Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Phocid Seal Leptin: Tertiary Structure and Hydrophobic Receptor Binding Site Preservation during Distinct Leptin Gene Evolution

The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids) have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR) binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re-inflation upon surfacing, while maintaining patent airways. We suggest that this additional surfactant requirement is met by the leptin pulmonary surfactant production pathway which normally appears only to function in the mammalian foetus

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The influence of wood quality on lumber drying distortion

Commercial experience with the sawing of logs from fast-grown plantations has shown that there can be significant drying distortion associated with the presence of juvenile wood. In New Zealand this is a growing concern due to the reduction of rotation ages for radiata pine (Pinus radiata D Don) to around 25-30 years. The purpose of this analysis was to use the results of sawing studies to identify some of the major factors affecting distortion of the final product (structural lumber in this case) and test the feasibility of modeling the relationships. Analyses of some 9 000 individual boards (100 x 40 and 100 x 50 mm) from 1 000 logs indicated the need to take into account a range of factors relating to the raw material (logs), secondary processing technology (sawing pattern, drying method and the influence of planing), product (lumber dimensions) and standards (grading rules). The strong propensity for lumber from small diameter and physiologically young logs to degrade was confirmed and over 90% of the problem was related to twist rather than crook or bow. In the worst cases (small juvenile logs, low temperature drying, no planing) up to 80% of the boards were categorized as 'rejects'. At the other extreme, large diameter mature logs dried according to recommended practices and those that were machined to final size showed around a 5% rate of rejection. Diameter was shown to be the most influential log property. Spiral grain was also important due to its influence on twist during drying; it is greatest in juvenile wood which forms a greater proportion in small diameter logs. The analyses showed that both diameter and spiral grain are related to twist. Unfortunately, spiral grain is a little known feature of plantation pines, and is only now gaining the research attention it deserves. The results presented here indicate that log diameter of radiata pine is a good indicator of the propensity for lumber to twist during drying. Since this can be predicted using forest management models, it is proposed to extend the capability of predictive models by modifying them to assess the yields of dried, finished products.L'effet de propriétés du bois sur les défauts du séchage. L'expérience industrielle récente de débit de grumes, provenant de plantations à croissance rapide, montre qu'un degré significatif de déclassement peut survenir au séchage. Ce déclassement serait associé à la présence de bois juvénile. Ce problème est préoccupant en Nouvelle-Zélande étant donné que la révolution en plantations de pin radiata (Pinus radiata D Don) a été réduite à environ 25-30 ans. La présente étude vise à utiliser les résultats d'études de séchage pour identifier les causes majeures de gauchissement dans des produits finaux (dans le cas présent, des membrures structurales) ainsi qu'à tester la faisabilité de la modélisation des causes et effets. L'analyse de quelque 9 000 débits (100 x 40 et 100 x 50 mm) provenant de 1 000 grumes indique la nécessité de considérer une série de facteurs reliés tant à la matière première (grumes) qu'aux procédés de transformation secondaires (schémas de débitage, méthode de séchage et influence du rabotage), aux produits (dimentions des débits) et aux standards (règles de classification). Une forte tendance au déclassement a été confirmée chez les débits provenant de grumes de faible diamètre et physiologiquement juvéniles et plus de 90 % des problèmes étaient reliés au gauchissement en torsion plutôt qu'au gauchissement de rive ou à plat. Dans les pires cas (grumes juvéniles de faible dimention, séchage à basse température, pas de rabotage) près de 80 % des débits entraient dans la catégorie des « rejets ». À l'autre extrême, les débits provenant de grumes matures et de fort diamètre, séchés à l'aide de cédules en usage dans l'industrie et rabotés montraient aussi peu que 5 % de rejet. La propriété qui contribuait le plus en termes d'explication de la dégradation était le diamètre. La fibre torse était également importante étant donné l'influence qu'elle peut avoir sur le gauchissement en torsion au séchage. La fibre torse est présente en plus grande quantité dans le bois juvénile, qui constitue une plus grande proportion des grumes de faible diamètre. Les analyses montrent que le diamètre et la fibre torse sont corrélées au gauchissement en torsion. Malheureusement, peu d'informations sont disponibles à propos de la configuration de la fibre torse dans les pins de plantation, et ça n'est que récemment que ce problème s'est attiré toute l'attention qu'il mérite. Les résultats indiquent que le diamètre des grumes de pin radiata est un bon indicateur de la propention au gauchissement en torsion des débits au séchage. Étant donné que cette variable peut être prédite à l'aide de modèles d'aménagement forestier, il est proposé d'étendre le champ d'application de ces modèles pour y inclure la prédiction des rendements en produits finis séchés

Cerebellar Transcranial Direct Current Stimulation Modulates Corticospinal Excitability During Motor Training

Background: Cerebellar activity can be modulated using cerebellar transcranial direct current stimulation (ctDCS) and, when applied concurrently with task training, has been shown to facilitate cognitive and motor performance. However, how ctDCS facilitates motor performance is not fully understood.Objective/Hypothesis: To assess the electrophysiological and motor performance effects of ctDCS applied during motor training.Methods: Fourteen healthy adults (age 28.8 ± 10.5 years) were randomly assigned to complete one session of finger tracking training with either simultaneous bilateral anodal or sham ctDCS. Training was completed in two 15 min epochs with a 5-min break (total 30 min stimulation, 2 mA). Tracking accuracy and corticospinal and intracortical excitability were measured immediately before and after the training period. Motor cortical excitability measures included resting motor threshold (RMT), motor evoked potential (MEP) amplitude, cortical silent period (CSP) and short interval intracortical inhibition (SICI).Results: There was a significant interaction of Group * Time for MEP amplitude and CSP duration (p < 0.01). Post hoc analysis revealed MEP amplitude was increased in the sham group (p < 0.01), indicating increased corticospinal excitability from baseline while the anodal group displayed a decrease in MEP amplitude (p = 0.023) and prolongation of CSP duration (p < 0.01). SICI and RMT remained unchanged following ctDCS and training. Task accuracy was improved in both groups at post-test with a significant effect of Time (p < 0.01); however, there was no effect of Group (p = 0.45) or interaction of Group * Time (p = 0.83). During training, there was a significant effect of Block (p < 0.01) but no significant effect of Group or interaction effect (p > 0.06).Conclusions: ctDCS applied during task training is capable of modulating or interfering with practice-related changes in corticospinal excitability without disrupting performance improvement

Corticospinal excitability measurements using transcranial magnetic stimulation are valid with intramuscular electromyography.

OBJECTIVES:Muscular targets that are deep or inaccessible to surface electromyography (sEMG) require intrinsic recording using fine-wire electromyography (fEMG). It is unknown if fEMG validly record cortically evoked muscle responses compared to sEMG. The purpose of this investigation was to establish the validity and agreement of fEMG compared to sEMG to quantify typical transcranial magnetic stimulation (TMS) measures pre and post repetitive TMS (rTMS). The hypotheses were that fEMG would demonstrate excellent validity and agreement compared with sEMG. MATERIALS AND METHODS:In ten healthy volunteers, paired pulse and cortical silent period (CSP) TMS measures were collected before and after 1200 pulses of 1Hz rTMS to the motor cortex. Data were simultaneously recorded with sEMG and fEMG in the first dorsal interosseous. Concurrent validity (r and rho) and agreement (Tukey mean-difference) were calculated. RESULTS:fEMG quantified corticospinal excitability with good to excellent validity compared to sEMG data at both pretest (r = 0.77-0.97) and posttest (r = 0.83-0.92). Pairwise comparisons indicated no difference between sEMG and fEMG for all outcomes; however, Tukey mean-difference plots display increased variance and questionable agreement for paired pulse outcomes. CSP displayed the highest estimates of validity and agreement. Paired pulse MEP responses recorded with fEMG displayed reduced validity, agreement and less sensitivity to changes in MEP amplitude compared to sEMG. Change scores following rTMS were not significantly different between sEMG and fEMG. CONCLUSION:fEMG electrodes are a valid means to measure CSP and paired pulse MEP responses. CSP displays the highest validity estimates, while caution is warranted when assessing paired pulse responses with fEMG. Corticospinal excitability and neuromodulatory aftereffects from rTMS may be assessed using fEMG

Effectiveness of rTMS and retraining in the treatment of focal hand dystonia

Though the pathophysiology of dystonia remains uncertain, two primary factors implicated in the development of dystonic symptoms are excessive cortical excitability and impaired sensorimotor processing. The aim of this study was to determine the functional efficacy of a sensorimotor intervention combining rTMS and sensorimotor retraining. A randomized, single-subject, multiple baseline design with crossover was used to examine participants with focal hand dystonia (FHD) (n=9). Intervention: 5 days rTMS + sensorimotor retraining (SMR) vs. 5 days rTMS + control therapy (CTL) (which included stretching and massage). The rTMS was applied to the premotor cortex at 1 Hz at 80% resting motor threshold for 1200 pulses. For sensorimotor retraining, a subset of the Learning-based Sensorimotor Training program was followed. Each session consisted of rTMS followed immediately by 30 minutes of the therapy intervention (SMR or CTL). Group analyses revealed no additional benefit from the SMR training vs CTL, which was contrary to our hypothesis. When analyzed across group however, there was significant improvement from first baseline in several measures, including tests of sensory ability and self-rated changes. The patient rated improvements were accompanied by a moderate effect size suggesting clinical meaningfulness. These results provide encouragement for further investigation of rTMS in FHD with a need to optimized a secondary intervention and determine likely responders vs. non-responders

The relationship between sEMG and fEMG.

<p>Pretest data (top row) and posttest (bottom row). Data from 10 subjects, 10 trials/session/person, total of 100 data point in each plot. Note, the boxes on SICI graphs: fEMG responses cluster near 0 (y-distribution) while surface EMG response is more varied (x-distribution). Each color represents a single subject.</p

Simultaneous surface and fine-wire EMG trace.

<p>Example of a single pulse motor evoked potential response in a single subject.</p