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Antimicrobial resistance is a serious and rapidly growing threat to global health. Bdellovibrio bacteriovorus can prey upon an extensive range of Gram-negative bacterial pathogens and thus has promising potential as a novel antibacterial therapeutic and is a source of antibacterial enzymes. Here, we elucidate the role of a unique secreted lytic transglycosylase from B. bacteriovorus which acts on the septal peptidoglycan of its prey.

Over 1.2 million deaths are attributed to multi-drug-resistant (MDR) bacteria each year. Persistence of MDR bacteria is primarily due to the molecular mechanisms that permit fast replication and rapid evolution. As many pathogens continue to build resistance genes, current antibiotic treatments are being rendered useless and the pool of reliable treatments for many MDR-associated diseases is thus shrinking at an alarming rate. In the development of novel antibiotics, DNA replication is still a largely underexplored target. This review summarises critical literature and synthesises our current understanding of DNA replication initiation in bacteria with a particular focus on the utility and applicability of essential initiation proteins as emerging drug targets. A critical evaluation of the specific methods available to examine and screen the most promising replication initiation proteins is provided.

Lymphedema prevention surgery (LPS), which identifies, preserves, and restores lymphatic flow via lymphaticovenous bypasses (LVB), has demonstrated potential to decrease lymphedema in breast cancer patients requiring axillary lymph node dissection. Implementing this new operating technique requires additional operating room (OR) time and coordination. This study sought to evaluate the improvement of LPS technique and OR duration over time. A prospective database of patients who underwent LPS at our institution from 2016 to 2019 was queried. Type of breast and reconstruction surgery, number of LVB performed, and OR times were collected. LPS details were compared by surgical group and year performed. Ninety-four patients underwent LPS, and 88 had complete OR time data available for analysis. Average age was 51 years, body mass index of 28, with an average of 15 lymph nodes removed. Reconstructive treatment groups included prosthetic reconstruction 56% (49), oncoplastic reduction 10% (9), and no reconstruction 34% (30). The number of patients undergoing LPS increased significantly from 2016 to 2019, and average number of LVB per patient doubled. In patients without reconstruction, the average time for LPS improved significantly from 212 to 87 min from 2016 to 2019 (p = 0.015) and similarly in patients undergoing LPS with prosthetic reconstruction from 238 to 160 min (p = 0.022). LVB is an emerging surgical lymphedema prevention technique. While requiring additional surgical time, our results show that with refinement of technique, over 4 years, we were able to perform double the number of LVB per patient in half the OR time.

Adjuvant radiation therapy has been associated with improved local control following breast-conserving surgery. Traditionally, treatment has been delivered with whole breast irradiation over 3-6 weeks or partial breast irradiation over 1-3 weeks. However, intraoperative radiation therapy (IORT) has emerged as a technique that delivers a single dose of radiotherapy at the time of surgery for early-stage breast cancers. We report initial outcomes and acute toxicities with intraoperative radiation from a single institution. Patients with DCIS or Stage I-II breast cancer who underwent lumpectomy and sentinel lymph node biopsy (nodal sampling excluded in some cases) were included. All patients in this analysis were treated with IORT as at the time of surgery, 20 Gy in 1 fraction with 50 kV x-ray. Patients were treated at a single institution between 2011 and 2019. Follow-up was per standard institutional protocol. Two hundred and one patients were included in the analysis, with a median follow-up of 23 months (range: 0-73 months). Median age was 71 years old. Overall, 4 (2.0%) patients had DCIS, 186 (92.5%) patients had Stage 1 disease, and 11 patients had (5.5%) Stage 2 disease. All patients were estrogen receptor-positive, 175 (87.9%) progesterone receptor-positive, and 1 (0.5%) HER2 amplified. The crude rate of local recurrence was 2.0% (n = 4) and distant metastasis rate was 0.5% (n = 1). The rate of arm lymphedema was 0.5% (n = 1) and chronic telangiectasia rate was 1.1% (n = 2). Intraoperative radiation therapy, in a cohort of low-risk patients, demonstrated low rates of recurrence and reproducibility in a multi-disciplinary setting. Further follow-up, analysis of patient satisfaction and cosmesis, and comparison to whole breast irradiation and partial breast techniques is necessary in order to further validate these findings.

No clear standards regarding number or type of narcotics for adequate postoperative pain control have been established in breast surgery. The authors of this study reviewed their opioid-prescribing patterns and implemented a planned change, evaluated the effectiveness of a departmental practice adjustment, and prospectively evaluated patient narcotic usage. The narcotic prescriptions for 100 consecutive breast surgery patients were reviewed to establish baseline postoperative narcotic-prescribing patterns. The median of narcotics prescribed was used to educate surgeons and implement a planned change in prescribing practices. Data on narcotic prescriptions for 100 consecutive breast surgery patients then were prospectively collected, and the number of pain pills the patients actually took after discharge was recorded using a standardized template. A baseline review of narcotic-prescribing practices showed that the median number of pills given was 15 for excisional biopsy/lumpectomy, 20 for mastectomy, and 28 for mastectomy with reconstruction. After departmental education, the median number decreased to 10 for excisional biopsy/lumpectomy (p

Summary Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF-R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll-like receptor (TLR)-9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-22, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor (TGF)-β were significantly elevated in TRAPS patients’ sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR-9 ligand (ODN2006) triggered significantly greater up-regulation of proinflammatory signalling intermediates [TNF receptor-associated factor (TRAF 3), IL-1 receptor-associated kinase-like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor-β-activated kinase 1 (pTAK), transforming growth factor-β-activated kinase-binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN-regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF-κB) p65, phosphorylated NF-κB p65 (pNF-κB p65) and mitogen-activated protein kinase kinase (MEK1/2)] in TRAPS patients’ PBMCs. This up-regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide-ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway-specific therapeutic treatments for this disease.

Background: Gender disparities in academic promotion and leadership are well documented. Scholarly impact is essential for promotion. The Hirsch-index (h-index) is a measure of impact using number ...

Background: Lymphedema is a complication of breast cancer therapy associated with substantial anxiety. We designed a prospective, randomized study to assess the psychosocial impact of different sur...

Background Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time. Methods A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ2 tests. Results Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P

TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through- put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

The increasing numbers of breast cancer survivors from newly diagnosed to metastatic requires more personalised management by the medical breast cancer community. The increasing numbers of breast cancer survivors from newly diagnosed to metastatic requires more personalised management by the medical breast cancer community. Whereas oncology specialists provide useful information, patients may not hear it. An equal partnership between patients and their doctors is proposed. Patient involvement is more than patient surveys. Patients need appropriate information which they can understand and trust and is tailored to their specific needs at each step of the care pathway. Patients are facing difficulties navigating all the information and available options. Physicians need to understand that patients receive information from multiple sites. Many tools are available to help in shared decision-making.

Background A lymphedema (LE) prevention surgery (LPS) paradigm for patients undergoing axillary lymphadenectomy (ALND) was developed to protect against LE through enhanced lymphatic visualization during axillary reverse mapping (ARM) and refinement in decision making during lymphaticovenous bypass (LVB). Methods A retrospective analysis of a prospective database was performed evaluating patients with breast cancer who underwent ALND, ARM, and LVB from September 2016 to December 2018. Patient and tumor characteristics, oncologic and reconstructive operative details, complications and LE development were analyzed. Results LPS was completed in 58 patients with a mean age of 51.7 years. An average of 14 lymph nodes (LN) were removed during ALND. An average of 2.1 blue lymphatic channels were visualized with an average of 1.4 LVBs performed per patient. End to end anastomosis was performed in 37 patients and a multiple lymphatic intussusception technique in 21. Patency was confirmed 96.5% of patients. Adjuvant radiation was administered to 89% of patients. Two patients developed LE with a median follow-up of 11.8 months. Conclusion We report on our experience using a unique LPS technique. Refinements in ARM and a systematic approach to LVB allows for maximal preservation of lymphatic continuity, identification of transected lymphatics, and reestablishment of upper extremity lymphatic drainage pathways.

Background: To increase awareness, search for solutions, and drive change, disparity-related research needs to be strategically disseminated. This study aimed to quantify whether a social ...

Triple-negative breast cancers (TNBCs), negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, account for 15 to 20% of all female breast cancers. TNBC is heterogeneous based on gene expression microarray, and identification of TNBC subtypes and their behavior has the potential to enable more targeted, neoadjuvant, and adjuvant interventions. TNBCs usually are higher grade (Nottingham score 3) and are more common in younger, Hispanic, and African American women. They are more aggressive, have an increased likelihood of distant disease and mortality, are larger at presentation, and are more likely to be associated with lymph node metastases. Patients with TNBC are at a higher risk for visceral metastases early in the course of the disease. Genetic risk evaluation is recommended for patients with TNBC diagnosed at or before 60 years of age. Surgical management may be influenced by gene testing results. Standard adjuvant chemotherapy is anthracycline or taxane based. This review contains 5 figures, 8 tables, and 51 references. Key Words: adjuvant, BRCA, chemotherapy, hormone receptor negative, neoadjuvant, genetics, triple-negative breast cancer, breast neoplasm.

Objectives The aim was to investigate if offering symptomatic therapy (Uva-ursi or ibuprofen) alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). Methods A 2 × 2 factorial placebo controlled randomized trial in primary care. The participants were 382 women aged 18–70 years with symptoms of dysuria, urgency, or frequency of urination and suspected by a clinician to have a lower UTI. The interventions were Uva-ursi extract and/or ibuprofen advice. All women were provided with a delayed or ‘back-up' prescription for antibiotics. Missing data were imputed using multiple imputation methods (ISRCTN registry: ISRCTN43397016). Results An ITT analysis of mean score for frequency symptoms assessed on Days 2–4 found no evidence of a difference between Uva-ursi vs. placebo –0.06 (95% CI –0.33 to 0.21; p 0.661), nor ibuprofen vs. no ibuprofen advice –0.01 (95% CI –0.27 to 0.26; p 0.951). There was no evidence of a reduction in antibiotic consumption with Uva-ursi (39.9% vs. placebo 47.4%; logistic regression odds ratio (OR) 0.59 (95% CI 0.22–1.58; p 0.293) but there was a significant reduction for ibuprofen advice (34.9% vs. no advice 51.0%; OR 0.27 (95% CI 0.10 to 0.72; p 0.009). There were no safety concerns and no episodes of upper tract infection were recorded. Conclusions We found no evidence of an effect of either intervention on the severity of frequency symptoms. There is evidence that advice to take ibuprofen will reduce antibiotic consumption without increasing complications. For every seven women given this advice, one less will use antibiotics.

In assessing the potential of predatory bacteria, such as Bdellovibrio bacteriovorus, to become live therapeutic agents against bacterial infections, it is crucial to understand and quantify Bdellovibrio host cell interactions at a molecular level. Here, we quantify the interactions of live B. bacteriovorus with human phagocytic cells, determining the uptake mechanisms, persistence, associated cytokine responses and intracellular trafficking of the non-growing B. bacteriovorus in PMA-differentiated U937 cells. B. bacteriovorus are engulfed by U937 cells and persist for 24 h without affecting host cell viability and can be observed microscopically and recovered and cultured post-uptake. The uptake of predators is passive and depends on the dynamics of the host cell cytoskeleton; the engulfed predators are eventually trafficked through the phagolysosomal pathway of degradation. We have also studied the prevalence of B. bacteriovorus specific antibodies in the general human population. Together, these results quantify a period of viable persistence and the ultimate fate of B. bacteriovorus inside phagocytic cells. They provide new knowledge on predator availability inside hosts, plus potential longevity and therefore potential efficacy as a treatment in humans and open up future fields of work testing if predators can prey on host-engulfed pathogenic bacteria.

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease involving recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNF receptor superfamily 1A gene localised to exons encoding the ectodomain of the p55 TNF receptor, TNF receptor-1 (TNFR1). The aim of this study was to investigate the role of cell surface TNFR1 in TRAPS, and the contribution of TNF-dependent and TNF-independent mechanisms to the production of cytokines. HEK-293 and SK-HEP-1 cell lines were stably transfected with WT or TRAPS-associated variants of human TNF receptor superfamily 1A gene. An anti-TNFR1 single domain antibody (dAb), and an anti-TNFR1 mAb, bound to cell surface WT and variant TNFR1s. In HEK-293 cells transfected with death domain-inactivated (R347A) TNFR1, and in SK-HEP-1 cells transfected with normal (full-length) TNFR1, cytokine production stimulated in the absence of exogenous TNF by the presence of certain TNFR1 variants was not inhibited by the anti-TNFR1 dAb. In SK-Hep-1 cells, specific TRAPS mutations increased the level of cytokine response to TNF, compared to WT, and this augmented cytokine production was suppressed by the anti-TNFR1 dAb. Thus, TRAPS-associated variants of TNFR1 enhance cytokine production by a TNF-independent mechanism and by sensitising cells to a TNF-dependent stimulation. The TNF-dependent mechanism requires cell surface expression of TNFR1, as this is blocked by TNFR1-specific dAb.

Granulomatous mastitis is an uncommon inflammatory disease that typically presents with painful breast lesions. Recent publications have brought to light a specific subset of granulomatous mastitis patients with a distinct histological pattern of disease termed, "cystic neutrophilic granulomatous mastitis" (CNGM). Although many cases of granulomatous lobular mastitis have been thought to be idiopathic, this rare subset of an uncommon disease has been linked to infections with Corynebacterium species. Herein, a cohort of CNGM patients from a large, tertiary care, North-American, academic medical center is presented. Correlative demographic, clinical, radiographic, pathologic, microbiologic, management, and outcomes data are provided. Collaborative communication between specialists to accurately diagnose and manage these patients is essential to decreasing potential morbidity.

In worldwide conditions of increasingly antibiotic-resistant hospital infections, it is important to research alternative therapies. Bdellovibrio bacteriovorus bacteria naturally prey on Gram-negative pathogens, including antibiotic-resistant strains and so B. bacteriovorus have been proposed as “living antibiotics” to combat antimicrobially-resistant pathogens. Predator-prey interactions are complex and can be altered by environmental components. To be effective B. bacteriovorus predation needs to work in human body fluids such as serum where predation dynamics may differ to that studied in laboratory media. Here we combine mathematical modelling and lab experimentation to investigate the predation of an important carbapenem-resistant human pathogen, Klebsiella pneumoniae, by B. bacteriovorus in human serum versus buffer. We show experimentally that B. bacteriovorus is able to reduce prey numbers in each environment, on different timescales. Our mathematical model captures the underlying dynamics of the experimentation, including an initial predation-delay at the predator-prey-serum interface. Our research shows differences between predation in buffer and serum and highlights both the potential and limitations of B. bacteriovorus acting therapeutically against K. pneumoniae in serum, informing future research into the medicinal behaviours and dosing of this living antibacterial.

Introduction Intraoperative radiation with Intrabeam™ (IORT) for breast cancer is a newer technology recently implemented into the operating room (OR). This procedure requires time and coordination between the surgeon and radiation oncologist, who both perform their treatments in a single operative setting. We evaluated the surgeons at our center who perform IORT and their OR times to examine changes in OR times following implementation of this new surgical procedure. We hypothesized that IORT is a technique for which timing could be improved with the increasing number of cases performed. Methods A prospectively maintained IRB approved database was queried for OR times (incision and close) in patients who underwent breast conserving surgery (BCS), sentinel lymph node biopsy with and without IORT using the Intrabeam™ system at our institution from 2011 to 2015. The total OR times were compared for each surgeon individually and over-time. Next, the OR times of each surgeon were compared to each other. Continuous variables were summarized and then a prediction model was created using IORT time, OR time, surgeon, and number of cases performed. Results There were 5 surgeons performing IORT at our institution during this time period with a total of 96 cases performed. There was a significant difference observed in baseline surgeon specific OR time for BSC (p=0.03) as well as for BCS with IORT (p

Twitter social media is being used to disseminate medical meeting information. Meeting attendees and other interested parties have the ability to follow and participate in conversations related to meeting content. We analyzed Twitter activity generated from the 2013–2016 American Society of Breast Surgeons Annual Meetings. The Symplur Signals database was used to determine number of tweets, tweets per user, and impressions for each meeting. The number of unique physicians, patients/caregivers/advocates, and industry participants was determined. Physician tweeters were cross-referenced with membership and attendance rosters. Tweet transcripts were analyzed for content and tweets were categorized as either scientific, social, administrative, industry promotion, or irrelevant. From 2013 to 2016, the number of tweets increased by 600 %, the number of Twitter users increased by 450 %, and the number of physician tweeters increased by 457 %. The number of impressions (tweets × followers) increased from more than 3.5 million to almost 20.5 million, an increase of 469 %. The majority of tweets were informative (70–80 %); social tweets ranged from 13 to 23 %. A small percentage (3–6 %) of tweets were related to administrative matters. There were very few industry or irrelevant tweets. Twitter social media use at the American Society of Breast Surgeons annual meeting showed a substantial increase during the time period evaluated. The use of Twitter during professional meetings is a tremendous opportunity to share information. The authors feel that medical conference organizers should encourage Twitter participation and should be educating attendees on the proper use of Twitter.

Survivorship medicine is fairly new in the realm of oncology. As we broaden our focus from treatment and prevention to include survivorship there is substantial opportunity to enhance the care of the patient. Important in successful management of recovery after cancer treatment is managing the side effects of therapy and improving quality of life. This ranges from sexual dysfunction, depression to lymphedema. Guideline-based surveillance after treatment with clear communication of care plans to the patient and their providers, especially primary care, is paramount. Thoughtful pre-surgical treatment planning, which may include neoadjuvant approaches or consideration of fertility preservation, results in superior long-term patient outcomes. Understanding the importance of the teachable moment in effecting behavioral and lifestyle changes that reduce risk of recurrence is also an essential component of excellent cancer survivor patient care. We identified the following areas for focus as they represent the key areas for accreditation and patient driven needs. Development of survivorship plans, post treatment surveillance, sexuality and fertility preservation, lymphedema management and risk reduction lifestyle and behavioral changes.

Objective To analyze the effects of tumor necrosis factor receptor–associated periodic syndrome (TRAPS)–associated mutant tumor necrosis factor receptor type I (TNFRI) expression in a cell type directly relevant to the inflammation in TRAPS, and to identify novel markers associated with mutant TNFRI expression. Methods Transcriptome analysis on 30,000 human genes was performed on SK-Hep-1 human endothelial cells transfected with either wild-type (WT) or TRAPS-associated mutant TNFRI. Quantitative reverse transcriptase–polymerase chain reaction and protein expression levels measured by enzyme-linked immunosorbent assay verified transcriptional changes for selected genes both in supernatants from cells expressing mutant TNFRI and in patient plasma. Results Cells expressing mutant TNFRI showed up-regulation of multiple proinflammatory genes relative to WT transfectants, including genes for pentraxin 3, granulocyte–macrophage colony-stimulating factor, granulocyte colony-stimulating factor, CCL2, and CCL5, which were also expressed as proteins. In addition, the expression of most of these markers was increased in the plasma and peripheral blood mononuclear cells from TRAPS patients relative to those from healthy controls. The cysteine mutations (C33Y and C52F), which are associated with a more severe clinical phenotype, induced more genes than the low-penetrance mutation R92Q, which is associated with a milder phenotype. The expression of most genes was induced by a death domain (DD)–dependent mechanism, since they were not induced by expression of TNFRI mutants with an inactivated DD. Conclusion TRAPS-associated TNFRI mutants induce the expression of multiple genes encoding inflammatory molecules, cellular receptors, transcription factors, and regulators of apoptosis in endothelial cells that require the cytoplasmic signaling properties of the receptor. Different mutants have specific expression profiles, indicating mutation-specific effects. The expression of some of these markers was also elevated in samples from TRAPS patients.

The premise underlying this paper is that one of the best ways of improving education in the United States, short of totally restructuring the public schools, is to teach pre-service teachers how to use systems approach principles and to work to insure that they employ those principles when they become teachers. The paper begins with a rationale for this premise and goes on to describe the systems approach principles likely to be most rel evant to teachers. A detailed examination of the real world of teacher planning and the factors likely to influence teachers' planning activities is also presented. In light of those factors, the authors suggest a number of steps that can be taken in order to increase the likelihood that future teachers will employ systems approach principles as they engage in instructional planning.

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at ∈ European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better fu treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. © 2016 Ferrata Storti Foundation.

For several years the UK Met. Office has initialised tropical cyclones (TCs) in its global model by use of ‘bogus’ observations representing a simple symmetric vortex. Although this has yielded acceptable results, in terms of the verification of TC tracks in the short and medium range, it was felt certain improvements could be made. A new scheme has been developed which addresses two major deficiencies of the old scheme; the representation of the radial structure of winds and the asymmetry of the TC vortex. Preliminary tests of the new scheme resulted in the reduction of three-day track forecast errors by 52%. Subsequently, a 19-day trial of the new scheme running in parallel with the old scheme was undertaken. There were 12 active TCs during this period. The improvement in the track forecast verification statistics during the trial was striking. Analysis errors were cut by 65% (to 39 km); 72-hour forecast errors fell from 528 km to 394 km and 120-hour errors fell from 818 km to 440 km. The model's skill over a standard climatological/persistence forecast also improved dramatically. The new scheme was introduced operationally on 25 October 1994. Since then, mean forecast errors have been considerably lower than mean statistics from recent years.

Over the last decade global numerical weather prediction models have become sufficiently sophisticated to forecast the movement of tropical cyclones with a reasonable degree of accuracy. This paper describes the work being done at the Met. Office in Bracknell, UK, to improve and verify track forecasts, looking particularly at methods of ‘bogussing’ the initial conditions and of verifying the forecasts.

Objective To investigate the effect of mutations in tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in TNFR-associated periodic syndrome (TRAPS) on the binding of anti-TNFRSF1A monoclonal antibodies (mAb), and to investigate the subcellular distribution of mutant versus wild-type (WT) TNFRSF1A in patients with TRAPS. Methods HEK 293 cells transfected with WT and/or mutant TNFRSF1A were used to investigate the interaction of anti-TNFRSF1A mAb with the WT and mutant proteins. Monoclonal antibodies that differentially bound to C33Y TNFRSF1A were used to investigate the distribution of WT and mutant TNFRSF1A in TRAPS patients with the C33Y mutation. Results We identified a mAb whose binding to TNFRSF1A was completely abolished by the C33Y or C52F TRAPS-associated mutations, whereas other mutations (T50M, C88Y, R92Q) had lesser effects on the binding of this mAb. A different mAb was found to bind efficiently to all of the mutant forms of TNFRSF1A examined as well as to the WT receptor. Exploitation of the differential binding properties of these mAb indicated that mutant (as distinct from WT) TNFRSF1A showed abnormal intracellular retention in the neutrophils of TRAPS patients with the C33Y mutation, with little if any expression of mutant TNFRSF1A on the cell surface or as soluble receptor in plasma. Conclusion TRAPS-associated mutant TNFRSF1A has an antigenically altered structure and shows abnormal retention in the leukocytes of patients with TRAPS, which is consistent with previous findings from in vitro and transgenic model systems. This is consistent with a misfolded protein response contributing to the pathophysiology of TRAPS.

Objective To investigate the effect of mutations in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene on the conformation and behavior of the TNFRSF1A protein. Mutations in TNFRSF1A cause the autosomal-dominant, autoinflammatory TNFR-associated periodic syndrome (TRAPS). Methods The expression of recombinant TNFRSF1A was compared in SK–HEp-1 endothelial cells and HEK 293 epithelial cells stably transfected with full-length R347A or Δsig constructs of wild-type or TRAPS-associated mutant TNFRSF1A. TNF binding was assessed in HEK 293 cell lines expressing R347A wild-type or mutant TNFRSF1A. Homology modeling of the 3-dimensional structure of the ectodomains of wild-type and mutant TNFRSF1A was performed. Results TRAPS-associated mutant and wild-type TNFRSF1A behaved differently and had different localization properties within the cell, as a direct result of mutations in the ectodomains of TNFRSF1A. From a structural perspective, mutants with a predicted structure similar to that of the wild-type protein (e.g., R92Q) behaved similarly to wild-type TNFRSF1A, whereas forms of TNFRSF1A with mutations predicted to drastically destabilize the protein structure (e.g., cysteine mutations) showed defects in cell surface expression and TNF binding. Conclusion The results obtained from the in vitro experiments, in combination with the modeled structures, indicate that the phenotype and clinical differences between different TRAPS-associated mutants of TNFRSF1A result from different conformations of the TNFRSF1A ectodomains.

The development of animal welfare science has had a fundamental influence on the development of public policy towards the treatment of animals, not only in individual countries such as the United Kingdom, but also within the institutions of the European Union. This has led to a new a body of legislation which is intended to promote welfare and to complement the traditional prohibition on causing cruelty. If this process is to continue, however, it is important that conducting research should not be regarded as the sole function of animal welfare scientists. It is essential that they are also fully engaged in ethical debate, policy formulation, regulatory mechanisms, and their enforcement.

Objective To investigate the effect of mutations in tumor necrosis factor receptor superfamily 1A (TNFRSF1A) on the ability of the receptors to be cleaved from the cell surface upon stimulation. The mutations we studied are associated with clinically distinct forms of TNF receptor–associated periodic syndrome (TRAPS). We also investigated different cell types within the same form of TRAPS. Methods The shedding of TNFRSF1A in response to stimulation with phorbol myristate acetate was assessed in leukocytes and dermal fibroblasts from patients with C33Y TRAPS, and in HEK 293 cell lines stably transfected with constructs containing wild-type TNFRSF1A and/or TNFRSF1A mutants identified in TRAPS patients. Results The shedding of TNFRSF1A differed between cell types within the same form of TRAPS. In particular, dermal fibroblasts, but not leukocytes, from C33Y TRAPS patients demonstrated reduced shedding of TNFRSF1A. Shedding of both wild-type and mutant TNFRSF1A from the transfected HEK 293 cells showed minor differences, but was in all cases induced to a substantial extent. Conclusion Differences in TNFRSF1A shedding are not purely a function of the TNFRSF1A structure, but are also influenced by other features of genetic makeup and/or cellular differentiation. It is unlikely that a defect in TNFRSF1A shedding per se can fully explain the clinical features that are common to TRAPS patients with different TNFRSF1A mutations.

Background: The heavy usage of coxibs in Australia far outstrips the predicted usage that was based on the treatment of patients with risk factors for upper gastro-intestinal adverse events from conventional anti--inflammatory agents. This raises questions regarding the appropriateness of prescribing. Aims: To determine: (i) the relationship between prescriptions for cyclooxygenase 2 (COX-2) inhibitors and objective evidence of inflammatory arthritis, (ii) prior experience with paracetamol and/or conventional non-steroidal anti-inflammatory drugs (NSAIDs), and (iii) contraindications to the use of NSAIDs. Methods: Drug utilization evaluation and rheumato-logical assessment was conducted on 70 consecutive patients admitted on COX-2 inhibitors to a 480-bed metropolitan hospital. The main outcome measures were: the indication for COX-2 inhibitor; objective -evidence of inflammatory arthritis; previous trial of -paracetamol or conventional NSAIDs; and patient -satisfaction. Results: Only 11 patients (16%) had symptoms or signs of an inflammatory arthropathy, and met Pharmaceut-ical Benefits Schedule criteria for prescribing a COX-2 inhibitor. Fifty-nine patients (84%) had chronic osteo-arthritis, degenerative spinal disease, injury or malignancy, without overt active inflammation. Fourteen patients (20%) had trialled regular paracetamol prior to using any NSAID treatment. Conventional NSAIDs had been previously used by 51 patients (73%). Eleven patients (16%) reported previous adverse gastrointestinal effects from conventional NSAIDs. On the basis of significant renal impairment (creatinine clearance 5/10). Conclusions: Drug utilization data indicate that COX-2 inhibitors are frequently used first line for degenerative osteoarthritis in the absence of overt inflammation, without prior adequate trial of paracetamol and with disregard for the cautions and contraindications of these agents. These findings may explain the unprecedented Pharmaceutical Benefits Schedule expenditure on COX-2 inhibitors in Australia.

Bone is a frequent site of tumour metastasis and is the third most common site of metastatic carcinoma. With advances in the use of immunotherapy, hormonal manipulation, chemotherapy and radiation for the palliation of patients with metastatic bone disease, significant improvements in survival, wellbeing and overall quality of life have been achieved.

Low-rate, high-intensity behaviors, such as aggression and violence, are not uncommon in school settings. This study evaluated the utility of descriptive methods (e.g., record reviews, interviews) of functional assessment in documenting behavior function for low-rate, high-intensity behaviors. The participant, a 13-year-old boy with ADHD, exhibited low rates of aggression toward peers in school. A comprehensive record review of archival data sources (i.e., office referrals, previous school records) indicated aggression was more likely to occur during unstructured activities (e.g., recess), primarily following negative peer approaches (e.g., teasing, name-calling, or physical aggression). Descriptive information and observations led to the development and selection of potential intervention strategies. Direct observational data indicated that the peer buddy intervention was effective in reducing the number of inappropriate responses to negative peer approaches, as well as the number of aggressive incidents. Implications for utilizing descriptive data to document predictor variables and maintaining variables for low-rate, high-intensity behaviors are discussed.

Objective: To determine the effect of a request form, together with removal of proton pump inhibitors (PPIs) from ward stock, on concordance between use of PPIs and prescribing guidelines, and compare the results with a previous non-interventional audit. Design: Drug utilisation review. Setting: 800-bed metropolitan hospital. Participants: 101 patients with a completed PPI request form. Data were compared to a previous audit undertaken on 253 patients in 1999. Main outcome measures: Recorded upper gastrointestinal pathology; compliance with prescribing guidelines; PPI usage data. Results: The proportion of patients appropriately investigated increased from 72% (183/253) in 1999 to 92% (93/101, p = 0.004). Compliance with prescribing criteria increased from 23% (57/253) in 1999 to 43% (43/101, p = 0.003). PPI usage decreased by 30% compared with the corresponding quarter of 1999. Conclusions: The removal of PPIs from ward imprest along with the introduction of a PPI request form was associated with a significant improvement in compliance with prescribing guidelines, an increase in the proportion of patients appropriately investigated, and a reduction in PPI usage.