Richter's transformation: Transforming the clinical landscape.

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease.

Reversal of warfarin anticoagulation using prothrombin complex concentrate at 25 IU kg-1 : results of the RAPID study.

BACKGROUND: Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. OBJECTIVE: To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. METHODS: We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. RESULTS: Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). CONCLUSION: The RAPID protocol reduces unwarranted delays without compromising efficacy.

Construction of a GP integration model.

There are frequent calls to improve integration of health services, within and between primary and secondary care sectors. In Australia, general medical practitioners (GPs) are central to these endeavours. This paper aims to better conceptualise GP integration and to develop a model and index based on this. A conceptualisation of integration is proposed based on integration fundamentally as an activity or process not structure. Integration process is the frequency and quality of episodes of information exchange involving the GP and another practitioner or patient and aimed at fulfilling the objectives of the health care system with regard to patient care. These are both direct responses to structural forces and emergent GP capacities and dispositions. The content of this typology was studied using Concept Mapping in 11 groups of GPs, consumers and other practitioners. Clusters of related statements within thematic domains were used as the basis for a provisional model. This was tested using confirmatory factor analysis in a data set derived from a national probability sample of 501 GPs. Some re-specification of the model was necessary, with three integration process factors needing to be subdivided. One factor congeneric model assumptions were used to identify the constituent items for these factors. The result was a model in which 50 items measured nine integration process factors and 20 items measured five enabling factors. Two distinct but correlated higher order factors, relating to individual patient care and public (or community) health--in contrast to a single higher order factor for integration--were identified. The re-specified model was tested with a new sample of 151 GPs and exhibited strong psychometric properties. Reliability and validity were acceptable to this stage of the indices' development. Further testing of the index is necessary to demonstrate factor invariance of the indices in other contexts as well as their utility in cross-structural analysis. That said, the indices have immediate uses.

Integration from the Australian GP's perspective.

OBJECTIVE: To report on what general practitioners' perceptions are about their role in relation to activities that support integration and what they are doing. METHOD: General practitioner perceived integrative behaviour was measured using a survey containing 114 statements about, 'what constitutes a well integrated GP'. Four hundred and forty-eight GPs were randomly sampled from the Health Insurance Commission (HIC) Medicare billing database in 1996. A response rate of 47% was obtained, yielding 208 surveys for analysis. RESULTS: General practitioners reported integrative activities such as being accessible to patients and working within a multidisciplinary team as currently occurring optimally. Not occurring optimally were: hospital and community involvement; participation in local projects; student education; and payment for working with others. Rural practitioners reported significantly more hospital and community involvement compared with metropolitan practitioners. Less than one-third of GPs reported that they were linked to other services by computer and used a computer for storage/communication of patient information. DISCUSSION: There are many obstacles preventing integrative activities in daily general practice. Policy and attitudinal changes as well as financial incentives are required to enable GPs to practise in an integrated manner. Infrastructure support to encourage GP education, training and information technology are essential to improve GP integration. Many such initiatives are currently in progress, and will require future evaluation. Findings from this 1996 survey will provide some useful baseline information assisting with future evaluation studies.

General practice integration in Australia. Primary health services provider and consumer perceptions of barriers and solutions.

OBJECTIVE: To identify practical examples of barriers and possible solutions to improve general practice integration with other health service providers. METHOD: Twelve focus groups, including one conducted by teleconference, were held across Australia with GPs and non GP primary health service providers between May and September, 1996. Focus groups were embedded within concept mapping sessions, which were used to conceptually explore the meaning of integration in general practice. Data coding, organising and analysis were based on the techniques documented by Huberman and Miles. RESULTS: Barriers to integration were perceived to be principally due to the role and territory disputes between the different levels of government and their services, the manner in which the GP's role is currently defined, and the system of GP remuneration. Suggestions on ways to improve integration involved two types of strategies. The first involves initiatives implemented 'top down' through major government reform to service structures, including the expansion of the role of divisions of general practice, and structural changes to the GP remuneration systems. The second type of strategy suggested involves initiatives implemented from the 'bottom up' involving services such as hospitals (e.g. additional GP liaison positions) and the use of information technology to link services and share appropriate patient data. CONCLUSION: The findings support the need for further research and evaluation of initiatives aimed at achieving general practice integration at a systems level. There is little evidence to suggest which types of initiatives improve integration. However, general practice has been placed in the centre of the health care debate and is likely to remain central to the success of such initiatives. Clarification of the future role and authority of general practice will therefore be required if such integrative strategies are to be successful at a wider health system level.

The concept mapping method. An alternative to focus group inquiry in general practice.

BACKGROUND: The concept mapping rationale and process are explained step by step. The concept mapping method produces a two dimensional conceptual map of ideas produced by the group which can be analysed at the level of individual statements, clusters of statements, and groups of similar clusters. An example of concept mapping conducted with four general practitioner (GP) groups from different practice types and demographic locations is provided. A total of 51 participating GPs were asked to complete an 'evaluation questionnaire' at the end of each group session. The majority of GP participants (68%) rated the method as highly useful. OBJECTIVE: To describe the concept mapping method and its interpretation for use in general practice research. To report on its perceived usefulness and acceptability by general practitioners. DISCUSSION: Concept mapping is a very useful method combining benefits from qualitative and quantitative approaches for exploring the breadth of a topic in its entirety, especially for abstract concepts. GPs found the concept mapping method to be efficient for group inquiry, rating it high on utility. There is scope to refine the method, reducing time spent in some stages of the session, and substituting more time on final analysis.

Characterization of murine monoclonal antibodies to the tat protein from human immunodeficiency virus type 1.

A panel of murine monoclonal antibodies (MAbs) to the human immunodeficiency virus type 1 trans-activator tat protein were characterized. The anti-tat MAbs were mapped to the different domains of the tat protein by Western blot (immunoblot) and Pepscan analyses. One-half of the MAbs tested mapped to the amino-terminal proline-rich region, and one-third of the MAbs tested mapped to the lysine-arginine-rich region of tat. The individual MAbs were tested for inhibition of tat-mediated trans activation, using a cell-based in vitro assay system. MAbs which mapped to the amino-terminal region of the tat protein demonstrated the highest degree of inhibition, whereas MAbs reactive to other portions of the molecule exhibited a less pronounced effect on tat function.