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Objective.Closed-loop neuromodulation technology is a rapidly expanding category of therapeutics for a broad range of indications. Development of these innovative neurological devices requires high-throughput systems for closed-loop stimulation of model organisms, while monitoring physiological signals and complex, naturalistic behaviors. To address this need, we developed CLARA, a closed-loop automated reaching apparatus.Approach.Using breakthroughs in computer vision, CLARA integrates fully-automated, markerless kinematic tracking of multiple features to classify animal behavior and precisely deliver neural stimulation based on behavioral outcomes. CLARA is compatible with advanced neurophysiological tools, enabling the testing of neurostimulation devices and identification of novel neurological biomarkers.Results.The CLARA system tracks unconstrained skilled reach behavior in 3D at 150 Hz without physical markers. The system fully automates trial initiation and pellet delivery and is capable of accurately delivering stimulation in response to trial outcome with short latency. Kinematic data from the CLARA system provided novel insights into the dynamics of reach consistency over the course of learning, suggesting that learning selectively improves reach failures but does not alter the kinematics of successful reaches. Additionally, using the closed-loop capabilities of CLARA, we demonstrate that vagus nerve stimulation (VNS) improves skilled reach performance and increases reach trajectory consistency in healthy animals.Significance.The CLARA system is the first mouse behavior apparatus that uses markerless pose tracking to provide real-time closed-loop stimulation in response to the outcome of an unconstrained motor task. Additionally, we demonstrate that the CLARA system was essential for our investigating the role of closed-loop VNS stimulation on motor performance in healthy animals. This approach has high translational relevance for developing neurostimulation technology based on complex human behavior.

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BACKGROUND: Underutilization of vaccination programs remains a significant public health concern. Pharmacists serve as educators, facilitators, and in some jurisdictions, as administrators of vaccines. Though pharmacists have been involved with immunizations in various ways for many years, there has yet to be a systematic review assessing the impact of pharmacists as immunizers in these three roles. OBJECTIVE: To complete a systematic review of the literature on the impact of pharmacists as educators, facilitators, and administrators of vaccines on immunization rates. METHODS: We identified 2825 articles searching the following databases from inception until October 2015: PubMed, EMBASE, Cochrane Libraries, Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, Google Scholar. Grey literature was identified through use of the Canadian Agency for Drugs and Technology in Health "Grey Matters" search tool. Content from relevant journals and references of included studies were also searched. Inclusion criteria were clinical or epidemiologic studies in which pharmacists were involved in the immunization process. Studies were excluded if no comparator was reported. Two reviewers independently completed data extraction and bias assessments using standardized forms. RESULTS: Thirty-six studies were included in the review, 22 assessed the role of pharmacists as educators and/or facilitators and 14 assessed their role as administrators of vaccines. All studies reviewed found an increase in vaccine coverage when pharmacists were involved in the immunization process, regardless of role (educator, facilitator, administrator) or vaccine administered (e.g., influenza, pneumococcal), when compared to vaccine provision by traditional providers without pharmacist involvement. Limitations of the results include the large number of non-randomized trials and the heterogeneity between study designs. CONCLUSIONS: Pharmacist involvement in immunization, whether as educators, facilitators, or administrators of vaccines, resulted in increased uptake of immunizations. PROSPERO Registration: CRD42013005067.

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OBJECTIVE: Radiotherapy treatments of post-mastectomy chest walls are complex, requiring treatment close to skin, necessitating bolus use. Commonly used 5- and 10-mm-thick boluses develop full skin dose, needing removal for the latter half of treatment and requiring two treatment plans to be generated. Can a thinner bolus be used for all treatment fractions, requiring only one plan? METHODS: Investigation of doses received using (A) a half-time 10-mm-thick Vaseline® bolus (current situation); (B) a brass mesh (Whiting & Davis, Attleboro Falls, MA) and (C) 3- and 5-mm Superflab™ (Mick Radio-Nuclear Instruments, Mount Vernon, NY) for 6 and 15 MV. Dosimetric measurements in Barts WT1 solid water and an anthropomorphic phantom, using ionization chambers and thermoluminescent dosemeters, were used to study the effect of different bolus regimes on the photon depth-dose curves (DDCs) and skin doses. RESULTS: Measured skin doses for the current 10-mm-thick Vaseline bolus, brass mesh and 3-mm bolus were compared (5 mm bolus has been rejected). The brass mesh has the least effect on the DDC, with changes <0.7% for depths greater than dmax. Brass mesh conforms superiorly to skin surfaces. Measurements on an anthropomorphic phantom demonstrate an increased skin dose compared with our current treatment protocol. CONCLUSION: Brass mesh has the smallest effect on the DDC, whilst sufficiently increasing surface dose. It can be removed at any fraction, based on a clinical decision, without the need for generating a new plan. Treating with one plan significantly reduces planning times. ADVANCES IN KNOWLEDGE: Quantification of skin doses required and achieved from wax-on/wax-off treatment compared with alternative available breast boluses.

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OBJECTIVE: The objective of this study was to reduce central line-associated blood stream infections (CLABSIs) among 13 collaborating regional neonatal intensive care units by 25%. We tested the hypothesis that change could be attributed to the quality improvement collaborative by testing for 'special cause' variation. STUDY DESIGN: Our prevention project included five features: (1) leadership commitment, (2) potentially best practices, (3) collaborative processes, (4) audit and feedback tools and (5) quality improvement techniques. Baseline (1 January 2006 to 30 August 2006) data were compared with the intervention (1 September 2006 to 30 June 2007) and post-intervention (1 July 2007 to 30 December 2007) periods and analyzed using statistical process control (SPC) methods. RESULT: We detected special cause variation, suggesting that the collaborative was associated with reduced infection rates, from 4.32 to 3.22 per 1000 line days (a 25% decrease) when comparing the baseline with the follow-up period. CONCLUSION: The collaborative's process was associated with fewer infections. SPC suggested that systematic changes occurred. The remaining challenges include sustaining or even further reducing the infection rate.

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We assessed the prevalence and 3-month change in glucose tolerance status in consecutive non-ST-elevation myocardial infarction (NSTEMI; European Society of Cardiology 2007 definition) patients (N=49; mean (S.D.) age 65 (11) years) admitted to a coronary care unit, without known diabetes. These patients underwent an oral glucose tolerance test (OGTT) 36-hour (median, IQR: 18-72) after admission and at 3 months. Undiagnosed abnormal glucose tolerance (AGT: impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or new diabetes) was common (61% at admission and 41% at 3 months, p<0.05) and the majority (approximately 3/4) had IGT. Glucose tolerance status improved in a higher proportion of patients than it worsened (31% vs. 8%, p=0.04). At 3 months, fasting glucose was unchanged but 2-hour OGTT glucose was lower (mean (S.D.): 8.5 (2.7) mmol/L vs. 7.7 (2.7) mmol/L, p=0.004). 'Stress hyperglycaemia' could explain higher admission glucose levels and this raises the question about the optimal timing of OGTT in relation to myocardial infarction. Newly diagnosed diabetes was present in approximately 10% of patients and this was not reliably detected by fasting plasma glucose. In NSTEMI patients OGTT is the only reliable strategy to identify subjects with IGT and diabetes.

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Inclusive fitness models predict many commonly observed behaviours: among humans, studies of within-household violence, the allocation of food and child care find that people favour those to whom they are more closely related. In some cases however, kin-altruism effects appear to be modest. Do individuals favour kin to the extent that kin-altruism models predict? Data on remittances sent by South African migrant workers to their rural households of origin allow an explicit test, to our knowledge the first of its kind for humans. Using estimates of the fitness benefits and costs associated with the remittance, the genetic relatedness of the migrant to the beneficiaries of the transfer, and their age- and sex-specific reproductive values, we estimate the level of remittance that maximizes the migrant worker's inclusive fitness. This is a much better predictor of observed remittances than is average relatedness, even when we take account (by means of a multiple regression) of covarying influences on the level of remittance. But the effect is modest: less than a third of the observed level of remittances can be explained by our kin-altruism model.

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We propose an explanation of cooperation among unrelated members of a social group in which cooperation evolves because it constitutes an honest signal of the member's quality as a mate, coalition partner or competitor, and therefore results in advantageous alliances for those signaling in this manner. Our model is framed as a multi-player public goods game that involves no repeated or assortative interactions, so that non-cooperation would be a dominant strategy if there were no signaling benefits. We show that honest signaling of underlying quality by providing a public good to group members can be evolutionarily stable, and can proliferate in a population in which it is initially rare, provided that certain plausible conditions hold, including a link between group-beneficial signaling and underlying qualities of the signaler that would be of benefit to a potential mate or alliance partner. Our model applies to a range of cooperative interactions, including unconditionally sharing individually consumable resources, participating in group raiding or defense, and punishing free-riding or other violations of social norms.

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This study was conducted at NASA Ames Research Center as a part of a larger research project assessing the impact of captain's personality on crew performance and perceived stress in 24 air transport crews (5). Three different personality types for captains were classified based on a previous cluster analysis (3). Crews were comprised of three crewmembers: captain, first officer, and second officer/flight engineer. A total of 72 pilots completed a 1.5-d full-mission simulation of airline operations including emergency situations in the Ames Manned Vehicle System Research Facility B-727 simulator. Crewmembers were tested for perceived stress on four dimensions of the NASA Task Load Index after each of five flight legs. Crews were divided into three groups based on rankings from combined error and rating scores. High performance crews (who committed the least errors in flight) reported experiencing less stress in simulated flight than either low or medium crews. When comparing crew positions for perceived stress over all the simulated flights no significant differences were found. However, the crews led by the "Right Stuff" (e.g., active, warm, confident, competitive, and preferring excellence and challenges) personality type captains typically reported less stress than crewmembers led by other personality types.

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The management of post-operative pain has been an area of concern for many years, with many studies focusing on the knowledge and beliefs of nurses working in this area. Following the report of the Royal College of Surgeons & College of Anaesthetists (1990) in the UK, there has been a rapid expansion in the development of Acute Pain Services (APS) in an attempt to counter these concerns. This descriptive study considers the possible impact the introduction of an APS had on the knowledge and beliefs of nurses working in the surgical area. A closed-answer questionnaire was used to replicate an earlier study (Mackintosh, 1994) which took place before the introduction of the APS. Findings demonstrate a consistent but mainly statistically non-significant trend in all areas towards an improved knowledge base and more appropriate beliefs about pain.

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Single-neuron recording and electrical microstimulation suggest three roles for the mesencephalic reticular formation (MRF) in oculomotor control: 1) saccade triggering, 2) computation of the horizontal component of saccade amplitude (a feed-forward function), and 3) feedback of an eye velocity signal from the paramedian zone of the pontine reticular formation (PPRF) to higher structures. These ideas were tested using reversible inactivation of the MRF with pressure microinjection of muscimol, a GABA(A) agonist, in four rhesus monkeys prepared for chronic single-neuron and eye movement recording. Reversible inactivation revealed two subregions of the MRF: ventral-caudal and rostral. The ventral-caudal region, which corresponds to the central MRF, the cMRF, or nucleus subcuneiformis, is the focus of this paper and is located lateral to the oculomotor nucleus and caudal to the posterior commissure (PC). Inactivation of the cMRF produced contraversive, upward saccade hypermetria. In three of eight injections, the velocity of hypermetric saccades was too fast for a given saccade amplitude, and saccade duration was shorter. The latency for initiation of most contraversive saccades was markedly reduced. Fixation was also destabilized with the development of macrosaccadic square-wave jerks that were directed toward a contraversive goal in the hypermetric direction. Spontaneous saccades collected in total darkness were also directed toward the same orbital goal, up and to the contraversive side. Three of eight muscimol injections were associated with a shift in the initial position of the eyes. A contralateral head tilt was also observed in 5 out of 8 caudal injections. All ventral-caudal injections with head tilt showed no evidence of vertical postsaccadic drift. This suggested that the observed changes in head movement and posture resulted from inactivation of the caudal MRF and not spread of the muscimol to the interstitial nucleus of Cajal (INC). Evidence of hypermetria strongly supports the idea that the ventral-caudal MRF participates in the feedback control of saccade accuracy. However, development of goal-directed eye movements, as well as a shift in the initial position following some of the cMRF injections, suggest that this region also contributes to the generation of an estimate of target or eye position coded in craniotopic coordinates. Last, the observed reduction in contraversive saccade latency and development of macrosaccadic square-wave jerks supports a role of the MRF in saccade triggering.

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Electrical microstimulation and single-unit recording have suggested that a group of long-lead burst neurons (LLBNs) in the mesencephalic reticular formation (MRF) just lateral to the interstitial nucleus of Cajal (INC) (the peri-INC MRF, piMRF) may play a role in the generation of vertical rapid eye movements. Inactivation of this region with muscimol (a GABA(A) agonist) rapidly produced vertical saccade hypometria (6 injections). In three of six injections, there was a marked reduction in the velocity of vertical saccades out of proportion to saccade amplitude (i.e., saccades fell below the main sequence). This was associated with a moderate increase in saccade duration. Inadvertent inactivation of the INC could not account for these observations because vertical, postsaccadic drift was not observed. Similarly, pure downward saccade hypometria, the hallmark of rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) inactivation, was always preceded by loss of upward saccades in our experiments. We also found a downward and ipsiversive displacement of initial eye position and evidence of a contraversive head tilt following piMRF injections. Saccade latency was shorter after two of six injections. Simulation of a local feedback model provided three possible explanations for vertical saccade hypometria: 1) a shift in the input to the model to request smaller saccades, 2) a reduction of LLBN input to the vertical saccade medium lead burst neurons (MLBNs), or 3) an increase in the gain of the feedback pathway. However, when the second hypothesis was coupled to a shortened duration of the saccade trigger (i.e., the discharge of the omnipause neurons), the physiological observations of piMRF inactivation could be replicated. This suggested that muscimol had targeted structures that provided both long-lead burst activity to the MLBNs in the riMLF and were critical for reactivation of the omnipause neurons. Evidence of markedly reduced vertical saccade amplitude, curved saccade trajectories, increased saccade duration, and saccades that fall below the amplitude/velocity main sequence in these monkeys closely parallels the oculomotor findings of patients with progressive supranuclear palsy (PSP).

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AIM: To determine risk factors for failure of temporary dialysis catheters, we prospectively studied the outcome of 178 non-tunneled dual lumen catheters placed in 126 consecutive patients requiring treatment of acute renal failure (ARF) or end-stage renal disease (ESRD). METHODS: Internal jugular (IJ) or subclavian (SC) catheters were used in 122 instances and femoral catheters were employed in 56. RESULTS: IJ or SC catheters with tips in the right atrium or superior vena cava (n = 112) failed (defined as a blood flow < 250 ml/min) 17% of the time, compared with a 40% failure rate for catheters with more peripherally located tips (n = 10), p < 0.05, chi2 testing. In a multivariate analysis, use in ESRD and location peripheral to the SVC were risk factors for catheter failure. Use of one of three catheter brands was associated with a lower failure rate. Although mean venous pressures at 200 ml/min blood flow were higher in IJ or SC catheters that failed, the presence of a high venous pressure, number of catheter uses, IJ vs. SC placement, inpatient vs. outpatient status, and fresh venipuncture vs. placement over a guidewire passed through a previous catheter did not predict catheter malfunction. With femoral catheters, the only risk factor for failure was use in ESRD. CONCLUSION: Of the factors that can be influenced by placement technique, catheter tip location is most important. Whether one catheter brand is superior awaits further confirmation.

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When a spontaneous abortion is followed by complicated bereavement, the primary care physician may not consider the diagnosis of acute stress disorder or post-traumatic stress disorder. The major difference between these two conditions is that, in acute stress disorder, symptoms such as dissociation, reliving the trauma, avoiding stimuli associated with the trauma and increased arousal are present for at least two days but not longer than four weeks. When the symptoms persist beyond four weeks, the patient may have post-traumatic stress disorder. The symptoms of distress response after spontaneous abortion include psychologic, physical, cognitive and behavioral effects; however, patients with distress response after spontaneous abortion often do not meet the criteria for acute or post-traumatic stress disorder. After spontaneous abortion, as many as 10 percent of women may have acute stress disorder and up to 1 percent may have post-traumatic stress disorder. Critical incident stress debriefing, which may be administered by trained family physicians or mental health practitioners, may help patients who are having a stress disorder after a spontaneous abortion.

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The role played by a hospital pharmacy department in managing an influenza outbreak at an affiliated long-term-care facility is described. In February 1998 an outbreak of influenza A was confirmed in a 570-bed long-term-care facility. During the outbreak, a total of 48 cases of influenza-like illness (ILI) were reported to infection control, and 62 staff members missed work because of ILI. Infection control measures included a recommendation for prophylaxis with amantadine. Pharmacists assumed responsibility for educating patients and families about amantadine prophylaxis, providing individualized dosing, evaluating reported adverse effects, and drug distribution. Pharmacists developed an information sheet on amantadine for patients and met with patients and their families. The overall acceptance rate for chemoprophylaxis was 91%. Of the 349 patients receiving amantadine during the outbreak, 203 (58%) were given 100 mg daily, 136 (39%) were given 100 mg every other day, and 10 (3%) were prescribed 100 mg weekly. Pharmacists confirmed a total of 22 adverse effects; generally the problem was solved by reducing the dosage rather than discontinuing the drug. In all cases, the first dose of amantadine was provided to the nursing units within three hours of an order being written. Pharmacists played an active role in managing an influenza A outbreak at a long-term-care facility.

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UNLABELLED: While sleep disorders are common in the elderly, the use of non-prescription products for sleep in this population has not been fully evaluated. The objectives of this project were to assess the use, perceived effectiveness and toxicity of non-prescription sleep products in an ambulatory elderly population. METHODS: A self-administered 20-question survey was distributed to seniors, aged 60 years or more, during hospital or pharmacy visits. RESULTS: Of the total respondents (N=176, mean age 74+/-7 years, 59% female), 84 (48%) indicated that they had used one or more therapies for sleep within the past year. These included non-prescription products (50% of therapies), prescription products (17%) and non-drug activities such as walking or drinking milk (34%). For those individuals who had used a non-prescription product in the past year (N=47, 27% of total respondents), the most frequently used products were: dimenhydrinate (21%), acetaminophen (19%), diphenhydramine (15%), alcohol (13%) and herbal products (11%). Most took them at least 1 day per week (79%) and 32% took them daily. These products subjectively improved sleep latency (mean 32 vs 61 minutes, p<0.001), number of nocturnal awakenings (mean 2 vs 3 awakenings, p<0.001) and total hours of sleep (mean 6.6 vs 5.4 hours, p<0.001). Mild side-effects were reported by 35 respondents (75%), the most common being dry mouth (N=22) and daytime drowsiness (N=13). Respondents were taking an average of four (SD+/-3, range 0-10) other medications currently. CONCLUSIONS: Non-prescription products are widely used by this population of ambulatory elderly for sleep disturbances. Most of the products were not marketed for sleep; however, they were perceived to be efficacious with low toxicity. The potential for drug interaction is high. Further research is warranted to evaluate the safety and effectiveness of non-prescription sleep products in the elderly.

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OBJECTIVE: To describe the steady-state pharmacokinetics of (R)-, (S)- and racemic (rac) propranolol in 15 normotensive, male volunteers in a double-blind, randomized, 3-way, crossover study. METHODS: (R)-propranolol 80 mg, (S)-propranolol 80 mg, or rac-propranolol 160 mg was administered twice daily for 3 days. Multiple blood samples were collected for up to 12 hours on the fourth day to characterize the steady-state pharmacokinetic profile of each enantiomer. RESULTS: (R)-propranolol bound to plasma proteins to a lesser extent than (S)-propranolol when it was administered both as a racemic mixture (15.8% versus 13.0%) and as a pure enantiomer (15.8% versus 12.9%), respectively (p < 0.05). No stereoselective pharmacokinetic differences were observed between total (bound and unbound) and unbound (R)- and (S)-propranolol. The AUC(0-720) of (R)-propranolol was significantly higher when administered as a racemic mixture than when given as a pure enantiomer (p < 0.01), suggesting the disposition of (R)-propranolol may be influenced by (S)-propranolol. CONCLUSION: Stereoselective steady-state pharmacokinetic differences in AUC(0-720) were observed between (R)- and (S)-propranolol.

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Day case surgery is an expanding area within the NHS. However, pain following day case procedures remains a constant concern for healthcare professionals. An audit of postoperative pain following a range of day case procedures over a 2-year period at a general hospital in the north of England found that 17-20% of patients experienced unacceptable levels of pain. However, very few of these patients were worried about the pain they experienced and none contacted their GP. This implies that healthcare professionals overestimate the significance of postoperative pain for the patients concerned.

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OBJECTIVES: To establish that serological indicators of synthesis of collagens I and III in humans with normally healing tibial shaft fractures will display a temporal pattern consistent with the sequence of expression of these collagens observed histologically in animal models of fracture healing. DESIGN: Prospective. SETTING: Four district general hospitals in the United Kingdom supported by an academic unit. PARTICIPANTS: Twenty consecutive patients with isolated tibial shaft fractures were studied. On clinical and radiological grounds, seventeen of the cases united within twenty weeks; these seventeen cases formed the material for this review. INTERVENTIONS: Nineteen patients were treated conservatively, and a functional brace was applied at five weeks. One patient treated with an external fixator had a functional brace applied at twelve weeks. MAIN OUTCOME MEASURES: Assays of collagen I carboxy-terminal propeptide (PICP), collagen III amino-terminal propeptide (PIIINP), and collagen I carboxy-terminal telopeptide (ICTP) were made in serum samples taken at standard intervals from twenty-four hours to twenty weeks after fracture. RESULTS: PICP showed a significant, transient early drop, whereas ICTP rose, indicating early breakdown with uncoupling of collagen I formation and degradation. PIIINP levels rose significantly from day eight to week five, in keeping with early expression of collagen III in experimental fracture callus. PICP levels showed a gradual rise, consistent with later expression of collagen I. CONCLUSIONS: The changes observed are in keeping with previous histological work on animal fracture models, suggesting that serological measures may reflect events occurring at the fracture site and thus offer a means for noninvasive and dynamic observation of collagen synthesis after fracture. Final proof that such measurements reflect bony healing per se, as opposed to events in other tissues, would require comparison with similar data from a soft tissue injury model.

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