Constraints of vigilance-dependent noradrenergic signaling to mouse cerebellar Bergmann glia.

Behavioral state plays an important role in determining astroglia Ca2+ signaling. In particular, locomotion-mediated elevated vigilance has been found to trigger norepinephrine-dependent whole cell Ca2+ elevations in astroglia throughout the brain. For cerebellar Bergmann glia it has recently been found that locomotion-induced transient Ca2+ elevations depend on their α1A -adrenergic receptors. With increasing availability and implementation of locomotion as behavioral parameter it becomes important to understand the constraints of noradrenergic signaling to astroglia. Here we evaluated the effect of speed, duration and interval of locomotion on Ca2+ signals in Bergmann glia as well as cerebellar noradrenergic axon terminals. We found almost no dependence on locomotion speed, but following the initial Ca2+ transient prolonged locomotion events revealed a steady-state Ca2+ elevation. Comparison of time course and recovery of transient Bergmann glia and noradrenergic terminal Ca2+ dynamics suggested that noradrenergic terminal Ca2+ activity determines Bergmann glia Ca2+ activation and does not require noradrenergic receptor desensitization to account for attenuation during prolonged locomotion. Further, analyzing the correlation among Ca2+ dynamics within regions within the field of observation we found that coordinated activity among noradrenergic terminals accounts for fluctuations of steady-state Bergmann glia Ca2+ activity. Together, our findings will help to better understand astroglia Ca2+ dynamics during less controlled awake behavior and may guide the identification of behavioral contexts preferably dependent on astroglia Ca2+ signaling.

Continuous positive airway pressure (CPAP) for apnoea of prematurity.

BACKGROUND: Apnoea of prematurity (AoP) is defined as a pause in breathing for 20 seconds or longer, or for less than 20 seconds when accompanied by bradycardia and hypoxaemia, in a preterm infant. An association between the severity of apnoea and neurodevelopmental delay has been reported. Continuous positive airway pressure (CPAP) is a form of non-invasive ventilatory assistance that has been shown to be relatively safe and effective in preventing and treating respiratory distress among preterm infants. It is less clear whether CPAP treatment is safe and effective in the prevention and treatment of AoP. OBJECTIVES: 1. To assess the effects of CPAP on AoP in preterm infants (this may be compared to supportive care or mechanical ventilation). 2. To assess the effects of different CPAP delivery systems on AoP in preterm infants. SEARCH METHODS: Searches were conducted in September 2022 in the following databases: Cochrane Library, MEDLINE, Embase, and CINAHL. We also searched clinical trial registries and the reference lists of studies selected for inclusion. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials (RCTs) in which researchers determined that CPAP was necessary for AoP in preterm infants (born before 37 weeks). Cross-over studies were also included, provided sufficient data were available for analysis. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and Cochrane Neonatal, including independent assessment of risk of bias and extraction of data by at least two review authors. Discrepancies were resolved by involvement of a third author. We used the GRADE approach to assess the certainty of evidence for the following outcomes: 1) failed CPAP; 2) apnoea; 3) adverse effects of CPAP. MAIN RESULTS: We included four single-centre trials conducted in Malaysia, Spain, Germany, and North America, involving 138 infants with a mean/median gestation of 26 to 28 weeks. Two studies were parallel-group RCTs and two were cross-over trials. None of the studies compared CPAP with supportive care. All trials compared one form of CPAP with another. Two compared a variable flow device with ventilator CPAP, one compared two different variable flow devices, and one compared a variable flow device with bubble CPAP. Interventions were administered for periods ranging between six and 48 hours, with pressures between 4 and 6 cm H2O. We assessed all trials as having a high risk of bias for blinding of participants and personnel, and two studies for blinding of outcome assessors. We found a high risk of a carry-over effect in two studies where the washout period was not adequately described, and a high risk of bias in a study that appeared to use an analysis method not generally accepted for cross-over studies. Comparison 1. CPAP and supportive care compared to supportive care alone We did not identify any study for inclusion in this comparison. Comparison 2. CPAP delivered by different types of devices 2a. Variable flow compared to ventilator CPAP Two studies were included in this comparison. We are very uncertain whether there is any difference in the incidence of failed CPAP, defined as the need for mechanical ventilation (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.01 to 2.90; 1 study, 26 participants; very low-certainty). We are very uncertain whether there is any difference in the frequency of apnoea events (mean difference (MD) per four-hour interval -0.10, 95% CI -1.30 to 1.10; 1 study, 26 participants; very low-certainty). We are uncertain whether there is any difference in adverse events. Neurodevelopmental outcomes were not reported. 2b. Variable flow compared to bubble CPAP We included one study in this comparison, but it did not report our pre-specified outcomes. 2c. Infant Flow variable flow CPAP compared to Medijet variable flow CPAP We are very uncertain whether there is any difference in the incidence of failed CPAP (RR 2.62, 95% CI 0.91 to 7.53; 1 study, 80 participants; very low-certainty). The frequency of apnoea was not reported, and we do not know whether there is any difference in adverse events. Neurodevelopmental outcomes were not reported. Comparison 3. CPAP compared to mechanical ventilation We did not identify any studies for inclusion in this comparison. AUTHORS' CONCLUSIONS: Due to the limited available evidence, we are very uncertain whether any CPAP device is more effective than other forms of supportive care, other CPAP devices, or mechanical ventilation for the prevention and treatment of AoP. The devices used in these studies included two types of variable flow CPAP device: bubble CPAP and ventilator CPAP. For each comparison, data were only available from a single study. There are theoretical reasons why these devices might have different effects on AoP, therefore further trials are indicated.

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle.

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.

Effect of chitinase-3-like protein 1 on glucose metabolism: In vitro skeletal muscle and human genetic association study.

We investigated the effect of chitinase-3-like protein 1 (CHI3L1) on glucose metabolism and its underlying mechanisms in skeletal muscle cells, and evaluated whether the observed effects are relevant in humans. CHI3L1 was associated with increased glucose uptake in skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner, and with increased intracellular calcium levels via PAR2. The improvement in glucose metabolism observed in an intraperitoneal glucose tolerance test on male C57BL/6J mice supported this association. Inhibition of the CaMKK was associated with suppression of CHI3L1-mediated glucose uptake. Additionally, CHI3L1 was found to influence glucose uptake through the PI3K/AKT pathway. Results suggested that CHI3L1 stimulated the phosphorylation of AS160 and p38 MAPK downstream of AMPK and AKT, and the resultant GLUT4 translocation. In primary myoblast cells, stimulation of AMPK and AKT was observed in response to CHI3L1, underscoring the biological relevance of CHI3L1. CHI3L1 levels were elevated in cells under conditions that mimic exercise in vitro and in exercised mice in vivo, indicating that CHI3L1 is secreted during muscle contraction. Finally, similar associations between CHI3L1 and metabolic parameters were observed in humans alongside genotype associations between CHI3L1 and diabetes at the population level. CHI3L1 may be a potential therapeutic target for the treatment of diabetes.

Single Muscle Fibre Contractility Testing in Rats to Quantify Ischaemic Muscle Damage During Reperfusion Injury.

OBJECTIVES: In this study, the aim was to investigate the potential for single muscle fibre contractility (SMFC) testing to detect the extent of reperfusion injury following various reperfusion periods. The hypothesis was that force generated by muscle fibres will correlate inversely with the extent of reperfusion injury. METHODS: Twenty-four Lewis rats were distributed among five groups. Group 1 served as normal muscle control. In all other groups, femoral artery flow was occluded for four hours. Muscle biopsies were obtained at 0 hour, six hours, day two, and day seven after reperfusion in Groups 2, 3, 4, and 5, respectively. Samples then underwent ultrastructural analysis (H&E stain) and SMFC testing. RESULTS: The maximum isometric force (mN) generated on Days two and seven after reperfusion decreased from baseline by 21% (p < 0.05), and 53% (p < .001), respectively. The specific force (kPa) followed a similar pattern with a 13% decrease at Day two (p > 0.05) and 31% decrease at Day 7 (p < .001). These results correlated inversely with the extent of quantitative injury on histology. CONCLUSIONS: The study demonstrated an inverse relationship between single muscle fibre contractility testing and neutrophil infiltration during the reperfusion phase. Further clinical studies are needed to evaluate its potential in providing prognostic information for patient outcomes.

Improving the Visibility of Intravenous (IV) Site in Pediatric Patients to Reduce IV Site Related Complications - An Evidence-based Utilization Project.

PURPOSE: This project aims to improve the visibility of the IV site using more adhesive transparent dressings to attain 90% compliance based on the frequent and proper inspection of the IV site and decrease the incidence of IV complications. DESIGN AND METHOD: The project was conducted in a 43-bedded general pediatric ward from March 2016 to February 2017. To address the poor visibility of the IV site due to bandaging caused by poor adhesive strength of the IV securement dressing, a more adhesive securement dressing was introduced. The study team conducted pre-implementation, immediate post-implementation, and sustainment audits, cost-analysis, and comparison of the number of reported occurrences of phlebitis and extravasation between 2015 and 2017. RESULTS: The post-implementation audit showed 100% visibility of the IV site, from 73% pre-implementation, and 87% compliance on frequent IV site inspection, from 70% pre-implementation. Both criteria attained 100% compliance during the sustainment audit. Incidences of extravasation and phlebitis were reduced from eight to seven, an improvement of 13%. These seven cases were also generally less severe compared to those from the previous year. CONCLUSION: This project has greatly improved the visibility of the IV site as well as nurses' compliance in checking the IV site. This is because nurses can monitor the IV site without having to remove any additional bandage over the site and causing unnecessary distress to fretful pediatric patients. IMPLICATIONS: The use of an adhesive transparent dressing can lead to prevention and earlier detection of phlebitis and extravasation. Additionally, the new IV securement dressing brought about manpower cost savings enabling staff time directed to other patient care activities.

Effectiveness of a Web-Based Simulation in Improving Nurses' Workplace Practice With Deteriorating Ward Patients: A Pre- and Postintervention Study.

BACKGROUND: Nurses play an important role in detecting patients with clinical deterioration. However, the problem of nurses failing to trigger deteriorating ward patients still persists despite the implementation of a patient safety initiative, the Rapid Response System. A Web-based simulation was developed to enhance nurses' role in recognizing and responding to deteriorating patients. While studies have evaluated the effectiveness of the Web-based simulation on nurses' clinical performance in a simulated environment, no study has examined its impact on nurses' actual practice in the clinical setting. OBJECTIVE: The objective of this study was to evaluate the impact of Web-based simulation on nurses' recognition of and response to deteriorating patients in clinical settings. The outcomes were measured across all levels of Kirkpatrick's 4-level evaluation model with clinical outcome on triggering rates of deteriorating patients as the primary outcome measure. METHODS: A before-and-after study was conducted on two general wards at an acute care tertiary hospital over a 14-month period. All nurses from the two study wards who undertook the Web-based simulation as part of their continuing nursing education were invited to complete questionnaires at various time points to measure their motivational reaction, knowledge, and perceived transfer of learning. Clinical records on cases triggered by ward nurses from the two study wards were evaluated for frequency and types of triggers over a period of 6 months pre- and 6 months postintervention. RESULTS: The number of deteriorating patients triggered by ward nurses in a medical general ward increased significantly (P<.001) from pre- (84/937, 8.96%) to postintervention (91/624, 14.58%). The nurses reported positively on the transfer of learning (mean 3.89, SD 0.49) from the Web-based simulation to clinical practice. A significant increase (P<.001) on knowledge posttest score from pretest score was also reported. The nurses also perceived positively their motivation (mean 3.78, SD 0.56) to engage in the Web-based simulation. CONCLUSIONS: This study provides evidence on the effectiveness of Web-based simulation in improving nursing practice when recognizing and responding to deteriorating patients. This educational tool could be implemented by nurse educators worldwide to address the educational needs of a large group of hospital nurses responsible for patients in clinical deterioration.

Symptom burden and medication use in adult sarcoma patients.

PURPOSE: Limited data are available on how symptom burden affects health-related quality of life (HRQoL) in patients with sarcoma. This study aims to describe the symptom burden, HRQoL, and medication use in adult sarcoma patients. METHODS: A single-center, cross-sectional study was conducted, and 79 patients were evaluated using three tools: the Rotterdam Symptom Checklist (RSCL), the Beck Anxiety Inventory (BAI), and the Functional Assessment of Cancer Therapy scale-General (FACT-G). Patients' demographic and clinical information, medication history, and use of concomitant medications were recorded. The proportion of patients with clinically significant RSCL score for a particular symptom was compared with the percentage of patients receiving medication for that symptom. RESULTS: The mean age was 57.3 ± 15.2 years, with majority of the patients diagnosed with stromal tumor (46.8 %), leiomyosarcoma (15.2 %), and liposarcoma (10.1 %). The most prevalent physical symptoms experienced were tiredness (2.38 ± 1.00), lack of energy (2.04 ± 1.02), and difficulty sleeping (2.00 ± 1.15). The most common psychological symptoms experienced were irritability (1.92 ± 1.01), worrying (1.86 ± 0.90), and anxiety (1.68 ± 0.74). Few (6.3 %) patients received hypnotics while 33.0 % of patients reported difficulty sleeping. A proportion of patients (27.9 %) reported experiencing lack of appetite with only 1.3 % received appetite stimulants. CONCLUSION: Adult sarcoma patients experience significant physiological and psychological symptom burden, which has a strong negative impact on HRQoL, with a number of physiological symptoms undertreated with pharmacotherapy.

A noisy-channel account of crosslinguistic word-order variation.

The distribution of word orders across languages is highly nonuniform, with subject-verb-object (SVO) and subject-object-verb (SOV) orders being prevalent. Recent work suggests that the SOV order may be the default in human language. Why, then, is SVO order so common? We hypothesize that SOV/SVO variation can be explained by language users' sensitivity to the possibility of noise corrupting the linguistic signal. In particular, the noisy-channel hypothesis predicts a shift from the default SOV order to SVO order for semantically reversible events, for which potential ambiguity arises in SOV order because two plausible agents appear on the same side of the verb. We found support for this prediction in three languages (English, Japanese, and Korean) by using a gesture-production task, which reflects word-order preferences largely independent of native language. Other patterns of crosslinguistic variation (e.g., the prevalence of case marking in SOV languages and its relative absence in SVO languages) also straightforwardly follow from the noisy-channel hypothesis.

Reliability and variability of physiotherapists scoring freezing of gait through video analysis.

BACKGROUND: The "gold standard" marker for freezing of gait severity is percentage of time spent with freezing observed through video analysis. OBJECTIVE: This study examined inter- and intra-rater reliability and variability of physiotherapists rating freezing of gait severity through video analysis and explored the effects of experience. METHODS: Thirty physiotherapists rated 14 videos of Timed Up and Go performance by people with Parkinson's and gait freezing. Ten videos were unique, while four were repeated. Freezing frequency, total duration, and percentage of time spent with freezing were computed. Reliability and variability were estimated using ICC (2,1) and mean absolute differences. Between-group differences were calculated with the one-way ANOVA. RESULTS: Inter- and intra-rater reliability ranged from moderate to good (ICC: inter-rater frequency = 0.63, duration = 0.78, percentage = 0.50; intra-rater frequency = 0.84, duration = 0.89, percentage = 0.50). Variability for freezing frequency was two episodes. Inter- and intra-rater variability for total freezing duration was 18.8 and 12.3 seconds, respectively. For percentage of time spent with freezing, this was 15.2% and 13.5%. Physiotherapy experience had no effect. CONCLUSION: Physiotherapists demonstrated sufficient reliability, but variability was large enough to cause changes in severity classifications on existing rating scales. Percentage of time spent with freezing was the least reliable marker, supporting the use of freezing frequency or total duration instead.

Frail patients having vascular surgery during the early COVID-19 pandemic experienced high rates of adverse perioperative events and amputation.

BACKGROUND: Frailty predicts adverse perioperative outcomes and increased mortality in patients having vascular surgery. Frailty assessment is a potential tool to inform resource allocation, and shared decision-making about vascular surgery in the resource constrained COVID-19 pandemic environment. This cohort study describes the prevalence of frailty in patients having vascular surgery and the association between frailty, mortality and perioperative outcomes. METHODS: The COVID-19 Vascular Service in Australia (COVER-AU) prospective cohort study evaluates 30-day and six-month outcomes for consecutive patients having vascular surgery in 11 Australian vascular units, March-July 2020. The primary outcome was mortality, with secondary outcomes procedure-related outcomes and hospital utilization. Frailty was assessed using the nine-point visual Clinical Frailty Score, scores of 5 or more considered frail. RESULTS: Of the 917 patients enrolled, 203 were frail (22.1%). The 30 day and 6 month mortality was 2.0% (n = 20) and 5.9% (n = 35) respectively with no significant difference between frail and non-frail patients (OR 1.68, 95%CI 0.79-3.54). However, frail patients stayed longer in hospital, had more perioperative complications, and were more likely to be readmitted or have a reoperation when compared to non-frail patients. At 6 months, frail patients had twice the odds of major amputation compared to non-frail patients, after adjustment (OR 2.01; 95% CI 1.17-3.78), driven by a high rate of amputation during the period of reduced surgical activity. CONCLUSION: Our findings highlight that older, frail patients, experience potentially preventable adverse outcomes and there is a need for targeted interventions to optimize care, especially in times of healthcare stress.

Potential and Realized Impact of Astroglia Ca2 + Dynamics on Circuit Function and Behavior.

Astroglia display a wide range of spontaneous and behavioral state-dependent Ca2+ dynamics. During heightened vigilance, noradrenergic signaling leads to quasi-synchronous Ca2+ elevations encompassing soma and processes across the brain-wide astroglia network. Distinct from this vigilance-associated global Ca2+ rise are apparently spontaneous fluctuations within spatially restricted microdomains. Over the years, several strategies have been pursued to shed light on the physiological impact of these signals including deletion of endogenous ion channels or receptors and reduction of intracellular Ca2+ through buffering, extrusion or inhibition of release. Some experiments that revealed the most compelling behavioral alterations employed chemogenetic and optogenetic manipulations to modify astroglia Ca2+ signaling. However, there is considerable contrast between these findings and the comparatively modest effects of inhibiting endogenous sources of Ca2+. In this review, we describe the underlying mechanisms of various forms of astroglia Ca2+ signaling as well as the functional consequences of their inhibition. We then discuss how the effects of exogenous astroglia Ca2+ modification combined with our knowledge of physiological mechanisms of astroglia Ca2+ activation could guide further refinement of behavioral paradigms that will help elucidate the natural Ca2+-dependent function of astroglia.

To sling or not to sling? Impact of intraoperative sling procedures during radical prostatectomy on postoperative continence outcomes: A systematic review and meta-analysis.

Purpose: This systematic review and meta-analysis investigates the efficacy of intraoperative sling procedures in reducing postprostatectomy urinary incontinence compared to having no slings. Methods: A comprehensive search of PubMed, Medline, Embase, and the Cochrane library from inception to November 2020 was performed. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized studies and Newcastle-Ottawa Scale for nonrandomized studies. The GRADE approach was used for critical appraisal of evidences and meta-analyses were conducted using random-effects models. Results: Ten studies were included (n = 1,447). Quality of evidence ranged from moderate to very low. Sling procedure was generally favorable for short-term continence outcomes, although discrepancies exist due to variability in continence definition. Sling procedure resulted in reduced urinary pad weight at 1 month postoperatively (MD: 21.55; 95%CI: 12.58 to 30.52). Patient-reported questionnaires were also favorable for the sling group for up to 3 months (IPSS; (MD: 1.44; 95%CI: 0.14 to 2.74), ICIQ-SF; (MD: 2.25; 95%CI: 1.26 to 3.24), EPIC-U; (MD: 5.30; 95%CI: 1.12 to 9.39)) postoperatively. Sling procedure improved the number of continent patients at 1 month with continence definition of zero pad use/day (RR:1.41; 95%CI: 1.10 to 1.83) but not with the definition of ≤ 1pad/day. Similarly, it reduced the time to continence with the ≤ 1 pad/day definition (MD: 0.5; 95%CI: 0.1 to 0.9) but not with the zero pad/day definition. Conclusion: The current literature suggests that intraoperative sling procedures during radical prostatectomy may promote early return of continence compared to having no sling, however, there are no long-term differences.

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

Specialized pro-resolving mediators actively limit inflammation and support tissue regeneration, but their role in age-related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography-tandem mass spectrometry and tested whether treatment with the pro-resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro-resolving mediators 8-oxo-RvD1, resolvin E3, and maresin 1, as well as many anti-inflammatory cytochrome P450-derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro-inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2 ) and 12-lipoxygenase (e.g., 12-hydroxy-eicosatetraenoic acid), but aged mice produced fewer markers of pro-resolving mediators including the lipoxins (15-hydroxy-eicosatetraenoic acid), D-resolvins/protectins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and maresins (14-hydroxy-docosahexaenoic acid). Similar absences of downstream pro-resolving mediators including lipoxin A4 , resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro-resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non-steroidal anti-inflammatory drugs.

Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells.

Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry-based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation-induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.

Syntactic complexity effects in sentence production.

Syntactic complexity effects have been investigated extensively with respect to comprehension (e.g., Demberg & Keller, 2008; Gibson, 1998, 2000; Gordon et al., 2001, 2004; Grodner & Gibson, 2005; King & Just, 1991; Lewis & Vasishth, 2005; Lewis et al., 2006; McElree et al., 2003; Wanner & Maratsos, 1978). According to one prominent class of accounts (experience-based accounts; e.g., Hale, 2001; Levy, 2008; Gennari & MacDonald, 2008, 2009; Wells et al., 2009), certain structures cause comprehension difficulty due to their scarcity in the language. But why are some structures less frequent than others? In two elicited-production experiments we investigated syntactic complexity effects in relative clauses (Experiment 1) and wh-questions (Experiment 2) varying in whether or not they contained non-local dependencies. In both experiments, we found reliable durational differences between subject-extracted structures (which only contain local dependencies) and object-extracted structures (which contain nonlocal dependencies): Participants took longer to begin and produce object-extractions. Furthermore, participants were more likely to be disfluent in the object-extracted constructions. These results suggest that there is a cost associated with planning and uttering the more syntactically complex, object-extracted structures, and that this cost manifests in the form of longer durations and disfluencies. Although the precise nature of this cost remains to be determined, these effects provide one plausible explanation for the relative rarity of object-extractions: They are more costly to produce.

Cross-linguistic gestures reflect typological universals: a subject-initial, verb-final bias in speakers of diverse languages.

In communicating events by gesture, participants create codes that recapitulate the patterns of word order in the world's vocal languages (Gibson et al., 2013; Goldin-Meadow, So, Ozyurek, & Mylander, 2008; Hall, Mayberry, & Ferreria, 2013; Hall, Ferreira, & Mayberry, 2014; Langus & Nespor, 2010; and others). Participants most often convey simple transitive events using gestures in the order Subject-Object-Verb (SOV), the most common word order in human languages. When there is a possibility of confusion between subject and object, participants use the order Subject-Verb-Object (SVO). This overall pattern has been explained by positing an underlying cognitive preference for subject-initial, verb-final orders, with the verb-medial order SVO order emerging to facilitate robust communication in a noisy channel (Gibson et al., 2013). However, whether the subject-initial and verb-final biases are innate or the result of languages that the participants already know has been unclear, because participants in previous studies all spoke either SVO or SOV languages, which could induce a subject-initial, verb-late bias. Furthermore, the exact manner in which known languages influence gestural orders has been unclear. In this paper we demonstrate that there is a subject-initial and verb-final gesturing bias cross-linguistically by comparing gestures of speakers of SVO languages English and Russian to those of speakers of VSO languages Irish and Tagalog. The findings show that subject-initial and verb-final order emerges even in speakers of verb-initial languages, and that interference from these languages takes the form of occasionally gesturing in VSO order, without an additional bias toward other orders. The results provides further support for the idea that improvised gesture is a window into the pressures shaping language formation, independently of the languages that participants already know.