shunt infection is a major complication affecting approximately 10% of procedures. Propionibacterium acnes, an anaerobic skin bacterium, is increasingly recognized as a shunt pathogen, causing up to 14% of infections. Though susceptible to penicillin and cephalosporins, P. acnes shunt infections are not preventable by means of perioperative prophylaxis, due to poor cerebrospinal fluid penetration. Antimicrobial shunts with activity against staphylococci are available, but their activity against P. acnes is unknown, and the study was designed to determine this. Three methods of evaluation were used in order to determine the emergence of resistance when exposure is to high inocula for long periods, the time taken to kill 100% of the bacteria attached to the shunt, and the duration of activity under constant flow conditions with repeated bacterial challenge. Despite repeated exposure to high bacterial inocula over 70 days, no resistance was seen. The time taken to kill all attached bacteria, 96 h, was twice that taken to kill attached staphylococci. Nevertheless, under constant flow conditions with repeated challenges, the antimicrobial catheters resisted colonization by P. acnes for 56 days. Using tests that were designed to be clinically predictive when done together, the results suggest that the antimicrobial catheters will be able to prevent colonization of hydrocephalus shunts by P. acnes.

A 38yr-old male with a ventriculoatrial shunt presented with nonspecific symptoms (headache, back pain, night sweats) and inconclusive laboratory results. He showed an extremely high titre of antibody to Staphylococcus epidermidis which proved diagnostic of shunt infection. This was confirmed on shunt removal and he was successfully treated.

Cerebrospinal fluid (CSF) shunts used to treat hydrocephalus have an overall infection rate of about 10% of operations. The commonest causative bacteria are Staphylococcus epidermidis, followed by Staphylococcus aureus and enterococci. Major difficulties are encountered with nonsurgical treatment due to biofilm development in the shunt tubing and inability to achieve sufficiently high CSF drug levels by intravenous administration. Recently, three cases of S. epidermidis CSF shunt infection have been treated by intravenous linezolid without surgical shunt removal, and we therefore investigated vancomycin and linezolid against biofilms of these bacteria in vitro. A continuous-perfusion model of shunt catheter biofilms was used to establish mature (1-week) biofilms of Staphylococcus aureus, Staphylococcus epidermidis (both methicillin resistant [MRSA and MRSE]), Enterococcus faecalis, and Enterococcus faecium. They were then “treated” with either vancomycin or linezolid in concentrations achievable in CSF for 14 days. The biofilms were then monitored for 1 week for eradication and for regrowth. Enterococcal biofilms were not eradicated by either vancomycin or linezolid. Staphylococcal biofilms were eradicated by both antibiotics after 2 days and did not regrow. No resistance was seen. Linezolid at concentrations achievable by intravenous or oral administration was able to eradicate biofilms of both S. epidermidis (MRSE) and S. aureus (MRSA). Neither vancomycin at concentrations achievable by intrathecal administration nor linezolid was able to eradicate enterococcal biofilms. It is hoped that these in vitro results will stimulate further clinical trials with linezolid, avoiding surgical shunt removal.

Objectives External Ventricular Drain (EVD) insertion is a common neurosurgical procedure. EVD- related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the United Kingdom (UK) and Ireland and determine key factors influencing the infection risk. Methods A prospective multi-centre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox Regression Model was used for multivariate analysis to calculate Hazard Ratios (HR). Results A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in-situ for 4700 days (median 8 days; interquartile range 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days [HR=2.47 (1.12-5.45); p=0.03], regular sampling (daily sampling [HR=4.73 (1.28-17.42), p=0.02] and alternate day sampling [HR=5.28 (2.25-12.38); p<0.01]). There was no association between catheter type or tunnelling distance and ERI. Conclusions In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.

Prosthetic joint infection is usually caused by staphylococci. Among the coagulase-negative staphylococci, Staphylococcus lugdunensis is important because it behaves as a pathogen similar to S aureus. It also develops biofilms, and the biofilm phenotype can appear as small-colony variants. Although genetically indistinguishable, they differ in size and antibiotic susceptibility from the parent strain and are responsible for chronic persistent infection and failure of antibiotic treatment. They can also lead to misinterpretation of results. The patient reported here underwent total knee replacement and 2 years later presented with prosthetic joint infection. Tissue samples and prosthesis taken at revision grew S lugdunensis, the majority of which were small-colony variants. Recommendations are made for their detection and identification.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus.. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.