Paired associative stimulation as a tool to assess plasticity enhancers in chronic stroke

Background and Purpose: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke. Methods: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period. Results: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study. Conclusion: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement

Robotic arm rehabilitation in chronic stroke patients with aphasia may promote speech and language recovery (but effect is not enhanced by supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS

PRImary care Streptococcal Management (PRISM) study:In vitro study, diagnostic cohorts and a pragmatic adaptive randomised controlled trial with nested qualitative study and cost-effectiveness study

Background: Antibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci. Objective: This study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing. Design: The study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies. Setting: The setting was UK primary care general practices. Participants: Participants were patients aged ≥ 3 years with acute sore throat. Interventions: An internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score. Main outcome measures: The main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2-4 days). Results: The IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci [FeverPAIN: Fever; Purulence; Attend rapidly (≤ 3 days); severe Inflammation; and No cough or coryza] had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored ≤ 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1; n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (-0.33; 95% confidence interval -0.64 to -0.02; p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (-0.30; -0.61 to 0.00; p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95; p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98; p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals' concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience. Conclusions: Targeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals' concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians' perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia.Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol.Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS.Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS

Delayed antibiotics for respiratory infections (Review)

BACKGROUND: Modest benefits of antibiotics for acute upper respiratory tract infections have to be weighed against common adverse reactions, cost and antibacterial resistance. There has been interest in ways to reduce antibiotic prescribing. One strategy is to provide the prescription, but advise delay of more than 48 hours before use, in the hope symptoms resolve first. Advocates suggest this will preserve patient satisfaction. This review asks what effect delayed antibiotics have on clinical outcomes of respiratory infections, antibiotic use and patient satisfaction. OBJECTIVES: To evaluate the prescribing strategy of delayed antibiotics for acute respiratory tract infections compared to immediate or no antibiotics for clinical outcomes, antibiotic use and patient satisfaction. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2006); MEDLINE (January 1966 to January Week 2, 2007), EMBASE (1990 to Week 2, 2007) and Current Contents - ISI Web of Knowledge (1998 to January 2007). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving patients of all ages defined as having an acute respiratory infection were included in which delayed antibiotics were compared to antibiotics used immediately or no antibiotics. Outcomes measured included clinical outcomes, antibiotic use and patient satisfaction. DATA COLLECTION AND ANALYSIS: Data were collected and analysed by three review authors. MAIN RESULTS: Nine trials were eligible on the basis of design and relevant outcomes. For most clinical outcomes there was no difference between delayed, immediate and no antibiotics. Antibiotics prescribed immediately were more effective than delayed for fever, pain and malaise in some studies of patients with acute otitis media and sore throat but for other studies there was no difference. There was no difference for the common cold and bronchitis. Delaying antibiotic prescriptions reduced antibiotic use, and in three studies, reduced patient satisfaction compared to immediate antibiotics. In the other two studies comparing delayed and immediate antibiotics measuring satisfaction, there was no difference. Two studies also included a 'no antibiotics' arm for bronchitis and sore throat: there was no difference in symptom resolution nor patient satisfaction from antibiotic delay. In one study, but not the other, antibiotic use was significantly decreased with no, rather than delayed, antibiotics. AUTHORS' CONCLUSIONS: For most clinical outcomes there is no difference between the strategies. Immediate antibiotics was the strategy most likely to provide the best clinical outcomes in patients with sore throat and otitis media. Delaying or avoiding antibiotics, rather than providing them immediately, reduces antibiotic use for acute respiratory infections. Delay also reduced patient satisfaction in three trials, compared to immediate antibiotics with no difference in two other trials. Delaying antibiotics seems to have little advantage over avoiding them altogether where it is safe to do so

An analysis of single amino acid repeats as use case for application specific background models

Background Sequence analysis aims to identify biologically relevant signals against a backdrop of functionally meaningless variation. Increasingly, it is recognized that the quality of the background model directly affects the performance of analyses. State-of-the-art approaches rely on classical sequence models that are adapted to the studied dataset. Although performing well in the analysis of globular protein domains, these models break down in regions of stronger compositional bias or low complexity. While these regions are typically filtered, there is increasing anecdotal evidence of functional roles. This motivates an exploration of more complex sequence models and application-specific approaches for the investigation of biased regions. Results Traditional Markov-chains and application-specific regression models are compared using the example of predicting runs of single amino acids, a particularly simple class of biased regions. Cross-fold validation experiments reveal that the alternative regression models capture the multi-variate trends well, despite their low dimensionality and in contrast even to higher-order Markov-predictors. We show how the significance of unusual observations can be computed for such empirical models. The power of a dedicated model in the detection of biologically interesting signals is then demonstrated in an analysis identifying the unexpected enrichment of contiguous leucine-repeats in signal-peptides. Considering different reference sets, we show how the question examined actually defines what constitutes the 'background'. Results can thus be highly sensitive to the choice of appropriate model training sets. Conversely, the choice of reference data determines the questions that can be investigated in an analysis. Conclusions Using a specific case of studying biased regions as an example, we have demonstrated that the construction of application-specific background models is both necessary and feasible in a challenging sequence analysis situation

Red de reservas marinas para la Región de las Grandes Islas, Golfo de California: protocolo del proyecto de planeación y reporte de los talleres del equipo de planeación [Marine reserves network for the Midriff Islands Region, Gulf of California, Mexico: planning protocol and progress report to the WWF Mexico & Carlos Slim Foundation Alliance]

La Región de las Grandes Islas (RGI), localizada en el acuario del mundo, el Golfo de California, es reconocida a nivel mundial por su espectacular belleza, diversidad y productividad; en ocasiones se le ha denominada como "las Galápagos del Hemisferio Norte" (Figura 1). En sus 45 islas, incluyendo las dos más grandes de México, Tiburón e Isla Ángel de la Guarda, se han registrado más de 400 especies de plantas, anfibios, reptiles y mamíferos terrestres, algunas de ellas endémicas a una o varias de las islas. En algunas de estas islas, como Rasa y San Pedro Mártir, llegan a anidar cientos de miles de aves marinas. Alrededor de este gran archipiélago, se pueden observar hasta 23 especies de mamíferos marinos, incluyendo la súper agregación de cachalotes en la cuenca San Pedro Mártir. Así como también es un sitio usado por cinco especies de tortugas marinas para hibernar y alimentarse. [English] In collaboration with researchers, agencies and NGOs, we aim to guide the design and implementation of a network of marine reserves for Midriff Islands, Gulf of California, a marine conservation hotspot. The area is one of the most important fishing regions in Mexico and livelihoods of coastal communities are threatened by depletion of fish stocks and climate change. The project aims to develop a practical approach to design networks of marine reserves that consider ecological connectivity and the effects of climate change. The project is an example of interdisciplinary and collaborative applied research, including over 25 researchers and managers from NGOs (COBI, Pronatura), universities (James Cook University, The University of Queensland, Arizona State University, SCRIPPS, The University of Arizona), and national (Mexico’s Commissions for Protected Areas and Biodiversity) and international agencies (NOAA)

BMP and Hedgehog regulate distinct AGM hematopoietic stem cells ex vivo

Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment