An Enduring Role for Hippocampal Pattern Completion in Addition to an Emergent Nonhippocampal Contribution to Holistic Episodic Retrieval after a 24†h Delay.

Episodic memory retrieval is associated with the holistic neocortical reinstatement of all event information, an effect driven by hippocampal pattern completion. However, whether holistic reinstatement occurs, and whether hippocampal pattern completion continues to drive reinstatement, after a period of consolidation is unclear. Theories of systems consolidation predict either a time-variant or time-invariant role of the hippocampus in the holistic retrieval of episodic events. Here, we assessed whether episodic events continue to be reinstated holistically and whether hippocampal pattern completion continues to facilitate holistic reinstatement following a period of consolidation. Female and male human participants learned "events" that comprised multiple overlapping pairs of event elements (e.g., person-location, object-location, location-person). Importantly, encoding occurred either immediately before or 24 h before retrieval. Using fMRI during the retrieval of events, we show evidence for holistic reinstatement, as well as a correlation between reinstatement and hippocampal pattern completion, regardless of whether retrieval occurred immediately or 24 h after encoding. Thus, hippocampal pattern completion continues to contribute to holistic reinstatement after a delay. However, our results also revealed that some holistic reinstatement can occur without evidence for a corresponding signature of hippocampal pattern completion after a delay (but not immediately after encoding). We therefore show that hippocampal pattern completion, in addition to a nonhippocampal process, has a role in holistic reinstatement following a period of consolidation. Our results point to a consolidation process where the hippocampus and neocortex may work in an additive, rather than compensatory, manner to support episodic memory retrieval.

Sleep bolsters schematically incongruent memories.

Our ability to recall memories is improved when sleep follows learning, suggesting that sleep facilitates memory consolidation. A number of factors are thought to influence the impact of sleep on newly learned information, such as whether or not we rehearse that information (e.g. via restudy or retrieval practice), or the extent to which the information is consistent with our pre-existing schematic knowledge. In this pre-registered, online study, we examined the effects of both rehearsal and schematic congruency on overnight consolidation. Participants learned noun-colour pairings (e.g. elephant-red) and rated each pairing as plausible or implausible before completing a baseline memory assessment. Afterwards, participants engaged in a period of restudy or retrieval practice for the pairings, and then entered a 12 h retention interval of overnight sleep or daytime wakefulness. Follow-up assessments were completed immediately after sleep or wake, and again 24 h after learning. Our data indicated that overnight consolidation was amplified for restudied relative to retested noun-colour pairings, but only when sleep occurred soon after learning. Furthermore, whereas plausible (i.e. schematically congruent) pairings were generally better remembered than implausible (i.e. schematically incongruent) pairings, the benefits of sleep were stronger for implausible relative to plausible memories. These findings challenge the notion that schema-conformant memories are preferentially strengthened during post-learning sleep.

Applying Cefepime Population Pharmacokinetics to Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients' demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT>MIC was 100% (27%-100%) and fT>4×MIC was 64% (0%-100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.

Future-relevant memories are not selectively strengthened during sleep.

Overnight consolidation processes are thought to operate in a selective manner, such that important (i.e. future-relevant) memories are strengthened ahead of irrelevant information. Using an online protocol, we sought to replicate the seminal finding that the memory benefits of sleep are enhanced when people expect a future test [Wilhelm et al., 2011]. Participants memorised verbal paired associates to a criterion of 60 percent (Experiment 1) or 40 percent correct (Experiment 2) before a 12-hour delay containing overnight sleep (sleep group) or daytime wakefulness (wake group). Critically, half of the participants were informed that they would be tested again the following day, whereas the other half were told that they would carry out a different set of tasks. We observed a robust memory benefit of overnight consolidation, with the sleep group outperforming the wake group in both experiments. However, knowledge of an upcoming test had no impact on sleep-associated consolidation in either experiment, suggesting that overnight memory processes were not enhanced for future-relevant information. These findings, together with other failed replication attempts, show that sleep does not provide selective support to memories that are deemed relevant for the future.

Losing Control: Sleep Deprivation Impairs the Suppression of Unwanted Thoughts.

Unwanted memories often enter conscious awareness when individuals confront reminders. People vary widely in their talents at suppressing such memory intrusions; however, the factors that govern suppression ability are poorly understood. We tested the hypothesis that successful memory control requires sleep. Following overnight sleep or total sleep deprivation, participants attempted to suppress intrusions of emotionally negative and neutral scenes when confronted with reminders. The sleep-deprived group experienced significantly more intrusions (unsuccessful suppressions) than the sleep group. Deficient control over intrusive thoughts had consequences: Whereas in rested participants suppression reduced behavioral and psychophysiological indices of negative affect for aversive memories, it had no such salutary effect for sleep-deprived participants. Our findings raise the possibility that sleep deprivation disrupts prefrontal control over medial temporal lobe structures that support memory and emotion. These data point to an important role of sleep disturbance in maintaining and exacerbating psychiatric conditions characterized by persistent, unwanted thoughts.

Phase-locked auditory stimulation of theta oscillations during rapid eye movement sleep.

Auditory closed-loop stimulation is a non-invasive technique that has been widely used to augment slow oscillations during non-rapid eye movement sleep. Based on the principles of closed-loop stimulation, we developed a novel protocol for manipulating theta activity (3-7 Hz) in rapid eye movement (REM) sleep. Sixteen healthy young adults were studied in two overnight conditions: Stimulation and Sham. In the Stimulation condition, 1 s of 5 Hz amplitude-modulated white noise was delivered upon detection of two supra-threshold theta cycles throughout REM sleep. In the Sham condition, corresponding time points were marked but no stimulation was delivered. Auditory stimulation entrained EEG activity to 5 Hz and evoked a brief (~0.5 s) increase in theta power. Interestingly, this initial theta surge was immediately followed by a prolonged (~3 s) period of theta suppression. Stimulation also induced a prolonged (~2 s) increase in beta power. Our results provide the first demonstration that the REM sleep theta rhythm can be manipulated in a targeted manner via auditory stimulation. Accordingly, auditory stimulation might offer a fruitful avenue for investigating REM sleep electrophysiology and its relationship to behavior.

Massage therapy in the breast imaging department: repurposing an ancient anxiety reducing method.

BACKGROUND: Massage therapy's ability to mitigate breast imaging associated anxiety has not been previously studied. Anxiety is, however, often cited as a harm of screening mammography with few options offered to diminish anxiety other than not screening. Reducing anxiety may improve compliance, and reduce breast cancer mortality and morbidity. A complimentary massage therapy program evaluated patient acceptance, anxiety perception and perceived value of massage. METHODS: Over 10 weeks, verbal agreement was obtained from 113 breast imaging patients who desired a hand or shoulder/neck massage. Licensed massage therapists performed massages before, and/or during, or after, or in between imaging tests. After the massage, questionnaires assessed patients' self-rated perceptions of anxiety before and after massage on a scale from 0 to 10. Participants' age-group, reason for appointment, self-rated value of massage service, and willingness to return to and willingness to refer to the facility were reported. Changes in perceived average anxiety were estimated using a linear mixed effects model. Fisher's exact test was used to evaluate associations among categorical variables. RESULTS: A significant decrease in perceived anxiety was observed following massage (d = -3.2, p < 0.001). 107/108 (99%) of respondents reported an improved patient experience with massage. 84/106 (79%) reported willingness to pay at least $5 for massage service. CONCLUSION: Massage therapy improves the patient experience and decreases perceptions of anxiety. It may be associated with improved breast imaging compliance. Patients' willingness to pay for the service may defray some cost of a massage program.

Sleep deprivation induces fragmented memory loss.

Sleep deprivation increases rates of forgetting in episodic memory. Yet, whether an extended lack of sleep alters the qualitative nature of forgetting is unknown. We compared forgetting of episodic memories across intervals of overnight sleep, daytime wakefulness, and overnight sleep deprivation. Item-level forgetting was amplified across daytime wakefulness and overnight sleep deprivation, as compared to sleep. Importantly, however, overnight sleep deprivation led to a further deficit in associative memory that was not observed after daytime wakefulness. These findings suggest that sleep deprivation induces fragmentation among item memories and their associations, altering the qualitative nature of episodic forgetting.

Sleep Preserves Physiological Arousal in Emotional Memory.

Traumatic experiences are associated with increased emotional arousal. Overnight consolidation strengthens the episodic content of emotional memories, but it is still unclear how sleep influences the associated arousal response. To investigate this question, we compared the effects of sleep and wake on psychophysiological and subjective reactivity during emotional memory retrieval. Participants provided affective ratings for negative and neutral images while heart rate deceleration (HRD) and skin conductance responses (SCRs) were monitored. Following a 12-hour delay of sleep or wakefulness, participants completed an image recognition task where HRD, SCRs and affective ratings were recorded again. HRD responses to previously-encoded ("old") negative images were preserved after sleep but diminished after wakefulness. No between-group difference in HRD was observed for novel negative images at recognition, indicating that the effects of sleep for old images were not driven by a generalised overnight increase in visceral activity, or circadian factors. No significant effects of sleep were observed for SCRs or subjective ratings. Our data suggest that cardiac arousal experienced at the time of encoding is sensitive to plasticity-promoting processes during sleep in a similar manner to episodic aspects of emotional memory.

The Effect of Modified Ultrafiltration on Serum Vancomycin Levels During Cardiopulmonary Bypass in Cardiac Surgery.

OBJECTIVE: The aim of this study was to investigate whether the use of modified ultrafiltration at the end of cardiopulmonary bypass for cardiac surgical procedures significantly changes vancomycin serum concentrations. DESIGN: Prospective study. SETTING: Single tertiary cardiac center. PARTICIPANTS: Twenty-six elective adult patients undergoing cardiac surgery with cardiopulmonary bypass from April 2014 to April 2015. INTERVENTIONS: Serum vancomycin concentrations were measured just before cardiopulmonary bypass; during cardiopulmonary bypass at 5, 30, 60 minutes and then every 60 minutes; after completion of cardiopulmonary bypass before initiation of modified ultrafiltration; and at the end of modified ultrafiltration. MEASUREMENTS AND MAIN RESULTS: Seventeen patients received modified ultrafiltration at the end of cardiopulmonary bypass. Serum vancomycin concentrations prior to cardiopulmonary bypass (45.9 ± 17.3 µg/mL) were significantly higher (P < 0.0001) than each time point following cardiopulmonary bypass (5 min 20.4 ± 6.4 µg/mL, 30 min 18.8 ± 5.4 µg/mL, 60 min 16.6 ± 4.9 µg/mL, and 120 min 14.3 ± 4.7 µg/mL). In the modified ultrafiltration group, serum vancomycin concentrations were 14.7 ± 4.6 µg/mL prior to modified ultrafiltration and 13.9 ± 4.3 µg/mL after ultrafiltration; this difference was statistically significant (P  =  0.0288). The mean modified ultrafiltration volume was 465 ± 158 mL. CONCLUSIONS: Using modified ultrafiltration at the end of cardiopulmonary bypass significantly decreases serum vancomycin levels, but not by a clinically relevant amount. The decrease is to a concentration that is still significantly higher than the minimum inhibitory concentration for Staphylococcus epidermidis and Staphylococcus aureus; thus additional vancomycin administration is not recommended.

Advanced practice physiotherapy-led triage in Irish orthopaedic and rheumatology services: national data audit.

BACKGROUND: Many people with musculoskeletal (MSK) disorders wait several months or years for Consultant Doctor appointments, despite often not requiring medical or surgical interventions. To allow earlier patient access to orthopaedic and rheumatology services in Ireland, Advanced Practice Physiotherapists (APPs) were introduced at 16 major acute hospitals. This study performed the first national evaluation of APP triage services. METHOD: Throughout 2014, APPs (n = 22) entered clinical data on a national database. Analysis of these data using descriptive statistics determined patient wait times, Consultant Doctor involvement in clinical decisions, and patient clinical outcomes. Chi square tests were used to compare patient clinical outcomes across orthopaedic and rheumatology clinics. A pilot study at one site identified re-referral rates to orthopaedic/rheumatology services of patients managed by the APPs. RESULTS: In one year, 13,981 new patients accessed specialist orthopaedic and rheumatology consultations via the APP. Median wait time for an appointment was 5.6 months. Patients most commonly presented with knee (23%), lower back (22%) and shoulder (15%) disorders. APPs made autonomous clinical decisions regarding patient management at 77% of appointments, and managed patient care pathways without onward referral to Consultant Doctors in more than 80% of cases. Other onward clinical pathways recommended by APPs were: physiotherapy referrals (42%); clinical investigations (29%); injections administered (4%); and surgical listing (2%). Of those managed by the APP, the pilot study identified that only 6.5% of patients were re-referred within one year. CONCLUSION: This national evaluation of APP services demonstrated that the majority of patients assessed by an APP did not require onward referral for a Consultant Doctor appointment. Therefore, patients gained earlier access to orthopaedic and rheumatology consultations in secondary care, with most patients conservatively managed.

Work Outcomes in Patients Who Stay at Work Despite Musculoskeletal Pain.

Purpose To assess self-reported work impacts and associations between psychosocial risk factors and work impairment amongst workers seeking care for musculoskeletal pain while continuing to work. Methods Patients were recruited from Musculoskeletal Assessment Clinics at 5 hospitals across Ireland. Participants completed questionnaires including assessments of work impairment (Work Productivity and Activity Impairment Questionnaire), work ability (single item from the Work Ability Index) and work performance (Work Role Functioning Questionnaire; WRFQ). Logistic and hierarchical regressions were conducted to analyse the relation between psychosocial variables and work outcomes. Results 155 participants (53.5% female; mean age = 46.50 years) who were working at the time of assessment completed the questionnaires. Absenteeism was low, yet 62.6% were classified as functioning poorly according to the WRFQ; 52.3% reported having poor work ability. Logistic regression analyses indicated that higher work role functioning was associated with higher pain self-efficacy (OR 1.51); better work ability was associated with older age (OR 1.063) and lower functional restriction (OR 0.93); greater absenteeism was associated with lower pain self-efficacy (OR 0.65) and poorer work expectancy (OR 1.18). Multiple regression analysis indicated that greater presenteeism was associated with higher pain intensity (ß = 0.259) and lower pain self-efficacy (ß = - 0.385). Conclusions While individuals continue to work with musculoskeletal pain, their work performance can be adversely affected. Interventions that target mutable factors, such as pain self-efficacy, may help reduce the likelihood of work impairment.

A role for consolidation in cross-modal category learning.

The ability to categorize objects and events is a fundamental human skill that depends upon the representation of multimodal conceptual knowledge. This study investigated the acquisition and consolidation of categorical information that required participants to integrate information across visual and auditory dimensions. The impact of wake- and sleep-dependent consolidation was investigated using a paradigm in which training and testing were separated by a delay spanning either an evening of sleep or daytime wakefulness, with a paired-associate episodic memory task used as a measure of classic sleep-dependent consolidation. Participants displayed good evidence of category learning, but did not show any wake- or sleep-dependent changes in memory for category information immediately following the delay. This is in contrast to paired-associate learning, where a sleep-dependent benefit was observed in memory recall. To replicate real-world concept learning, in which knowledge is acquired across multiple distinct episodes, participants were given a second opportunity for category learning following the consolidation delay. Here we found an interaction between consolidation and learning; with greater improvements in category knowledge as a result of the second learning session for those participants who had a sleep-filled delay. These results suggest a role for sleep in the consolidation of recently acquired categorical knowledge; however this benefit does not emerge as an immediate benefit in memory recall, but by enhancing the effectiveness of future learning. This study therefore provides insights into the processes responsible for the formation and development of conceptual representations.

No effect of targeted memory reactivation during slow-wave sleep on emotional recognition memory.

Recent work has suggested that the benefits of sleep for memory consolidation are enhanced for highly salient (versus non-salient) memories. Using a technique known as targeted memory reactivation, it is possible to selectively strengthen newly learned memories by re-exposing the sleeping brain to auditory cues. The aim of the current study was to examine whether emotionally salient memories are also more responsive to targeted memory reactivation in slow-wave sleep than neutral memories. In an initial training phase, participants memorised emotionally negative and neutral pictures, which were each paired with a semantically related sound. Recognition for the pictures was assessed before and after a 90-min nap opportunity, during which half the sounds were re-presented during slow-wave sleep (as assessed via online polysomnographic sleep monitoring). We observed no effect of targeted memory reactivation on the recognition of emotionally negative or neutral memories. Our results highlight the importance of the memory paradigm used to assess targeted memory reactivation, and suggest that the robust and durable nature of recognition memory may make it an insensitive measure of behavioural targeted memory reactivation benefits. To fully assess the impacts of targeted memory reactivation on emotional memory processing in sleep, future studies should adopt experimental paradigms that maximise the salience of emotional stimuli while also providing a sensitive index of memory accuracy.

Early interventions to promote work participation in people with regional musculoskeletal pain: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness of early multidisciplinary interventions in promoting work participation and reducing work absence in adults with regional musculoskeletal pain. DATA SOURCES: Seven databases (CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, OT Seeker, PEDro; 1990 to December 2016) were searched for eligible studies. REVIEW METHODS: Trials were included if they reported on work-based outcomes for participants experiencing difficulties at work or ≤ three months' sick leave. Interventions had to include two or more elements of the biopsychosocial model delivered as a coordinated programme. Quality was assessed using the GRADE criteria. Results were analysed by hazard ratios for return to work data; continuous outcomes were analysed as standardised mean difference with 95% confidence intervals. RESULTS: A total of 20 randomized controlled trials, with 16,319 participants were included; the interventions were grouped according to their main components for meta-analyses. At 12-months follow-up, moderate quality evidence suggests that programmes involving a stepped care approach (four studies) were more effective than the comparisons in promoting return to work (hazard ratio (HR) 1.29 (95% confidence interval (CI) 1.03 to 1.61), p = 0.03), whereas case management (two studies) was not (HR 0.92 (95% CI 0.69 to 1.24), p = 0.59). Analyses suggested limited effectiveness in reducing sickness absences, in pain reduction or functional improvement across the intervention categories. CONCLUSION: There is uncertainty as to the effectiveness of early multicomponent interventions owing to the clinical heterogeneity and varying health and social insurance systems across the trials.

tDCS to temporoparietal cortex during familiarisation enhances the subsequent phonological coherence of nonwords in immediate serial recall.

Research has shown that direct current stimulation (tDCS) over left temporoparietal cortex - a region implicated in phonological processing - aids new word learning. The locus of this effect remains unclear since (i) experiments have not empirically separated the acquisition of phonological forms from lexical-semantic links and (ii) outcome measures have focused on learnt associations with a referent rather than phonological stability. We tested the hypothesis that left temporoparietal tDCS would strengthen the acquisition of phonological forms, even in the absence of the opportunity to acquire lexical-semantic associations. Participants were familiarised with nonwords paired with (i) photographs of concrete referents or (ii) blurred images where no clear features were visible. Nonword familiarisation proceeded under conditions of anodal tDCS and sham stimulation in different sessions. We examined the impact of these manipulations on the stability of the phonological trace in an immediate serial recall (ISR) task the following day, ensuring that any effects were due to the influence of tDCS on long-term learning and not a direct consequence of short-term changes in neural excitability. We found that only a few exposures to the phonological forms of nonwords were sufficient to enhance nonword ISR overall compared to entirely novel items. Anodal tDCS during familiarisation further enhanced the acquisition of phonological forms, producing a specific reduction in the frequency of phoneme migrations when sequences of nonwords were maintained in verbal short-term memory. More of the phonemes that were recalled were bound together as a whole correct nonword following tDCS. These data show that tDCS to left temporoparietal cortex can facilitate word learning by strengthening the acquisition of long-term phonological forms, irrespective of the availability of a concrete referent, and that the consequences of this learning can be seen beyond the learning task as strengthened phonological coherence in verbal short-term memory.

Emerging roles for pharmacists in clinical implementation of pharmacogenomics.

Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype-guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel-CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25-30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice-based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models.