Disease progression in heterosexual patients infected with closely related subtype B strains of HIV type 1 with differing coreceptor usage properties

Previously we described a heterosexual outbreak of HIV-1 subtype B in a town in the north of England (Doncaster) where 11 of 13 infections were shown to be linked by phylogenetic analysis of the env gp120 region. The 11 infections were related to a putative index case, Don1, and further divided into two groups based on the patients' disease status, their viral sequences, and other epidemiological information. Here we describe two further findings. First, we found that viral isolates and gp120 recombinant viruses derived from patients from one group used the CCR5 coreceptor, whereas viruses from the other group could use both the CCR5 and CXCR4 coreceptors. Patients with the X4/R5 dual tropic strains were symptomatic when diagnosed and progressed rapidly, in contrast to the other patient group that has remained asymptomatic, implying a link between the tropism of the strains and disease outcome. Second, we present additional sequence data derived from the index case, demonstrating the presence of sequences from both clades, with an average interclade distance of 9.56%, providing direct evidence of a genetic link between these two groups. This new study shows that Don1 harbored both strains, implying he was either dually infected or that over time intrahost diversification from the R5 to R5/X4 phenotype occurred. These events may account for/have led to the spread of two genetically related strains with different pathogenic properties within the same heterosexual community.

Intensive case management for severe psychotic illness: is there a general benefit for patients with complex needs? A secondary analysis of the UK700 trial data

The UK700 trial failed to demonstrate an overall benefit of intensive case management (ICM) in patients with severe psychotic illness. This does not discount a benefit for particular subgroups, and evidence of a benefit of ICM for patients of borderline intelligence has been presented. The aim of this study is to investigate whether this effect is part of a general benefit for patients with severe psychosis complicated by additional needs. In the UK700 trial patients with severe psychosis were randomly allocated to ICM or standard case management. For each patient group with complex needs the effect of ICM is compared with that in the rest of the study cohort. Outcome measures are days spent in psychiatric hospital and the admission and discharge rates. ICM may be of benefit to patients with severe psychosis complicated by borderline intelligence or depression, but may cause patients using illicit drugs to spend more time in hospital. There was no convincing evidence of an effect of ICM in a further seven patient groups. ICM is not of general benefit to patients with severe psychosis complicated by additional needs. The benefit of ICM for patients with borderline intelligence is an isolated effect which should be interpreted cautiously until further data are available.

Continuity of care for carers of people with severe mental illness: results of a longitudinal study

Introduction: Continuity of care has been demonstrated to be important for service users and carer groups have voiced major concerns over disruptions of care. We aimed to assess the experienced continuity of care in carers of patients with both psychotic and non-psychotic disorders and explore its association with carer characteristics and psychological well-being. Methods: Friends and relatives caring for two groups of service users in the care of community mental health teams (CMHTs), 69 with psychotic and 38 with non-psychotic disorders, were assessed annually at three and two time points, respectively. CONTINUES, a measure specifically designed to assess continuity of care for carers themselves, was utilized along with assessments of psychological well-being and caregiving. Results: One hundred and seven carers participated. They reported moderately low continuity of care. Only 22 had had a carer’s assessment and just under a third recorded psychological distress on the GHQ. For those caring for people with psychotic disorders, reported continuity was higher if the carer was male, employed, lived with the user and had had a carer’s assessment; for those caring for people with non-psychotic disorders, it was higher if the carer was from the service user’s immediate family, lived with them and had had a carer’s assessment. Conclusion: The vast majority of the carers had not had a carer’s assessment provided by the CMHT despite this being a clear national priority and being an intervention with obvious potential to increase carers’ reported low levels of continuity of care. Improving continuity of contact with carers may have an important part to play in the overall improvement of care in this patient group and deserves greater attention.

Looking in the wrong place for healthcare improvements: a system dynamics study of an accident and emergency department

Accident and Emergency (A&E) units provide a route for patients requiring urgent admission to acute hospitals. Public concern over long waiting times for admissions motivated this study, whose aim is to explore the factors which contribute to such delays. The paper discusses the formulation and calibration of a system dynamics model of the interaction of demand pattern, A&E resource deployment, other hospital processes and bed numbers; and the outputs of policy analysis runs of the model which vary a number of the key parameters. Two significant findings have policy implications. One is that while some delays to patients are unavoidable, reductions can be achieved by selective augmentation of resources within, and relating to, the A&E unit. The second is that reductions in bed numbers do not increase waiting times for emergency admissions, their effect instead being to increase sharply the number of cancellations of admissions for elective surgery. This suggests that basing A&E policy solely on any single criterion will merely succeed in transferring the effects of a resource deficit to a different patient group.

An adaptive approach to implementing bivariate group sequential clinical trial designs

In clinical trials, situations often arise where more than one response from each patient is of interest; and it is required that any decision to stop the study be based upon some or all of these measures simultaneously. Theory for the design of sequential experiments with simultaneous bivariate responses is described by Jennison and Turnbull (Jennison, C., Turnbull, B. W. (1993). Group sequential tests for bivariate response: interim analyses of clinical trials with both efficacy and safety endpoints. Biometrics 49:741-752) and Cook and Farewell (Cook, R. J., Farewell, V. T. (1994). Guidelines for monitoring efficacy and toxicity responses in clinical trials. Biometrics 50:1146-1152) in the context of one efficacy and one safety response. These expositions are in terms of normally distributed data with known covariance. The methods proposed require specification of the correlation, ρ between test statistics monitored as part of the sequential test. It can be difficult to quantify ρ and previous authors have suggested simply taking the lowest plausible value, as this will guarantee power. This paper begins with an illustration of the effect that inappropriate specification of ρ can have on the preservation of trial error rates. It is shown that both the type I error and the power can be adversely affected. As a possible solution to this problem, formulas are provided for the calculation of correlation from data collected as part of the trial. An adaptive approach is proposed and evaluated that makes use of these formulas and an example is provided to illustrate the method. Attention is restricted to the bivariate case for ease of computation, although the formulas derived are applicable in the general multivariate case.

Cognitive behaviour therapy for psychosis: current evidence and future directions

The past decade has seen considerable growth in the evidence base of cognitive behavioural therapy for psychosis. Consistent reports of moderate effect sizes have led to such interventions being recommended as part of routine clinical practice. Most of this evidence is based on a generic form of CBT for psychosis applied to a heterogeneous group. An increase in the effectiveness of cognitive behavioural interventions may require new protocols. Such therapeutic developments should be based on the theoretical understanding of the psychological processes associated with specific forms of psychotic presentation. The current evidence base of CBT for psychosis is reviewed, and barriers that have held back the development of this research are discussed.