A Finite Element Model to Investigate the Stability of Osteochondral Grafts Within a Human Tibiofemoral Joint.

Osteochondral grafting has demonstrated positive outcomes for treating articular cartilage defects by replacing the damaged region with a cylindrical graft consisting of bone with a layer of cartilage. However, factors that cause graft subsidence are not well understood. The aim of this study was to develop finite element (FE) models of osteochondral grafts within a tibiofemoral joint, suitable for an investigation of parameters affecting graft stability. Cadaveric femurs were used to experimentally calibrate the bone properties and graft-bone frictional forces for use in corresponding image-based FE models, generated from µCT scan data. Effects of cartilage defects and osteochondral graft repair were measured by examining contact pressure changes using further in vitro tests. Here, six defects were created in the femoral condyles, which were subsequently treated with osteochondral autografts or metal pins. Matching image-based FE models were created, and the contact patches were compared. The bone material properties and graft-bone frictional forces were successfully calibrated from the initial tests with good resulting levels of agreement (CCC = 0.87). The tibiofemoral joint experiment provided a range of cases that were accurately described in the resultant pressure maps and were well represented in the FE models. Cartilage defects and repair quality were experimentally measurable with good agreement in the FE model pressure maps. Model confidence was built through extensive validation and sensitivity testing. It was found that specimen-specific properties were required to accurately represent graft behaviour. The final models produced are suitable for a range of parametric testing to investigate immediate graft stability.

What factors in the workplace enable success in antimicrobial stewardship in paediatric intensive care? An exploration of antimicrobial stewardship excellence through thematic analysis of appreciative inquiry interviews with healthcare staff.

OBJECTIVES: Antimicrobial resistance (AMR) is a major global health problem. Efforts to mitigate AMR prioritise antimicrobial stewardship (AMS) interventions. These interventions typically focus on deficiencies in practice and providing negative or normative feedback. This approach may miss opportunities to learn from success. We aimed to identify factors that enable success in AMS practices in the paediatric intensive care unit (PICU) by analysing the data obtained from interviews with staff members who had achieved success in AMS. DESIGN: Qualitative study design using thematic analysis of appreciative inquiry interviews with healthcare staff. SETTING: 31-bedded PICU in the UK between January 2017 and January 2018. PARTICIPANTS: 71 staff who had achieved success in AMS in the PICU. RESULTS: Six themes were identified: (1) cultural factors including psychological safety, leadership and positive attitude are important enablers for delivering good clinical care; (2) ergonomic design of the physical environment and ready availability of tools and resources are key elements to support good practice and decision-making; (3) expertise and support from members of the multidisciplinary team contribute to good care delivery; (4) clarity of verbal and written communication is important for sharing mental models and aims of care within the clinical team; (5) a range of intrinsic factors influences the performance of individual HCPs, including organisation skill, fear of failure, response to positive reinforcement and empathetic considerations towards peers; (6) good clinical care is underpinned by a sound domain knowledge, which can be acquired through training, mentorship and experience. CONCLUSION: The insights gained in this study originate from frontline staff who were interviewed about successful work-as-done. This strengths-based approach is an understudied area of healthcare, and therefore offers authentic intelligence which may be leveraged to effect tangible improvement changes. The methodology is not limited to AMS and could be applied to a wide range of healthcare settings.

Effect of meniscus modelling assumptions in a static tibiofemoral finite element model: importance of geometry over material.

Finite element studies of the tibiofemoral joint have increased use in research, with attention often placed on the material models. Few studies assess the effect of meniscus modelling assumptions in image-based models on contact mechanics outcomes. This work aimed to assess the effect of modelling assumptions of the meniscus on knee contact mechanics and meniscus kinematics. A sensitivity analysis was performed using three specimen-specific tibiofemoral models and one generic knee model. The assumptions in representing the meniscus attachment on the tibia (shape of the roots and position of the attachment), the material properties of the meniscus, the shape of the meniscus and the alignment of the joint were evaluated, creating 40 model instances. The values of material parameters for the meniscus and the position of the root attachment had a small influence on the total contact area but not on the meniscus displacement or the force balance between condyles. Using 3D shapes to represent the roots instead of springs had a large influence in meniscus displacement but not in knee contact area. Changes in meniscus shape and in knee alignment had a significantly larger influence on all outcomes of interest, with differences two to six times larger than those due to material properties. The sensitivity study demonstrated the importance of meniscus shape and knee alignment on meniscus kinematics and knee contact mechanics, both being more important than the material properties or the position of the roots. It also showed that differences between knees were large, suggesting that clinical interpretations of modelling studies using single geometries should be avoided.

Dynamic Acetabular Cup Orientation during Gait: A Study of Fast- and Slow-Walking Total Hip Replacement Patients.

The dynamic orientation of total hip replacement acetabular cups during walking may vary substantially from their assumed position at surgical implantation and may vary between individuals. The scale of this effect is of interest for both pre-clinical device testing and for pre-operative surgical planning. This work aimed to evaluate (1) patient variation in dynamic cup orientation; (2) whether walking speed was a candidate proxy measure for the dynamic cup orientation; and (3) the relationships between dynamic cup orientation angles and planar pelvic angles. Pelvic movement data for patients with fast (20 patients) and slow (19 patients) self-selected walking speeds were used to calculate acetabular cup inclination and version angles through gait. For aim 1, the range and extremes of acetabular cup orientation angles were analysed for all patients. A large patient-to-patient variation was found in the ranges of both inclination angle (1° to 11°) and version angle (4° to 18°). The version angle was typically retroverted in comparison to the implantation position (greatest deviation 27°). This orientation is substantially different to the static, 0° version, simplifying assumptions in pre-clinical 'edge loading' testing. For aim 2, the cup orientation angles were compared between the fast- and slow-walking groups using statistical parametric mapping. The only significant differences observed were for cup version angle, during ~12% of the gait cycle before toe-off (p < 0.05). Therefore, self-selected walking speed, in isolation, is not a sufficient proxy measure for dynamic acetabular orientation. For aim 3, correlations were recorded between the acetabular cup orientation angles and the planar pelvic angles. The cup inclination angle during gait was strongly correlated (Spearman's coefficient -1) with pelvic obliquity alone, indicating that simple planar assessment could be used to anticipate inclination angle range. The cup version angle was correlated with both pelvic rotation and tilt (Spearman's coefficient 0.8-1), indicating that cup version cannot be predicted directly from any single pelvic movement. This complexity, along with the interaction between inclination angle and range of version angle, supports the use of computational tools to aid clinical understanding.

The Impact of Morbidities Following Pediatric Cardiac Surgery on Family Functioning and Parent Quality of Life.

We previously selected and defined nine important post-operative morbidities linked to paediatric cardiac surgery, and prospectively measured their incidence following 3090 consecutive operations. Our aim was to study the impact of these morbidities on family functioning and parental quality of life over 6 months in a subset of cases. As part of a prospective case matched study in five of the ten children's cardiac centers in the UK, we compared outcomes for parents of children who had a 'single morbidity', 'multiple morbidities', 'extracorporeal life support (ECLS)' or 'no morbidity'. Outcomes were evaluated using the PedsQL Family impact module (FIM) at 6 weeks and 6 months post-surgery. Outcomes were modelled using mixed effects regression, with adjustment for case mix and clustering within centers. We recruited 340 patients with morbidity (60% of eligible patients) and 326 with no morbidity over 21 months. In comparison to the reference group of 'no morbidity', after adjustment for case mix, at 6 weeks parent health-related quality of life (HRQoL) and total FIM sores were lower (worse) only for ECLS (p < 0.005), although a higher proportion of parents in both the ECLS and multi-morbidity groups had low/very low scores (p < .05). At 6 months, parent outcomes had improved for all groups but parent HRQoL and total score for ECLS remained lower than the 'no morbidity' group (p < .05) and a higher proportion of families had low or very low scores in the ECLS (70%) group (p < .01). Post-operative morbidities impact parent HRQoL and aspects of family functioning early after surgery, with this impact lessening by 6 months. Families of children who experience post-operative morbidities should be offered timely psychological support.

The Impact of High-Frequency Chest-Wall Compression on Mechanical Ventilation Delivery and Flow Bias.

BACKGROUND: It is unclear if high-frequency chest-wall compression (HFCWC) has a role to assist with secretion clearance in patients on mechanical ventilation. The effect of HFCWC on the delivery of mechanical ventilation is unknown. This study describes the effect of HFCWC on mechanical ventilation delivery and flow bias in an orally intubated and mechanically ventilated bench model. METHODS: An orally intubated mannequin was mechanically ventilated in 5 commonly used modes of ventilation at settings that reflect current practice. HFCWC was applied via a randomized combination of oscillation frequencies and pressure settings. Mechanical ventilator flow, flow bias, and breathing frequency were measured before and during the application of HFCWC. RESULTS: HFCWC led to 3- to 7-fold increases in ventilator-delivered breathing frequency during synchronized intermittent mandatory ventilation, bi-level (with pressure support), bi-level-assist, and pressure-regulated volume control modes of ventilation. Only in the bi-level mode without pressure support was the ventilator breathing frequency unaffected by HFCWC. During HFCWC, peak inspiratory flow to peak expiratory flow ratios toward an expiratory flow bias, particularly at higher HFCWC pressures, only in pressure-regulated volume control and synchronized intermittent mandatory ventilation modes were peak inspiratory flow to peak expiratory flow ratios of <0.9 generated that would facilitate secretion clearance. CONCLUSIONS: HFCWC led to 3- to 7-fold increases in ventilator breathing frequency delivered by mechanical ventilation except in the bi-level mode. The bi-level mode may be the optimal mode to use HFCWC to minimize disruption to the delivered ventilator breathing frequency. The peak inspiratory flow to peak expiratory flow ratios < 0.9, the optimal flow bias for secretion clearance, was only achieved in the pressure-regulated volume control and synchronized intermittent mandatory ventilation modes. However, the findings in this bench model with a fixed low compliance may not be generalizable to the patient in the ICU, and we recommend further investigation into the effects of HFCWC in the patient in the ICU.

Dynamic finite element analysis of hip replacement edge loading: Balancing precision and run time in a challenging model.

An important aspect in evaluating the resilience of hip replacement designs is testing their performance under adverse conditions that cause edge loading of the acetabular liner. The representation of edge loading conditions in finite element models is computationally challenging due to the changing contact locations, need for fine meshes, and dynamic nature of the system. In this study, a combined mesh and mass-scaling sensitivity study was performed to identify an appropriate compromise between convergence and solution time of explicit finite element analysis in investigating edge loading in hip replacement devices. The optimised model was then used to conduct a sensitivity test investigating the effect of different hip simulator features (the mass of the translating fixture and mediolateral spring damping) on the plastic strain in the acetabular liner. Finally, the effect of multiple loading cycles on the progressive accumulation of plastic strain was then also examined using the optimised model. A modelling approach was developed which provides an effective compromise between mass-scaling effects and mesh refinement for a solution time per cycle of less than 1 h. This 'Recommended Mesh' model underestimated the plastic strains by less than 10%, compared to a 'Best Estimate' model with a run time of ∼190 h. Starting with this model setup would therefore significantly reduce any new model development time while also allowing the flexibility to incorporate additional complexities as required. The polyethylene liner plastic strain was found to be sensitive to the simulator mass and damping (doubling the mass or damping had a similar magnitude effect to doubling the swing phase load) and these should ideally be described in future experimental studies. The majority of the plastic strain (99%) accumulated within the first three load cycles.

The Relationship Between Postoperative Complications and Children's Quality of Life: A Mediation Analysis to Explore the Role of Family Factors.

OBJECTIVES: To explore whether postoperative morbidities after pediatric cardiac surgery affected children's health-related quality of life (HRQOL) at 6 months, through potentially modifiable parental psychological factors. DESIGN: We undertook a mediation analysis, to explore the causal pathway, based on data from a prospective, case-matched cohort study. PATIENTS: Six hundred sixty-six children undergoing cardiac surgery. SETTING: Five centers in the United Kingdom. INTERVENTIONS: No intervention. MEASUREMENTS AND MAIN RESULTS: Cases of morbidity were identified early after pediatric cardiac surgery, and matched controls with no morbidities were identified at discharge. Four mediators were assessed at 6 weeks after surgery, using the PedsQL Family Impact Module (Parent HRQOL and Family Function) and the PHQ-4 (Anxiety and Depression). The study outcome of child HRQOL was assessed at 6 months with the PedsQL. Of 666 children, 408 (65% of those surviving) contributed to the primary outcome. Children who had extracorporeal life support (ECLS) ( n = 11) ( p < 0.05) and multiple morbidities ( n = 62) ( p < 0.01) had worse 6-month HRQOL than those with a single morbidity ( n = 125) or no morbidity ( n = 209). After adjustment for case mix complexity and sociodemographic variables, there were significant indirect effects of parent HRQOL at 6 weeks, on the PedsQL Total Score (ECLS, -5.1 [-8.4 to -1.8]; p = 0.003; multiple morbidities, -2.1 [-3.7 to -0.5]; p = 0.01), PedsQL Physical Score (ECLS, -5.1 [-8.7 to -1.4]; p = 0.007; multiple morbidities, -2.1 [-3.8 to -0.4]; p = 0.016), and PedsQL Psychosocial Score (ECLS: -5.3 [-8.7 to -1.8); p = 0.003; multiple morbidities, -2.2 [-3.9 to -0.5]; p = 0.01). The proportion of the total effect of ECLS and multiple morbidity on the study outcomes mediated through parent HRQOL ranges between 18% and 61%. There was no evidence that the other three mediators had indirect effects on the study outcome. CONCLUSIONS: Parental HRQOL at 6 weeks after surgery contributes to child HRQOL at 6 months, among those with the severest types of morbidity, and as such should be a target for future interventions.

Can a Computational Model Predict the Effect of Lesion Location on Cam-type Hip Impingement?

BACKGROUND: The Warwick consensus defined femoroacetabular impingement syndrome as a motion-related clinical disorder of the hip with a triad of symptoms, clinical signs, and imaging findings representing symptomatic premature contact between the proximal femur and acetabulum. Several factors appear to cause labral and cartilage damage, including joint shape and orientation and patient activities. There is a lack of tools to predict impingement patterns in a patient across activities. Current computational modeling tools either measure pure ROM of the joint or include complexity that reduces reliability and increases time to achieve a solution. QUESTIONS/PURPOSES: The purpose of this study was to examine the efficacy of a low computational cost approach to combining cam-type hip shape and multiple hip motions for predicting impingement. Specifically, we sought to determine (1) the potential to distinguish impingement in individual hip shapes by analyzing the difference between a cam lesion at the anterior femoral neck and one located at the superior femoral neck; (2) sensitivity to three aspects of hip alignment, namely femoral neck-shaft angle, femoral version angle, and pelvic tilt; and (3) the difference in impingement measures between the individual activities in our hip motion dataset. METHODS: A model of the shape and alignment of a cam-type impinging hip was created and used to describe two locations of a cam lesion on the femoral head-neck junction (superior and anterior) based on joint shape information available in prior studies. Sensitivity to hip alignment was assessed by varying three aspects from a baseline (typical alignment described in prior studies), namely, femoral neck-shaft angle, femoral version, and pelvic tilt. Hip movements were selected from an existing database of 18 volunteers performing 13 activities (10 male, eight female; mean age 44 ± 19 years). A subset was selected to maximize variation in the range of joint angles and maintain a consistent number of people performing each activity, which resulted in nine people per activity, including at least three of each sex. Activities included pivoting during walking, squatting, and golf swing. All selected hip motion cases were applied to each hip shape model. For the first part of the study, the number of motion cases in which impingement was predicted was recorded. Quantitative analyses of the depth of penetration of the cam lesion into the acetabular socket and qualitative observations of impingement location were made for each lesion location (anterior and superior). In the second part of the study, in which we aimed to test the sensitivity of the findings to hip joint orientation, full analysis of both cam lesion locations was repeated for three modified joint orientations. Finally, the results from the first part of the analysis were divided by activity to understand how the composition of the activity dataset affected the results. RESULTS: The two locations of cam lesion generated impingement in a different percentage of motion cases (anterior cam: 56% of motion cases; superior cam: 13% of motion cases) and different areas of impingement in the acetabulum, but there were qualitatively similar penetration depths (anterior cam: 6.8° ± 5.4°; superior cam: 7.9° ± 5.8°). The most substantial effects of changing the joint orientation were a lower femoral version angle for the anterior cam, which increased the percentage of motion cases generating impingement to 67%, and lower neck-shaft angle for the superior cam, which increased the percentage of motion cases generating impingement to 37%. Flexion-dominated activities (for example, squatting) only generated impingement with the anterior cam. The superior cam generated impingement during activities with high internal-external rotation of the joint (for example, the golf swing). CONCLUSION: This work demonstrated the capability of a simple, rapid computational tool to assess impingement of a specific cam-type hip shape (under 5 minutes for more than 100 motion cases). To our knowledge, this study is the first to do so for a large set of motion cases representing a range of activities affecting the hip, and could be used in planning surgical bone removal. CLINICAL RELEVANCE: The results of this study imply that patients with femoroacetabular impingement syndrome with cam lesions on the superior femoral head-neck junction may experience impinging during motions that are not strongly represented by current physical diagnostic tests. The use of this tool for surgical planning will require streamlined patient-specific hip shape extraction from imaging, model sensitivity testing, evaluation of the hip activity database, and validation of impingement predictions at an individual patient level.

A Wide Range of Flavoring-Carrier Fluid Adducts Form in E-Cigarette Liquids.

A range of flavoring molecules are used in electronic cigarette liquids (e-liquids), some of which have been shown to form cyclic acetal adducts with e-liquid solvent components propylene glycol (PG) and vegetable glycerine (VG). The objective of this study was to identify the range of flavoring molecules which form adducts in e-liquid products. Common e-liquid flavoring molecules (N = 36) from a range of chemical class groups were exposed to PG, VG, or methanol and analyzed by GC-MS over a time frame of 4 weeks to identify possible reaction products. Adduct formation was observed, with 14 of the flavoring molecules reacting with methanol, 10 reacting with PG, and 10 reacting with VG. Furfural PG and VG acetals, valeraldehyde PG and VG acetals, veretraldehyde PG and VG acetals, p-anisaldehyde PG and VG acetals, and piperonal VG acetal were confirmed for the first time. Adducts formed by reaction with ketone-containing flavoring molecules were also observed for the first time. The presence of these acetals was confirmed in 32% of commercial e-liquid products analyzed (N = 142). This study has established a range of flavoring molecules which are able to react with solvent components PG and VG in e-liquids under standard storage conditions. These newly identified adducts need to be further assessed to determine their toxicological safety.

Surveillance of Hospital-Presenting Intentional Self-Harm in Western Sydney, Australia, During the Implementation of a New Self-Harm Reporting Field.

Background: Hospital-presenting self-harm is a strong predictor of suicide and has substantial human and health service costs. Aims: We aimed to identify changes in case ascertainment after implementation of a new self-harm reporting field at a tertiary hospital in New South Wales, and to report event rates, demographic, and clinical characteristics. Method: Self-harm events presenting to the emergency department (October 2017 to August 2020) were identified using clinical documentation and a new reporting field. Changes in the frequency of self-harm in the period after implementation of the self-harm field were assessed through Poisson regression models. Results: A twofold increase in the frequency of self-harm was detected following the implementation of the new reporting field. The annual average age-standardized event rate of self-harm was 110.4 per 100,000 (120.8 per 100,000 for females; 100.1 per 100,000 for males). The highest rates by age and sex were for females aged 15-19 years (375 per 100,000) and males aged 20-24 years (175 per 100,000). Limitations: Self-harm identification relies on clinician coding practice, which is subject to variability and potential under-enumeration. Conclusion: These findings highlight the value of a self-harm reporting field in hospital record systems for accurate recording and long-term monitoring of self-harm event rates.

The clinical and laboratory impact of reporting faecal elastase-1 in watery stool samples.

BACKGROUND: Low faecal elastase-1 (FE-1) results are suggestive of pancreatic insufficiency, but watery diarrhoea may lead to falsely low results. METHODS: FE-1 results reported on watery samples over a three-year period were reviewed. Results in watery samples were compared to those from a formed sample. The follow-up of patients in whom an FE-1 result ≤199 ug/g stool (Schebo ELISA) was reported on a watery sample was also reviewed. RESULTS: In total, 288 watery samples were identified. All results (19/19) ≥200 ug/g in watery samples were also ≥200 ug/g when measured in a formed sample from the same patient. There were 41 results ≤199 ug/g in watery samples, of which 29 (71%) were ≥200 ug/g when measured in a formed sample. Thirty-seven patients with a single FE-1 value ≤199 ug/g from a watery sample were followed up. Pancreatic Enzyme Replacement Therapy (PERT) was commenced in 15 patients. This was inappropriate in at least one patient. Reporting practice was subsequently changed to not report FE-1 values ≤199 ug/g in watery samples. This change was assessed after 12 months. Repeat samples were received from 15/56 (27%) of patients. Overall, 10/15 (67%) of samples were ≥200 ug/g on repeat. PERT was not commenced inappropriately in any of these patients. CONCLUSIONS: There is value in measuring FE-1 in watery samples, as 144/288 (50%) of watery samples analysed were ≥200 ug/g, enabling a diagnosis of exocrine pancreatic insufficiency to be excluded. Not reporting FE-1 values ≤199 ug/g in a first-time watery stool samples appears clinically safe and has potentially reduced inappropriate diagnoses and prescribing.

Vaping preferences of individuals who vaporise dry herb cannabis, cannabis liquids and cannabis concentrates.

In 2019 an estimated 200 million people aged 15-64 used cannabis, making cannabis the most prevalent illicit substance worldwide. The last decade has seen a significant expansion in the cannabis vaporiser market, introducing cannabis vaporisation as a common administration method alongside smoking and ingestion. Despite reports of increased prevalence of cannabis vaporisation there has been little research into the use of these devices. To remedy the current dearth of data in this area this study utilised an anonymous online survey of individuals who self-reported past cannabis vaporisation. The respondents (N = 557) were predominantly young (<35 years) and male. Most (91.4 %) stated they had ever vaped dry herb cannabis, 59.1 % reported vaporisation of cannabis oil or liquids, and 34.0 % reported vaporisation of cannabis concentrates. This study identifies the types of vaporisation devices (including brands and models) employed by cannabis vapers, as well as the vaporisation temperatures and puff durations commonly used for dry herb, cannabis liquids and cannabis concentrates. To the best of our knowledge, this is the first time the usual operating temperatures of these vaporisation devices and user specific consumption patterns such as puff duration have been reported for cannabis vaping. This information will allow for a more realistic understanding of patterns of recreational use and improve experimental conditions in research settings to reflect the user's context.

Development of robust finite element models to investigate the stability of osteochondral grafts within porcine femoral condyles.

Osteoarthritis (OA) is the most prevalent chronic rheumatic disease worldwide with knee OA having an estimated lifetime risk of approximately 14%. Autologous osteochondral grafting has demonstrated positive outcomes in some patients, however, understanding of the biomechanical function and how treatments can be optimised remains limited. Increased short-term stability of the grafts allows cartilage surfaces to remain congruent prior to graft integration. In this study methods for generating specimen specific finite element (FE) models of osteochondral grafts were developed, using parallel experimental data for calibration and validation. Experimental testing of the force required to displace osteochondral grafts by 2 mm was conducted on three porcine knees, each with four grafts. Specimen specific FE models of the hosts and grafts were created from registered µCT scans captured from each knee (pre- and post-test). Material properties were based on the µCT background with a conversion between µCT voxel brightness and Young's modulus. This conversion was based on the results of the separate testing of eight porcine condyles and optimization of specimen specific FE models. The comparison between the experimental and computational push-in forces gave a strong agreement with a concordance correlation coefficient (CCC) = 0.75, validating the modelling approach. The modelling process showed that homogenous material properties based on whole bone BV/TV calculations are insufficient for accurate modelling and that an intricate description of the density distribution is required. The robust methodology can provide a method of testing different treatment options and can be used to investigate graft stability in full tibiofemoral joints.

Postoperative morbidities with infant cardiac surgery and toddlers' neurodevelopment.

OBJECTIVE: To evaluate the relationship between morbidities after infant cardiac surgery and neurodevelopment and behaviour at age 2-3 years. DESIGN/SETTING: A prospective cohort follow-up study, in four paediatric cardiac centres. We excluded children with known syndromes. Home-based neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) were undertaken in 81 children and secondary outcome measures of development and behaviour were completed by parents. A further 41 families completed the secondary outcome measures remotely. RESULTS: Children were grouped as multiple morbidities/extracorporeal life support (ECLS) (n=19), single morbidities (n=36) and no morbidities (n=59). Group comparisons found that children with multiple morbidities/ECLS, compared with no morbidities, had: (a) lower adjusted mean scores for core Bayley-III composites (none reached the level of statistical significance), with mean differences of cognitive -6.1 (95% CI -12.4 to 0.1) p=0.06, language -9.1 (95% CI -18.6 to 0.3) p=0.06 and motor -4.4 (95% CI -12.0 to 3.1) p=25; (b) greater adjusted odds of at least one low or borderline Bayley-III composite result 4.0 (95% CI 1.0 to 16.0) (p=0.05); (c) greater adjusted risk of an abnormal Ages and Stages Questionnaire (ASQ) result 5.3 (95% CI 1.3 to 21.1) (p=0.03) and a borderline ASQ result 4.9 (95% CI 1.0 to 25.0) (p=0.05); and no difference in the risk of an abnormal Strengths and Difficulties Questionnaire result 1.7 (95% CI 0.3 to 10.4) p=0.58. These outcomes were not statistically different between the single morbidity and no morbidity groups. CONCLUSIONS: Children who experience multiple morbidities/ECLS after infant heart surgery are at a greater risk of neurodevelopmental difficulties than their peers who had no complications and should be prioritised for neurodevelopmental follow-up.

Acute effects of Δ9-tetrahydrocannabinol and cannabidiol on auditory mismatch negativity.

RATIONALE: Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity. OBJECTIVES: The current study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN). METHODS: In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBDlow]; (5) THC 12 mg + CBD 400 mg [THC + CBDhigh]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each). RESULTS: Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users. CONCLUSIONS: The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.