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Objective and Methods: A review conducted in 2005 identified many of the communication difficulties experienced by patients and doctors when discussing phase 1 (P1) oncology trials. The current paper is an update of the area and focuses on studies that measure patient comprehension of information given during the P1 trial discussion and ways to enhance understanding. A literature search was performed for relevant articles published between January 2005 and July 1st 2009.Results: Only 12/109 studies met the criteria for inclusion in the review. One study recorded the actual trial discussion and compared patients' understanding with what the clinician had communicated. The others used interview techniques and surveys to elicit patients' understanding of P1 trials, motivations for considering trials and expectations of benefit. Two examined interventions to aid patient understanding.Conclusion: Explaining potential participation in a P1 trial with a patient with cancer is not an easy task: the doctor must ensure that the patient has an accurate understanding of their condition and that standard treatments have now been exhausted. This must be followed by admission of the probable lack of any therapeutic benefit from the P1 drug together with the possibility that there might be unwanted side effects, many of which are unknown. These are all challenging subjects. New educational initiatives informed through research conducted with patients and health care professionals are currently being developed and clearly much needed. [ABSTRACT FROM AUTHOR]

Healthcare professionals often censor their information giving to patients in an attempt to protect them from potentially hurtful, sad or bad news. There is a commonly expressed belief that what people do not know does not harm them. Analysis of doctor and nurse/patient interactions reveals that this well-intentioned but misguided assumption about human behaviour is present at all stages of cancer care. Less than honest disclosure is seen from the moment that a patient reports symptoms, to the confirmation of diagnosis, during discussions about the therapeutic benefits of treatment, at relapse and terminal illness. This desire to shield patients from the reality of their situation usually creates even greater difficulties for patients, their relatives and friends and other members of the healthcare team. Although the motivation behind economy with the truth is often well meant, a conspiracy of silence usually results in a heightened state of fear, anxiety and confusion - not one of calm and equanimity. Ambiguous or deliberately misleading information may afford short-term benefits while things continue to go well, but denies individuals and their families opportunities to reorganize and adapt their lives towards the attainment of more achievable goals, realistic hopes and aspirations. In this paper, some examples and consequences of accidental, deliberate, if well-meaning, attempts to disguise the truth from patients, taken verbatim from interviews, are given, together with cases of unintentional deception or misunderstandings created by the use of ambiguous language. We also provide evidence from research studies showing that although truth hurts, deceit may well hurt more. 'I think the best physician is the one who has the providence to tell to the patients according to his knowledge the present situation, what has happened before, and what is going to happen in the future' (Hippocrates). [ABSTRACT FROM AUTHOR]

Abstract Background The General Health Questionnaire (GHQ) - 12 was designed as a short questionnaire to assess psychiatric morbidity. Despite the fact that studies have suggested a number of competing multidimensional factor structures, it continues to be largely used as a unidimensional instrument. This may have an impact on the identification of psychiatric morbidity in target populations. The aim of this study was to explore the dimensionality of the GHQ-12 and to evaluate a number of alternative models for the instrument. Methods The data were drawn from a large heterogeneous sample of cancer patients. The Partial Credit Model (Rasch) was applied to the 12-item GHQ. Item misfit (infit mean square ≥ 1.3) was identified, misfitting items removed and unidimensionality and differential item functioning (age, gender, and treatment aims) were assessed. The factor structures of the various alternative models proposed in the literature were explored and optimum model fit evaluated using Confirmatory Factor Analysis. Results The Rasch analysis of the 12-item GHQ identified six misfitting items. Removal of these items produced a six-item instrument which was not unidimensional. The Rasch analysis of an 8-item GHQ demonstrated two unidimensional structures corresponding to Anxiety/Depression and Social Dysfunction. No significant differential item functioning was observed by age, gender and treatment aims for the six- and eight-item GHQ. Two models competed for best fit from the confirmatory factor analysis, namely the GHQ-8 and Hankin's (2008) unidimensional model, however, the GHQ-8 produced the best overall fit statistics. Conclusions The results are consistent with the evidence that the GHQ-12 is a multi-dimensional instrument. Use of the summated scores for the GHQ-12 could potentially lead to an incorrect assessment of patients' psychiatric morbidity. Further evaluation of the GHQ-12 with different target populations is warranted.

Background: Respiratory syncytial virus (RSV) causes significant disease burden in older adults. MVA-BN-RSV is a novel poxvirus-vectored vaccine encoding internal and external RSV proteins., Methods: In a phase 2a randomized double-blind, placebo-controlled trial, healthy participants aged 18 to 50 years received MVA-BN-RSV or placebo, then were challenged 4 weeks later with RSV-A Memphis 37b. Viral load was assessed from nasal washes. RSV symptoms were collected. Antibody titers and cellular markers were assessed before and after vaccination and challenge., Results: After receiving MVA-BN-RSV or placebo, 31 and 32 participants, respectively, were challenged. Viral load areas under the curve from nasal washes were lower (P = .017) for MVA-BN-RSV (median = 0.00) than placebo (median = 49.05). Total symptom scores also were lower (median = 2.50 and 27.00, respectively; P = .004). Vaccine efficacy against symptomatic, laboratory-confirmed or culture-confirmed infection was 79.3% to 88.5% (P = .022 and .013). Serum immunoglobulin A and G titers increased approximately 4-fold after MVA-BN-RSV vaccination. Interferon-γ-producing cells increased 4- to 6-fold after MVA-BN-RSV in response to stimulation with the encoded RSV internal antigens. Injection site pain occurred more frequently with MVA-BN-RSV. No serious adverse events were attributed to vaccination., Conclusions: MVA-BN-RSV vaccination resulted in lower viral load and symptom scores, fewer confirmed infections, and induced humoral and cellular responses., Clinical Trials Registration: NCT04752644., Competing Interests: Potential conflicts of interest. G. K. is a former employee of hVIVO. E. J., S. S., G. S., D. Sc., D. St., B. M., V. J., H. W., and L. D. M. are current employees of Bavarian Nordic and hold stock or stock options in the company. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Respiratory syncytial virus (RSV) is a common cause of paediatric respiratory tract infection and causes a significant health burden in older adults. Natural immunity to RSV is incomplete, permitting recurrent symptomatic infection over an individual's lifespan. When combined with immunosenescence, this increases older adults' susceptibility to more severe disease symptoms. As RSV prophylaxis is currently limited to infants, older adults represent an important target population for RSV vaccine development. The relationship between RSV and our immune systems is complex, and these interactions require deeper understanding to tailor an effective vaccine candidate towards older adults. To date, vaccine candidates targeting RSV antigens, including pre-F, F, G (A), G (B), M2-1, and N, have shown efficacy against RSV infection in older adults in clinical trial settings. Although vaccine candidates have demonstrated robust neutralising IgG and cellular responses, it is important that research continues to investigate the RSV immune response in order to further understand how the choice of antigenic target site may impact vaccine effectiveness. In this article, we discuss the Phase 3 vaccine candidates being tested in older adults and review the hurdles that must be overcome to achieve effective protection against RSV.

Health control measures instituted in 2020 to mitigate the COVID-19 pandemic decreased the case numbers of many infectious diseases across Europe. One notable exception was tick-borne encephalitis (TBE). In Austria, Germany, Switzerland, Lithuania, and the Czech Republic, the upturn was significantly higher compared to the average of the three years previously (P<0.05), with increases of 88%, 48%, 51%, 28%, and 18%, respectively. Six countries reported TBE incidences of ≥5 cases/100,000, defined as highly endemic by the World Health Organization (WHO). Possible factors contributing to this surge may include increased participation in outdoor activities in endemic regions and increased tick counts/tick activity. In highly endemic regions, the WHO recommends that vaccination be offered to all age groups, including children., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Adult vaccination in Australia is suboptimal. For instance, as few as one in nine people have received a pertussis vaccine in adolescence or adulthood, despite increasing disease burden and evidence of a positive correlation between older age and hospitalization rates. The objectives of this study were to describe general practitioners' (GPs) and adult consumers' knowledge and attitudes toward adult vaccination, with an emphasis on pertussis. Australian GPs and consumers were recruited in two nationally representative online surveys repeated annually between 2014 and 2018. Vaccination discussions occurred in a minority of adult/GP encounters. Pertussis was among the five most frequently identified vaccine preventable diseases but was unlikely to be proactively discussed with adults not in contact with young children. Among consumers, only one in three recalled ever receiving a pertussis vaccination. GPs are a strong predictor of adults receiving a pertussis vaccine. Possible factors contributing to low uptake are misconceptions around pertussis disease, vaccination requirements and lack of GP recommendation for adult vaccination. GPs have a key role to play in increasing adult vaccination coverage with their recommendation.

Infectious diseases can impact chronic medical conditions. However, it is currently not clear how pertussis correlates with preexisting or underlying disorders. We reviewed literature from the last 25 years to describe the burden and impact of pertussis infection in specific risk groups in individuals aged ≥11 years. Our literature search returned 543 hits, of which 18 were eligible for this review. Adolescents and adults with underlying conditions, such as asthma, chronic obstructive pulmonary disease (COPD), or obesity are potentially at increased risk of pertussis infection. Immunodeficiency and smoking have also been associated with worsened pertussis symptoms and an increased pertussis-related hospitalization rate. In patients with pertussis and preexisting asthma or COPD, symptoms were worsened, and health-care costs were consequently increased. Further efforts are needed to close the knowledge gap and to understand the burden of pertussis in at-risk adolescent and adult populations to help inform vaccination strategies and recommendations.

Introduction Infants too young to be fully immunized are the most vulnerable to severe pertussis disease. To close this susceptibility gap, passive infant immunization through vaccination of pregnant women against pertussis was first introduced in 2011 in the United States and has been extended since then to more than 40 countries. Areas covered We conducted two systematic literature searches to describe the worldwide burden of pertussis disease in infants <6 months of age since 2005, and the effectiveness and impact of maternal pertussis vaccination in preventing infant pertussis since 2011. Expert opinion Pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Virtually all pertussis deaths occurred in this age group. Data from Africa, Eastern Mediterranean, and Asia were limited, but suggest a similar or higher disease burden than in Europe or the Americas. Estimates of effectiveness of second/third trimester pertussis vaccination in preventing pertussis disease in <2-3 months old infants were consistently high (69%-93%) across the observational studies reviewed, conducted in various settings with different designs. Maternal vaccination programs appear to be achieving their goal of reducing the burden of disease in very young infants. Plain language summary What is the context? Pertussis, also known as whooping cough, is a highly contagious disease of the respiratory tract. Infants too young to be fully vaccinated are at the highest risk of severe pertussis disease, hospitalization, and death. Vaccinating pregnant women against pertussis with a Tdap vaccine is recommended in more than 40 countries as a safe and effective strategy to protect infants for the first months of life. What is new? This review summarizes recent literature describing the burden of pertussis disease in infants worldwide prior to the introduction of maternal vaccination programs; pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Immunization of pregnant women with a Tdap vaccine can prevent about 70-90% of pertussis disease and up to 90.5% of pertussis hospitalizations in infants under 3 months of age. What is the impact? Limited available data suggest that incidence rates of pertussis disease after the introduction of Tdap maternal immunization have declined in infants. Current knowledge supports the implementation of Tdap maternal immunization programs.

Objective: Sexual well-being can contribute significantly to the overall quality of women's lives. This qualitative study aimed to examine sexual activity, functioning, and satisfaction in a large sample of postmenopausal women from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) METHODS:: Thematic analysis was used to evaluate the free-text data of the Fallowfield Sexual Activity Questionnaire (FSAQ) completed by UKCTOCS participants at baseline before annual screening., Results: A total of 24,305 women completed the baseline FSAQ and 4,525 (19%) provided free-text data, with 4,418 comments eligible for analysis. Median age was 64 years; 65% had a partner and 22.5% were sexually active. Four interrelated themes were derived: partner availability, physical and sexual health, mental well-being, and interpersonal relationships. Primary reason for absence of sexual activity was lack of a partner, mainly due to widowhood (n = 1,000). Women discussed how partner's medical condition (27%) or sexual dysfunction (13.5%), their own physical health (18%) or menopause-related symptoms (12.5%), and prescribed medication (7%) affected sexual activity. Impact of low libido in self (16%) or partner (7%), relationship problems (10.5%) or logistics (6%), and perceptions of ageing (9%) were also mentioned. Few (3%) referred to positive sexual experiences or had sought medical help for sexual problems (6%)., Conclusions: This qualitative analysis explored postmenopausal women's perspective on their sexual functioning. Having an intimate partner and good physical health are key factors for continuation of sexual activity and satisfaction. Further sexual education for healthcare professionals is needed to raise awareness about sexuality and sexual difficulties in later life. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A426.

Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.

Purpose: The use of novel and often expensive drugs offering limited survival benefit in advanced disease is controversial. Treatment recommendations are influenced by patient characteristics and trial data showing overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). PFS is frequently the primary outcome in licencing studies., Patients and Methods: As part of a longitudinal study Assessing the 'VALue' to patients of PROgression Free Survival (AVALPROFS), oncologists completed checklists at baseline following consultations with patients. Questions probed perceived clinical benefits of the drugs to populations in general. Patients completed study-specific interview schedules at baseline, 6 weeks into treatment, and at withdrawal due to toxicity or progression. Patients also completed tumour- and treatment-specific quality of life questionnaires monthly for their time in the study. Only baseline results are reported here., Results: Thirty-two UK oncologists discussed management options with 90 patients with heterogeneous advanced cancers. Oncologists' estimates of medical benefit in general from treatment varied between 10 and 80 %. They expected 46/90 (51 %) of their patients to derive some clinical benefit from the prescribed treatment but were either unsure or expected none for 44/90 (49 %). Predictions of life expectancy were variable but 62 % (56/90) of patients were expected to survive longer with treatment. A majority of patients 51/90 (57 %) had 'no idea' or were 'unclear' what PFS meant and 45/90 (50 %) thought extension of life was the primary therapeutic aim of treatment., Conclusion: Discussions between doctors and patients with metastatic disease about future management plans and likely therapeutic gains are challenging. Factors influencing decisions about putative benefits of novel drugs are often applied inconsistently can be overly optimistic and may even contradict published data.

The majority of men treated for prostate cancer will eventually develop castrate-resistant disease (CRPC) with metastases (mCRPC). There are several options for further treatment: chemotherapy, third-line hormone therapy, radium, immunotherapy, and palliation. Current ASCO guidelines for survivors of prostate cancer recommend that an individual's information needs at all stages of disease are assessed and that patients are provided with or referred to the appropriate sources for information and support. Earlier reviews have highlighted the dearth of such services and we wished to see if the situation had improved more recently. Unfortunately, we conclude that there is still a lack of good-quality congruent information easily accessible specifically for men with mCRPC and insufficient data regarding the risks, harms, and benefits of different management plans. More research providing a clear evidence base about treatment consequences using patient reported outcome measures is required.

A key component to the success of Mycobacterium tuberculosis as a pathogen is the ability to sense and adapt metabolically to the diverse range of conditions encountered in vivo, such as oxygen tension, environmental pH and nutrient availability. Although nitrogen is an essential nutrient for every organism, little is known about the genes and pathways responsible for nitrogen assimilation in M. tuberculosis. In this study we have used transcriptomics and chromatin immunoprecipitation and high-throughput sequencing to address this. In response to nitrogen starvation, a total of 185 genes were significantly differentially expressed (96 up-regulated and 89 down regulated; 5% genome) highlighting several significant areas of metabolic change during nitrogen limitation such as nitrate/nitrite metabolism, aspartate metabolism and changes in cell wall biosynthesis. We identify GlnR as a regulator involved in the nitrogen response, controlling the expression of at least 33 genes in response to nitrogen limitation. We identify a consensus GlnR binding site and relate its location to known transcriptional start sites. We also show that the GlnR response regulator plays a very different role in M. tuberculosis to that in non-pathogenic mycobacteria, controlling genes involved in nitric oxide detoxification and intracellular survival instead of genes involved in nitrogen scavenging., (© 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Background: Appreciation of the barriers and drivers affecting enrolment in randomised clinical trials (RCTs) is important for future trial design, communication and information provision., Methods: As part of an intervention to facilitate UK multidisciplinary team communication about RCTs, women with breast cancer who discussed trials with doctors or research nurses completed questionnaires examining i) clarity of trial information and ii) reasons for their trial decision., Results: 152 women completed the questionnaires; 113/152 (74%) consented to RCT enrolment. Patients' satisfaction with communication about the trial information was very good, irrespective of participation decisions. Acceptors' and decliners' responses to 9/16 statements concerning decisions about trial participation differed significantly. 'Wanting to help with doctor's research' influenced 100% acceptors compared to 57% of decliners (p < 0.001). Decliners were more likely to be 'worried about randomisation' (20 vs. 39%; p < 0.035) and to 'want doctor to choose treatment rather than be randomised' (31 vs. 53%; p < 0.031). Primary reason for trial acceptance was altruism; 'I feel that others with my illness will benefit from the results of the trial', 58/108 (54%)., Conclusion: A majority of women accepted RCT entry citing altruistic motivations as the primary driver for participation. Trial design and setting (metastatic or adjuvant) had little impact on participation.

Background: Intravenous (IV) drug delivery is commonly used for its rapid administration and immediate drug effect. Most studies compare IV to subcutaneous (SC) delivery in terms of safety and efficacy, but little is known about what patients prefer., Methods: A systematic review was conducted by searching seven electronic databases for articles published up to February 2014. Included studies were randomized controlled trials (RCTs) and/or crossover designs investigating patient preference for SC versus IV administration. The risk of bias in the RCTs was determined using the Cochrane Collaboration tool. Reviewers independently extracted data and assessed the risk of bias. Any discrepancies were resolved by consensus., Results: The search identified 115 publications, but few (6/115) met the inclusion criteria. Patient populations and drugs investigated were diverse. Four of six studies demonstrated a clear patient preference for SC administration. Main factors associated with SC preference were time saving and the ability to have treatment at home. Only three studies used study-specific instruments to measure preference., Conclusions: Results suggest that patients prefer SC over IV delivery. Patient preference has clearly been neglected in clinical research, but it is important in medical decision making when choosing treatment methods as it has implications for adherence and quality of life. If the safety and efficacy of both administration routes are equivalent, then the most important factor should be patient preference as this will ensure optimal treatment adherence and ultimately improve patient experience or satisfaction. Future drug efficacy and safety studies should include contemporaneous, actual patient preference where possible, utilizing appropriate measures.

Background: The ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown., Results: A global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation., Conclusions: Application of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments.

Background: Nitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms., Results: We investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding., Conclusions: We have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions.

Background: Previous research has shown that communication between members of multidisciplinary teams (MDTs) is often suboptimal and communication about trials between MDTs and their patients is difficult. Educational interventions can help dyadic exchanges with different aspects of trial recruitment but less work has focussed on team interventions., Methods: 22 multidisciplinary cancer teams in the UK participated in an RCT of a novel Teams Talking Trials (TTT) Workshop aimed at improving the following: awareness, involvement, communication and recruitment to cancer trials. MDTs were randomised following either 6 or 12 months of audits, which were repeated after the intervention. Audits included numbers approached about trials, team members' attitudes, involvement and awareness of their teams' trial portfolios., Results: There was no significant difference in the rate of approaching patients about trials post workshop (estimated improvement 22% higher regression coefficient of 0.2, exp. (0.2)=1.22). There was improvement in team members' involvement in trials in 4 areas (p≤0.04): the pressure to enter patients into RCTs, the likelihood of a start-up meeting to discuss a newly accepted trial, the informational role played by individuals and recognition of this HCP's role by other team members. Also, confidence in communication about RCTS increased and awareness of different aspects of trial management improved on all 14 aspects (p=0.001)., Conclusion: Attendance by teams at focussed workshops designed to enhance communication and trial recruitment improved several aspects of team functioning, but a significant impact on the number of patients approached could not be demonstrated., (Copyright © 2013 Elsevier Inc. All rights reserved.)

PII proteins are pivotal regulators of nitrogen metabolism in most prokaryotes, controlling the activities of many targets, including nitrogen assimilation enzymes, two component regulatory systems and ammonium transport proteins. Escherichia coli contains two PII-like proteins, PII (product of glnB) and GlnK, both of which are uridylylated under nitrogen limitation at a conserved Tyrosine-51 residue by GlnD (a uridylyl transferase). PII-uridylylation in E. coli controls glutamine synthetase (GS) adenylylation by GlnE and mediates the NtrB/C transcriptomic response. Mycobacteria contain only one PII protein (GlnK) which in environmental Actinomycetales is adenylylated by GlnD under nitrogen limitation. However in mycobacteria, neither the type of GlnK (PII) covalent modification nor its precise role under nitrogen limitation is known. In this study, we used LC-Tandem MS to analyse the modification state of mycobacterial GlnK (PII), and demonstrate that during nitrogen limitation GlnK from both non-pathogenic Mycobacterium smegmatis and pathogenic Mycobacterium tuberculosis is adenylylated at the Tyrosine-51 residue; we also show that GlnD is the adenylyl transferase enzyme responsible. Further analysis shows that in contrast to E. coli, GlnK (PII) adenylylation in M. tuberculosis does not regulate GS adenylylation, nor does it mediate the transcriptomic response to nitrogen limitation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Nitrogen is an essential element for bacterial growth, and as such, bacteria have evolved several pathways to assimilate nitrogen and adapt to situations of nitrogen limitation. However, the adaptation of mycobacteria to nitrogen stress and the regulation of the stress response pathways is unknown. Identification of key metabolites produced by mycobacteria during nitrogen stress could therefore provide important insights into mycobacterial survival strategies. Here we used NMR-based metabolomics to monitor and quantify intracellular and extracellular metabolite levels (metabolic footprinting) in Mycobacterium smegmatis grown under nitrogen-limiting and nitrogen-rich conditions. There were several metabolic differences between the two conditions: following nitrogen run-out, there was an increase in intracellular α-ketoglutarate and a decrease in intracellular glutamine and glutamate levels. In addition, a sugar-derived compound accumulated in nitrogen-starved cells that was subsequently assigned as glucosylglycerate (GGA). Free GGA production was responsive to nitrogen stress in M. smegmatis but not to oxidative or osmotic stress; lack of a functional GGA synthesis pathway slightly reduced growth and decreased ammonium uptake rates under nitrogen-limiting conditions. Hence, GGA could contribute to the fitness of mycobacteria under nitrogen limitation.

Nitrogen is an essential element required for bacterial growth and consequently bacteria must adapt to situations of nitrogen limitation for survival. The transcriptional response to nitrogen limitation in Mycobacterium smegmatis is thought to be regulated by GlnR, although, to date, only five nitrogen metabolism genes have been shown to be under its direct control. GlnR belongs to the OmpR family of two-component response regulators that are typically activated by phosphorylation of a conserved aspartate residue. The M. smegmatis GlnR protein contains the highly conserved aspartate residue (D48) corresponding to the phosphorylation sites identified in other OmpR family regulators. In this study, we replaced GlnR D48 with alanine and constructed a GlnR deletion mutant. Under nitrogen-limiting conditions, both the GlnR&#95;D48A and GlnR deletion mutants exhibited reduced growth rates compared with wild type. Transcriptional analysis showed both mutants failed to up-regulate the expression of GlnR-controlled genes under nitrogen-limiting conditions. We therefore demonstrate that the GlnR aspartate (D48) residue is essential for its function as a nitrogen-stress transcriptional response regulator in M. smegmatis., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Background: Discussing early-phase cancer trials is challenging; most offer little personal benefit to patients with life-limiting illnesses who frequently have a poor understanding of and misconceptions about the therapeutic aims. We evaluated an evidence-based training program aimed at enhancing communication., Methods: Prior to and after the intervention, 47 health care professionals (HCPs) experienced in early-phase trial recruitment were audio taped discussing trials with patient simulators who completed postinterview evaluations. Coders rated the interviews for the presence of information areas required to elicit ethical consent. HCPs reported their self-confidence on 15 different aspects of trial discussion., Results: Significant objective and subjective improvements in communication were found after the workshop. Analyses of audio tapes showed positive shifts in: establishing the patient's knowledge of their prognosis (odds ratio [OR], 2.7; p = .002), discussing symptomatic care (OR, 3.8; p < .001), the aims of the trial (OR, 2.6; p =.002), and the unlikelihood of medical benefit (OR, 3.0; p = .021). Patient simulator ratings showed improvements in: the awareness of palliative care and symptom control (OR, 2.1; p = .004), the voluntariness of participation (OR, 3.7; p = .015), the opportunity to ask questions (OR, 2.9; p = .044), and the time to consider participation (OR, 6.1; p = .009). HCPs' self-confidence increased significantly for all 15 items (OR range, 1.5-2.9; p ≤ .001)., Conclusion: This short, intensive workshop changed communication skills competency and self-efficacy in ways likely to promote valid, ethically informed consent from patients contemplating trial entry.

Objectives: To determine the views of patients and members of the public about who should pay for expensive new cancer drugs not recommended by the National Institute for Health and Clinical Excellence (NICE)., Design: A study-specific questionnaire was used to elicit the views of patients and the general public between April and June 2010. It examined whether participants thought patients should be told about all possible cancer treatments, if the NHS should always fund non-NICE recommended drugs and attitudes towards self-funding/co-payments. The influence of sociodemographic factors on responses was also examined., Setting: Oncology clinics in Sussex and various locations including old persons' lunch clubs, parks, sports venues and support groups., Participants: Two hundred and 10 patients with common solid tumours, and 416 members of the general public, Main Outcome Measures: Frequencies of responses to items regarding payments for expensive anti-cancer drugs stratified by sociodemographic factors and comparison of responses between patients and members of the public., Results: Most respondents (70% [147/210] of patients and 64% [266/416] of the general public) had heard of NICE. Both groups believed that doctors should tell patients about all available cancer treatments even if the NHS cannot pay (94%, 196/208; 93%, 388/415). However, only 49% (101/207) of patients and 36% (146/409) of the public believed that the NHS should always fund all new cancer drugs that have failed health technology assessments. Strong predictors of willingness to purchase expensive new cancer drugs included younger age (<45 years), sex (female) and higher educational level., Conclusion: The general population appear realistic about the difficulties of providing funding for expensive new drugs. A communication skills training course has been developed to help clinicians with these difficult consultations.

Background: Mild cognitive impairments have been recorded in cross-sectional studies of women with breast cancer receiving endocrine treatment. More comprehensive studies were warranted because aromatase inhibitors are being used increasingly in both chemoprevention and adjuvant settings. We report findings from the cognitive subprotocol of the International Breast Intervention Study (IBIS II), a double-blind placebo-controlled trial of anastrozole in postmenopausal women at high risk of developing breast cancer. We aimed to study and compare the effect of anastrozole versus placebo on memory and attention in these women., Methods: Between Jan 3, 2003, and Dec 21, 2005, participants were recruited into the cognitive subprotocol from five UK centres. Cognitive assessments were done before randomisation, at 6 months, and at 24 months. 227 of 249 women approached completed a comprehensive set of standardised cognitive tasks at baseline and were randomly assigned to receive anastrozole (1 mg/day for 5 years) or placebo. Psychological morbidity, endocrine symptoms, and self-reported cognitive complaints were also measured. The main outcomes were cognitive task scores at baseline, 6 months, and 24 months. Analyses were done by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN31488319., Findings: 111 women were assigned to anastrozole and 116 women to placebo. At 6 months, ten women in each group were excluded from analysis, leaving a total of 207 of 227 (91%) women available for further assessments. At 24 months, 24 women were excluded from the anastrozole group and 32 from the placebo group, leaving 151 of 227 (67%) women. We did not note any significant differences between the groups for any of the cognitive tasks. By 6 months, 13 women in both groups reported changes to their memory and this had decreased to five women in the placebo group and three women in the anastrozole group by the 24-month assessment. Significantly more women in the anastrozole group complained of hot flushes at 24 months (23 of 76 [30%] vs 11 of 73 [15%], p=0.032, not corrected for multiple comparison), but this was the only difference in reported endocrine symptoms., Interpretation: These findings show little or no impairment of cognitive performance with the use of anastrozole compared with placebo in postmenopausal women at high risk of developing breast cancer who were able to tolerate endocrine-related side-effects. Future studies assessing cognition should be done within randomised trials with baseline assessments to ascertain the true extent of the putative effects that treatments for breast cancer might have on memory and attention., Funding: Cancer Research UK, London, UK (grant numbers C6280/A3162 and C6280/A6764).

Phase 1 (P1) trials are vital to the development of cancer treatments; however, the patients involved in these trials are unlikely to receive any therapeutic benefit, and there are significant possibilities that they will experience serious side effects. Ethical requirements stipulate that patients must be adequately informed before they consent to participate in P1 trials. This review focuses on studies that have measured patient comprehension of information given during the informed consent process of P1 cancer trials. Patients consenting to participate in P1 trials currently have a limited understanding of trial purpose, an unrealistic expectation of the benefits and risks associated with trial participation and a questionable appreciation of their right to abstain or withdraw. Health care professionals recruiting to P1 trials need clear and practical guidelines and training packages designed to ensure that all details of P1 trials are communicated effectively to eligible patients.

Objective: To examine, in a prospective study, the influence that temporary reversible medical castration for localized prostate cancer has on cognition, by assessing whether temporary 3-5 month treatment with a luteinizing-hormone releasing hormone (LHRH) agonist before radical radiotherapy had a short- or long-term affect on cognitive function., Patients, Subjects and Methods: Thirty-two patients with localized prostate cancer had cognitive assessments at baseline (T1) before the start of drug treatment, at 3 months (T2) or on completing drug treatment but before radiotherapy, and 9 months later (T3). Eighteen men with no prostate cancer (controls subjects) completed the cognitive tests at the same times. In addition, psychological functioning and quality of life were assessed at the same times, together with serum free and bound testosterone, beta-oestradiol and sex hormone-binding globulin levels., Results: There was a significant cognitive decline (on at least one cognitive task) at T2 in 15 (47%) patients vs three (17%) of controls (odds ratio 4.412, P = 0.033). Most patients (nine of 15) who had a change in performance declined on tasks of spatial memory and ability. At T3 there was significant cognitive decline in 11 (34%) patients and five (28%) control subjects (odds ratio 1.37, P = 0.631)., Conclusion: This pilot study suggests that short-term LHRH therapy for early-stage prostate cancer has modest short-term consequences on men's cognitive functioning; a larger prospective study is warranted.

Aim: To conduct a commissioned survey of multidisciplinary breast team members' expectations of their own and each other's roles in providing different kinds of information to women with breast cancer., Design: Questionnaire based survey., Setting and Participants: Health professionals from five multidisciplinary breast care centres within a Sussex health authority., Main Outcome Measures: Interdisciplinary awareness of informational roles played by different team members., Results and Conclusions: The results of the team survey suggest that, in most cases, health professionals fulfilled the roles expected of them by the team, with two or three individuals identified as the main providers of information for each topic. However, many more professionals were involved in major discussions without the team's knowledge. The professional consistently playing a major "unseen" role was the breast nurse specialist.

As part of a larger study designed to improve doctor-patient communication in randomised clinical trials (RCT), we audiotaped the discussions between doctor and patient in which consent was being obtained for a RCT. This paper reports on 82 discussions conducted by 5 clinical oncologists in both District General and University Hospital outpatient departments. When introducing the subject of trials, uncertainty about treatment decisions was expressed by the doctors in the majority of cases (79, 96.3%). This was most often stated in a general sense (78, 95.1%), but some mentioned personal uncertainty (12, 14.6%), an approach which helps to maintain a trusting doctor-patient relationship. The word randomization was mentioned in 51 (62.2%) consultations, although the process itself was usually described implicitly (78, 95.1%), e.g. by telling the patient that they would be allocated either one or other treatment. Analogies were used in 28 (34.1%) cases to describe the randomisation process. In addition, although treatments and side-effects were described frequently, (68, 82.9%) and (72, 87.8%) respectively, information leaflets about the trials were not given to 23 (28%) patients. The study shows that U.K. clinicians adopt individual methods when providing information and eliciting consent to trials.

We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.