Technological aids for the rehabilitation of memory and executive functioning in children and adolescents with acquired brain injury (Review).

Background The use of technology in healthcare settings is on the increase and may represent a cost-effective means of delivering rehabilitation. Reductions in treatment time, and delivery in the home, are also thought to be benefits of this approach. Children and adolescents with brain injury often experience deficits in memory and executive functioning that can negatively affect their school work, social lives, and future occupations. Effective interventions that can be delivered at home, without the need for high-cost clinical involvement, could provide a means to address a current lack of provision. We have systematically reviewed studies examining the effects of technology-based interventions for the rehabilitation of deficits in memory and executive functioning in children and adolescents with acquired brain injury. Objectives To assess the effects of technology-based interventions compared to placebo intervention, no treatment, or other types of intervention, on the executive functioning and memory of children and adolescents with acquired brain injury. Search methods We ran the search on the 30 September 2015. We searched the Cochrane Injuries Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), EMBASE Classic + EMBASE (OvidSP), ISI Web of Science (SCI-EXPANDED, SSCI, CPCI-S, and CPSI-SSH), CINAHL Plus (EBSCO), two other databases, and clinical trials registers. We also searched the internet, screened reference lists, and contacted authors of included studies. Selection criteria Randomised controlled trials comparing the use of a technological aid for the rehabilitation of children and adolescents with memory or executive-functioning deficits with placebo, no treatment, or another intervention. Data collection and analysis Two review authors independently reviewed titles and abstracts identified by the search strategy. Following retrieval of full-text manuscripts, two review authors independently performed data extraction and assessed the risk of bias. Main results Four studies (involving 206 participants) met the inclusion criteria for this review. Three studies, involving 194 participants, assessed the effects of online interventions to target executive functioning (that is monitoring and changing behaviour, problem solving, planning, etc.). These studies, which were all conducted by the same research team, compared online interventions against a 'placebo' (participants were given internet resources on brain injury). The interventions were delivered in the family home with additional support or training, or both, from a psychologist or doctoral student. The fourth study investigated the use of a computer program to target memory in addition to components of executive functioning (that is attention, organisation, and problem solving). No information on the study setting was provided, however a speech-language pathologist, teacher, or occupational therapist accompanied participants. Two studies assessed adolescents and young adults with mild to severe traumatic brain injury (TBI), while the remaining two studies assessed children and adolescents with moderate to severe TBI. Risk of bias We assessed the risk of selection bias as low for three studies and unclear for one study. Allocation bias was high in two studies, unclear in one study, and low in one study. Only one study (n = 120) was able to conceal allocation from participants, therefore overall selection bias was assessed as high. One study took steps to conceal assessors from allocation (low risk of detection bias), while the other three did not do so (high risk of detection bias). Primary outcome 1: Executive functioning: Technology-based intervention versus placebo Results from meta-analysis of three studies (n = 194) comparing online interventions with a placebo for children and adolescents with TBI, favoured the intervention immediately post-treatment (standardised mean difference (SMD) -0.37, 95% confidence interval (CI) -0.66 to -0.09; P = 0.62; I2 = 0%). (As there is no 'gold standard' measure in the field, we have not translated the SMD back to any particular scale.) This result is thought to represent only a small to medium effect size (using Cohen’s rule of thumb, where 0.2 is a small effect, 0.5 a medium one, and 0.8 or above is a large effect); this is unlikely to have a clinically important effect on the participant. The fourth study (n = 12) reported differences between the intervention and control groups on problem solving (an important component of executive functioning). No means or standard deviations were presented for this outcome, therefore an effect size could not be calculated. The quality of evidence for this outcome according to GRADE was very low. This means future research is highly likely to change the estimate of effect. Primary outcome 2: Memory One small study (n = 12) reported a statistically significant difference in improvement in sentence recall between the intervention and control group following an eight-week remediation programme. No means or standard deviations were presented for this outcome, therefore an effect size could not be calculated. Secondary outcomes Two studies (n = 158) reported on anxiety/depression as measured by the Child Behavior Checklist (CBCL) and were included in a meta-analysis. We found no evidence of an effect with the intervention (mean difference -5.59, 95% CI -11.46 to 0.28; I2 = 53%). The GRADE quality of evidence for this outcome was very low, meaning future research is likely to change the estimate of effect. A single study sought to record adverse events and reported none. Two studies reported on use of the intervention (range 0 to 13 and 1 to 24 sessions). One study reported on social functioning/social competence and found no effect. The included studies reported no data for other secondary outcomes (that is quality of life and academic achievement). Authors' conclusions This review provides low-quality evidence for the use of technology-based interventions in the rehabilitation of executive functions and memory for children and adolescents with TBI. As all of the included studies contained relatively small numbers of participants (12 to 120), our findings should be interpreted with caution. The involvement of a clinician or therapist, rather than use of the technology, may have led to the success of these interventions. Future research should seek to replicate these findings with larger samples, in other regions, using ecologically valid outcome measures, and reduced clinician involvement.

STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

A Wii Bit of Fun: A Novel Platform to Deliver Effective Balance Training to Older Adults

BACKGROUND: Falls and fall-related injuries are symptomatic of an aging population. This study aimed to design, develop, and deliver a novel method of balance training, using an interactive game-based system to promote engagement, with the inclusion of older adults at both high and low risk of experiencing a fall.

STUDY DESIGN: Eighty-two older adults (65 years of age and older) were recruited from sheltered accommodation and local activity groups. Forty volunteers were randomly selected and received 5 weeks of balance game training (5 males, 35 females; mean, 77.18 ± 6.59 years), whereas the remaining control participants recorded levels of physical activity (20 males, 22 females; mean, 76.62 ± 7.28 years). The effect of balance game training was measured on levels of functional balance and balance confidence in individuals with and without quantifiable balance impairments.

RESULTS: Balance game training had a significant effect on levels of functional balance and balance confidence (P < 0.05). This was further demonstrated in participants who were deemed at high risk of falls. The overall pattern of results suggests the training program is effective and suitable for individuals at all levels of ability and may therefore play a role in reducing the risk of falls.

CONCLUSIONS: Commercial hardware can be modified to deliver engaging methods of effective balance assessment and training for the older population.

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.

PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.

RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.

CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Identification of potentially pathogenic variants in candidate breast and ovarian cancer susceptibility genes in BRCAX patients

Mutations within the BRCA1 and BRCA2 genes account for approximately 20% of hereditary breast cancers, with a further 10%–15% being attributable to rare mutations in moderate-risk genes and common variants in low-risk genes. The genes harbouring mutations in the remaining ∼65% of hereditary breast cancers are unknown. The identification of mutation carriers in hereditary breast and ovarian cancer (hboc) families is critical for determining who is most at risk of developing the disease and therefore who should be offered risk-reducing procedures or more intensive screening, or both.

Many of the high- and moderate-risk genes for hereditary breast cancers encode proteins that work in concert to maintain genomic stability and in dna damage signalling and repair. A novel BRCA1 protein complex identified within the research group whose target genes are involved in dna repair provided novel candidates for hboc susceptibility genes. These 12 candidate genes were sequenced in a cohort of 675 affected individuals from the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) with hereditary breast or ovarian cancer, but with no mutations in known susceptibility genes (BRCAx patients). This analysis identified 20 individuals (each from a different BRCAx family) with different potentially pathogenic variants across 6 of the candidate hboc susceptibility genes. The family members of each BRCAx index case were tested for the presence of the specific mutation identified in the proband to examine segregation with disease. To further expand on the potential role of the novel candidate hboc susceptibility genes identified in this study, the genetic variation of a second cohort of 520 Northern Irish BRCAx patients is being characterized using a 61-gene panel.

Human Papillomavirus (HPV): Making the case for “Immunisation for All”

Human Papillomavirus (HPV) contributes to the most common sexually transmitted infections, with repeated and persistent infection with particular types causing disease in both men and women. Infection with low-risk HPV types can lead to genital warts and benign lesions of the oral cavity, while high-risk types can cause various HPV-related malignancies. The incidence of head and neck cancer has been rising in the past number of decades mostly due to oropharyngeal cancer linked to HPV infection. HPV vaccination has been shown to be effective for cervical and other anogenital HPV-related cancers, and there is significant potential for HPV vaccination to prevent oropharyngeal cancers, given that the HPV types implicated in this disease can be protected against by the HPV vaccine. Few countries have implemented a universal HPV vaccination programme for males and females, with many countries arguing that female only vaccination programmes protect males via herd immunity, and that men-who-have-sex-with-men will be protected via targeted vaccination programmes. We argue these may be limited in their effectiveness. We propose that the most effective, practical, ethical and potentially cost effective solution is universal HPV vaccination that might lead to control of HPV-related diseases in men and women alike.

Effect of eucaloric high- and low-sucrose diets with identical macronutrient profile on insulin resistance and vascular risk - A randomized controlled trial

The long-term impact of dietary carbohydrate type, in particular sucrose, on insulin resistance and the development of diabetes and atherosclerosis is not established. Current guidelines for the healthy population advise restriction of sucrose intake. We investigated the effect of high- versus low-sucrose diet (25 vs. 10%, respectively, of total energy intake) in 13 healthy subjects aged 33 +/- 3 years (mean +/- SE), BMI 26.6 +/- 0.9 kg/m(2), in a randomized crossover design with sequential 6-week dietary interventions separated by a 4-week washout. Weight maintenance, eucaloric diets with identical macronutrient profiles and fiber content were designed. All food was weighed and distributed. Insulin action was assessed using a two-step euglycemic clamp; glycemic profiles were assessed by the continuous glucose monitoring system and vascular compliance by pulse-wave analysis. There was no change in weight across the study. Peripheral glucose uptake and suppression of endogenous glucose production were similar after each diet. Glycemic profiles and measures of vascular compliance did not change. A rise in total and LDL cholesterol was observed. In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects.

Low-fat versus low-carbohydrate weight reduction diets:Effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial

OBJECTIVE Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.

RESEARCH DESIGN AND METHODS We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.

RESULTS Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.

CONCLUSIONS This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.