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Fortnightly Review Lower respiratory tract infection incorporates a spectrum of disease from acute bronchitis to pneumonia. The division between bronchitis and pneumonia is not always clear, but patients with focal [...]

Gail Jones' novel "One Another" explores the life of Joseph Conrad, the famous author of "Heart of Darkness," and the transformative potential of reading. The novel intertwines Conrad's life with that of Helen Ross, a young Australian postgraduate student studying Conrad's works. The narrative reveals parallels and crossings between the two characters, highlighting their shared experiences of journeying, outsider status, and awareness of the violence of colonialism. "One Another" is a novel about the power of reading and the intimate connection between reader and writer, offering a unique perspective on Conrad's life and works. [Extracted from the article]

Fms-like tyrosine kinase 3 (Flt3) is expressed on progenitor cells and acute myeloid leukemia (AML) blasts. Fms-like tyrosine kinase 3 ligand (Flt3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Conversely, Flt3+ AML is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering complete remission (CR) but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the bone marrow. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 140 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib or placebo. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney UP < .0001). Day 26 Flt3L was also associated with survival; Flt3L ≤291 pg/mL was associated with inferior event-free survival (EFS), and Flt3L >1185 pg/mL was associated with higher overall survival (OS; P = .0119). The separation of EFS and OS curves increased when minimal residual disease (MRD) status was combined with Flt3L measurement, and Flt3L retained a near-significant association with survival after adjusting for MRD in a proportional hazards model. Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML illustrates the potential value of monitoring Flt3L to identify relapse. Measurement of Flt3L is a noninvasive test with the potential to inform clinical decisions in patients with AML.

LJE & ZM and EMW & SJS contributed equally

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.

This study reports on the development of a Setswana tonal minimal pair word list, which could be implemented as research tool in the field of Bantu language linguistics and in speech pathology in South Africa. The development of the list was conducted in four phases. These are described as four separate studies. All involved Setswana L1 participants living in the urban areas of Gauteng. In Study 1, a 45-pair preliminary list was compiled from dictionaries. During Study 2, eleven L1 speakers’ familiarity with each word was determined. Based on these results the list was narrowed down to 20 pairs. Study 3 entailed the validation of pictorial stimuli, which illustrate the target words. Ten different participants took part. Four pairs were not consistently familiar and were removed, resulting in the experimental list of 16 pairs. This list was validated in Study 4 and involved nine typical L1 speakers and five listeners. Word-specific analyses revealed that some words had a negative impact on the results. Six pairs were removed. A final list of 10 pairs rendered results more aligned to the expectation of typical speakers and listeners. Validation should continue to determine applicability in populations from exclusively rural or urban areas.

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3–tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively.

When Shirley Hazzard received the National Book Award in 2003 for The Great Fire in the Marriot Ballroom in Times Square, the other guest of honour was Stephen King, who was there to receive a Medal for Distinguished Contribution to American Letters. Read more: The Australian women expats who found liberation in the US The major novels Hazzard is most cherished for the distinctive achievement of her two major novels, The Transit of Venus (1980) and The Great Fire (2003). From dysfunction and provincialism to an elegant literary life: Gail Jones reviews the "brilliant" first biography of Shirley Hazzard. [Extracted from the article]

It is predicted by industry analysts that by the year 2013, 30 percent of the international air freight market will be controlled by integrated operators. We can reasonably presume that [...]

This study examined students’ perceptions of the risks associated with microbial transmission before and after taking a microbiology class. Participants included undergraduate students (n = 132) enrolled in a microbiology course at two universities and one community college. Students completed a survey at the beginning and end of the course and a sub-sample of students also participated in pre- and post-course interviews. The survey results showed that there were changes in students’ knowledge of microbes and microbial transmission as well as changes in reported behaviors related to microbial transmission. The behavior changes primarily involved perceptions of microbial transmission via touch such as using a public telephone, touching a faucet in a public bathroom, handling money, borrowing soap from a friend while camping, working in the dirt without gloves, and taking out the trash. There were no differences in behaviors related to oral transmission (eating, drinking, and kissing) or for preventative behavior (use of sanitizing items or frequency of hand washing). Exploratory factor analysis showed a subtle shift in the conceptualization of transmission risks from pre- to post-course. Pre- and post-interviews revealed that although students gained a more sophisticated concept of the positive role of microbes in the ecosystem, they were not more likely to report changing their behaviors related to vaccines to avoid getting sick from pathogenic microbes.

The SHIELD program for Hodgkin lymphoma in patients 60 years of age or older, prospectively evaluated clinical features and outcome in a large patient cohort (n = 175). The central element was a phase 2 study of VEPEMB chemotherapy (n = 103, median age 73 years) incorporating comorbidity assessment. A total of 72 other patients were treated off-study but registered prospectively and treated concurrently with: ABVD (n = 35); CLVPP (n = 19), or other (n = 18). Of VEPEMB patients, 31 had early-stage disease (stage 1A/2A) and received VEPEMB 3 times plus radiotherapy. Median follow-up was 36 months. Complete remission (CR) rate (intention-to-treat) was 74% and 3-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. A total of 72 patients had advanced-stage disease (stage 1B/2B/3 or 4) and received VEPEMB 6 times. CR rate was 61% with 3-year OS and PFS of 66% and 58%, respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. Overall treatment-related mortality was 7%. In patients treated with curative intent with VEPEMB, ABVD, and CLVPP (n = 157), CR linked to several factors in univariate analysis. In a Cox regression model only, obtaining CR remained significant for OS and CR plus comorbidity and age for PFS. RS-EBV status had no significant effect on outcome.

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position −1377 (rs2234767) in the core promoter of the CD95cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the −1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P= .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P= .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P= .03). The −1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.

The aim of this study was to investigate the association between object relations and emotional processing deficits among a general sample of psychiatric outpatients. The sample consisted of 104 patients consecutively referred to 2 outpatient clinics. Participants completed measures of object relations, emotional processing deficits, and general psychiatric distress. After controlling for the effect of current symptom distress, we found that object relations impairment was significantly associated with emotional processing deficits relating to unregulated emotions, signs of unprocessed emotions, and emotion suppression. These findings support the notion that patients with impoverished mental structures possess maladaptive strategies for modulating intense affects.

The goal of this study was to develop a sense of how borderline personality disorder (BPD) is treated in the community. The focus was on psychotherapeutic treatments.

Presents the short story "Something Unbroken," by Gail Jones.

Objective: This paper describes the responses of 100 parents of children born with cleft lip and/or palate in South East Wales to a postal questionnaire survey of their experiences of the services available to help with the feeding of their children in the immediate postnatal period.Results and Conclusions: Prior to birth, the majority of mothers intended to breast feed their child; after birth, the majority of infants were bottle fed. The majority of mothers felt that they had been a pan of the decision to change methods. Advice on feeding was obtained from a variety of sources, both in hospital and on discharge. Mothers of cleft children who were first born in the family were less critical of the support offered in hospital than were mothers whose cleft child was a second or subsequent child. Isolated clefts of the palate were associated with a high proportion of feeding via nasogastric tube both on discharge from hospital and at home. The major criticism of the service offered to parents and their children was the poor quality of advice on feeding their children, both in hospital and on discharge. A variety of mechanisms for service improvement are suggested.

The Canadian Professional Coaching Association (CPCA) recently developed a code of ethics for coaches that was based on the Canadian Psychological Association's ethical code. Because the CPCA did not use coaches' actual experiences to develop their code, we solicited sport-related ethical concerns from coaches to determine the comprehensiveness of the code. Twelve male and seven female coaches from both individual and team sports, as well as from various levels of sport, participated in focus group sessions. Content analyses of the transcribed sessions identified nine major areas of ethical concern. Illustrations of these nine areas are presented and discussed in relation to the four principles that form the basis of CPCA's Code of Ethics.

Presents the short story `Queenie the Wordless.'

Presents the short story `The Reincarnation of Madame Tussaud.'

In the original version of this article, the mention of ‘ifosfamide 1500 mg/m2days 1–3’ should, in fact, read ‘ifosfamide 1500 mg/m2bd days 1–3’. This has now been updated in the original version of the article.

Stoelzel: JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Personalised medicine is predicted to significantly improve outcomes for cancer patients, but implementation requires comprehensive genetic characterisation of malignant cells to identify therapeutically exploitable vulnerabilities. Using an isogenic cell model system with CRISPR-inactivated TET2in HEL acute myeloid leukemia (AML) cells and an orthotopic mouse xenograft model we demonstrate that mutant TET2allele dosage significantly affects sensitivity to 5-azacitidine hypomethylating therapy in AML, with biallelic mutation conferring hypersensitivity relative to monoallelic mutation. In the presence of 5-azacitidine, cell clones with biallelic TET2mutation had significantly lower cloning efficiency (P= 3 x 10-3) and proliferation in liquid culture (P< 1 x 10-4) compared to isogenic clones with monoallelic TET2mutation. Mixed populations of monoallelic and biallelicTET2mutated HEL AML cells were transplanted via intrafemoral injection into Rag2−/−Il2rg−/−129×Balb/c mice, and treatment with 5-azacitidine resulted in significant negative in vivoselection against TET2null cells relative to cells with monoallelic TET2mutation (P= 4 x 10-4). Methylation analysis revealed the acquisition of an overall hypermethylation phenotype in TET2null cells and RNA sequencing identified significant down-regulation of ABCB1transcript, resulting in concomitant pronounced down-regulation of the MDR1 drug efflux transporter at the protein level. RNA sequencing pathway analysis also identified a global effect on ribosome pathway (KEGG pathway ko03010) transcript levels (Padjusted= 0.002), evidenced by down-regulation of numerous RNA polymerase II components in cells with bi-allelic TET2mutation compared to cells with monoallelic TET2mutation.

Pollard: Vertex Pharmaceuticals (Europe) Ltd.: Employment.

A personal narrative is presented which explores the author's experience of visiting Windjana Gorje in Kimberley Region, Western Australia to witness the staging of "Jandamarra," a play dedicated to the life of the Bunuba lawman and warrior who fought against colonial settlers from 1894-1897.

This article explores the creation of an original collage theater with teen theatre students addressing the issue of eating disorders among teenagers. Information is presented on the goal for the acting ensemble. The process involved instructing students to write a dramatic material in various forms including poetry, songs or monologues. Lessons learned during the rehearsal process are discussed, along with observations about the process and production of "Starving for Perfection."

No relevant conflicts of interest to declare.

Off Label Use: Gemtuzumab Ozogamicin for AML.

Central venous catheter bloodstream infections (CVC BSIs) cause substantial morbidity and are extremely costly. The Michigan Keystone Intensive Care Unit (ICU) project in 2004-5 demonstrated that interventions designed to reduce the incidence of CVC BSIs significantly reduced infection rates in US ICU patients (NEJM 2006;355:2725-32). The ‘Matching Michigan’ initiative in England between 2009-11 ascertained that the adoption of these interventions also led to a reduction of CVC BSIs in patients managed in English ICUs (BMJ Qual Saf 2013;22:110-23). This strong evidence base and involvement in local National Health Service Commissioning for Quality and Innovation (CQUIN) schemes, designed to incentivise hospitals to meet quality targets, led us to collect data on CVC BSIs in hematology patients within our hospital trust. Information was collected before and after the implementation of best practice guidance regarding the insertion and maintenance of CVCs, using complex strategies similar to those employed by the Keystone ICU project.Data was collected prospectively from all patients managed in the cancer unit at Newcastle upon Tyne Hospitals, UK. Our unit undertakes approximately 80 allografts and 80-100 autografts annually and is a regional centre for high dose chemotherapy for acute leukemia and lymphoma. Over a 23 month period, between July 2011-May 2013, we collected data on CVC patient days and CVC BSIs. Clinical and microbiological data were correlated monthly. Using these data, a clinical team determined whether infections were unrelated to the CVC, CVC associated (CABSI) or CVC related (CRBSI). Standardised definitions and a standardised decision tree were used as per the ‘Matching Michigan’ methods. In April 2012, interventions aimed at minimising CVC BSIs were introduced and developed over several months. These technical and non-technical interventions were based on national best practice guidance. They included observation and standardisation of nursing and medical catheter care and catheter insertion, focused staff and patient education and monthly feedback of outcomes at ward level. From April 2012, reduction of CVC BSIs became a CQUIN quality target for our unit.There were 2530 mean CVC patient days per month between July 2011-May 2013. More than 95% of those days related to long-term rather than short-term catheters. During this period there were 254 CVC BSIs. Pre-intervention the average rate of infection (CRBSI and CABSI) per 1000 CVC days over a quarterly period was 6.2. Post-intervention, there was a significant reduction in the rate of infection during a quarterly period to 3.56 per 1000 CVC days (p=<0.05).Implementation of best practice guidance, measurement of infection rates and real-time feedback to staff, led to a significant reduction in CVC BSIs in hematology patients. Our findings support the evidence that targeting specific practices significantly reduces the rate of CVC BSIs. They also demonstrate, for the first time, that these methods can be translated from an ICU setting to hematology patients.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 756

The article presents several physicians' reactions regarding the American Urological Association's (AUA) recommendations that prostate-specific antigen (PSA) testing should start at age 40. Maury Jayson seconds the recommendation saying that he has seen prostate cancer cases at early ages. Jeffrey W. Zipkin comments that he is still not sure of having the age 40 as the baseline testing. Gail Reede Jones expresses her concerns on regarding the baseline testing age.

We report our experience of alemtuzumab at 30mg (day -2) for MRD and 60mg (30mg day -4 and day -2) for MUD transplants, which was adopted as standard GVHD prophylaxis for FM transplantation at our centre in 2006. We avoided giving alemtuzumab on day -1, since there is a steep drop in alemtuzumab level in the first 24 hours after infusion and the timing of stem cell infusion may vary considerably, especially with unrelated donor grafts. From May 2006 to May 2009, 24 patients received MRD and 27 patients received MUD transplants. Post transplant serum samples were available from 19 MRD transplants and 15 MUD transplants at day +1. In addition, day +3 samples were identified from 10 patients previously transplanted with 100mg alemtuzumab, 10 MUD receiving 60mg and 10 MRD transplants receiving 30mg. All patients gave consent for clinical follow up and post transplant serum sampling for research purposes, according to protocols approved by the local research ethics committee of Northumberland and North Tyneside. Alemtuzumab concentration was measured by a validated flow cytometry assay, as previously described.The mean (SEM) alemtuzumab concentration (micrograms/ml) on day +1 was 2.9 (0.3) after 30mg and 4.6 (0.6) after 60mg (t test p<0.01). On day +3 the levels were 2.4 (0.2); 4.0 (0.6); 8.4 (1.9) after 30mg, 60mg and historical controls of 100mg, respectively (p<0.05 between each dosing level). There were significant inverse correlations between patient surface area and alemtuzumab concentration by linear regression for both 30mg (r2 0.51 p<0.01) and 60mg dosing (r2 0.18 p<0.05). A trend for lower alemtuzumab with increasing cell dose was also observed, although this may be related indirectly to patient weight. All patients achieved >95% myeloid engraftment by day 100. Median (range) T cell engraftment was variable and significantly higher after MUD transplants: 70% (9-99%) than MRD transplants: 21% (5-85%; Mann Witney p <0.05). T cell chimerism was inversely correlated with alemtuzumab level in MRD transplants by linear regression (r2 0.37; p <0.05) but this trend was not apparent in MUD transplants. The incidence of acute GVHD was also greater after MUD transplantation at 47% (grade I or II) compared with 11% (grade I only) for MRD recipients. There was no significant relationship between GVHD grade and alemtuzumab level in either group. There were 2/24 non-relapse deaths after MRD and 3/27 following MUD transplantation; none were due to GVHD. The incidence of chronic GVHD is currently being evaluated.This analysis demonstrates predictable dose and surface-area relationships with alemtuzumab level in patients receiving FM conditioning. It also reveals that significantly less than 100mg alemtuzumab confers reliable GVHD prophylaxis in both MRD and MUD recipients, although at least twice the level of alemtuzumab is required to achieve comparable GVHD control in MUD transplants. Finally, it is notable that T cell chimerism at day 100 is directly related to alemtuzumab level at day +1 in MRD transplants. We conclude that optimisation of immune reconstitution and GVHD control using alemtuzumab in vivo depends upon due consideration of both recipient and donor factors, notably the size of the recipient and the origin of the graft.Groves: BioAnaLab: Employment. Hale:BioAnaLab: Employment, Equity Ownership.

Gail Jones from Broadgreen International School describes her experience of the National Learning Platforms Conference 2009

In 1993, the ASCP Board of Registry began a 10-year prospective study of the career patterns of 412 newly MT(ASCP)-certified persons. The Board examined the changes in core, advanced technical, and management job tasks of these MTs during their first 5 years of work. In the first year, the MTs did core tasks more frequently than advanced technical or management tasks. Five years later, they still did core tasks frequently and had acquired additional advanced technical and management tasks. The entry-level task mix of MTs was the same regardless of gender, ethnicity, job title, facility location, or degree.