Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Interaction between non-executive and executive directors in English National Health Service trust boards: an observational study

Research funded by Burdett FoundationBackground National Health Service (NHS) trusts, which provide the majority of hospital and community health services to the English NHS, are increasingly adopting a ‘public firm’ model with a board consisting of executive directors who are trust employees and external non-executives chosen for their experience in a range of areas such as finance, health care and management. In this paper we compare the non-executive directors’ roles and interests in, and contributions to, NHS trust boards’ governance activities with those of executive directors; and examine non-executive directors’ approach to their role in board meetings. Methods Non-participant observations of three successive trust board meetings in eight NHS trusts (primary care trusts, foundation trusts and self-governing (non-foundation) trusts) in England in 2008–9. The observational data were analysed inductively to yield categories of behaviour reflecting the perlocutionary types of intervention which non-executive directors made in trust meetings. Results The observational data revealed six main perlocutionary types of questioning tactic used by non-executive directors to executive directors: supportive; lesson-seeking; diagnostic; options assessment; strategy seeking; and requesting further work. Non-executive board members’ behaviours in holding the executive team to account at board meetings were variable. Non-executive directors were likely to contribute to finance-related discussions which suggests that they did see financial challenge as a key component of their role. Conclusions The pattern of behaviours was more indicative of an active, strategic approach to governance than of passive monitoring or ‘rubber-stamping’. Nevertheless, additional means of maintaining public accountability of NHS trusts may also be required

Rational use of antibiotics by community health workers and caregivers for children with suspected pneumonia in Zambia: A cross-sectional mixed methods study

Background: Antibiotic resistance is an issue of growing global concern. One key strategy to minimise further development of resistance is the rational use of antibiotics, by providers and patients alike. Through integrated community case management (iCCM), children diagnosed with suspected pneumonia are treated with antibiotics; one component of an essential package to reduce child mortality and increase access to health care for remote populations. Through the use of clinical algorithms, supportive supervision and training, iCCM also offers the opportunity to improve the rational use of antibiotics and limit the spread of resistance in resource-poor contexts. This study provides evidence on antibiotic use by community health workers (CHWs) and caregivers to inform iCCM programmes, safeguarding current treatments whilst maximising access to care. Methods: 1497 CHW consultations were directly observed by non-clinical researchers, with measurement of respiratory rate by CHWs recorded by video. Videos were used to conduct a retrospective reference standard assessment of respiratory rate by experts. Fifty-five caregivers whose children were prescribed a 5-day course of antibiotics for suspected pneumonia were followed up on day six to assess adherence through structured interviews and pill counts. Six focus group discussions and nine in depth interviews were conducted with CHWs and caregivers to supplement quantitative findings. Results: The findings indicate that CHWs adhered to treatment guidelines for 92 % of children seen, prescribing treatment corresponding to their assessment. However, only 65 % of antibiotics prescribed were given for children with experts' confirmed fast breathing pneumonia. Qualitative data indicates that CHWs have a good understanding of pneumonia diagnosis, and although caregivers sometimes applied pressure to receive drugs, CHWs stated that treatment decisions were not influenced. 46 % of caregivers were fully adherent and gave their child the full 5-day course of dispersible amoxicillin. If caregivers who gave treatment for 3 to 5 days were considered, adherence increased to 76 %. Conclusions: CHWs are capable of prescribing treatment corresponding to their assessment of respiratory rate. However, rational use of antibiotics could be strengthened through improved respiratory rate assessment, and better diagnostic tools. Furthermore, a shorter course of dispersible amoxicillin could potentially improve caregiver adherence, reducing risk of resistance and cost

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations.

It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and universal, as long as nutritional and health needs are met

Barriers to prompt and effective malaria treatment among the poorest population in Kenya

<p>Abstract</p> <p>Background</p> <p>Prompt access to effective malaria treatment is central to the success of malaria control worldwide, but few fevers are treated with effective anti-malarials within 24 hours of symptoms onset. The last two decades saw an upsurge of initiatives to improve access to effective malaria treatment in many parts of sub-Saharan Africa. Evidence suggests that the poorest populations remain least likely to seek prompt and effective treatment, but the factors that prevent them from accessing interventions are not well understood. With plans under way to subsidize ACT heavily in Kenya and other parts of Africa, there is urgent need to identify policy actions to promote access among the poor. This paper explores access barriers to effective malaria treatment among the poorest population in four malaria endemic districts in Kenya.</p> <p>Methods</p> <p>The study was conducted in the poorest areas of four malaria endemic districts in Kenya. Multiple data collection methods were applied including: a cross-sectional survey (n = 708 households); 24 focus group discussions; semi-structured interviews with health workers (n = 34); and patient exit interviews (n = 359).</p> <p>Results</p> <p>Multiple factors related to affordability, acceptability and availability interact to influence access to prompt and effective treatment. Regarding affordability, about 40 percent of individuals who self-treated using shop-bought drugs and 42 percent who visited a formal health facility reported not having enough money to pay for treatment, and having to adopt coping strategies including borrowing money and getting treatment on credit in order to access care. Other factors influencing affordability were seasonality of illness and income sources, transport costs, and unofficial payments. Regarding acceptability, the major interrelated factors identified were provider patient relationship, patient expectations, beliefs on illness causation, perceived effectiveness of treatment, distrust in the quality of care and poor adherence to treatment regimes. Availability barriers identified were related to facility opening hours, organization of health care services, drug and staff shortages.</p> <p><b>Conclusions</b></p> <p>Ensuring that all individuals suffering from malaria have prompt access to effective treatment remains a challenge for resource constrained health systems. Policy actions to address the multiple barriers of access should be designed around access dimensions, and should include broad interventions to revitalize the public health care system. Unless additional efforts are directed towards addressing access barriers among the poor and vulnerable, malaria will remain a major cause of morbidity and mortality in sub-Saharan Africa.</p

SARS-CoV-2 infection, antibody positivity and seroconversion rates in staff and students following full reopening of secondary schools in England: A prospective cohort study, September-December 2020.

Background: Older children have higher SARS-CoV-2 infection rates than younger children. We investigated SARS-CoV-2 infection, seroprevalence and seroconversion rates in staff and students following the full reopening of all secondary schools in England. Methods: Public Health England (PHE) invited secondary schools in six regions (East and West London, Hertfordshire, Derbyshire, Manchester and Birmingham) to participate in SARS-CoV-2 surveillance during the 2020/21 academic year. Participants had nasal swabs for RT-PCR and blood samples for SARS-CoV-2 antibodies at the beginning (September 2020) and end (December 2020) of the autumn term. Multivariable logistic regression was used to assess independent risk factors for seropositivity and seroconversion. Findings: Eighteen schools in six regions enrolled 2,209 participants, including 1,189 (53.8%) students and 1,020 (46.2%) staff. SARS-CoV-2 infection rates were not significantly different between students and staff in round one (5/948; [0.53%] vs. 2/876 [0.23%]; p = 0.46) or round two (10/948 [1.05%] vs. 7/886 [0.79%]; p = 0.63), and similar to national prevalence. None of four and 7/15 (47%) sequenced strains in rounds 1 and 2 were the highly transmissible SARS-CoV-2 B.1.1.7 variant. In round 1, antibody seropositivity was higher in students than staff (114/893 [12.8%] vs. 79/861 [9.2%]; p = 0.016), but similar in round 2 (117/893 [13.1%] vs.117/872 [13.3%]; p = 0.85), comparable to local community seroprevalence. Between the two rounds, 8.7% (57/652) staff and 6.6% (36/549) students seroconverted (p = 0.16). Interpretation: In secondary schools, SARS-CoV-2 infection, seropositivity and seroconversion rates were similar in staff and students, and comparable to local community rates. Ongoing surveillance will be important for monitoring the impact of new variants in educational settings

Induction of Cytoprotective Pathways Is Central to the Extension of Lifespan Conferred by Multiple Longevity Pathways

Many genetic and physiological treatments that extend lifespan also confer resistance to a variety of stressors, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of cytoprotective pathways is essential for lifespan extension or merely correlated. Using a panel of GFP-fused stress response genes, we identified the suites of cytoprotective pathways upregulated by 160 gene inactivations known to increase Caenorhabditis elegans longevity, including the mitochondrial UPR (hsp-6, hsp-60), the ER UPR (hsp-4), ROS response (sod-3, gst-4), and xenobiotic detoxification (gst-4). We then screened for other gene inactivations that disrupt the induction of these responses by xenobiotic or genetic triggers, identifying 29 gene inactivations required for cytoprotective gene expression. If cytoprotective responses contribute directly to lifespan extension, inactivation of these genes would be expected to compromise the extension of lifespan conferred by decreased insulin/IGF-1 signaling, caloric restriction, or the inhibition of mitochondrial function. We find that inactivation of 25 of 29 cytoprotection-regulatory genes shortens the extension of longevity normally induced by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, without disrupting normal longevity nearly as dramatically. These data demonstrate that induction of cytoprotective pathways is central to longevity extension and identify a large set of new genetic components of the pathways that detect cellular damage and couple that detection to downstream cytoprotective effectors.National Institute on Aging (AG16636

Breast cancer prognostic classification in the molecular era: the role of histological grade

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers. © 2010 BioMed Central Lt