Effectiveness and cost-effectiveness of a brief school-based group programme for parents of children at risk of ADHD: a cluster randomised controlled trial.

BACKGROUND: National Institute for Health and Care Excellence guidelines recommend a stepped care approach for the identification and management of children with, or at risk of, attention-deficit/hyperactivity disorder (ADHD). We investigated the effectiveness, cost-effectiveness and acceptability of a group parenting intervention programme (+/- a teacher session) for children at risk of ADHD. METHODS: In a three-arm cluster randomised controlled trial, 12 primary schools were randomly assigned to control, parent-only and combined (parent + teacher) intervention arms. Eligible children had high levels of parent-rated hyperactivity/inattention (n = 199). At 6 month follow-up, the primary outcome measure was the parent-completed Conners' Rating Scale - Revised (ADHD index). Secondary outcomes included the Conners' sub-scales (hyperactivity, cognitive problems/inattention and oppositional behaviour), the teacher-completed Conners' Rating Scale - Revised, child health-related quality of life, parental burden and parental mental health. The cost-effectiveness analyses reflected a health and personal social services perspective. TRIAL REGISTRATION: ISRCTN87634685. RESULTS: Follow-up data were obtained from 76 parents and 169 teachers. There was no effect of the parent-only (mean difference = -1.1, 95% CI -5.1,2.9; p = 0.57) or combined interventions (mean difference = -2.1, 95% CI -6.4,2.1; p = 0.31) on the ADHD index. The combined intervention was associated with reduced parent-reported hyperactivity symptoms (mean difference = -5.3; 95% CI -10.5,-0.01; p = 0.05) and the parent-only intervention with improved parental mental health (mean difference = -1.9; 95% CI -3.2,-0.5; p = 0.009). The incremental costs of the parent-only and the combined interventions were £73 and £123, respectively. Above a willingness-to-pay of £31 per one-point improvement in the ADHD index, the parent-only programme had the highest probability of cost-effectiveness. Participants found the interventions acceptable. CONCLUSIONS: For children at risk of ADHD, this school-based parenting programme was not associated with improvement in core ADHD symptoms. Secondary analyses suggested a possible reduction in parent-reported hyperactivity and parental mental health problems. Future research should compare targeted interventions against watchful waiting and specialist referral.

c-Fos induction in mesotelencephalic dopamine pathway projection targets and dorsal striatum following oral intake of sugars and fats in rats.

Overconsumption of nutrients high in fats and sugars can lead to obesity. Previous studies indicate that sugar or fat consumption activate individual brain sites using Fos-like immunoreactivity (FLI). Sugars and fats also elicit conditioned flavor preferences (CFP) that are differentially mediated by flavor-flavor (orosensory: f/f) and flavor-nutrient (post-ingestive: f/n) processes. Dopamine (DA) signaling in the medial prefrontal cortex (mPFC), the amygdala (AMY) and the nucleus accumbens (NAc), has been implicated in acquisition and expression of fat- and sugar-CFP. The present study examined the effects of acute consumption of fat (corn oil: f/f and f/n), glucose (f/f and f/n), fructose, (f/f only), saccharin, xanthan gum or water upon simultaneous FLI activation of DA mesotelencephalic nuclei (ventral tegmental area (VTA)) and projections (infralimbic and prelimbic mPFC, basolateral and central-cortico-medial AMY, core and shell of NAc as well as the dorsal striatum). Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell. Glucose intake significantly increased FLI in both AMY areas, dorsal striatum and NAc core, but not in either mPFC area, VTA or Nac shell. Correspondingly, fructose intake significantly increased FLI in the both AMY areas, the infralimbic mPFC and dorsal striatum, but not the prelimbic mPFC, VTA or either NAc area. Saccharin and xanthan gum intake failed to activate FLI relative to water. When significant FLI activation occurred, highly positive relationships were observed among sites, supporting the idea of activation of a distributed brain network mediating sugar and fat intake.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Occupational therapy predischarge home visits for patients with a stroke (HOVIS): results of a feasibility randomized controlled trial.

OBJECTIVE: To assess the feasibility of conducting a randomized controlled trial of occupational therapy predischarge home visits for people after stroke. DESIGN: Randomized controlled trial and cohort study. We randomized eligible patients for whom there was clinical uncertainty about the need to conduct a home visit to a randomized controlled trial; patients for whom a visit was judged 'essential' were enrolled into a cohort study. SETTING: Stroke rehabilitation unit of teaching hospital. PARTICIPANTS: One hundred and twenty-six participants hospitalized following recent stroke. INTERVENTIONS: Predischarge home visit or structured, hospital-based interview. MAIN OUTCOME MEASURES: The primary objective was to collect information on the feasibility of a randomized controlled trial, including eligibility, control intervention and outcome assessments. The primary outcome measure was the Nottingham Extended Activities of Daily Living Scale at one month after discharge from hospital. Secondary outcomes included mood, quality of life and costs at one week and one month following discharge. RESULTS: Ninety-three people were allocated to the randomized controlled trial; 47 were randomized to intervention and 46 to control. Thirty-three were enrolled into the cohort study. More people were allocated to the randomized controlled trial as the study progressed. One hundred and thirteen people (90%) received the proposed intervention, although there was a need for stricter protocol adherence. Follow-up was good: at one month 114 (90%) were assessed. There were no significant differences between the groups in the randomized controlled trial for the primary outcome measure at one month. The average cost of a home visit was £208. CONCLUSION: A trial is feasible and warranted given the resource implications of predischarge occupational therapy home visits.

Critical role of NMDA but not opioid receptors in the acquisition of fat-conditioned flavor preferences in rats.

Animals learn to prefer flavors associated with the intake of dietary fats such as corn oil (CO) solutions. We previously reported that fat-conditioned flavor preferences in rats were relatively unaffected by systemic treatment with dopamine D1 and D2 antagonsits. The present study examined whether systemic opioid (naltrexone, NTX) or NMDA (MK-801) receptor antagonists altered the acquisition and/or expression of CO-CFP. The CFP was produced by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in a 3.5% CO solution and another flavor (CS-, e.g., grape) in a 0.9% CO solution. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 d. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), NTX (0.1-5 mg/kg) or MK-801 (50-200 µg/kg). Rats displayed a robust CS+ preference following VEH treatment (85-88%) which was significantly though moderately attenuated by NTX (69-70%). The lower doses of MK-801 slightly reduced the CS+ preference; the high dose blocked the CS+ preference (49%) but also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH or NTX (0.1, 0.5, 1mg/kg) or MK-801 (100 µg/kg) 0.5h prior to 1-bottle training trials with CS+/3.5% CO and CS-/0.9% CO training solutions. Additional Limited VEH groups were trained with intakes limited to that of the NTX and MK-801 groups. Subsequent two-bottle CS+ vs. CS- tests were conducted without injections. Significant and persistent CS+ preferences were observed in VEH (77-84%) and Limited VEH (88%) groups. NTX treatment during training failed to block the acquisition of CO-CFP although the magnitude of the CS+ preference was reduced by 0.5 (70%) and 1.0 (72%) mg/kg doses relative to the Limited VEH treatment (88%). In contrast, MK-801 (100 µg/kg) treatment during training blocked the acquisition of the CO-CFP. These data suggest a critical role for NMDA, but not opioid receptor signaling in the acquisition of a fat conditioned flavor preferences, and at best limited involvement of NMDA and opioid receptors in the expression of a previously learned preference.

Roles of dopamine D1 and D2 receptors in the acquisition and expression of fat-conditioned flavor preferences in rats.

Sugars and fats elicit innate and learned flavor preferences with the latter mediated by flavor-flavor (orosensory) and flavor-nutrient (post-ingestive) processes. Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC), but not opioid antagonists blocked the acquisition and expression of flavor-flavor preferences conditioned by sugars. In addition, systemic D1, but not D2 or opioid antagonists blocked the acquisition of flavor-nutrient preferences conditioned by intragastric (IG) sugar infusions. Given that DA antagonists reduce fat intake, the present study examined whether systemic D1 or D2 antagonists altered the acquisition and/or expression of conditioned flavor preferences (CFP) produced by pairing one novel flavor (CS+, e.g., cherry) with a 3.5% corn oil (CO: fat) solution relative to another flavor (CS-, e.g., grape) paired with a 0.9% CO solution. In an expression study, food-restricted rats were trained to drink either flavored 3.5% or 0.9% CO solutions on alternate days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), SCH (50-800 nmol/kg) or RAC (50-800 nmol/kg). The rats displayed a robust CS+ preference following VEH treatment (87-88%) the expression of which was attenuated by treatment with moderate doses of RAC, and to a lesser degree, SCH. In an acquisition study, six groups of rats received VEH, SCH (25, 50, 200 nmol/kg) or RAC (50, 200 nmol/kg) 0.5 h prior to 1-bottle training trials with CS+ flavored 3.5% and CS- flavored 0.9% (CS-) CO solutions. A seventh Limited VEH group was trained with its training intakes limited to that of the SCH and RAC groups. Subsequent two-bottle tests were conducted with the CS+ and CS- flavors presented in 0.9% CO without injections. Significant and persistent CS+ preferences were observed in VEH (75-82%), Limited VEH (70-88%), SCH25 (75-84%), SCH50 (64-87%), SCH200 (78-91%) and RAC200 (74-91%) groups. In contrast, the group trained with RAC50 displayed a significant initial CS+ preference (76%) which declined over testing to 61%. These data indicate limited DA D1 and D2 receptor signaling involvement in the expression and acquisition of a fat-CFP relative to previous robust effects for sugar-CFP.

Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft.

Composite facial allotransplantation is emerging as a treatment option for severe facial disfigurements. The technical feasibility of facial transplantation has been demonstrated, and the initial clinical outcomes have been encouraging. We report an excellent functional and anatomical restoration 1 year after face transplantation. A 59-year-old male with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore midfacial form and function. An initial potent antirejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient demonstrated facial redness during the initial postoperative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life. Composite facial allotransplantation, along with minimal and well-tolerated immunosuppression, was successfully utilized to restore facial form and function in a patient with severe disfigurement of the midface.

Are Upper Paleolithic blade cores more productive than Middle Paleolithic discoidal cores? A replication experiment.

It is widely believed that the change from discoidal flake production to prismatic blade-making during the Middle-Upper Paleolithic transition in Europe led to enhanced technological efficiency. Specifically, blade-making is thought to promote higher rates of blank production, more efficient and complete reduction of the parent core, and a large increase in the total length of cutting edge per weight of stone. Controlled replication experiments using large samples, computer-assisted measurements, and statistical tests of several different measures failed to support any of these propositions. When resharpened, the use-life of flake edges actually surpasses that of blades of equivalent mass because the narrower blades are more rapidly exhausted by retouch. Our results highlight the need to replace static measurements of edge length that promote an illusion of efficiency with a more dynamic approach that takes the whole reduction sequence into account. An unexpected by-product of our replications was the discovery that real gains in cutting-edge length per weight of stone are linked to surface area. There is now a need to test the proposition that all the perceived advantages currently bestowed upon blades only occurred during the shift from macroblade to bladelet production. If our results are duplicated in further experiments, the notion of "economical" blades will have to be rejected and alternative explanations sought for their appearance in the early Upper Paleolithic. While Aurignacian bladelet (Dufour) production could signal the advent of composite tool technology (wooden handles or shafts with bladelet inserts), this does not help to explain why macroblades were also produced in large numbers. We may need to reexamine the notion that macroblades were of more symbolic than functional significance to their makers.

Falls and stumbles in myotonic dystrophy.

OBJECTIVE: To investigate falls and risk factors in patients with myotonic dystrophy type 1 (DM1) compared with healthy volunteers. METHODS: 13 sequential patients with DM1 from different kindreds were compared with 12 healthy volunteers. All subjects were evaluated using the Rivermead Mobility Index, Performance Oriented Mobility Assessment, and modified Activities Specific Balance Confidence scale. Measures of lower limb muscle strength, gait speed, and 7-day ambulatory activity monitoring were recorded. Subjects returned a weekly card detailing stumbles and falls. RESULTS: 11 of 13 patients (mean age 46.5 years, seven female) had 127 stumbles and 34 falls over the 13 weeks, compared with 10 of 12 healthy subjects (34.4 years, seven female) who had 26 stumbles and three falls. Patients were less active than healthy subjects but had more falls and stumbles per 5000 right steps taken (mean (SD) events, 0.21 (0.29) v 0.02 (0.02), p = 0.007). Patients who fell (n = 6) had on average a lower Rivermead Mobility score, slower self selected gait speed, and higher depression scores than those who did not. CONCLUSIONS: DM1 patients stumble or fall about 10 times more often than healthy volunteers. Routine inquiry about falls and stumbles is justified. A study of multidisciplinary intervention to reduce the risk of falls seems warranted.

Coronary artery bypass graft imaging using ECG-gated multislice computed tomography: comparison with catheter angiography.

AIM: To compare the value of multislice computerized tomography (MSCT) in imaging coronary artery bypass grafts (CABGs) by direct quantitative comparison with standard invasive angiography. METHODS: Using MSCT, 50 consecutive patients who had previously undergone CABG surgery and had recently undergone invasive angiography for recurrent angina pectoris, were studied further using MSCT after intravenous injection of non-ionic contrast agent; cardiac imaging was performed during a single breath-hold. Graft anatomy was quantified, using both quantitative coronary angiography (QCA) and MSCT, by different investigators blinded to each other. Reproducibility was quantified using the standard error of the measurement expressed as a percentage in log-transformed values (CV%) and intraclass correlation (ICC). RESULTS: All 150 grafts were imaged using MSCT; only 4 patent grafts were not imaged using selective angiography. Good agreement was achieved between MSCT and QCA on assessment of proximal anastomoses (CV% 25.2, ICC 0.84), mid-vessel luminal diameter (CV% 15.5, ICC 0.91) and aneurysmal dilations (CV% 14.3). Reasonable agreement was reached on assessment of distal anastomoses (CV% 26.7, ICC 0.66) and categorization of distal run-off (ICC 0.73). Good agreement was observed for stenoses of over 50% luminal loss (CV% 8.7, ICC 0.97) but agreement on assessment of less severe lesions was poor (CV% 208.7, ICC 0.51). CONCLUSION: This study demonstrates that CABGs can be quantitatively evaluated using MSCT, and that significant lesions present in all CABG segments can be reliably identified. Agreement between MSCT and QCA for lesions of less than 50% luminal loss was poor.

Maternal diabetes mellitus is associated with altered deposition of fibrin-type fibrinoid at the villous surface in term placentae.

Placentae from control and diabetic patients were used to test three null hypothesis: (1) there are no significant group differences in the volumes of villous syncytiotrophoblast compartments or intervillous fibrin-type fibrinoid, (2) perivillous fibrin-type fibrinoid is deposited randomly at the surface of trophoblast, and (3) amounts and deposition patterns of perivillous fibrin-type fibrinoid do not vary between groups. Term placentae were collected from non-diabetic subjects and five groups of diabetic women classified according to duration, severity and insulin dependence. Tissue specimens and sections were obtained by uniform random sampling. Volumes and surface areas of fibrin-type fibrinoid and trophoblast compartments (thin, syncytial knot, syncytial bridge and denuded regions) were estimated stereologically and compared using variance, chi-squared and contingency table analyses. As to null hypothesis (1), no group differences in volumes of trophoblast compartments were found but volumes of intervillous fibrin-type fibrinoid were greater in the non-insulin-dependent diabetic group. As to null hypothesis (2), regardless of group, fibrin-type fibrinoid was deposited preferentially at sites of denudation in every placenta examined. As to null hypothesis (3), villous surface areas occupied by perivillous fibrin-type fibrinoid were greater in type 1 (insulin-dependent) diabetics with complications (diabetic nephropathy or retinopathy). The surfaces of trophoblast occupied by fibrin-type fibrinoid were also notably larger in non-insulin-dependent diabetics and type 1 diabetics with complications. Except for the surface of denudation sites (which also increased in diabetes), there were no differences in the surfaces of trophoblast regions. These results confirm that the haemostatic steady state is perturbed in the diabetic placenta, that perivillous fibrin-type fibrinoid is deposited preferentially at sites of epithelial loss/damage, and that some diabetic groups are affected differentially.

A review of computer-aided body surface area determination: SAGE II and EPRI's 3D Burn Vision.

Estimates of percent body surface area (%BSA) burns correlate well with fluid needs, nutritional requirements, and prognosis. Most burn centers rely on the Lund Browder chart and "rule of nines," to calculate the %BSA. Computer-based methods may improve precision and data analysis. We studied two new methods of determining %BSA: a two-dimensional Web-based program (Sage II) and a three-dimensional computer-aided design program (EPRI 3D Burn Vision). Members of our burn team found the Sage II program easy to use and found many of the features useful for patient care. The EPRI program has the advantage of 3D images and different body morphologies but required training to use. Computer-aided methods offer the potential for improved precision and data analysis of %BSA measurements.

Transforming growth factor-beta has contrasting effects in the presence or absence of exogenous interleukin-12 on the in vitro activation of cells that transfer experimental autoimmune thyroiditis.

Mouse thyroglobulin (MuTg)-sensitized spleen cells activated in vitro with MuTg induce experimental autoimmune thyroiditis (EAT) in recipient mice with a thyroid infiltrate consisting primarily of lymphocytes. A more severe and histologically distinct granulomatous form of EAT (G-EAT) is induced when donor cells are activated with MuTg together with anti-interferon-gamma (IFN-gamma), anti-interleukin-2 receptor (IL-2R) monoclonal antibody (mAb), and IL-12. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that can both suppress and exacerbate autoimmune diseases and often has inhibitory effects on lymphocytes. To determine if TGF-beta could modulate the in vitro activation of effector cells for G-EAT, TGF-beta was added to cultures of MuTg-sensitized donor spleen cells together with MuTg. Cells activated in the presence of 2 ng/ml TGF-beta induced moderately severe G-EAT in recipient mice. G-EAT induced by cells activated in the presence of TGF-beta was histologically similar but less severe than the G-EAT induced by cells activated in the presence of IL-12. IL-12 and TGF-beta modulate the activation of G-EAT effector cells by distinct mechanisms, as cells activated by TGF-beta could induce G-EAT in the presence of anti-IL-12, and TGF-beta inhibited the effects of IL-12 on EAT effector cells. TGF-beta exerted its activity during the first 24 h of the 72-h culture, whereas IL-12 functioned primarily during the final 24 h of culture. These results indicate that thyroid lesions with granulomatous histopathology can be induced by both IL-12-dependent and IL-12-independent mechanisms, and TGF-beta can exert both positive and negative effects on the effector cells for G-EAT.

Genetic analysis of the complete gag and env genes of HIV type 1 subtype C primary isolates from South Africa.

South Africa has one of the fastest growing HIV-1 epidemics, with an estimated 4.7 million people infected. To better understand the genetic diversity of this epidemic and its potential impact on vaccine development, we have cloned and sequenced the complete gag and env genes of 13 primary virus isolates. Phylogenetic analysis of our sequences and 69 complete env genes from the Los Alamos and GenBank databases revealed multiple subclusters within subtype C. The V3 loop region was relatively conserved in all our strains when compared with other subtypes, but the region immediately downstream was highly variable. No intersubtype recombinant forms were observed when comparing the gag and env sequences. Characterization of the complete gag and env genes enabled us to select specific strains for further vaccine development.