Visual function and dysfunction in early and late age-related maculopathy

Late age-related maculopathy (ARM) is responsible for the majority of blind registrations in the Western world among persons over 50 years of age. It has devastating effects on quality of life and independence and is becoming a major public health concern. Current treatment options are limited and most aim to slow progression rather than restore vision; therefore, early detection to identify those patients most suitable for these interventions is essential. In this work, we review the literature encompassing the investigation of visual function in ARM in order to highlight those visual function parameters which are affected very early in the disease process. We pay particular attention to measures of acuity, contrast sensitivity (CS), cone function, electrophysiology, visual adaptation, central visual field sensitivity and metamorphopsia. We also consider the impact of bilateral late ARM on visual function as well as the relationship between measures of vision function and self-reported visual functioning. Much interest has centred on the identification of functional changes which may predict progression to neovascular disease; therefore, we outline the longitudinal studies, which to date have reported dark-adaptation time, short-wavelength cone sensitivity, colour-match area effect, dark-adapted foveal sensitivity, foveal flicker sensitivity, slow recovery from glare and slower foveal electroretinogram implicit time as functional risk factors for the development of neovascular disease. Despite progress in this area, we emphasise the need for longitudinal studies designed in light of developments in disease classification and retinal imaging, which would ensure the correct classification of cases and controls, and provide increased understanding of the natural course and progression of the disease and further elucidate the structure-function relationships in this devastating disorder.

Training-induced modifications of corticospinal reactivity in severely affected stroke survivors

When permitted access to the appropriate forms of rehabilitation, many severely affected stroke survivors demonstrate a capacity for upper limb functional recovery well in excess of that formerly considered possible. Yet, the mechanisms through which improvements in arm function occur in such profoundly impaired individuals remain poorly understood. An exploratory study was undertaken to investigate the capacity for brain plasticity and functional adaptation, in response to 12-h training of reaching using the SMART Arm device, in a group of severely affected stroke survivors with chronic upper limb paresis. Twenty-eight stroke survivors were enroled. Eleven healthy adults provided normative data. To assess the integrity of ipsilateral and contralateral corticospinal pathways, transcranial magnetic stimulation was applied to evoke responses in triceps brachii during an elbow extension task. When present, contralateral motor-evoked potentials (MEPs) were delayed and reduced in amplitude compared to those obtained in healthy adults. Following training, contralateral responses were more prevalent and their average onset latency was reduced. There were no reliable changes in ipsilateral MEPs. Stroke survivors who exhibited contralateral MEPs prior to training achieved higher levels of arm function and exhibited greater improvements in performance than those who did not initially exhibit contralateral responses. Furthermore, decreases in the onset latency of contralateral MEPs were positively related to improvements in arm function. Our findings demonstrate that when severely impaired stroke survivors are provided with an appropriate rehabilitation modality, modifications of corticospinal reactivity occur in association with sustained improvements in upper limb function.

Improving clinician self-efficacy does not increase asthma guideline use by primary care clinicians

Objective: The purpose of this study was to show the association between changes in clinician self-efficacy and readiness to change and implementation of an asthma management program (Easy Breathing). Methods: A 36 month randomized, controlled trial was conducted involving 24 pediatric practices (88 clinicians). Randomized clinicians received interventions designed to enhance clinician self-efficacy and readiness to change which were measured at baseline and 3 years. Interventions consisted of an educational toolbox, seminars, teleconferences, mini-fellowships, opinion leader visits, clinician-specific feedback, and pay for performance. The primary outcome was program utilization (number of children enrolled in Easy Breathing/year); secondary outcomes included development of a written treatment plan and severity-appropriate therapy. Results: At baseline, clinicians enrolled 149 ± 147 (mean ± SD) children/clinician/year; 84% of children had a written treatment plan and 77% of plans used severity-appropriate therapy. At baseline, higher self-efficacy scores were associated with greater program utilization (relative rate [RR], 1.34; 95% confidence interval [CI], 1.04-1.72; P =.04) but not treatment plan development (RR, 0.63; 95% CI, 0.29-1.35; P =.23) or anti-inflammatory use (RR, 1.76; 95% CI, 0.92-3.35; P =.09). Intervention clinicians participated in 17 interventions over 36 months. At study end, self-efficacy scores increased in intervention clinicians compared to control clinicians (P =.01) and more clinicians were in an action stage of change (P =.001) but these changes were not associated with changes in primary or secondary outcomes. Conclusions: Self-efficacy scores correlated with program use at baseline and increased in the intervention arm, but these increases were not associated with greater program-related activities. Self-efficacy may be necessary but not sufficient for behavior change. Copyright © 2012 by Academic Pediatric Association.

Effect of a multifaceted intervention on adherence to hand hygiene among healthcare workers:A cluster-randomized trial

OBJECTIVES. Adherence to hand hygiene among healthcare workers (HCWs) is widely believed to be a key factor in reducing the spread of healthcare-associated infection. The objective of this study was to evaluate the impact of a multifaceted intervention to increase rates of adherence to hand hygiene among HCWs and to assess the effect on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) colonization. DESIGN. Cluster-randomized controlled trial. SETTING. Thirty hospital units in 3 tertiary care hospitals in Hamilton, Ontario, Canada. INTERVENTION. After a 3-month baseline period of data collection, 15 units were randomly assigned to the intervention arm (with performance feedback, small-group teaching seminars, and posters) and 15 units to usual practice. Hand hygiene was observed during randomly selected 15-minute periods on each unit, and the incidence of MRSA colonization was measured using weekly surveillance specimens from June 2007 through May 2008. RESULTS. We found that 3,812 (48.2%) of 7,901 opportunities for hand hygiene in the intervention group resulted in adherence, compared with 3,205 (42.6%) of 7,526 opportunities in the control group (P <.001; independent t test). There was no reduction in the incidence of hospital-acquired MRSA colonization in the intervention group. CONCLUSION. Among HCWs in Ontario tertiary care hospitals, the rate of adherence to hand hygiene had a statistically significant increase of 6% with a multifaceted intervention, but the incidence of MRSA colonization was not reduced.

Conformation-specific crosslinking of mitochondrial complex I

Complex I is the only component of the eukaryotic respiratory chain of which no high-resolution structure is yet available. A notable feature of mitochondrial complex I is the so-called active/de-active conformational transition of the idle enzyme from the active (A) to the de-active, (D) form. Using an amine- and sulfhydryl-reactive crosslinker of 6.8 Å length (SPDP) we found that in the D-form of complex I the ND3 subunit crosslinked to the 39 kDa (NDUFA9) subunit. These proteins could not be crosslinked in the A-form. Most likely, both subunits are closely located in the critical junction region connecting the peripheral hydrophilic domain to the membrane arm of the enzyme where the entrance path for substrate ubiquinone is and where energy transduction takes place.

Pneumonia and lower respiratory infections in nursing home residents:Predictors of hospitalization and mortality

OBJECTIVES: To compare predictors of hospitalization and death in nursing home residents with pneumonia and other lower respiratory infections (LRIs). DESIGN: A nested cohort study. SETTING: Nine nursing homes in southern Ontario. PARTICIPANTS: Three hundred fifty-three nursing home residents with LRIs (enrolled in the control arm of a clinical trial). MEASUREMENTS: Comorbidities, vaccination status, age, health-related quality of life, functional status, and vital statistics were evaluated as potential predictors of hospitalization and mortality at 30 days. RESULTS: Moderate to high disease severity score on a practical severity scale was a strong independent predictor of hospitalization (odds ratio (OR)=7.12, P

Cost-effectiveness of internal limiting membrane peeling versus no peeling for patients with an idiopathic full-thickness macular hole:Results from a randomised controlled trial

Aim: To determine whether internal limiting membrane (ILM) peeling is cost-effective compared with no peeling for patients with an idiopathic stage 2 or 3 full-thickness macular hole. Methods: A cost-effectiveness analysis was performed alongside a randomised controlled trial. 141 participants were randomly allocated to receive macular-hole surgery, with either ILM peeling or no peeling. Health-service resource use, costs and quality of life were calculated for each participant. The incremental cost per quality-adjusted life year (QALY) gained was calculated at 6 months. Results: At 6 months, the total costs were on average higher (£424, 95% CI -182 to 1045) in the No Peel arm, primarily owing to the higher reoperation rate in the No Peel arm. The mean additional QALYs from ILM peel at 6 months were 0.002 (95% CI 0.01 to 0.013), adjusting for baseline EQ-5D and other minimisation factors. A mean incremental cost per QALY was not computed, as Peeling was on average less costly and slightly more effective. A stochastic analysis suggested that there was more than a 90% probability that Peeling would be cost-effective at a willingness-to-pay threshold of £20 000 per QALY. Conclusion: Although there is no evidence of a statistically significant difference in either costs or QALYs between macular hole surgery with or without ILM peeling, the balance of probabilities is that ILM Peeling is likely to be a cost-effective option for the treatment of macular holes. Further long-term follow-up data are needed to confirm these findings.

Activation of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis Enhances the Reparative Function of Dysfunctional Diabetic Endothelial Progenitors

We tested the hypothesis that activation of the protective arm of the renin angiotensin system, the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis, corrects the vasoreparative dysfunction typically seen in the CD34(+) cells isolated from diabetic individuals. Peripheral blood CD34(+) cells from patients with diabetes were compared with those of nondiabetic controls. Ang-(1-7) restored impaired migration and nitric oxide bioavailability/cGMP in response to stromal cell-derived factor and resulted in a decrease in NADPH oxidase activity. The survival and proliferation of CD34(+) cells from diabetic individuals were enhanced by Ang-(1-7) in a Mas/phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. ACE2 expression was lower, and ACE2 activators xanthenone and diminazine aceturate were less effective in inducing the migration in cells from patients with diabetes compared with controls. Ang-(1-7) overexpression by lentiviral gene modification restored both the in vitro vasoreparative functions of diabetic cells and the in vivo homing efficiency to areas of ischemia. A cohort of patients who remained free of microvascular complications despite having a history of longstanding inadequate glycemic control had higher expression of ACE2/Mas mRNA than patients with diabetes with microvascular complications matched for age, sex, and glycemic control. Thus, ACE2/Ang-(1-7)\Mas pathway activation corrects existing diabetes-induced CD34(+) cell dysfunction and also confers protection from development of this dysfunction.

Reducing the psychological distress of family caregivers of home-based palliative care patients: short-term effects from a randomised controlled trial

BACKGROUND: Palliative care is expected to incorporate comprehensive support for family caregivers given that many caregivers suffer psychological morbidity. However, systematically implemented evidence-based psychological support initiatives are lacking.
AIM: The objective of this study was to prepare caregivers for the role of supporting a patient with advanced cancer receiving home-based palliative care by offering a one-to-one psycho-educational intervention. We hypothesised that primary family caregivers who participated in the intervention would report decreased psychological distress (primary outcome), fewer unmet needs and increased levels of perceived preparedness, competence and positive emotions.
METHODS: A three-arm randomised controlled trial was conducted comparing two versions of the intervention (one face-to-face visit versus two visits) plus standard care to a control group (standard care) across four sites in Australia.
RESULTS: A total of 298 participants were recruited; 148 were in the Control condition, 57 in Intervention 1 (one visit) and 93 in Intervention 2 (two visits). Relative to participants in the control group; the psychological well-being of participants in the intervention condition was improved by a small amount but non-significantly. No significant reduction in unmet needs or improvements in positive aspects of caregiving amongst the intervention group were identified. However, the intervention demonstrated significant improvements in participants' levels of preparedness and competence for Intervention 2.
CONCLUSION/IMPLICATIONS: This research adds to accumulating body of evidence demonstrating that relatively short psycho-educational interventions can enable family caregivers to feel more prepared and competent in the role of supporting a dying relative. Further investigation is required to determine the longer term outcomes of such interventions. 

Physical Activity Loyalty Cards for Behavior Change:A Quasi-Experimental Study

Background: Financial incentives have been advocated by the UK and U.S. governments to encourage adoption of healthy lifestyles. However, evidence to support the use of incentives for changing physical activity (PA) behavior is sparse.
Purpose:To investigate the effectiveness of?nancial incentives to increase PA in adults in the workplace.
Design: Two-arm quasi-experimental design.
Setting/participants: Employees (n¼406) in a workplace setting in Belfast, Northern Ireland, UK.
Intervention: Using a loyalty card to collect points and earn rewards, participants (n¼199) in the Incentive Group monitored their PA levels and received ?nancial incentives (retail vouchers) for minutes of PA completed over the course of a 12-week intervention period. Participants (n¼207) in the comparison group used their loyalty card to self-monitor their PA levels but were not able to earn points or obtain incentives (No Incentive Group).
Main outcome measures:The primary outcome was minutes of PA objectively measured using a novel PA tracking system at baseline (April 2011); Week 6 (June 2011); and Week 12 (July 2011).
Other outcomes, including a self-report measure of PA, were collected at baseline, Week 12, and 6 months (October 2011). Data were analyzed in June 2012.
Results: No signi?cant differences between groups were found for primary or secondary outcomes at the 12-week and 6-month assessments. Participants in the Incentive Group recorded 17.52 minutes of PA/week (95% CI¼12.49, 22.56) compared to 16.63 minutes/week (95% CI¼11.76, 21.51) in the No Incentive Group at Week 12 (p¼0.59). At 6 months, participants in the Incentive Group recorded 26.18 minutes of PA/week (95% CI¼20.06, 32.29) compared to 24.00 minutes/week (95% CI¼17.45, 30.54) in the No Incentive Group (p¼0.45).
Conclusions: Financial incentives did not encourage participants to undertake more PA than selfmonitoring PA. This study contributes to the evidence base and has important implications for increasing participation in physical activity and fostering links with the business sector. (Am J Prev Med 2013;45(1):56–63) © 2013 American Journal of Preventive Medicine

Contribution of primary motor cortex to compensatory balance reactions

Background: Rapid compensatory arm reactions represent important response strategies following an unexpected loss of balance. While it has been assumed that early corrective actions arise largely from sub-cortical networks, recent findings have prompted speculation about the potential role of cortical involvement. To test the idea that cortical motor regions are involved in early compensatory arm reactions, we used continuous theta burst stimulation (cTBS) to temporarily suppress the hand area of primary motor cortex (M1) in participants prior to evoking upper limb balance reactions in response to whole body perturbation. We hypothesized that following cTBS to the M1 hand area evoked EMG responses in the stimulated hand would be diminished. To isolate balance reactions to the upper limb participants were seated in an elevated tilt-chair while holding a stable handle with both hands. The chair was held vertical by a magnet and was triggered to fall backward unpredictably. To regain balance, participants used the handle to restore upright stability as quickly as possible with both hands. Muscle activity was recorded from proximal and distal muscles of both upper limbs.

Results: Our results revealed an impact of cTBS on the amplitude of the EMG responses in the stimulated hand muscles often manifest as inhibition in the stimulated hand. The change in EMG amplitude was specific to the target hand muscles and occasionally their homologous pairs on the non-stimulated hand with no consistent effects on the remaining more proximal arm muscles.

Conclusions: Present findings offer support for cortical contributions to the control of early compensatory arm reactions following whole-body perturbation.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia:results from the LRF AML14 and NCRI AML16 pick-a-winner comparison

The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

FPGA Prototyping of Emerging Manycore Architectures for Parallel Programming Research using Formic Boards

Performance evaluation of parallel software and architectural exploration of innovative hardware support face a common challenge with emerging manycore platforms: they are limited by the slow running time and the low accuracy of software simulators. Manycore FPGA prototypes are difficult to build, but they offer great rewards. Software running on such prototypes runs orders of magnitude faster than current simulators. Moreover, researchers gain significant architectural insight during the modeling process. We use the Formic FPGA prototyping board [1], which specifically targets scalable and cost-efficient multi-board prototyping, to build and test a 64-board model of a 512-core, MicroBlaze-based, non-coherent hardware prototype with a full network-on-chip in a 3D-mesh topology. We expand the hardware architecture to include the ARM Versatile Express platforms and build a 520-core heterogeneous prototype of 8 Cortex-A9 cores and 512 MicroBlaze cores. We then develop an MPI library for the prototype and evaluate it extensively using several bare-metal and MPI benchmarks. We find that our processor prototype is highly scalable, models faithfully single-chip multicore architectures, and is a very efficient platform for parallel programming research, being 50,000 times faster than software simulation.

Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions

Posterior parietal cortex (PPC) constitutes a critical cortical node in the sensorimotor system in which goal-directed actions are computed. This information then must be transferred into commands suitable for hand movements to the primary motor cortex (M1). Complexity arises because reach-to-grasp actions not only require directing the hand towards the object (transport component), but also preshaping the hand according to the features of the object (grip component). Yet, the functional influence that specific PPC regions exert over ipsilateral M1 during the planning of different hand movements remains unclear in humans. Here we manipulated transport and grip components of goal-directed hand movements and exploited paired-pulse transcranial magnetic stimulation (ppTMS) to probe the functional interactions between M1 and two different PPC regions, namely superior parieto-occipital cortex (SPOC) and the anterior region of the intraparietal sulcus (aIPS), in the left hemisphere. We show that when the extension of the arm is required to contact a target object, SPOC selectively facilitates motor evoked potentials, suggesting that SPOC-M1 interactions are functionally specific to arm transport. In contrast, a different pathway, linking the aIPS and ipsilateral M1, shows enhanced functional connections during the sensorimotor planning of grip. These results support recent human neuroimaging findings arguing for specialized human parietal regions for the planning of arm transport and hand grip during goal-directed actions. Importantly, they provide new insight into the causal influences these different parietal regions exert over ipsilateral motor cortex for specific types of planned hand movements