The Economic Potential of Smoking Cessation Interventions at the Point of Diagnosis of Non-Small Cell Lung Cancer.

OBJECTIVES: Stopping smoking has proven benefits in nearly all illnesses but the impact and health economic benefits of stopping smoking after a diagnosis of lung cancer are less well defined. We assessed the cost-effectiveness of smoking cessation (SC) services for patients with newly diagnosed lung cancer against current usual care, where patients are unlikely to receive SC service referral. METHODS: A health economic model was constructed in Excel. The modelled population comprised of patients with a new diagnosis of non-small cell lung cancer (NSCLC). Data from the LungCast data set (Clinical Trials Identifier NCT01192256) were used to estimate model inputs. A structured search of published literature identified inputs not represented in LungCast, including healthcare resource use and costs. Costs were estimated from a 2020/2021 UK National Health Service and Personal Social Services perspective. The model estimated the incremental quality-adjusted life-year (QALY) gained in patients with newly diagnosed NSCLC receiving targeted SC intervention than those receiving no intervention. Extensive one-way sensitivity analyses explored input and data set uncertainty. RESULTS: In the 5-year base case, the model estimated an incremental cost of £14 904 per QALY gained through SC intervention. Sensitivity analysis estimated an outcome range of between £9935 and £32 246 per QALY gained. The model was most sensitive to the estimates of relative quit rates and expected healthcare resource use. CONCLUSION: This exploratory analysis indicates that SC intervention for smokers with patients with newly diagnosed NSCLC should be a cost-effective use of UK National Health Service resources. Additional research with focused costing is needed to confirm this positioning.

Wellbeing and burnout among medical students in Wales.

Medical students' wellbeing and mental health requires nurturing in order for them to build success in their careers, help people while doing so, and to be happy. To better characterise the current state of wellbeing in medical schools in Wales, medical students from Cardiff and Swansea Universities were asked to complete an online survey as part of a larger international survey regarding their mental health and wellbeing. 266 students responded out of approximately 2150, a rate of 12%. 44 students received a mental health diagnosis whilst at medical school (predominantly depression or anxiety), 65 scored threshold for concerning alcohol consumption using the CAGE questionnaire, and 224 and 230 students reached threshold for the disengagement and exhaustion components of the Oldenburg Burnout Scale, respectively.

Developing a standardised approach to the aggregation of inpatient episodes into person-based spells in all specialties and psychiatric specialties.

BACKGROUND: Electronic health record (EHR) data are available for research in all UK nations and cross-nation comparative studies are becoming more common. All UK inpatient EHRs are based around episodes, but episode-based analysis may not sufficiently capture the patient journey. There is no UK-wide method for aggregating episodes into standardised person-based spells. This study identifies two data quality issues affecting the creation of person-based spells, and tests four methods to create these spells, for implementation across all UK nations. METHODS: Welsh inpatient EHRs from 2013 to 2017 were analysed. Phase one described two data quality issues; transfers of care and episode sequencing. Phase two compared four methods for creating person spells. Measures were mean length of stay (LOS, expressed in days) and number of episodes per person spell for each method. RESULTS: 3.5% of total admissions were transfers-in and 3.1% of total discharges were transfers-out. 68.7% of total transfers-in and 48.7% of psychiatric transfers-in had an identifiable preceding transfer-out, and 78.2% of total transfers-out and 59.0% of psychiatric transfers-out had an identifiable subsequent transfer-in. 0.2% of total episodes and 4.0% of psychiatric episodes overlapped with at least one other episode of any specialty. Method one (no evidence of transfer required; overlapping episodes grouped together) resulted in the longest mean LOS (4.0 days for all specialties; 48.5 days for psychiatric specialties) and the fewest single episode person spells (82.4% of all specialties; 69.7% for psychiatric specialties). Method three (evidence of transfer required; overlapping episodes separated) resulted in the shortest mean LOS (3.7 days for all specialties; 45.8 days for psychiatric specialties) and the most single episode person spells; (86.9% for all specialties; 86.3% for psychiatric specialties). CONCLUSIONS: Transfers-in appear better recorded than transfers-out. Transfer coding is incomplete, particularly for psychiatric specialties. The proportion of episodes that overlap is small but psychiatric episodes are disproportionately affected. The most successful method for grouping episodes into person spells aggregated overlapping episodes and required no evidence of transfer from admission source/method or discharge destination codes. The least successful method treated overlapping episodes as distinct and required transfer coding. The impact of all four methods was greater for psychiatric specialties.

The impact of maternal prenatal and postnatal anxiety on children's emotional problems: a systematic review.

Maternal mental health problems during pregnancy and the postnatal period are a major public health issue. Despite evidence that symptoms of both depression and anxiety are common during pregnancy and the postpartum, the impact of maternal anxiety on the child has received relatively less attention than the impact of maternal depression. Furthermore, the evidence base for the direct impact of maternal anxiety during pregnancy and the postpartum on children's emotional outcomes lacks cohesion. The aim of this systematic review is to summarise the empirical evidence regarding the impact of maternal prenatal and postnatal anxiety on children's emotional outcomes. Overall, both maternal prenatal and postnatal anxiety have a small adverse effect on child emotional outcomes. However, the evidence appears stronger for the negative impact of prenatal anxiety. Several methodological weaknesses make conclusions problematic and replication of findings is required to improve the identification of at-risk parents and children with appropriate opportunities for intervention and prevention.

In vitro tissue culture model validation-the influence of tissue culture components on IPL energy output.

Intense pulsed light (IPL) has been used therapeutically in a number of clinical settings and has been shown to have a photobiomodulatory effect on connective tissue cells, such as those derived from skin and tendon. In vitro cell culture models are essential tools preclinically in investigating such treatment modalities, as they help in optimising parameters for successful treatment. However, as culture system components have been reported to absorb part of the irradiated energy, which in turn has a bearing on the amount of light reaching the cells, it is important to establish specific parameters for the particular in vitro model used. This study, therefore, investigates the effect of our tissue culture system components on the IPL energy delivered. Individual wells of multi-well plates were irradiated with IPL at different device settings and under variable culture conditions (e.g. in the absence or presence of cell culture media with or without the pH indicator dye, phenol red), and the energy lost through the culture system determined. Our data demonstrated that the IPL device delivered significantly lower outputs than those published, and energy absorption by the culture equipment would further reduce fluencies delivered to the cell monolayer. Furthermore, energy absorption by media containing phenol red was marginally greater than clear media and resulted in only a small increase in temperature, which would not be harmful to cells. The use of phenol red-containing media therefore is valid and physiologically relevant when examining light-culture system interactions.

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria.

Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an 'endectocidal transmission blocking' paradigm.

In vitro studies to evaluate the effect of varying culture conditions and IPL fluencies on tenocyte activities.

Tendons are dense, fibrous connective tissues which carry out the essential physiological role of transmitting mechanical forces from skeletal muscle to bone. From a clinical perspective, tendinopathy is very common, both within the sporting arena and amongst the sedentary population. Studies have shown that light therapy may stimulate tendon healing, and more recently, intense pulsed light (IPL) has attracted attention as a potential treatment modality for tendinopathy; however, its mechanism of action and effect on the tendon cells (tenocytes) is poorly understood. The present study therefore investigates the influence of IPL on an in vitro bovine tendon model. Tenocytes were irradiated with IPL at different devise settings and under variable culture conditions (e.g. utilising cell culture media with or without the pH indicator dye phenol red), and changes in tenocyte viability and migration were subsequently investigated using Alamar blue and scratch assays, respectively. Our data demonstrated that IPL fluencies of up to 15.9 J/cm2 proved harmless to the tenocyte cultures (this was the case using culture media with or without phenol red) and resulted in a significant increase in cell viability under certain culture conditions. Furthermore, IPL treatment of tenocytes did not affect the rate of cell migration. This study demonstrates that irradiation with IPL is not detrimental to the tenocytes and may increase their viability under certain conditions, thus validating our in vitro model. Further studies are required to elucidate the effects of IPL application in the clinical situation.

Can routine data be used to estimate the mental health service use of children and young people living on Gypsy and Traveller sites in Wales? A feasibility study.

INTRODUCTION: Gypsies and Travellers have poorer physical and mental health than the general population, but little is known about mental health service use by Gypsy and Traveller children and young people. Finding this group in routine electronic health data is challenging, due to limited recording of ethnicity. We assessed the feasibility of using geographical markers combined with linked routine datasets to estimate the mental health service use of children and young people living on Traveller sites. METHODS: Welsh Government supplied a list of Traveller site postcodes included in Caravan Counts between 2012 and 2020. Using spatial filtering with data from the Adolescent Mental Health Data Platform (ADP) at Swansea University's SAIL Databank, we created a cohort of Traveller site residents aged 11-25 years old, 2010-2019. ADP algorithms were used to describe health service use, and to estimate incidence and prevalence of common mental disorders (CMD) and self-harm. RESULTS: Our study found a subgroup of young Gypsies and Travellers (n = 802). We found no significant differences between our cohort and the general population for rates of CMD or self-harm. The rate of non-attendance for psychiatric outpatient follow-up appointments was significantly higher in our cohort. Rates were higher (but not statistically significant) among Gypsies and Travellers for measures suggesting less well-managed care, including emergency department attendance and prescribed CMD medication without follow-up. The small size of the cohort resulted in imprecise estimates with wide confidence intervals, compared with those for the general population. CONCLUSIONS: Gypsies and Travellers are under-represented in routine health datasets, even using geographical markers, which find only those resident in authorised traveller sites. Routine data is increasingly relied upon for needs assessment and service planning, which has policy and practice implications for this underserved group. To address health inequalities effort is required to ensure that health datasets accurately capture ethnicity.

Quitting smoking improves two-year survival after a diagnosis of non-small cell lung cancer.

BACKGROUND: Smoking at diagnosis is associated with worse survival in lung cancer but the effects of quitting smoking on survival remain unclear. METHODS: In a UK multi-centre study (NCT01192256) we followed all 2751 patients with newly diagnosed non-small cell lung cancer (NSCLC) for up to 2 years or until death as part of the observational trial. Patients were offered smoking cessation advice and treatments according to national guidelines and local services. Smoking status was verified by exhaled carbon monoxide levels. Kaplan-Meier survival analysis and Cox Proportional Hazards Modelling examined the effects of quitting smoking on survival at 2 years. FINDINGS: 646 were current smokers at the time of diagnosis. The unadjusted two-year Kaplan-Meier survivor functions for quitters (0.45, 95 %CI 0.37 to 0.53) and continuers (0.32, 0.28 to 0.36) were significantly different (log-rank test p < 0.01). Median survival times were 659 days for quitters and 348 days for continuers. After adjusting for age, sex, stage, performance status, curative intent surgery, radical radiotherapy and comorbidity, the hazard ratio for quitting at diagnosis (0.75, 95 % CI 0.58 to 0.98) indicated a statistically significant reduction in the risk of death across the two-year study period. INTERPRETATION: Quitting smoking is independently and significantly associated with improved survival regardless of stage in NSCLC. We recommend that smoking cessation advice and treatments should be offered to smokers with lung cancer. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01192256. FUNDING: This work was supported by a 2010 Global Research Award for Nicotine Dependence (GRAND), Pfizer.

Incidence, Mortality and Survival in Young People with Co-Occurring Mental Disorders and Substance Use: A Retrospective Linked Routine Data Study in Wales.

INTRODUCTION: Mental disorder (MD) and substance use (SUD) are associated with poorer than average health and greater mortality. We analysed routine primary care (WLGP) and inpatient admission (PEDW) data to estimate incidence of co-occurring (CC) MD and SUD, and to estimate all-cause mortality and survival with CC, in children and young people in Wales, UK. METHODS: A retrospective population-based electronic cohort study using data from the Secure Anonymised Information Linkage (SAIL) Databank. Participants were 958,603 individuals aged 11-25 between 2008 and 2017. We estimated first ever incidence of CC, plotted Kaplan-Meier survival curves and carried out Cox regression to estimate hazard ratios (HR) for risk of death by condition group (CC; MD or SUD only; NC). RESULTS: Higher incidence of CC in WLGP and PEDW was associated with male sex, older age and greater deprivation. Male to female IRRs (95% CI) were 1.18 (1.12-1.24) in WLGP and 1.17 (1.10-1.24) in PEDW, oldest to youngest IRRs were 24.80 (21.20-29.40) in WLGP and 4.50 (4.08-4.98) in PEDW and most to least deprived IRRs were 3.28 (3.00-3.58) in WLGP and 2.59 (2.36-2.84) in PEDW. Incidence in WLGP significantly decreased between 2008 and 2017 (IRR = 0.88, 95% CI 0.78-0.99); the greatest reduction occurred in the most deprived quintile (IRR 0.67, 95% CI 0.54-0.82). Incidence of hospital admissions remained stable (IRR = 0.95, 95% CI 0.84-1.08). Risk of death was significantly higher for CC compared with NC (HR = 8.7, 95% CI 7.5-10.0). CONCLUSION: Male sex, older age and greater deprivation were associated with higher CC incidence, although the gap between WIMD quintiles has decreased. CC was associated with greater risk of death. Mental health and substance misuse services should be provided in ways that remove barriers, and are acceptable and accessible to all, particularly those at greatest risk, or who are less likely to engage.

Leveraging mathematical models of disease dynamics and machine learning to improve development of novel malaria interventions.

BACKGROUND: Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. METHODS: A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. RESULTS: We apply our approach to five malaria interventions under development. Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements. CONCLUSIONS: Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. This study highlights the role of mathematical models to support intervention development. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions.

Clinical characteristics and outcomes for patients with non­metastatic castration-resistant prostate cancer.

This study used linked, routinely-collected datasets to explore incidence, clinical characteristics and outcomes of prostate cancer (PC) patients who experience a rise in prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT), without evidence of metastases in their patient record, termed non-metastatic castration-resistant PC (nmCRPC). Routinely collected administrative data in Wales were used to identify patients diagnosed with PC and nmCRPC from 2000-2015. Logrank tests and Cox proportional hazard models were used to compare time-to-events across subgroups defined by PSA doubling time and age. Of 38,021 patients identified with PC, 1,465 met nmCRPC criteria. PC incidence increased over the study period, while nmCRPC categorizations reduced. Median time from PC diagnosis to nmCRPC categorization was 3.07 years (95% confidence interval [CI] 2.91-3.26) and from nmCRPC categorization to metastases/death was 2.86 years (95% CI 2.67-3.09). Shorter PSA doubling time (≤ 10 months, versus > 10 months) was associated with reduced time to metastases or death (2.11 years [95% CI 1.92-2.30] versus 5.22 years [95% CI 4.87-5.51]). Age was not significantly associated with time to metastases/death. Our findings highlight key clinical characteristics and outcomes for patients with nmCRPC prior to the introduction of recently approved treatments.

Using the Technology Acceptance Model to conceptualise experiences of the usability and acceptability of a self-management app (COPD.Pal®) for Chronic Obstructive Pulmonary Disease.

Chronic Obstructive Pulmonary Disease (COPD) is a long-term progressive inflammatory lung disease causing chronic breathlessness and many hospital admissions. It affects up to 1.2 million people in the UK. To help people with COPD self-manage their condition we developed, in partnership with healthcare users, a digital mobile phone app called COPD.Pal®. We report the first user feedback of COPD.Pal®, applying the Technology Acceptance Model (TAM) theoretical framework. 11 participants engaged with a click dummy version of COPD.Pal® before being asked questions relating to their experiences. A deductive, semantic, reflexive thematic analysis was conducted to analyse their individual and collective experiences. The study was registered at Clinical Trials.gov (NCT04142957). Two overarching themes resulted: Ease of Use and Perceived Usefulness. Within the former, participants discussed how they wanted flexibility and choice in how they engaged with the app; including how often they used it. Additionally, they discussed how the app layout should make it straightforward to use, whilst unanimously agreeing that COPD.Pal® provided this. Within Perceived Usefulness, participants discussed how they wanted the information they entered into the app to be useful, in addition to the app providing resources regarding COPD. Lastly, there was disagreement regarding preferences for further app development. We found that COPD.Pal® was usable and acceptable by people with COPD and TAM provided a useful theoretical framework for both structuring discussions with users and analysing their comments.

Feasibility and acceptability of a community pharmacy referral service for suspected lung cancer symptoms.

BACKGROUND: Lung cancer survival rates in the UK are among the lowest in Europe, principally due to late-stage diagnosis. Alternative routes to earlier diagnosis of lung cancer are needed in socioeconomically deprived communities that are disproportionately affected by poor lung cancer outcomes. We assessed the feasibility and acceptability of a community-based pharmacy referral service to encourage earlier symptomatic referral for chest X-rays. METHODS: Seventeen community pharmacies located in a deprived area of Wales participated between March 2019 and March 2020. Stakeholder interviews were conducted with four patients, seven pharmacy professionals and one general practitioner. Four focus groups were conducted, including one with healthcare professionals (n=6) and three with members of the public who were current and former smokers (n=13). Quantitative data regarding patient characteristics and clinical outcomes were collected from hospital records and patient referral questionnaires completed by pharmacists and analysed using descriptive statistics. Qualitative data sets were analysed thematically and triangulated. RESULTS: Twelve patients used the pharmacy referral service, all of whom were male. Average length of the pharmacy consultation was 13 min, with a mean 3 days to accessing chest X-rays in secondary care. Patients experienced a mean 46-day wait for results, with no lung cancer detected. Participants found the service to be acceptable and considered the pharmacy element to be broadly feasible. Perceived barriers included low awareness of the service and concerns about the role and capacity of pharmacists to deliver the service. Facilitators included perceived approachability and accessibility of pharmacists. A well-publicised, multifaceted awareness campaign was recommended. CONCLUSIONS: A community pharmacy referral service for lung symptoms was considered an acceptable alternative pathway to symptomatic diagnosis of lung cancer in deprived communities. Wider implementation of the service would require workforce capacity and training to be addressed to ensure optimum utilisation and promotion of the service.

Does home telemonitoring after pulmonary rehabilitation reduce healthcare use in optimized COPD? A pilot randomized trial.

AIM: To see if home telemonitors reduce healthcare use in those with optimized chronic obstructive pulmonary disease (COPD). METHODS: We randomized 40 stable patients with moderate to severe COPD, who had completed at least 12 sessions of outpatient pulmonary rehabilitation (PR), to receive standard care (Controls) for 52 weeks or standard care plus Docobo HealthHUB monitors at home for 26 weeks followed by 26 weeks standard care (Tm Group). During the monitoring period, the Tm Group completed symptoms and physical observations twice daily which were stored and then uploaded at 2 am through a freephone landline. Nurses could access the data through a secure web site and received alerting e-mails if certain combinations of data occurred. RESULTS: There were fewer primary care contacts for chest problems (p < 0.03) in the Tm group, but no differences between the groups in emergency room visits, hospital admissions, days in hospital or contacts to the specialist COPD community nurse team, during the monitoring period. After the monitors were removed, there were no differences between the groups for any of the health care contacts (p > 0.20 throughout). CONCLUSION: In stable, optimized COPD patients who have already completed PR, telemonitoring in addition to best care, reduces primary care chest contacts but not hospital or specialist team utilization.

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

What influences student experience of Graduate Entry Medicine? Qualitative findings from Swansea School of Medicine.

BACKGROUND: The Graduate Entry Programme (GEP) in Medicine delivered by Swansea University (currently in collaboration with Cardiff University) accepts students from a diverse range of academic backgrounds with no restriction in relation to the field of first degree. There is a growing body of literature, predominantly quantitative in nature, regarding the influence of academic background on student achievement but little published information on students' views. AIM: To examine students' views regarding the extent to which previous higher education and wider life experience influence their student experience on the GEP course. METHOD: Recruitment from three student cohorts and group interview data followed by descriptive thematic analysis of anonymized data. RESULTS: Data themes were: (1) previous study experience and its impact on present student experience; (2) the impact of life experience; (3) the impact of the present study on life experience; (4) skills, status and difference; (5) characteristics and expectations of the course; (6) finances and (7) next steps. Previous study experience had little impact on present student experience. However, previous life experience, with time between first degree and GEP, clearly enhances the learning experience. Added maturity and early clinical contact enables students to manage the challenges of the course and the NHS environment despite financial strain and heavy coursework. CONCLUSIONS: Analysing students' views is informative and provides richer insight into experience and expectations than that accessible from quantitative data alone.

GROUPS THAT DO AND DO NOT HAVE GROWING CONTEXT-SENSITIVE WORD PROBLEM.

We prove that a group has word problem that is a growing context-sensitive language precisely if its word problem can be solved using a non-deterministic Cannon's algorithm (the deterministic algorithms being defined by Goodman and Shapiro in [6]). We generalize results of [6] to find many examples of groups not admitting non-deterministic Cannon's algorithms. This adds to the examples of Kambites and Otto in [7] of groups separating context-sensitive and growing context-sensitive word problems, and provides a new language-theoretic separation result.

Social Facilitation of Laughter and Smiles in Preschool Children.

Surprisingly little is known about the social dimensions of laughter in preschool children. We studied children's responses to amusing video clips in the presence or absence of peers. The sample consisted of 9 boys and 11 girls aged 31-49 months (M 39.8, SD 4.2) who watched three cartoons under three different conditions: individually, in pairs, or in groups of 6 or 8. The social viewing conditions showed significantly higher numbers of laughs and smiles than the individual viewing condition. On average children laughed eight times as much in company as on their own and smiled almost three times as much. No differences were found between pairs and groups, and no association was found between subjective funniness ratings and group size. This suggests that the presence of even a single social partner can change behavior in response to humorous material. It supports the idea that laughter and smiles are primarily flexible social signals rather than reflexive responses to humor.

Inhibition of aggrecan turnover in short-term explant cultures of bovine tendon.

The large aggregating proteoglycan, aggrecan, better known for its physiological role in articular cartilage where it serves to facilitate resistance of compressive forces during joint articulation, is also present within the distinct functional regions of tendon (i.e., compressed/fibrocartilaginous and tensional). Previous studies demonstrate that an increased turnover of aggrecan occurs in tendon, which is mediated principally by the 'aggrecanases' and, as such, these proteinases may play an important role in the normal functioning of the tissue. In the present study, utilising bovine tendon explant culture systems, we demonstrated that aggrecanase-mediated tendon aggrecan turnover may be modulated by generic metalloproteinase inhibitors (i.e., the aggrecanase inhibitor, actinonin and the broad-spectrum MMP inhibitor, marimistat). As expected, no MMP-generated aggrecan catabolites were detected in the culture system, suggesting that tendon aggrecanases may be inhibited by marimistat. Furthermore, immunohistochemical analyses revealed that aggrecan metabolites are present in the endotenon, surrounding the collagen fibre bundles, suggesting that aggrecan may provide functions of water imbibement and resistance of reversible and repeated compressive loads manifest between the collagen fibres; these functions, in turn, may be associated with increased aggrecan turnover in this tissue. Thus, inhibition of tendon aggrecanases and consequently aggrecan turnover in this tissue, may be related to some of the deleterious effects observed in the tendons of patients undergoing drug therapy with broad-spectrum MMP inhibitors for cancer and arthritis.