Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Sampling from injured tissue as a blessing in disguise: tonic changes in cholinergic neurotransmission using microdialysis.

With the advent of enzyme-coated microelectrodes and the amperometric method for assessing synaptic acetylcholine (ACh) release [1], and following the demonstration of behavioral performance-associated cholinergic transients [2], microdialysis no longer appeared to be a useful or even justifiable method for measuring extracellular ACh concentrations. Numerous major limitations have been cited to plague this method, ranging from the implications of tissue injury resulting from the implantation of relatively large probes to the poor spatial definition of the area that contributes to recovered ACh. Moreover, microdialysis-based claims for (tonic) changes in ACh levels on the scale of minutes have been considered mere artifacts of the limits of detection of conventional analytical methods. The hypothesis that all cholinergic neurotransmission is phasic (scale of [milli-] seconds) contrasts with the hypothesis that low micromolar \u201cambient levels\u201d of extracellular ACh are regulated by levels of acetylcholinesterase (AChE) [3]. Because our experiments using choline oxidase (CO)-coated microelectrodes as well as electrodes with co-coatings of AChE plus CO did not indicate the presence of non-hydrolized ACh even after (massive) neuronal depolarization [4], the presence - or at least the concentration - of such \u201cambient levels\u201d of extracellular ACh has remain unsettled. Below we summarize evidence indicating that by using microdialysis we can observe systematic relationships between minutes-based extracellular ACh levels and behavioral/cognitive manipulations and performance, and that it is unlikely that these minute-based changes merely represent integrated cholinergic transients. We speculate that the pathological consequences of microdialysis probe insertion produces a sphere with reduced or absent AChE concentrations, allowing a tonic component of cholinergic neurotransmission to be detected by this method. Although the physiological significance of such measures remains unclear, their psychobiological relevance suggests that the aspects of the microdialysis method that were previously considered detrimental may in fact conspire to allow the measurement of meaningful, slow changes in cholinergic activity. Method

High temporal resolution microdialysis reveals cholinergic spikes preceding upshifts in attentional performance.

Prefrontal cholinergic neurotransmission mediates the cognitive control of attention and the detection of cues. Two modes of cholinergic neurotransmission can be separated. Relatively slow or tonic (tens of seconds or minutes) modulate cortical circuitry as a function of the demands on attention (St. Peters et al, 2011). Fast, second-based release events (or transients) are generated via local cortical circuitry and are necessary for the detection of cues (Hasselmo & Sarter 2011). Transients are recorded using amperometry and enzyme-coated microelectrodes. Tonic levels of cholinergic neurotransmission are monitored by microdialysis; importantly this is not a confound of the necessity of long collection intervals but our evidence indicates that tonic levels are not merely representing integrated transients. To further test this hypothesis and to explore the timescale of variations in tonic cholinergic activity in a given behavioral context and to refine the relationships between behavioral/cognitive processes and such variations, we employed a novel HPLC-tandem mass spectrometry (MS) method (Song et al, 2012) to detect acetylcholine (ACh) and several monoamines and amino acids from 3-min collections (1 \ub5L/min; no AChesterase inhibitor added). The focus on 3-min collections was based on our observation that rats performing the sustained attention task (SAT) frequently shift between good and poor levels of performance (defined as SAT scores >0.34 and at chance, or <0.17, respectively). Averaged across SAT sessions, ACh release levels corresponded with those previously obtained from 8-min collections and conventional HPLC-EC methods. However, performance-associated ACh levels fluctuated drastically across 3-min collections, ranging from pre-task baseline levels to 500% above baseline. Cholinergic spikes were observed just prior to shifts from random levels of performance to good levels of performance. Specifically, over 14 animals, 75% of such up-shifts were preceded by increases in cholinergic neurotransmission that were at least 3 SD above baseline levels. These findings indicate the usefulness of high temporal resolution microdialysis. The results are consistent with the hypothesis that tonic cholinergic activity modulates cortical target circuitry as a function of the subjects\u2019 motivation to enhance attentional performance and to orchestrate, the mechanisms designed to enhance signal processing, noise filtering and task compliance (Sarter & Paolone 2011). Tonic cholinergic activity in SAT performing animals is a major target of treatments designed to benefit cognitive performance in ADHD, schizophrenia, PD and other disorders

Sampling from injured tissue as a blessing in disguise: tonic changes in cholinergic neurotransmission using microdialysis.

Prefrontal cholinergic transmission in damaged and intact tissue from naive and treated rats via in-vivo microdialysi

GluN2A and GluN2B NMDA receptor subunits differentially modulate striatal output pathways and contribute to levodopa-induced abnormal involuntary movements in dyskinetic rats

Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopa-induced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it. 2013 American Chemical Societ

The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI10-01103 and PI13-00038) that were co-funded by the European Regional Development Fund (“A way to build Europe”). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), and the Generalitat de Catalunya (2009SGR220) is also acknowledgedPeer Reviewe

Proteomics tools reveal startlingly high amounts of oxytocin in plasma and serum

The neuropeptide oxytocin (OT) is associated with a plethora of social behaviors, and is a key topic at the intersection of psychology and biology. However, tools for measuring OT are still not fully developed. We describe a robust nano liquid chromatography-mass spectrometry (nanoLC-MS) platform for measuring the total amount of OT in human plasma/serum. OT binds strongly to plasma proteins, but a reduction/alkylation (R/A) procedure breaks this bond, enabling ample detection of total OT. The method (R/A + robust nanoLC-MS) was used to determine total OT plasma/serum levels to startlingly high concentrations (high pg/mL-ng/mL). Similar results were obtained when combining R/A and ELISA. Compared to measuring free OT, measuring total OT can have advantages in e.g. biomarker studies