A talking control for use in evaluating the effectiveness of cognitive-behavioral therapy.

OBJECTIVE: Common factors predict outcome in psychotherapy, but there is a dearth of research defining and standardising control conditions. A description and evaluation of a talking control (TC) used in a randomized controlled trial (RCT) of cognitive-behavioral therapy (CBT) for older people with depression in primary care is presented. METHODS: Two hundred and four older people participated in a RCT of CBT for people with a Geriatric Mental State diagnosis of Depression (Serfaty et al., 2009). One in 10 session of CBT or TC were evaluated using the Cognitive Therapy Scale (CTS) to examine common and specific factors in therapy. RESULTS: 1005 therapy sessions were delivered; 508 for TC and 497 CBT. There were higher total CTS scores (P<0.001) for CBT (median 55.0; QR 52.0-55.0) than TC (median 23.0; QR 21.0-24.0). CBT scored better than TC for specific techniques (median 23.7; IQR 21.0-24.0 versus median 0.70.0; IQR 0.0-0.0, P<0.001). Both interventions scored highly for interpersonal effectiveness, but no difference was observed. The TC was easily delivered, deemed acceptable by patients and was not associated with harm. CONCLUSIONS: Development, standardization and measurement of a TC intervention is possible and provides a useful comparator in evaluations of effectiveness of CBT.

Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis.

OBJECTIVE: Accurate prediction of neurodevelopmental outcome in neonatal encephalopathy (NE) is important for clinical management and to evaluate neuroprotective therapies. We undertook a meta-analysis of the prognostic accuracy of cerebral magnetic resonance (MR) biomarkers in infants with neonatal encephalopathy. METHODS: We reviewed all studies that compared an MR biomarker performed during the neonatal period with neurodevelopmental outcome at > or =1 year. We followed standard methods recommended by the Cochrane Diagnostic Accuracy Method group and used a random-effects model for meta-analysis. Summary receiver operating characteristic curves and forest plots of each MR biomarker were calculated. chi(2) tests examined heterogeneity. RESULTS: Thirty-two studies (860 infants with NE) were included in the meta-analysis. For predicting adverse outcome, conventional MRI during the neonatal period (days 1-30) had a pooled sensitivity of 91% (95% confidence interval [CI]: 87%-94%) and specificity of 51% (95% CI: 45%-58%). Late MRI (days 8-30) had higher sensitivity but lower specificity than early MRI (days 1-7). Proton MR spectroscopy deep gray matter lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio (days 1-30) had 82% overall pooled sensitivity (95% CI: 74%-89%) and 95% specificity (95% CI: 88%-99%). On common study analysis, Lac/NAA had better diagnostic accuracy than conventional MRI performed at any time during neonatal period. The discriminatory powers of the posterior limb of internal capsule sign and brain-water apparent diffusion coefficient were poor. CONCLUSIONS: Deep gray matter Lac/NAA is the most accurate quantitative MR biomarker within the neonatal period for prediction of neurodevelopmental outcome after NE. Lac/NAA may be useful in early clinical management decisions and counseling parents and as a surrogate end point in clinical trials that evaluate novel neuroprotective therapies.

Clinical effectiveness of individual cognitive behavioral therapy for depressed older people in primary care: a randomized controlled trial.

CONTEXT: In older people, depressive symptoms are common, psychological adjustment to aging is complex, and associated chronic physical illness limits the use of antidepressants. Despite this, older people are rarely offered psychological interventions, and only 3 randomized controlled trials of individual cognitive behavioral therapy (CBT) in a primary care setting have been published. OBJECTIVE: To determine the clinical effectiveness of CBT delivered in primary care for older people with depression. DESIGN: A single-blind, randomized, controlled trial with 4- and 10-month follow-up visits. PATIENTS: A total of 204 people aged 65 years or older (mean [SD] age, 74.1 [7.0] years; 79.4% female; 20.6% male) with a Geriatric Mental State diagnosis of depression were recruited from primary care. INTERVENTIONS: Treatment as usual (TAU), TAU plus a talking control (TC), or TAU plus CBT. The TC and CBT were offered over 4 months. OUTCOME MEASURES: Beck Depression Inventory-II (BDI-II) scores collected at baseline, end of therapy (4 months), and 10 months after the baseline visit. Subsidiary measures were the Beck Anxiety Inventory, Social Functioning Questionnaire, and Euroqol. Intent to treat using Generalized Estimating Equation and Compliance Average Causal Effect analyses were used. RESULTS: Eighty percent of participants were followed up. The mean number of sessions of TC or CBT was just greater than 7. Intent-to-treat analysis found improvements of -3.07 (95% confidence interval [CI], -5.73 to -0.42) and -3.65 (95% CI, -6.18 to -1.12) in BDI-II scores in favor of CBT vs TAU and TC, respectively. Compliance Average Causal Effect analysis compared CBT with TC. A significant benefit of CBT of 0.4 points (95% CI, 0.01 to 0.72) on the BDI-II per therapy session was observed. The cognitive therapy scale showed no difference for nonspecific, but significant differences for specific factors in therapy. Ratings for CBT were high (mean [SD], 54.2 [4.1]). CONCLUSION: Cognitive behavioral therapy is an effective treatment for older people with depressive disorder and appears to be associated with its specific effects. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18271323.

Randomized, single-blind, controlled trial of a specialist behavior therapy team for challenging behavior in adults with intellectual disabilities.

OBJECTIVE: Community-based specialist behavior therapy teams may be helpful in managing challenging behavior, but evidence of their effectiveness is limited. This study was designed to examine the effectiveness and costs associated with treatment by a specialist behavior therapy team. METHOD: This was a parallel-group, randomized, single-blind controlled trial carried out in an intellectual disabilities service in England. Participants were 63 male and female service users with mild to severe intellectual disability who presented with challenging behavior. The interventions were standard treatment plus applied behavioral analysis (N=32) and standard treatment only (N=31). The primary outcome measure was challenging behavior, as measured by total and subscale scores on the Aberrant Behavior Checklist 3 and 6 months after randomization. Secondary outcome measures were psychiatric comorbidity assessed at 3 and 6 months using the Psychiatric Assessment Schedule for Adults With a Developmental Disability Checklist (PAS-ADD) and total costs recorded at 6 months. Multilevel modeling was used to compare square root transformations of Aberrant Behavior Checklist scores. RESULTS: Significant differences were found in the transformed total scores on the Aberrant Behavior Checklist (difference=-0.89, 95% CI=-1.74 to -0.04) and transformed lethargy and hyperactivity subscale scores (common intervention effect=-0.56, 95% CI=-0.97 to -0.15). Standard care participants fared worse on the PAS-ADD comorbid organic disorder subscale. There was a clear trend for lower overall costs of the intervention. CONCLUSIONS: Use of a specialist behavior therapy team in addition to standard treatment appears to be more effective in improving challenging behavior and may have financial advantages over standard treatment.

Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial.

OBJECTIVE: To determine whether vaccination of care home staff against influenza indirectly protects residents. DESIGN: Pair matched cluster randomised controlled trial. SETTING: Large private chain of UK care homes during the winters of 2003-4 and 2004-5. PARTICIPANTS: Nursing home staff (n=1703) and residents (n=2604) in 44 care homes (22 intervention homes and 22 matched control homes). INTERVENTIONS: Vaccination offered to staff in intervention homes but not in control homes. MAIN OUTCOME MEASURES: The primary outcome was all cause mortality of residents. Secondary outcomes were influenza-like illness and health service use in residents. RESULTS: In 2003-4 vaccine coverage in full time staff was 48.2% (407/884) in intervention homes and 5.9% (51/859) in control homes. In 2004-5 uptake rates were 43.2% (365/844) and 3.5% (28/800). National influenza rates were substantially below average in 2004-5. In the 2003-4 period of influenza activity significant decreases were found in mortality of residents in intervention homes compared with control homes (rate difference -5.0 per 100 residents, 95% confidence interval -7.0 to -2.0) and in influenza-like illness (P=0.004), consultations with general practitioners for influenza-like illness (P=0.008), and admissions to hospital with influenza-like illness (P=0.009). No significant differences were found in 2004-5 or during periods of no influenza activity in 2003-4. CONCLUSIONS: Vaccinating care home staff against influenza can prevent deaths, health service use, and influenza-like illness in residents during periods of moderate influenza activity. TRIAL REGISTRATION: National Research Register N0530147256.

Evidence for onward transmission of HIV-1 non-B subtype strains in the United Kingdom.

An increasing proportion of new HIV diagnoses in the United Kingdom and other European countries are attributable to non-B subtype infections, mainly among black Africans with infections heterosexually acquired in sub-Saharan Africa. We examined whether there was evidence for onward transmission of non-B subtypes within an ethnically diverse HIV-1-infected cohort in South London. Three hundred eighty-four HIV-1-infected patients attending Kings College Hospital were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Epidemiologic data were obtained from medical chart review and the patients' physician and were used to establish the most likely source and country of infection. Overall, 344 patients (154 black African, 148 white UK-born, and 42 black Caribbean) had an identifiable subtype. The prevalence of non-B subtypes among the black African, white, and black Caribbean patients was 96.8%, 14.2%, and 31%, respectively. Most non-B subtype infections were identified in black Africans (149 of 183 cases) and were mainly acquired in sub-Saharan Africa, but 22.9% (42 of 183 cases) of all non-B infections were probably acquired in the United Kingdom. Among the 21 white UK-born patients infected with a non-B subtype, 15 probably acquired the infection in the United Kingdom and only 6 of these patients reported a source sexual partner from an HIV endemic area. All 13 black Caribbean patients with a non-B infection most likely acquired their infection in the United Kingdom, most of whom (8 of 13 patients) were probably infected by a partner from an HIV endemic area. Potential acquisition of HIV infection in the United Kingdom was lowest among black African patients with a non-B infection, and most of these infections were probably acquired from a partner originating from an HIV endemic area. This study provides the first evidence for onward transmission of non-B subtypes in the United Kingdom, particularly among the black Caribbean population.

High rates of clustering of strains causing tuberculosis in Harare, Zimbabwe: a molecular epidemiological study.

We examined the pattern of tuberculosis (TB) transmission (i.e., reactivation versus recent transmission) and the impact of human immunodeficiency virus (HIV) infection in Harare, Zimbabwe. Consecutive adult smear-positive pulmonary TB patients presenting to an urban hospital in Harare were enrolled. A detailed epidemiological questionnaire was completed, and tests for HIV type 1 and CD4 cell counts were performed for each patient. Molecular fingerprinting of the genomic DNA recovered from cultures of sputum was performed by two molecular typing methods: spacer oligonucleotide typing (spoligotyping) and analysis of variable number of tandem DNA repeats (VNTRs). A cluster was defined as isolates from two or more patients that shared the same spoligotype pattern or the same VNTR pattern, or both. DNA suitable for typing was recovered from 224 patients. The prevalence of HIV infection was 79%. Of 187 patient isolates (78.6%) typed by both spoligotyping and analysis of VNTRs, 147 were identified as part of a cluster by both methods. By spoligotyping alone, 84.1% of patient isolates were grouped into 20 clusters. The cluster size was generally <8 patient isolates, although three large clusters comprised 68, 25, and 23 patient isolates. A total of 89.4% of the patient isolates grouped into 12 clusters defined by analysis of VNTRs, with 2 large clusters consisting of 127 and 13 patient isolates, respectively. Thirty-six percent of patient isolates with a shared spoligotype and 17% with a shared VNTR pattern were geographically linked within Harare, but they were not linked on the basis of the patient's home district. In a multivariate analysis, there were no independent predictors of clustering, including HIV infection status. Comparison with the International Spoligotype database (Pasteur Institute, Pointe a Pitre, Guadeloupe) demonstrated that our three largest spoligotype clusters are well recognized and ubiquitous in Africa. In this epidemiologically well characterized urban population with a high prevalence of HIV infection, we identified a very high level of strain clustering, indicating substantial ongoing recent TB transmission. Geographic linkage could be detected in a proportion of these clusters. A small group of actively circulating strains accounted for most of the cases of TB transmission.

Possession of human leucocyte antigen DQ6 alleles and the rate of CD4 T-cell decline in human immunodeficiency virus-1 infection.

Polymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)-1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV-1 infected long-term non-progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan-Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/ micro l, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB1*15-DQB1*06 haplotype (hazard ratio (HR) 0.69, 95% CI 0.46-1.01, P = 0.06). A similar effect was not observed with the DRB1*13-DQB1*06 haplotype (HR 1.18, 95% CI 0.75-1.88, P = 0.46), but was observed when DQB1*06 alleles were considered irrespective of their DR association (HR 0.74, 95% CI 0.52-1.05, P = 0.06). Major HLA-DQ6 alleles encode aspartate (Asp) at position 57 on the DQbeta chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQbeta57 Asp+ alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over-represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow-up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB1*15-DQB1*06 haplotype compared to IPs at 14+ years (38.46 versus 18.18%), though this difference did not reach statistical significance. When DQB1*06 alleles irrespective of their DR association were considered, the protective effect was greater (76.9% LTNPs versus 18.18% IPs, P = 0.04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.

Use of flexibility tests in the manufacturing process of 60 degrees Björk-Shiley convexo-concave valves and the risk of outlet strut fracture.

OBJECTIVES: Outlet strut fracture remains a concern for 30,000 patients living with a Björk-Shiley convexo-concave heart valve (Shiley, Inc, Irvine, Calif, a subsidiary of Pfizer, Inc). Previous studies (Netherlands and United Kingdom) investigating valve manufacturing aspects identified multiple performance of the hook deflection test as a risk factor for 60 degrees valves. The present study validated this finding using new data with a greater number of valves implanted worldwide. Risks of outlet strut fracture associated with other manufacturing aspects were also investigated. METHODS: A matched case-control study design was used including 416 outlet strut fracture cases and 803 controls. RESULTS: Analyses similar to that of the Dutch and United Kingdom studies produced odds ratios of 3.4 (95% confidence interval [CI]: 1.1-10.3) and 2.8 (95% CI: 1.1-7.3), respectively, for multiple hook deflection tests. Load deflection test, which replaced the hook deflection test, showed a statistically significant association with outlet strut fracture: odds ratio of 5.0 (95% CI: 2.1-11.8) and 6.2 (95% CI: 2.2-18.0) for single and multiple load deflection tests, respectively. An analysis where hook deflection tests were separated from load deflection tests showed significantly elevated odds ratios with performance of any type of flexibility test, and the highest odds ratio was observed with a combined performance of load and hook deflection tests. CONCLUSIONS: Multiple hook deflection tests can now be considered for inclusion in the risk model used for guidelines on explant surgery to improve prediction of outlet strut fracture and provide patient reassurance. Load deflection tests and combined performance of hook and load deflection tests were found to be significant risk factors. No outlet strut fractures were reported for valves manufactured after March 1984 when the load deflection test was still in place. Examining manufacturing documents for these valves may identify new risk factors that could be responsible for the outlet strut fractures risk that remains unexplained to date.

Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection.

HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/ micro l. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-gamma and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2(+)IFN-gamma(-)) or IFN-gamma alone (IFN-gamma(+)IL-2(-)) did not differ between LTNPs and SPs. The decrease in p24-specific CD28(+)IL-2(+) cells with a concomitant increase of p24-specific CD28(-)IL-2(+) cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28(-)IL-2(+) cells were evident in LTNPs and SPs, whereas the CMV-specific CD28(-)IL-2(+) response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-gamma(+)IL-2(+) response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-gamma(+)IL-2(+) but not of IFN-gamma(+)IL-2(-) CD4s correlated inversely with virus load. The Gag-specific IFN-gamma(+)IL-2(+) CD4 response also correlated positively with the percentage of Gag-specific IFN-gamma(+) CD8 T cells in these subjects. Accumulation of specific CD28(-)IL-2(+) helpers and loss of IFN-gamma(+)IL-2(+) CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.