Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification

The purpose of this overview is to discuss the changes in the 2008 WHO classification of myeloid neoplasms, with exclusion of acute myeloid leukaemia. Specific mutations or rearrangements leading to constitutive activation of growth factor receptors or cytoplasmic tyrosine kinases are now recognised as recurrent genetic events characterising the group of myeloproliferative neoplasms (MPN). A newly introduced subgroup consists of patients with persistent eosinophilia and myeloid or lymphoid proliferations harbouring specific genetic changes involving platelet-derived growth factor receptors alpha and beta (PDGFRA and PDGFRB) or fibroblast growth factor receptor 1 (FGFR1). The clinical relevance of recognising myeloid neoplasms with aberrant tyrosine kinase activity is based in novel treatment options with tyrosine kinase inhibitors. The myelodysplastic syndromes (MDS) without increased blasts are further divided into subtypes of refractory cytopaenias with unilineage dysplasia. A new provisional entity is refractory cytopaenia of childhood. Down syndrome- and therapy-related myeloid neoplasms, including MDS, were moved to the section of acute myeloid leukaemia and related precursor neoplasms

Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies

BACKGROUND: Prospective studies of Zika virus in pregnancy have reported rates of congenital Zika syndrome and other adverse outcomes by trimester. However, Zika virus can infect and damage the fetus early in utero, but clear before delivery. The true vertical transmission rate is therefore unknown. We aimed to provide the first estimates of underlying vertical transmission rates and adverse outcomes due to congenital infection with Zika virus by trimester of exposure. METHODS: This was a Bayesian latent class analysis of data from seven prospective studies of Zika virus in pregnancy. We estimated vertical transmission rates, rates of Zika-virus-related and non-Zika-virus-related adverse outcomes, and the diagnostic sensitivity of markers of congenital infection. We allowed for variation between studies in these parameters and used information from women in comparison groups with no PCR-confirmed infection, where available. FINDINGS: The estimated mean risk of vertical transmission was 47% (95% credible interval 26 to 76) following maternal infection in the first trimester, 28% (15 to 46) in the second, and 25% (13 to 47) in the third. 9% (4 to 17) of deliveries following infections in the first trimester had symptoms consistent with congenital Zika syndrome, 3% (1 to 7) in the second, and 1% (0 to 3) in the third. We estimated that in infections during the first, second, and third trimester, respectively, 13% (2 to 27), 3% (-5 to 14), and 0% (-7 to 11) of pregnancies had adverse outcomes attributable to Zika virus infection. Diagnostic sensitivity of markers of congenital infection was lowest in the first trimester (42% [18 to 72]), but increased to 85% (51 to 99) in trimester two, and 80% (42 to 99) in trimester three. There was substantial between-study variation in the risks of vertical transmission and congenital Zika syndrome. INTERPRETATION: This preliminary analysis recovers the causal effects of Zika virus from disparate study designs. Higher transmission in the first trimester is unusual with congenital infections but accords with laboratory evidence of decreasing susceptibility of placental cells to infection during pregnancy. FUNDING: European Union Horizon 2020 programme

Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae

Intranasal infection of mice with certain strains of capsular group 19 Streptococcus pneumoniae can result in focal pneumonia in the absence of bacteremia. Using this model of murine pneumonia, we demonstrated that immunization with recombinant forms of either pneumococcal surface protein A (PspA) or PdB (a genetically detoxified derivative of pneumolysin) elicited significant protection against focal pulmonary infection. This may be the first demonstration that a proposed vaccine antigen can protect against pneumococcal pneumonia. The best protection was obtained by immunizing mice with a mixture of PspA and PdB, indicating that the protection elicited by these antigens can complement each other. This result is in agreement with previous studies that used pneumococcal sepsis and nasal colonization models and demonstrate that the best protein vaccines for prevention of infection may be those that include more than one protection-eliciting pneumococcal protein.David E. Briles, Susan K. Hollingshead, James C. Paton, Edwin W. Ades, Lea Novak, Frederik W. van Ginkel, and William H. Benjamin, Jr

From database to normbase

After the database concept, we are ready for the normbase concept. The object is to decouple organizational and technical knowledge that are now mixed inextricably together in the application programs we write today. The underlying principle is to find a way of specifying a social system as a system of norms. Our existing languages, developed to handle machine-like structures, do not enable us to embed our technical systems comfortably into the far more subtle human systems they should be serving.\ud \ud The present approach to the design of formal systems incorporates a philosophical position that obstructs one's thinking about the relationship between social systems and technical systems. The existing specification languages embody a view of the world as an objective reality. But social systems are constructed by their participants, so we propose a language that treats the world as essentially subjective. Our way of doing so introduces two fundamental postulates: (1) there is no reality without an agent, and (2) the agent only knows the world through actions. Based on these postulates, a formalism has been created that enables us to represent systems of social norms.\ud \ud In this system, meaning is regarded as a relationship between sign and behaviour (more strictly, invariants in the flux of behaviour). Semantic analysis is an essential prelude to norm analysis. A new prototype implementation of this normbase is under construction. The goal envisaged is explained in terms of an illustration of how the normbase would be used to develop a system. At every stage of design, the specification is turned immediately into a default version of a working system. The application programmer can then concentrate on tuning this system or developing another that can perform the business functions in the most efficient technical manner. Experiments have already shown the viability of the concepts and methods incorporated in this normbase

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Joint synthesis of conditionally related multiple outcomes makes better use of data than separate meta-analyses

Background: When there are structural relationships between outcomes reported in different trials, separate analyses of each outcome do not provide a single coherent analysis, which is required for decision-making. For example, trials of intrapartum anti-bacterial prophylaxis (IAP) to prevent early onset group B streptococcal (EOGBS) disease can report three treatment effects: the effect on bacterial colonisation of the newborn, the effect on EOGBS, and the effect on EOGBS conditional on newborn colonisation. These outcomes are conditionally related, or nested, in a multi-state model. This paper shows how to exploit these structural relationships, providing a single coherent synthesis of all the available data, while checking to ensure that different sources of evidence are consistent. Results: Overall, the use of IAP reduces the risk of EOGBS (RR: 0.03; 95% Credible Interval (CrI): 0.002-0.13). Most of the treatment effect is due to the prevention of colonisation in newborns of colonised mothers (RR: 0.08, 95% CrI: 0.04-0.14). Node-splitting demonstrated that the treatment effect calculated using only direct evidence was consistent with that predicted from the remaining evidence (p=0.15). The findings accorded with previously published separate meta-analyses of the different outcomes, once these are re-analysed correctly accounting for zero cells. Conclusion: Multiple outcomes should be synthesised together where possible, taking account of their structural relationships. This generates an internally coherent analysis, suitable for decision making, in which estimates of each of the treatment effects are based on all available evidence (direct and indirect). Separate meta-analyses of each outcome have none of these properties