Multidisciplinary neurosurgical rounds incorporating antimicrobial stewardship. Are they of benefit?

Background: In an era of increasing antimicrobial resistance, appropriate antimicrobials are essential to optimise patient outcomes. In 2017, antimicrobial use prevalence (AMU) on the two neurosurgical wards in our tertiary teaching hospital varied from 23% on ward A to 33% on ward B with 67% and 100% 'appropriate' prescriptions, respectively. In July 2018, a weekly antimicrobial stewardship multidisciplinary round led by a senior neurosurgery registrar commenced, attended by the antimicrobial stewardship team (AST). Research question: This report evaluates whether a multi-disciplinary approach on neurosurgical prescribing was beneficial, specifically in reducing AMU. Materials and methods: The following data was collected on AST rounds for 30 weeks in total from August 2018 to July 2019: number of patients on antimicrobials, appropriateness and stewardship actions. A questionnaire was distributed to neurosurgical doctors on two occasions to canvass opinions and attitudes on antimicrobial prescribing. Results: 1716 prescriptions were reviewed (mean 57.2 per week). Of these 321 (18.7%) included antimicrobial prescriptions; 200 on ward A (19.8%), and 121 on ward B (17%), representing a decrease in AMU from 2017. The majority of antimicrobial prescriptions, 271 (84.4%) were deemed appropriate. Stewardship actions were taken in 215 (67%) prescriptions.Fifteen questionnaires were completed by neurosurgical doctors. The majority, 87%, stated the AST round was helpful overall. 93% indicated that informal training on the AST round was a source of education in antibiotic prescribing. Discussion and conclusion: The weekly AST round provided a timely opportunity for multidisciplinary discussion, implementation of antimicrobial stewardship actions and opportunistic antimicrobial stewardship education.

Assessment of the management of carcinomatous meningitis from breast cancer globally: a study by the Breast International Group Brain Metastasis Task Force.

BACKGROUND: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. PATIENTS AND METHODS: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. RESULTS: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific. CONCLUSIONS: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area.

Risks for Surgical Site Infection after Infra-inguinal Bypass

Aims To define the burden of wound complications in patients with infra-inguinal bypass surgery. Methods A retrospective review of 50 consecutive patients from January 2012 to July 2017. Data collected included patient demographics, operative details, length of stay (LOS) and postoperative complications. Results The average age was 64 years (range 25-88 years) and 10 had a body mass index (BMI) ≥25 kg/m2. Pre-operative methicillin-resistant Staphylococcus aureus (MRSA) screening was performed in 17 patients (n=4 positive). Surgical antimicrobial prophylaxis (SAP) continued longer than 24 hours in 25. Surgical site infection (SSI) was the most common complication (n=10) and associated with female gender (p= 0.039), high BMI (p=0.017), shorter preoperative (p=0.039) and longer postoperative LOS (p=0.022). Three of 46 patients and four of 38 had graft occlusion at 30 days and one year respectively. Conclusion Pre-operative co-morbidity (e.g., BMI reduction), and MRSA screening optimization and SAP are areas identified for improvement.

Vulnerability of seagrass blue carbon to microbial attack following exposure to warming and oxygen.

Seagrass meadows store globally-significant quantities of organic 'blue' carbon. These blue carbon stocks are potentially vulnerable to anthropogenic stressors (e.g. coastal development, climate change). Here, we tested the impact of oxygen exposure and warming (major consequences of human disturbance) on rates of microbial carbon break-down in seagrass sediments. Active microbes occurred throughout seagrass sediment profiles, but deep, ancient sediments (~5000 yrs. old) contained only 3% of the abundance of active microbes as young, surface sediments (<2 yrs. old). Metagenomic analysis revealed that microbial community structure and function changed with depth, with a shift from proteobacteria and high levels of genes involved in sulfur cycling in the near surface samples, to a higher proportion of firmicutes and euraracheota and genes involved in methanogenesis at depth. Ancient carbon consisted almost entirely (97%) of carbon considered 'thermally recalcitrant', and therefore presumably inaccessible to microbial attack. Experimental warming had little impact on carbon; however, exposure of ancient sediments to oxygen increased microbial abundance, carbon uptake and sediment carbon turnover (34-38 fold). Overall, this study provides detailed characterization of seagrass blue carbon (chemical stability, age, associated microbes) and suggests that environmental disturbances that expose coastal sediments to oxygen (e.g. dredging) have the capacity to diminish seagrass sediment carbon stocks by facilitating microbial remineralisation.

Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters.

The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines results in serious, potentially life-threatening, adverse effects. By contrast, nucleic acid transfer via electroporation (EP) is a safe and effective method of delivering plasmid-encoded cytokines to tumors. Intratumoral delivery of IL-12 plasmid DNA by electroporation (IT-pIL12-EP) produced objective response rates in Phase 2 clinical trials in metastatic melanoma. However, only 17.9% of patients receiving IT-pIL12-EP show a complete therapeutic response. Here, we sought to improve the antitumor efficacy of our clinical IT-pIL12-EP plasmid electroporation platform. We evaluated multiple plasmid designs for IL-12 expression. IL-12 expression from a plasmid incorporating a picornavirus-derived co-translational P2A site was the most effective in expressing IL-12p70. In addition, modifying the electroporation parameters improved transfection efficiency and expression of plasmid-derived IL-12p70, as well as its downstream effector IFN-γ in vivo. Finally, using a murine melanoma model that is representative of the intended target patient population, we show that combining modified electroporation conditions with the pIL12-P2A plasmid expression enhances the systemic antitumor response. These improvements to the IT-pIL12-EP platform may improve patient clinical response rates and survival when translated to clinical trials.

Carbon sequestration by Australian tidal marshes.

Australia's tidal marshes have suffered significant losses but their recently recognised importance in CO2 sequestration is creating opportunities for their protection and restoration. We compiled all available data on soil organic carbon (OC) storage in Australia's tidal marshes (323 cores). OC stocks in the surface 1 m averaged 165.41 (SE 6.96) Mg OC ha-1 (range 14-963 Mg OC ha-1). The mean OC accumulation rate was 0.55 ± 0.02 Mg OC ha-1 yr-1. Geomorphology was the most important predictor of OC stocks, with fluvial sites having twice the stock of OC as seaward sites. Australia's 1.4 million hectares of tidal marshes contain an estimated 212 million tonnes of OC in the surface 1 m, with a potential CO2-equivalent value of $USD7.19 billion. Annual sequestration is 0.75 Tg OC yr-1, with a CO2-equivalent value of $USD28.02 million per annum. This study provides the most comprehensive estimates of tidal marsh blue carbon in Australia, and illustrates their importance in climate change mitigation and adaptation, acting as CO2 sinks and buffering the impacts of rising sea level. We outline potential further development of carbon offset schemes to restore the sequestration capacity and other ecosystem services provided by Australia tidal marshes.

Magnetic lateral flow immunoassay test strip development - Considerations for proof of concept evaluation.

Lateral flow immunoassays (LFIA) have grown to become the predominant test device format for the diagnostics and point-of-care industries. The demand for robust and reproducible LFIAs has been facilitated through scale-up production methods using specialized and automated instruments. However, the feasibility of a LFIA device can still be evaluated in a small-scale laboratory setting through controlled manual preparation methods. The advent of super-paramagnetic (SPMP) labels for use in lateral flow has heralded the possibility of highly sensitive and stable LFIAs. The methods used for the preparation of a magnetic LFIA prototype device using a reserved suite of laboratory equipment are described.

Measurement of the Postgraduate Educational Environment of Junior Doctors Training in Medicine at an Irish University Teaching Hospital.

BACKGROUND: A positive learning environment in which postgraduate doctors are supported, supervised and nurtured, is likely to lead to enhanced professional satisfaction and improved patient care. AIMS: The aims of the current study were to use the PHEEM inventory to determine the aspects of their current learning environment which junior doctors rate most and least positively. METHODS: The PHEEM questionnaire was administered to all junior doctors working in medical subspecialties at Galway University Hospitals in Ireland. A response rate of 60 % (n = 61) was obtained. RESULTS: The mean total PHEEM score was 82.88 ± 18.99, corresponding to an educational environment with more positive than negative aspects but with room for improvement. The mean total PHEEM score (±standard deviation) of registrars (89.65 ± 20.92) exceeded that of Interns (84.00 ± 15.26) and SHOs (75.12 ± 18.09). Over half (55 %) of the individual items were rated by the junior doctors as more positive than negative. Nineteen items (48 %) pointed to areas in need of enhancement, whilst 3 items were rated as satisfactory or better. Analysis of qualitative data confirmed that deficiencies exist in various aspects of the educational climate, including protected educational time, access to suitable learning opportunities, the nature of tasks performed by junior doctors, the hospital bleep protocol, implementation of the European Working Time Directive, feedback and career guidance. CONCLUSIONS: Recommendations stemming from this study should lead to improvements in the quality of the educational environment of junior doctors and may stimulate similar evaluations in other teaching hospitals.

Fine-scale spatial and temporal variations in diets of the pipefish Stigmatopora nigra within seagrass patches.

Diets of the pipefish Stigmatopora nigra were analysed to determine if food availability was causing S. nigra to distribute according to habitat edge effects. Gut analysis found little difference in the diets of S. nigra at the edge and interior of seagrass patches, regardless of time of day or season. Fish diets did, however, vary with seagrass density: S. nigra in denser seagrass consumed more harpacticoid copepods and fewer planktonic copepods. The lack of difference in prey eaten by S. nigra at the edge and interior of patches suggests either that food was not determining S. nigra distribution patterns within patches or that differences in fish densities across patches meant that relative fish-prey densities were similar at edge and interior positions. Alternatively, any edge effects in diet might be masked by gradients in seagrass structure.

Integrating edge effects into studies of habitat fragmentation: a test using meiofauna in seagrass.

Habitat fragmentation is thought to be an important process structuring landscapes in marine and estuarine environments, but effects on fauna are poorly understood, in part because of a focus on patchiness rather than fragmentation. Furthermore, despite concomitant increases in perimeter:area ratios with fragmentation, we have little understanding of how fauna change from patch edges to interiors during fragmentation. Densities of meiofauna were measured at different distances across the edges of four artificial seagrass treatments [continuous, fragmented, procedural control (to control for disturbance by fragmenting then restoring experimental plots), and patchy] 1 day, 1 week and 1 month after fragmentation. Experimental plots were established 1 week prior to fragmentation/disturbance. Samples were numerically dominated by harpacticoid copepods, densities of which were greater at the edge than 0.5 m into patches for continuous, procedural control and patchy treatments; densities were similar between the edge and 0.5 m in fragmented patches. For taxa that demonstrated edge effects, densities exhibited log-linear declines to 0.5 m into a patch with no differences observed between 0.5 m and 1 m into continuous treatments. In patchy treatments densities were similar at the internal and external edges for many taxa. The strong positive edge effect (higher densities at edge than interior) for taxa such as harpacticoid copepods implies some benefit of patchy landscapes. But the lack of edge effects during patch fragmentation itself demonstrates the importance of the mechanisms by which habitats become patchy.

Optical beam profile monitor and residual gas fluorescence at the relativistic heavy ion collider polarized hydrogen jet.

A gas fluorescence beam profile monitor has been implemented at the relativistic heavy ion collider (RHIC) using the polarized atomic hydrogen gas jet, which is part of the polarized proton polarimeter. RHIC proton beam profiles in the vertical plane of the accelerator are obtained as well as measurements of the width of the gas jet in the beam direction. For gold ion beams, the fluorescence cross section is sufficiently large so that profiles can be obtained from the residual gas alone, albeit with long light integration times. We estimate the fluorescence cross sections that were not known in this ultrarelativistic regime and calculate the beam emittance to provide an independent measurement of the RHIC beam. This optical beam diagnostic technique, utilizing the beam induced fluorescence from injected or residual gas, offers a noninvasive particle beam characterization and provides visual observation of proton and heavy ion beams.

Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl-2-dependent mechanism.

AIMS: Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The aim of the study was to evaluate cyclooxygenase (COX)-2 and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. METHODS AND RESULTS: COX-2 and Bcl-2 expression were examined immunohistochemically in tissue from 41 sporadic phaeochromocytoma patients followed up for a minimum of 5 years after diagnosis. There was a statistically significant association between COX-2 histoscore (intensity x proportion) and the development of tumour recurrence or metastases (P = 0.006). A significant relationship was observed between coexpression of COX-2 and Bcl-2 in the primary tumour and the presence of recurrent disease (P = 0.034). A highly significant association was observed between (i) tumour-associated expression of these two oncoproteins (P = 0.001) and (ii) COX-2 histoscore and the presence of Bcl-2 expression (P = 0.002). COX regression analysis demonstrated no significant relationship between (i) the presence or absence of either COX-2 or Bcl-2 and patient survival or (ii) COX-2 histoscore and patient survival. CONCLUSIONS: COX-2 and Bcl-2 may promote phaeochromocytoma malignancy, and these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

Collecting duct carcinoma of the kidney: a case report with variable immunohistochemistry.

BACKGROUND: Collecting duct carcinoma of the kidney is a rare tumour with distinctive clinical and histopathological features. Management of this malignancy remains a challenge because of advanced stage at presentation and aggressive clinical course. AIMS: We describe a case of Collecting Duct Carcinoma with variable immunohistochemistry and review the pathology and management. RESULTS: Our patient died shortly after commencing systemic chemotherapy. CONCLUSION: Advances in immunohistochemistry have aided in diagnosis of this tumour. Early detection and nephrectomy offer the best chance of cure. Newer chemotherapeutic regimens may improve survival in more advanced disease.

An investigation into the role of Bcl-2 in neuroendocrine differentiation.

INTRODUCTION: In addition to its role in apoptosis suppression, Bcl-2 has been reported to be co-expressed with neuroendocrine markers in several tissues, leading to speculation that this oncoprotein may promote neuroendocrine differentiation. AIM: This study investigated whether Bcl-2 modulated neuroendocrine biopeptide expression. METHODS: Levels of chromogranin A, neurone specific enolase, protein gene peptide 9.5, pancreatic polypeptide, and the chromogranin-derived peptides, intervening peptide and vasostatin-1 were examined by immunocytochemistry in rat phaeochromocytoma (PC12) cell lines genetically engineered to over-express Bcl-2 and their mock-transfected controls. Intensity of fluorescence was graded using a semi-quantitative scale from (-) indicating negative expression to (+++) indicating intense positivity. RESULTS: Mann-Whitney U analysis indicated that no significant differences in expression existed between control and Bcl2 over-expressing cell lines for any of the six peptides examined. CONCLUSIONS: The results of this study do not support the hypothesis that Bcl-2 promotes the acquisition of a neuroendocrine phenotype.

The skull and cervical spine radiographs of Tutankhamen: a critical appraisal.

BACKGROUND AND PURPOSE: Tutankhamen, the last pharaoh of the XVIIIth dynasty, died unexpectedly at approximately age 18 years. A cause of death has never been established, but theories that the young king was murdered by a blow to the head have been proposed based on skull radiographs obtained by a team from the University of Liverpool in 1968. We recently had the opportunity to evaluate the skull and cervical spine radiographs of Tutankhamen. The purpose of this study was to report our critical appraisal of the radiographs of Tutankhamen regarding the findings alleged to indicate traumatic death. METHODS: Copies of lateral, anteroposterior, and submental vertex skull radiographs of Tutankhamen were reviewed with special attention to the claims of a depressed skull fracture, intracranial bone fragments, and calcified membrane of a posterior fossa subdural hematoma. A phantom skull was radiographed to reproduce the appearance of the floor of the posterior fossa in the lateral projection. RESULTS: The skull radiographs of Tutankhamen show only postmortem artifacts that are explainable by an understanding of the methods of mummy preservation used at the time of his death. Some findings also relate to trauma inflicted by an autopsy performed in 1925. The alleged calcified membrane of a posterior fossa subdural hematoma is easily reproduced with a skull phantom. CONCLUSION: Our critical review of the skull and cervical spine radiographs of Tutankhamen does not support proposed theories of a traumatic or homicidal death.

Prospective patient-based assessment of effectiveness of palliative radiotherapy for bone metastases.

PURPOSE: The primary objective of this report is to prospectively evaluate pain control provided by palliative radiotherapy for all irradiated patients with bone metastases by using their own assessments. MATERIALS AND METHODS: A prospective database was set up for all patients referred for palliative radiotherapy for bone metastases. Patients were asked to rate their pain intensity using an 11 categorical point scale (0=lack of pain, 10=worst pain imaginable). Analgesic consumption during the preceding 24 h was recorded and converted into equivalent total daily dose of oral morphine. For those who received radiotherapy, follow-up was conducted via telephone interviews at week 1, 2, 4, 8 and 12 post treatment using the same pain scale and analgesic diary. Radiotherapy outcome was initially assessed by pain score alone. Complete response (CR) was defined as a pain score of 0. Partial response (PR) was defined as a reduction of score > or =2 or a> or =50% reduction of the pre-treatment pain score. We further analyzed outcomes using integrated pain and analgesic scores. Response was defined as either a reduction of pain score > or =2 with at least no increase in analgesics or at least stable pain score with a > or =50% reduction in analgesic intake. RESULTS: One hundred and five patients were treated with palliative radiotherapy. When response evaluation was by pain score alone, the PR rates at 2, 4, 8 and 12 weeks were 44, 42, 30 and 38%, respectively; while the CR rates were 24, 32, 31 and 29%, respectively. The overall response rate at 12 weeks was 67%. When assessed by the integrated pain and analgesic scores, the response rates were 50, 46, 43 and 43%, respectively. CONCLUSION: The response rate in our patient population is comparable with those reported in clinical trials. This is important when counselling our patients on the expected effectiveness of radiotherapy outside of clinical trials. Our observations confirm the generalizability of the trials conducted to date. While randomized trials still remain the gold standard of research, observational studies can serve as useful adjuncts to randomized trials to confirm the efficacy and guide the design of new controlled trials.

Non-invasive assessment of blood-brain barrier (BBB) permeability using a gamma camera to detect 99technetium-gluceptate extravasation in rat brain.

The blood-brain barrier (BBB) is a complex structure of endothelial cells, astroglia, pericytes, and perivascular macrophages enclosed by basal lamina. The BBB regulates the entry of blood-borne molecules and cells into the brain, but it is disrupted in various inflammatory conditions of the central nervous system (CNS). We previously showed that 30 min of immobilization stress increased 99technetium-gluceptate (99Tc) extravasation, measured by a gamma counter, in brain regions containing mast cells, an effect blocked by the mast cell stabilizer disodium cromoglycate [Brain Res. 888 (2001) 117]. Here we report the use of a gamma camera to assess BBB permeability by assessing 99Tc extravasation in the rat brain, during and following acute stress, without having to sacrifice the experimental animals. This method also allows for repeated experimentation on the same animal, since the half-life of 99Tc is only 6 h, and permits testing of potential inhibitors of BBB permeability.

Patients with advanced cancer: a survey of the understanding of their illness and expectations from palliative radiotherapy for symptomatic metastases.

We conducted a pilot study to examine patients' understanding of their illness and their expectations for palliative radiotherapy for symptomatic metastases. Participants were asked to complete a survey consisting of seven questions prior to the initial consultation. Demographic details and information on extent of disease were collected. Patients were asked to score their symptom distress using the modified Edmonton Symptom Assessment System. Sixty patients participated in the pilot study between January and April 1999. Their median age was 68 years (range 46-90). The most common primary tumours were lung, prostate and breast. Twenty-one patients (35%) believed that their cancer was curable. Twelve (20%) expected that palliative radiotherapy would cure their advanced cancer and 23 (38%) believed that palliative radiotherapy would prolong their lives. Twenty-one patients (35%) had concerns about the effectiveness of radiation therapy and twenty (33%) had concerns about the side-effects of radiotherapy. Fifty-two (87%) were not familiar with the concept of radiation treatment. Forty-seven patients (78%) reported that they were not given information about the radiation treatment; 51 (85%) were not satisfied with the information that their own doctors had provided regarding radiation treatment prior to the consultation at our clinic. A significant proportion of the patients in this pilot study had misconceptions regarding their illness and unrealistic expectations from palliative radiotherapy. We plan to provide educational pamphlets for use in referring doctors' surgeries and clinics in order to inform patients of the nature, rationale and anticipated benefits and side-effects of palliative radiotherapy.