Physical Activity, Inactivity and Sleep in Individuals with Hypertrophic Cardiomyopathy.

Physical activity presents an important cornerstone in the management and care of individuals with hypertrophic cardiomyopathy (HCM). Twenty-one individuals with HCM (age: 52±15 years old, body mass index (BMI): 30±7 kg/m2) completed 7-day monitoring using wrist-worn triaxial accelerometers (GENEActiv, ActivInsights Ltd, UK) and were compared to age and sex-matched healthy controls (age: 51±14 years old, BMI: 25±4 kg/m2). For individuals with HCM, clinical parameters (left atrial diameter and volume, peak oxygen consumption, NTproBNP and Minnesota Living with Heart Failure (MLHF)) were correlated with accelerometry. After adjusting for BMI, individuals with HCM spent less time in moderate-vigorous physical activity (MVPA) (86 (55-138) vs. 140 (121-149) minutes/day, p<0.05) compared to healthy controls. Individuals with HCM engaged in fewer MVPA-5 min (6 (2-15) vs. 27 (23-37) minutes/day, p<0.01) and MVPA-10 min bouts (9 (0-19) vs. 35 (17-54) minutes/day, p<0.01) versus healthy controls. For HCM only, peak oxygen consumption was correlated with MVPA (r=0.60, p<0.01) and MVPA-5 min bouts (r=0.47, p<0.05). MLHF score was correlated with sleep duration (r=0.45, p<0.05). Individuals with HCM should be encouraged to engage in moderate-intensity physical activity bouts and reduce prolonged periods of inactivity in order to potentially improve exercise tolerance and reduce disease burden.

Physical activity, inactivity and sleep in older patients with coronary artery disease following percutaneous coronary intervention: a longitudinal, observational study.

OBJECTIVES: Physical activity presents an important cornerstone in the management and care of coronary artery disease (CAD) patients following percutaneous coronary intervention (PCI) and research in older patients continues to be overlooked. This study evaluated differences in physical activity, inactivity and sleep of CAD patients following PCI for acute coronary syndrome consisting of ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) and elective admission of stable angina patients over 12 months. METHODS: This was an observational, longitudinal study. Fifty-eight patients were recruited (STEMI, n  = 20, NSTEMI, n  = 18 and stable angina, n  = 20) and completed 7-day monitoring (physical activity, inactivity and sleep) using wrist-worn tri-axial accelerometers (GENEActiv, ActivInsights Ltd, Kimbolton, Cambridgeshire, UK) upon discharge from a tertiary centre and repeated measurements at 3 months ( n  = 43), 6 months ( n  = 40) and 12 months ( n  = 33). RESULTS: Following PCI, CAD patients showed a general trend of increasing light and moderate-vigorous physical activity over the 12-month follow-up. Time in inactivity remained high but decreased over time. Sleep duration and sleep efficiency remained consistent. NSTEMI patients spent less time asleep, more time inactive and less time in light and moderate-vigorous physical activity in comparison to STEMI and stable angina patients. Differences between the groups over time were minimal. CONCLUSION: These findings suggest that older patients with CAD spend long periods in inactivity but the increasing trend of both light and moderate-vigorous physical activity over time presents a positive change in behaviour in the year following PCI.

l-Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes: A Systematic Review.

BACKGROUND AND OBJECTIVES: Stroke management in the context of primary mitochondrial disease is clinically challenging, and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review of the safety and efficacy of l-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease. METHODS: The systematic review was registered in PROSPERO (CRD42020181230). We searched 6 databases from inception to January 15, 2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting l-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion. Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodologic quality of case reports, case series, and a risk-of-bias checklist for nonrandomized studies. Quality of evidence was synthesized with the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to l-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow-up), as defined by the author. RESULTS: Thirty-seven articles met inclusion criteria (0 randomized controlled trials; 3 open-label; 1 retrospective cohort; 33 case reports/case series) (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute l-arginine, of which 40% were concomitantly treated with antiepileptic drugs. Improved headache at 24 hours was the greatest reported benefit in response to IV l-arginine in the open-label trials (31 of 39, 79%). In 15 of 48 patients (31%) who positively responded to prophylactic l-arginine, antiepileptic drugs were either used (7 of 15) or unreported (8 of 15). Moderate adverse events were reported in the follow-up of both IV and oral l-arginine treatment, and 11 patients (12%) died during follow-up or while on prophylactic treatment. DISCUSSION: The available evidence is of poor methodologic quality and classified as Level 5. IV and oral l-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, with more robust controlled trials required to assess its efficacy and safety profile.

Astrocytic Changes in Mitochondrial Oxidative Phosphorylation Protein Levels in Parkinson's Disease.

BACKGROUND: Mitochondrial dysfunction within neurons, particularly those of the substantia nigra, has been well characterized in Parkinson's disease and is considered to be related to the pathogenesis of this disorder. Dysfunction within this important organelle has been suggested to impair neuronal communication and survival; however, the reliance of astrocytes on mitochondria and the impact of their dysfunction on this essential cell type are less well characterized. OBJECTIVE: This study aimed to uncover whether astrocytes harbor oxidative phosphorylation (OXPHOS) deficiencies in Parkinson's disease and whether these deficiencies are more likely to occur in astrocytes closely associated with neurons or those more distant from them. METHODS: Postmortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key OXPHOS proteins across all five complexes. RESULTS: We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age. CONCLUSION: Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could have an impact on their reactivity and ability to support neurons in Parkinson's disease.

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

Age-associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon.

One of the hallmarks of aging is an accumulation of cells with defects in oxidative phosphorylation (OXPHOS) due to mutations of mitochondrial DNA (mtDNA). Rapidly dividing tissues maintained by stem cells, such as the colonic epithelium, are particularly susceptible to accumulation of OXPHOS defects over time; however, the effects on the stem cells are unknown. We have crossed a mouse model in which intestinal stem cells are labelled with EGFP (Lgr5-EGFP-IRES-creERT2) with a model of accelerated mtDNA mutagenesis (PolgAmut/mut ) to investigate the effect of OXPHOS dysfunction on colonic stem cell proliferation. We show that a reduction in complex I protein levels is associated with an increased rate of stem cell cycle re-entry. These changes in stem cell homeostasis could have significant implications for age-associated intestinal pathogenesis.

Supporting a Healthier Takeaway Meal Choice: Creating a Universal Health Rating for Online Takeaway Fast-Food Outlets.

Digital food ordering platforms are used by millions across the world and provide easy access to takeaway fast-food that is broadly, though not exclusively, characterised as energy dense and nutrient poor. Outlets are routinely rated for hygiene, but not for their healthiness. Nutritional information is mandatory in pre-packaged foods, with many companies voluntarily using traffic light labels to support making healthier choices. We wanted to identify a feasible universal method to objectively score takeaway fast-food outlets listed on Just Eat that could provide users with an accessible rating that can infer an outlet's 'healthiness'. Using a sample of takeaway outlets listed on Just Eat, we obtained four complete assessments by nutrition researchers of each outlet's healthiness to create a cumulative score that ranged from 4 to 12. We then identified and manually extracted nutritional attributes from each outlet's digital menu, e.g., number of vegetables that have the potential to be numerated. Using generalized linear modelling we identified which attributes were linear predictors of an outlet's healthiness assessment from nutritional researchers. The availability of water, salad, and the diversity of vegetables were positively associated with academic researchers' assessment of an outlet's healthiness, whereas the availability of chips, desserts, and multiple meal sizes were negatively associated. This study shows promise for the feasibility of an objective measure of healthiness that could be applied to all outlet listings on Just Eat and other digital food outlet aggregation platforms. However, further research is required to assess the metric's validity, its desirability and value to users, and ultimately its potential influence on food choice behaviour.

Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.

Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.

Investigation of mitochondrial biogenesis defects in single substantia nigra neurons using post-mortem human tissues.

Mitochondrial respiratory chain deficiency and mitochondrial DNA deletions are reported in substantia nigra neurons from healthy aged and Parkinson's disease cases, with extensive neuronal loss only seen in the latter. This study aimed to understand the pathological relevance of mitochondrial defects for neuronal survival. Using post-mortem human midbrain, substantia nigra neurons exposed to different types of mitochondrial defects (including mitochondrial DNA point mutations, single and multiple deletions) were compared to neurons from healthy aged and Parkinson's disease cases (either sex) at a single neuronal level. We identified mitochondrial deficiencies in all cases, though these deficiencies were more severe in the mitochondrial disease patients with multiple deletions. A significant reduction in TFAM expression was detected in Parkinson's disease compared to cases with other mitochondrial defects. Higher mitochondrial DNA copy number was detected in healthy aged neurons, despite a deletion level equivalent to Parkinson's disease. Our data support that in individuals with pathogenic mitochondrial defects, neurons respond to mitochondrial defect to survive and such an adaptation may involve TFAM.

Profiling embryonic stem cell differentiation by MALDI TOF mass spectrometry: development of a reproducible and robust sample preparation workflow.

MALDI TOF mass spectrometry (MS) is widely used to characterise and biotype bacterial samples, but a complementary method for profiling of mammalian cells is still underdeveloped. Current approaches vary dramatically in their sample preparation methods and are not suitable for high-throughput studies. In this work, we present a universal workflow for mammalian cell MALDI TOF MS analysis and apply it to distinguish ground-state naïve and differentiating mouse embryonic stem cells (mESCs), which can be used as a model for drug discovery. We employed a systematic approach testing many parameters to evaluate how efficiently and reproducibly each method extracted unique mass features from four different human cell lines. These data enabled us to develop a unique mammalian cell MALDI TOF workflow involving a freeze-thaw cycle, methanol fixing and a CHCA matrix to generate spectra that robustly phenotype different cell lines and are highly reproducible in peak identification across replicate spectra. We applied our optimised workflow to distinguish naïve and differentiating populations using multivariate analysis and reproducibly identify unique features. We were also able to demonstrate the compatibility of our optimised method for current automated liquid handling technologies. Consequently, our MALDI TOF MS profiling method enables identification of unique features and robust phenotyping of mESC differentiation in under 1 hour from culture to analysis, which is significantly faster and cheaper when compared with conventional methods such as qPCR. This method has the potential to be automated and can in the future be applied to profile other cell types and expanded towards cellular MALDI TOF MS screening assays.

Analysis of the functional capacity outcome measures for myotonic dystrophy.

OBJECTIVES: Defining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross-sectional analysis and subsequently 98 patients were followed for longitudinal analysis. We aimed to assess: (1) feasibility and best practice; (2) intra-session reliability; (3) validity; and (4) behavior over time, of these tests. RESULTS: OMMYD outcomes proved feasible as 96% of the participants completed at least one trial for all tests and more than half (n = 113) performed all three trials of each test. Body mass index and disease severity associate with functional capacity. There was a significant difference between the first and second trials of each test. There was a moderate to strong correlation between these functional outcomes and muscle strength, disease severity and patient-reported outcomes. All outcomes after 1 year detected a change in functional capacity except the nine-hole peg test. CONCLUSIONS: These tests can be used as a battery of outcomes or independently based on the shown overlapping psychometric features and strong cross-correlations. Due to the large and heterogeneous sample of this study, these results can serve as reference values for future studies.

Cognitive deficits in adult m.3243A>G- and m.8344A>G-related mitochondrial disease: importance of correcting for baseline intellectual ability.

OBJECTIVE: To determine the cognitive profile of adult patients with mitochondrial disease, and the effect of disease severity on cognition. METHODS: Using a prospective case-control design, we compared cognition of patients to normative data and to matched controls, assessed three times over 18 months. Forty-nine patients with m.3243A>G (N = 36) and m.8344A>G (N = 13) mtDNA mutations and 32 controls, matched by age (±5 years) and premorbid cognition (±10 WTAR FSIQ points), participated. Participants completed neuropsychological assessments of general cognition (WAIS-IV), executive function (D-KEFS), and memory (WMS-IV). Potential predictors of cognition were explored. RESULTS: Patients show mild-to-moderate premorbid cognitive impairment, but substantial impairment in current general cognition and distinct domains, including verbal comprehension, perceptual reasoning, working memory, processing speed, and memory retrieval. Executive dysfunction may be caused by slower decision-making. Patients performed worse than controls, except on memory tasks, indicating intact memory, when premorbid cognition is controlled for. Premorbid cognition and disease severity were consistent predictors of cognition in patients; however, cognitive decline appears slow and is unlikely in the short-term, when other disease-specific factors remain stable. INTERPRETATION: Patients should be monitored to facilitate early identification of a complex profile of cognitive deficits and individuals with higher disease burden should be followed up more closely. On development of cognitive difficulties, appropriate compensatory strategies should be determined through in-depth assessment. Using strategies such as slower presentation of information, multiple modes of presentation, active discussion to aid understanding and decision-making, and use of memory aids, may ameliorate difficulties.

Climate, human behaviour or environment: individual-based modelling of Campylobacter seasonality and strategies to reduce disease burden.

BACKGROUND: With over 800 million cases globally, campylobacteriosis is a major cause of food borne disease. In temperate climates incidence is highly seasonal but the underlying mechanisms are poorly understood, making human disease control difficult. We hypothesised that observed disease patterns reflect complex interactions between weather, patterns of human risk behaviour, immune status and level of food contamination. Only by understanding these can we find effective interventions. METHODS: We analysed trends in human Campylobacter cases in NE England from 2004 to 2009, investigating the associations between different risk factors and disease using time-series models. We then developed an individual-based (IB) model of risk behaviour, human immunological responses to infection and environmental contamination driven by weather and land use. We parameterised the IB model for NE England and compared outputs to observed numbers of reported cases each month in the population in 2004-2009. Finally, we used it to investigate different community level disease reduction strategies. RESULTS: Risk behaviours like countryside visits (t = 3.665, P < 0.001 and t = - 2.187, P = 0.029 for temperature and rainfall respectively), and consumption of barbecued food were strongly associated with weather, (t = 3.219, P = 0.002 and t = 2.015, P = 0.045 for weekly average temperature and average maximum temperature respectively) and also rain (t = 2.254, P = 0.02527). This suggests that the effect of weather was indirect, acting through changes in risk behaviour. The seasonal pattern of cases predicted by the IB model was significantly related to observed patterns (r = 0.72, P < 0.001) indicating that simulating risk behaviour could produce the observed seasonal patterns of cases. A vaccination strategy providing short-term immunity was more effective than educational interventions to modify human risk behaviour. Extending immunity to 1 year from 20 days reduced disease burden by an order of magnitude (from 2412-2414 to 203-309 cases per 50,000 person-years). CONCLUSIONS: This is the first interdisciplinary study to integrate environment, risk behaviour, socio-demographics and immunology to model Campylobacter infection, including pathways to mitigation. We conclude that vaccination is likely to be the best route for intervening against campylobacteriosis despite the technical problems associated with understanding both the underlying human immunology and genetic variation in the pathogen, and the likely cost of vaccine development.

Spatio-temporal models to determine association between Campylobacter cases and environment.

Background: Campylobacteriosis is a major cause of gastroenteritis in the UK, and although 70% of cases are associated with food sources, the remainder are probably associated with wider environmental exposure. Methods: In order to investigate wider environmental transmission, we conducted a spatio-temporal analysis of the association of human cases of Campylobacter in the Tyne catchment with weather, climate, hydrology and land use. A hydrological model was used to predict surface-water flow in the Tyne catchment over 5 years. We analysed associations between population-adjusted Campylobacter case rate and environmental factors hypothesized to be important in disease using a two-stage modelling framework. First, we investigated associations between temporal variation in case rate in relation to surface-water flow, temperature, evapotranspiration and rainfall, using linear mixed-effects models. Second, we used the random effects for the first model to quantify how spatial variation in static landscape features of soil and land use impacted on the likely differences between subcatchment associations of case rate with the temporal variables. Results: Population-adjusted Campylobacter case rates were associated with periods of high predicted surface-water flow, and during above average temperatures. Subcatchments with cattle on stagnogley soils, and to a lesser extent sheep plus cattle grazing, had higher Campylobacter case rates. Conclusions: Areas of stagnogley soils with mixed livestock grazing may be more vulnerable to both Campylobacter spread and exposure during periods of high rainfall, with resultant increased risk of human cases of the disease.

Does Maximal External Tibial Component Rotation Influence Tibiofemoral Load Distribution in the Primary Knee Arthroplasty Setting: A Comparison of Neutral vs Maximal Anatomical External Rotatory States.

BACKGROUND: Tibial component rotation at time of knee arthroplasty can influence conformity, load transmission across the polyethylene surface, and perhaps ultimately determined survivorship. Optimal tibial component rotation on the cut surface is reliant on standard per operative manual stressing. This subjective assessment aims to balance constraint and stability of the articulation through a full arc of movement. METHODS: Using a cadaveric model, computer navigation and under defined, previously validated loaded conditions mimicking the in vivo setting, the influence of maximal tibial component external rotation compared with the neutral state was examined for changes in laxity and tibiofemoral continuous load using 3D displacement measurement and an orthosensor continuous load sensor implanted within the polyethylene spacer in a simulated single radius total knee arthroplasty. RESULTS: No significant difference was found throughout arc of motion (0-115 degrees of flexion) for maximal varus and/or valgus or rotatory laxity between the 2 states. The neutral state achieved equivalence for mediolateral load distribution at each point of flexion. We have found that external rotation of the tibial component increased medial compartment load in comparison with the neutral position. Compared with the neutral state, external rotation consistently effected a marginal, but not significant reduction in lateral load under similar loading conditions. The effects were most pronounced in midflexion. CONCLUSION: On the basis of these findings, we would advocate for the midtibial tubercle point to determine tibial component rotation and caution against component external rotation.

Influence of increasing construct constraint in the presence of posterolateral deficiency at knee replacement: A biomechanical study.

When faced with posterolateral corner (PLC) deficiency, surgeons must choose a total knee replacement (TKR) construct that provides the appropriate level of constraint. This should match the internal constraint of the device to the soft tissue host laxity pattern. Little guidance is available peroperatively, with factors influencing final component choice remaining ill defined. This study aimed to quantify the effect of PLC insufficiency on the "envelope of laxity" (EoL) after TKR and the effect of increasingly component constraint upon knee behavior through a functional arc of flexion. Using computer navigation, mixed effect modeling and loaded cadaveric legs--laxity was quantified under separate states: the native knee, after implantation of a posterior stabilized (PS)-TKR, after sectioning the lateral (fibular) collateral ligament and popliteus tendon (PS-TKR-PLC), and after re-implantation with a semi-constrained "total stabilized" knee replacement (TS-TKR). Laxity was quantified from 0 to 110° of flexion for anterior draw, varus-valgus, and internal-external rotation. Implantation of the PS-TKR was consistently associated with increased constraint when compared to the native knee. PLC sectioning led to significantly increased laxity during varus stress from mid to deep flexion. Revision to a TS-TKR construct restored constraint mimicking that of the primary state but only for the arc of motion 0-90°. In a posterolateral deficient state, a fixed bearing semi-constrained TS-TKR restored the knee to near normal kinematics but this was only achieved from an arc of motion 0-90° of flexion. At higher flexion angles, there remained an unfavorable laxity pattern with varus stress opening.

Risk factors for the development of pleural empyema in children.

Pediatric pleural empyema has increased substantially over the past 20 years and reasons for this rise remain not fully explained. We investigated potential risk factors for the development of empyema in children by examining a cohort of patients with community-acquired pneumonia. Demographic, clinical, and socioeconomic characteristics, use of Ibuprofen prior to presentation and selected potential epidemiological risk factors were analyzed. Data were collected from a prospective etiological study of radiologically confirmed pneumonia in hospitalized children aged ≤16 years. One hundred sixty children were enrolled; 56% were male and 69% aged <5 years. Empyema complication developed in 40 (25%) children. Children with empyema were more frequently prescribed Ibuprofen prior to admission to hospital than those without (82% vs. 46.2%; OR 1.94, 97.5% credible interval 0.80-3.18). Bacterial infection was strongly associated with the development of empyema (OR 3.34, 97.5% credible interval 1.70-5.14). In contrast age, sex, maternal age, parental smoking, level of socioeconomic status, nursery attendance, asthma, household characteristics (bedrooms and number of occupants) were not significantly different between groups. In conclusion, children with pneumonia who developed empyema had more often received Ibuprofen prior to hospitalization and confirmed bacterial infection. We suggest a population-based study involving both primary and secondary care settings would help to investigate the role of Ibuprofen use in modulating the course of disease in children with pneumonia.

How does laxity after single radius total knee arthroplasty compare with the native knee?

Patients with total knee arthroplasties (TKAs) continue to report dissatisfaction in functional outcome. Stability is a major factor contributing to functionality of TKAs. Implants with single-radius (SR) femoral components are proposed to increase stability throughout the arc of flexion. Using computer navigation and loaded cadaveric legs, we characterized the "envelope of laxity" (EoL) offered by a SR cruciate retaining (CR)-TKA compared with that of the native knee through the arc of flexion in terms of anterior drawer, varus/valgus stress, and internal/external rotation. In both the native knee and the TKA laxity increased with increasing knee flexion. Laxities measured in the three planes of motion were generally comparable between the native knee and TKA from 0° to 110° of flexion. Our results indicate that the SR CR-TKA offers appropriate stability in the absence of soft tissue deficiency.