Left ventricular hypertrophy and incident cognitive decline in older adults with hypertension

The association between raised blood pressure and increased risk of subsequent cognitive decline is well known. Left ventricular hypertrophy (LVH), as a marker of hypertensive target organ damage, may help identify those at risk of cognitive decline. We assessed whether LVH was associated with subsequent cognitive decline or dementia in hypertensive participants aged ≥80 years in the randomized, placebo-controlled Hypertension in the Very Elderly Trial. LVH was assessed using 12-lead electrocardiography (ECG) based on the Cornell Product (CP-LVH), Sokolow-Lyon (SL-LVH), and Cornell Voltage (CV-LVH) criteria. The Mini-Mental State Examination (MMSE) was used to assess cognitive function at baseline and annually. A fall in MMSE to 3 points were defined as cognitive decline and triggered dementia screening (Diagnostic Statistical Manual IV). Death was defined as a competing event. Fine-Gray regression models were used to examine the relationship between baseline LVH and cognitive outcomes. There were 2645 in the analytical sample, including 201 (7.6%) with CP-LVH, 225 (8.5%) SL-LVH and 251 (9.5%) CV-LVH. CP-LVH was associated with increased risk of cognitive decline, subdistribution hazard ratio (sHR)1.3 (95% confidence interval (CI) 1.01–1.67) in multivariate analyses. SL-LVH and CV-LVH were not associated with cognitive decline (sHR1.06 (95% CI 0.82–1.37) and sHR1.13 (95% CI 0.89–1.43), respectively). LVH was not associated with dementia. LVH may be related to subsequent cognitive decline, but evidence was inconsistent depending on ECG criterion and there were no associations with incident dementia. Additional work is needed to understand the relationships between blood pressure, LVH assessment and cognition

the CUTHIVAC-001 randomized trial

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, and Env gp 140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p =  0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccineinduced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen

Receptionist rECognition and rEferral of Patients with Stroke (RECEPTS) : unannounced simulated patient telephone call study in primary care

Background: Stroke is a leading cause of morbidity and mortality. Timely recognition and referral are essential for treatment. Aim: To examine the ability of receptionists in general practices to recognise symptoms of stroke and direct patients to emergency care. Design and setting: Unannounced simulated patient telephone calls and prospective cross-sectional survey study in general practices in the Birmingham and Solihull area. Method: A total of 52 general practices participated in a total of 520 simulated telephone calls, with 183 receptionists completing questionnaires. Logistic regression analyses were used to examine likelihood of referral for immediate care by ease of vignette recognition and number of common stroke symptoms present. Results: General practice receptionists correctly referred 69% of simulated calls for immediate care. Calls classed as ‘difficult’ to recognise were less likely to be immediately referred. Compared with ‘easy’ calls: ‘difficult’ calls odds ratio (OR) 0.15, 95% confidence interval (CI) = 0.08 to 0.26; ‘moderate’ calls OR 0.55, 95% CI = 0.32 to 0.92. Similarly, calls including one or two ‘FAST’ symptoms were less likely to be referred immediately (compared with three FAST symptoms: one symptom OR 0.30, 95% CI = 0.13 to 0.72; two symptoms OR 0.35, 95% CI = 0.15 to 0.83). Conclusion: General practice receptionists refer patients with stroke for immediate care when they present with several symptoms; however, they are less likely to refer patients presenting with only one symptom or less common symptoms of stroke. Optimum management of acute stroke in primary care requires interventions that improve receptionists’ knowledge of lesser-known stroke symptoms

Effect of managed transition on mental health outcomes for young people at the child–adult mental health service boundary : a randomised clinical trial

Background: Poor transition planning contributes to discontinuity of care at the child–adult mental health service boundary (SB), adversely affecting mental health outcomes in young people (YP). The aim of the study was to determine whether managed transition (MT) improves mental health outcomes of YP reaching the child/adolescent mental health service (CAMHS) boundary compared with usual care (UC). Methods: A two-arm cluster-randomised trial (ISRCTN83240263 and NCT03013595) with clusters allocated 1:2 between MT and UC. Recruitment took place in 40 CAMHS (eight European countries) between October 2015 and December 2016. Eligible participants were CAMHS service users who were receiving treatment or had a diagnosed mental disorder, had an IQ ⩾ 70 and were within 1 year of reaching the SB. MT was a multi-component intervention that included CAMHS training, systematic identification of YP approaching SB, a structured assessment (Transition Readiness and Appropriateness Measure) and sharing of information between CAMHS and adult mental health services. The primary outcome was HoNOSCA (Health of the Nation Outcome Scale for Children and Adolescents) score 15-months post-entry to the trial. Results: The mean difference in HoNOSCA scores between the MT and UC arms at 15 months was −1.11 points (95% confidence interval −2.07 to −0.14, p = 0.03). The cost of delivering the intervention was relatively modest (€17–€65 per service user). Conclusions: MT led to improved mental health of YP after the SB but the magnitude of the effect was small. The intervention can be implemented at low cost and form part of planned and purposeful transitional care

Crossing survival curves: alternatives to the log-rank test.

Background: It is not uncommon for clinical trials to present results on survival time as Kaplan-Meier survival curves that cross, indicating non-proportional hazards. A recent example was given in a pivotal trial in advanced non-small cell lung cancer (The ‘IPASS study’ [1]). Trials such as these present a hazard ratio and log-rank test for treatment comparison as this is their planned primary analysis. However, the validity of such analysis is questionable and has received published criticism. This paper reviews the use of the log-rank test with crossing curves and considers alternatives that have been proposed. Methods: The review of the alternative approaches includes weighted log-rank tests (Wilcoxon, Tarone-Ware, Peto-Prentice and Fleming-Harrington), supremum versions of the log-rank test (modified Kolmogorov-Smirnov and Renyi-type tests) which are based on the maximum difference between estimates of two survivor functions and modified log-rank tests (Lin and Wang test using squared differences at each time point, and Levene-type test focusing on variance differences). In addition, methods based on splitting the analysis at the crossing point have also been proposed. Methods are compared and evaluated using both real and simulated datasets using Weibull and Weibull-Cox distributions representing realistic situations. Results: Crossing survival curves is generally a result of the survival times having greater variance in one treatment group than another. The performance of the log-rank test and alternatives depend on the type of crossing (early, mid or late) but in general the probability of a Type II error is increased for log-rank and weighted log-rank tests but performance is improved with the alternatives. The choice of time-point for the split-analysis is problematic. Standard software such as sts test (Stata), proc lifetest (SAS) and survfit (R) and routines-on-demand support some but not all the tests considered. Conclusions: There is a need in the clinical community to clarify methods that are appropriate when survival curves cross. Statistical analysis plans for clinical trials with survival as primary outcome measure should specify an analysis dependent on the proportionality of hazard rates and explicitly consider non-proportionality issues, powering the analyses based on log-rank alternatives. Modelling the survival data may be more appropriate than simple univariate hypothesis tests when hazards are not proportional. Finally, there are some feasibility issues regarding software for such analysis that remain to be tackled

Epidemiology and outcome of fracture of the hip in women aged 65 years and under : a cohort study

We examined prospectively collected data from 6782 consecutive hip fractures and identified 327 fractures in 315 women aged ≤65 years. We report on their demographic characteristics, treatment and outcome and compare them with a cohort of 4810 hip fractures in 4542 women aged > 65 years. The first significant increase in age-related incidence of hip fracture was at 45, rather than 50, which is when screening by the osteoporosis service starts in most health areas. Hip fractures in younger women are sustained by a population at risk as a result of underlying disease. Mortality of younger women with hip fracture was 46 times the background mortality of the female population. Smoking had a strong influence on the relative risk of 'early' (≤ 65 years of age) fracture. Lag screw fixation was the most common method of operative treatment. General complication rates were low, as were re-operation rates for cemented prostheses. Kaplan-Meier implant survivorship of displaced intracapsular fractures treated by reduction and lag screw fixation was 71% (95% confidence interval 56 to 81) at five years. The best form of treatment remains controversial

Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers

Prospective randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy for acute gallbladder disease

Background: This randomized controlled trial compared the cost–utility of early laparoscopic cholecystectomy with that for conventional management of newly diagnosed acute gallbladder disease. Methods: Adults admitted to hospital with a first episode of biliary colic or acute cholecystitis were randomized to an early intervention group (36 patients, operation within 72 h of admission) or a conventional group (36, elective cholecystectomy 3 months later). Costs were measured from a National Health Service and societal perspective. Quality‐adjusted life year (QALY) gains were calculated 1 month after surgery. Results: The mean(s.d.) total costs of care were £5911(2445) for the early group and £6132(3244) for the conventional group (P = 0·928), Mean(s.d.) societal costs were £1322(1402) and £1461(1532) for the early and conventional groups respectively (P = 0·732). Visual analogue scale scores of health were 72·94 versus 84·63 (P = 0·012) and the mean(s.d.) QALY gain was 0·85(0·26) versus 0·93(0·13) respectively (P = 0·262). The incremental cost per additional QALY gained favoured conventional management at a cost of £3810 per QALY gained. Conclusion: In this pragmatic trial, the cost–utilities of both the early and conventional approaches were similar, but the incremental cost per additional QALY gained favoured conventional management. Registration number: ISRCTN81663421 (http://www.controlled‐trials.com)