A four-year clinical and sonographic longitudinal follow-up of clubfeet treated according to Ponseti with normal references.

Purpose: To follow children with a clubfoot by ultrasonography during the entire treatment period up to 4 years and compare with controls. Method: Thirty clubfeet in 20 children treated using the Ponseti method and 29 controls were followed by repeated ultrasonography investigations from neonates to the age of 4 years. The previously established coronal medial and lateral, sagittal dorsal and posterior projections were used. Changes over time, correlations to the Diméglio score, and the course of treatment were studied. Results: The medial malleolus-navicular distance was shorter, while the talar tangent-navicular distance and the talo-navicular angle were larger in clubfeet than in controls even after the initial correction. The healthy feet in unilateral cases did not differ significantly from the controls. The range of motion in the talo-navicular joint was approximately 20° less in clubfeet than in controls during the first four years of life. The medial malleolus-navicular distance (r = -0.58) and the talo-navicular angle (r = 0.66) at the first ultrasonography showed the highest correlation to the number of casts needed to correct the deformities. Conclusion: Ultrasonography can be used to evaluate the initial degree of deformities in clubfeet and to follow the progress of the treatment and growth. Ultrasonography showed a clear difference between clubfeet and controls during the first four years of life. Although it was not possible to define specific limit values as benchmarks in the treatment, dynamic ultrasonography can provide valuable support in the decision-making process when complementary treatment may be needed. Level of evidence: III.

Effects of weathered polyethylene microplastic ingestion on sexual maturation, fecundity and egg quality in maturing broodstock Atlantic cod Gadus morhua.

Microplastics (MPs) have become a global issue as they are omnipresent in the ocean. Fish ingesting MPs through feed could be affected in their physiological function, e.g., disrupted enzyme production and function, reduction of feeding and reproductive failure. This study assessed the effects of feed containing naturally weathered MPs from the Oslofjord (Norway) on the reproductive physiology of Atlantic cod (Gadus morhua). Farmed cod broodstock were fed either control (C-diet) or feeds containing 1% microplastic (MP-diet) starting nine months prior to spawning, from June until May. No major differences were found between diet groups in overall biometrics or gonad histology. Sex steroid levels (testosterone, 11-ketotestosterone and 17ß-estradiol) resulted in expected profiles increasing over time without any significant differences between treatments. Gene expression levels of the steroidogenic enzyme 20ß-hydroxysteroid dehydrogenase (20ß-hsd) and vitellogenin1 (vtg1) showed significant differences between dietary treatments with lower expression in the control group. This can be a direct effect of MPs, but endocrine disrupting effects of potentially leachable plastic additives cannot be completely ruled out. Thus, these enzymes could be indicators of exposure to contaminants that disrupt sexual maturation by affecting the production of primarily maturation-inducing steroid. Although the concentration of MPs employed in this study may not be high enough to elicit any observable short-term biological effects, the observed gene expression suggests that long-term consequences should be considered caused by an expected increase of MPs in marine environments.

Efficient parameterisation of non-collinear energy landscapes in itinerant magnets.

Magnetic exchange interactions determine the magnetic groundstate, as well as magnetic excitations of materials and are thus essential to the emerging and fast evolving fields of spintronics and magnonics. The magnetic force theorem has been used extensively for studying magnetic exchange interactions. However, short-ranged interactions in itinerant magnetic systems are poorly described by this method and numerous strategies have been developed over the years to overcome this deficiency. The present study supplies a fully self-consistent method for systematic investigations of exchange interactions beyond the standard Heisenberg model. In order to better describe finite deviations from the magnetic ground state, an extended Heisenberg model, including multi-spin interactions, is suggested. Using cross-validation analysis, we show that this extended Heisenberg model gives a superior description for non-collinear magnetic configurations. This parameterisation method allows us to describe many different itinerant magnetic systems and can be useful for high-throughput calculations.

Tripartite Genuine Non-Gaussian Entanglement in Three-Mode Spontaneous Parametric Down-Conversion.

We show that the states generated by a three-mode spontaneous parametric down-conversion (SPDC) interaction Hamiltonian possess tripartite entanglement of a different nature to other paradigmatic three-mode entangled states generated by the combination of two-mode SPDC interactions. While two-mode SPDC generates Gaussian states whose entanglement can be characterized by standard criteria based on two-mode quantum correlations, these criteria fail to capture the entanglement generated by three-mode SPDC. We use criteria built from three-mode correlation functions to show that the class of states recently generated in a superconducting-circuit implementation of three-mode SPDC ideally have tripartite entanglement, contrary to recent claims in the literature. These criteria are suitable for triple SPDC but we show that they fail to detect tripartite entanglement in other states which are known to possess it, which illustrates the existence of two fundamentally different notions of tripartite entanglement in three-mode continuous-variable systems.

Observation of Broadband Entanglement in Microwave Radiation from a Single Time-Varying Boundary Condition.

Entangled pairs of microwave photons are commonly produced in the narrow frequency band of a resonator, which represents a modified vacuum density of states. We generate and investigate the entanglement of a stream of photon pairs, generated in a semi-infinite broadband transmission line, terminated by a superconducting quantum interference device (SQUID). A weak pump signal modulates the SQUID inductance, resulting in a single time-varying boundary condition, and we detect all four quadratures of the microwave radiation emitted at two different frequencies separated by 0.7 GHz. Power calibration is done in situ, and we find positive logarithmic negativity and two-mode squeezing below the vacuum in the observed radiation, indicating entanglement.

Current and emerging avenues for Alzheimer's disease drug targets.

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

Head trauma in sports - clinical characteristics, epidemiology and biomarkers.

Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt nonpenetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop postconcussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers.

Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.

The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

Risk of mortality and recurrent cardiovascular events in patients with acute coronary syndromes on high intensity statin treatment.

Several randomized controlled trials have shown a benefit of high-dose intensive statin treatment in reducing risk of death and second cardiovascular disease (CVD) events in patients previously diagnosed with an acute coronary syndrome (ACS). Non-randomized studies in clinical settings support these findings, but large, long-term, observational studies addressing CVD and non-CVD endpoints are lacking. In this retrospective longitudinal study, we followed ACS patients in Sweden during 2001-2012 using national health registry and medical record data. A total of 49,857 patients were identified, of whom 10,092 (20.2%) received high dose statins and 21,174 (42.7%) received no statins. Royston-Parmar parametric time-to-event models were implemented to model hazard for second CVD events and death, stratified by gender and diabetes diagnosis. We found that risk of a second CVD event developed similarly in both treatment groups, but was much higher in the no statin group. Risk of CVD-related death remained relatively constant for the high-statin group, while it increased over time for the no-statin group. Interestingly, males had higher mortality rates in the no-statin group, but not in the high-statin group. All-cause mortality and non-CVD-related death followed similar trends to those observed for CVD-related death. This work provides additional real-world evidence for effect of statins in CVD-related mortality. The hazard functions presented here can provide a basis for future survival modeling and health economic evaluation.

Mechanisms, patterns and outcomes of paediatric polytrauma in a UK major trauma centre.

Introduction Paediatric trauma is a significant burden to healthcare worldwide and accounts for a large proportion of deaths in the UK. Methods This retrospective study examined the epidemiological data from a major trauma centre in the UK between January 2012 and December 2014, reviewing all cases of moderate to severe trauma in children. Patients were included if aged ≤16 years and if they had an abbreviated injury scale score of ≥2 in one or more body region. Results A total of 213 patients were included in the study, with a mean age of 7.8 years (standard deviation [SD]: 5.2 years). The most common cause of injury was vehicle related incidents (46%). The median length of hospital stay was 5 days (interquartile range [IQR]: 4-10 days). Approximately half (52%) of the patients had to stay in the intensive care unit, for a median of 1 day (IQR: 0-2 days). The mortality rate was 6.6%. The mean injury severity score was 19 (SD: 10). Pearson's correlation coefficient showed a positive correlation for injury severity score with length of stay in hospital (p<0.001). Conclusions There is significant variation in mechanism of injury, severity and pattern of paediatric trauma across age groups. A multidisciplinary team approach is imperative, and patients should be managed in specialist centres to optimise their care and eventual functional recovery. Head injury remained the most common, with significant mortality in all age groups. Rib fractures and pelvic fractures should be considered a marker for the severity of injury, and should alert doctors to look for other associated injuries.

Lipid-lowering treatment patterns in patients with new cardiovascular events - estimates from population-based register data in Sweden.

OBJECTIVES: The aim of this study was to assess treatment patterns of lipid-lowering therapy (LLT) in patients with hyperlipidaemia or prior cardiovascular (CV) events who experience new CV events. METHODS: A retrospective population-based cohort study was conducted using Swedish medical records and registers. Patients were included in the study based on a prescription of LLT or CV event history and followed up for up to 7 years for identification of new CV events and assessment of LLT treatment patterns. Patients were stratified into three cohorts based on CV risk level. All outcomes were assessed during the year following index (the date of first new CV event). Adherence was defined as medication possession ratio (MPR) > 0.80. Persistence was defined as no gaps > 60 days in supply of drug used at index. RESULTS: Of patients with major cardiovascular disease (CVD) history (n = 6881), 49% were not on LLT at index. Corresponding data for CV risk equivalent and low/unknown CV risk patients were 37% (n = 3226) and 38% (n = 2497) respectively. MPR for patients on LLT at index was similar across cohorts (0.74-0.75). The proportions of adherent (60-63%) and persistent patients (56-57%) were also similar across cohorts. Dose escalation from dose at index was seen within all cohorts and 2-3% of patients switched to a different LLT after index while 5-6% of patients augmented treatment by adding another LLT. CONCLUSIONS: Almost 50% of patients with major CVD history were not on any LLT, indicating a potential therapeutic gap. Medication adherence and persistence among patients on LLT were suboptimal.

Work productivity loss and indirect costs associated with new cardiovascular events in high-risk patients with hyperlipidemia: estimates from population-based register data in Sweden.

OBJECTIVES: To estimate productivity loss and associated indirect costs in high-risk patients treated for hyperlipidemia who experience cardiovascular (CV) events. METHODS: Retrospective population-based cohort study conducted using Swedish medical records linked to national registers. Patients were included based on prescriptions of lipid-lowering therapy between 1 January 2006 and 31 December 2011 and followed until 31 December 2012 for identification of CV events and estimation of work productivity loss (sick leave and disability pension) and indirect costs. Patients were stratified into two cohorts based on CV risk level: history of major cardiovascular disease (CVD) and coronary heart disease (CHD) risk equivalent. Propensity score matching was applied to compare patients with new events (cases) to patients without new events (controls). The incremental effect of CV events was estimated using a difference-in-differences design, comparing productivity loss among cases and controls during the year before and the year after the cases' event. RESULTS: The incremental effect on indirect costs was largest in the CHD risk equivalent cohort (n = 2946) at €3119 (P value <0.01). The corresponding figure in the major CVD history cohort (n = 4508) was €2210 (P value <0.01). There was substantial variation in productivity loss depending on the type of event. Transient ischemic attack and revascularization had no significant effect on indirect costs. Myocardial infarction (€3465), unstable angina (€2733) and, most notably, ischemic stroke (€6784) yielded substantial incremental cost estimates (P values <0.01). CONCLUSIONS: Indirect costs related to work productivity losses of CV events are substantial in Swedish high-risk patients treated for hyperlipidemia and vary considerably by type of event.

Healthcare costs associated with cardiovascular events in patients with hyperlipidemia or prior cardiovascular events: estimates from Swedish population-based register data.

OBJECTIVES: To estimate healthcare costs of new cardiovascular (CV) events (myocardial infarction, unstable angina, revascularization, ischemic stroke, transient ischemic attack, heart failure) in patients with hyperlipidemia or prior CV events. METHODS: A retrospective population-based cohort study was conducted using Swedish national registers and electronic medical records. Patients with hyperlipidemia or prior CV events were stratified into three cohorts based on CV risk level: history of major cardiovascular disease (CVD), coronary heart disease (CHD) risk-equivalent, and low/unknown risk. Propensity score matching was applied to compare patients with new events to patients without new events for estimation of incremental costs of any event and by event type. RESULTS: A CV event resulted in increased costs over 3 years of follow-up, with the majority of costs occurring in the 1st year following the event. The mean incremental cost of patients with a history of major CVD (n = 6881) was €8588 during the 1st year following the event. This was similar to that of CHD risk-equivalent patients (n = 3226; €6663) and patients at low/unknown risk (n = 2497; €8346). Ischemic stroke resulted in the highest 1st-year cost for patients with a history of major CVD and CHD risk-equivalent patients (€10,194 and €9823, respectively); transient ischemic attack in the lowest (€3917 and €4140). Incremental costs remained elevated in all cohorts during all three follow-up years, with costs being highest in the major CVD history cohort. CONCLUSIONS: Healthcare costs of CV events are substantial and vary considerably by event type. Incremental costs remain elevated for several years after an event.

Young adults' views on the relevance of three measures for oral health-related quality of life.

OBJECTIVE: The aim of this study was to explore the views of young adults on the relevance of three measures of oral health-related quality of life (OHRQoL). METHODS: Sixteen young adults aged 21-29 years were interviewed. The selection was strategic with reference to age (21-25 years.; 26-30 years), sex and education (university degree; upper secondary school). The interview guide covered areas on the content and construction of the measures: The Oral Health Impact Profile (OHIP), the Oral Impacts on Daily Performances (OIDP) and the Oral Health-Related Quality of Life UK (OHRQoL-UK). The data were analysed using qualitative content analysis. RESULTS: A theme expressing the latent content was formulated during the data analysis: 'young adults' own experiences were reflected in their views on the OHRQoL measures'; that is, the experiences of young adults of own oral problems and aspects that were found to be especially important for their age group influenced their view on the measures. The self-reported ability to understand and answer the questions varied and the perceived advantages and disadvantages were almost equally distributed among the three measures. CONCLUSIONS: The OHIP, OIDP and OHRQoL-UK were evaluated as being equal by the young adults in this study, with regard both to their pros and cons. The clarity of the measures was regarded as the most important factor, while the length and assessment period were less significant.

Dynamical Casimir effect entangles artificial atoms.

We show that the physics underlying the dynamical Casimir effect may generate multipartite quantum correlations. To achieve it, we propose a circuit quantum electrodynamics scenario involving superconducting quantum interference devices, cavities, and superconducting qubits, also called artificial atoms. Our results predict the generation of highly entangled states for two and three superconducting qubits in different geometric configurations with realistic parameters. This proposal paves the way for a scalable method of multipartite entanglement generation in cavity networks through dynamical Casimir physics.

Regional changes in cerebral blood flow oxygenation can indicate global changes in cerebral blood flow during coronary artery occlusion in juvenile pigs.

Near infrared spectroscopy (NIRS) is a widely employed method for assessment of regional cerebral oxygenation (RcStO2). RcStO2 values are expected to vary with changes in the relative amount of oxyhaemoglobin. The present experimental study aimed to assess the response of RcStO2 to controlled alterations of carotid blood flow (CQ). Landrace pigs were anesthetized followed by surgical preparation. Cyclic variations in cardiac output were accomplished by intermittently occluding the main stem of the left coronary artery. A flow measurement probe for assessing CQ was placed around the left carotid artery. One NIRS probe was placed on the left ipsilateral forehead to assess regional cerebral oximetry. Simultaneous registration of CQ and RcStO2 was conducted. There was a strong correlation for variation in CQ and RcStO2 signal values. Based on coherence analysis the fraction of power of the RcStO2 that was coherent with the CQ signal reached 0.84 ± 0.12 (P < 0.05) for frequencies lower than 0.1 Hz. The agreement of the sample-to-sample co-variation, as assessed by the Pearson correlation coefficient, was 0.83 ± 0.08 (P < 0.05). One explanatory component for variations in cerebral oxygenation verified by NIRS should be attributed to variations in the cerebral blood flow.

Quantum nondemolition detection of a propagating microwave photon.

The ability to nondestructively detect the presence of a single, traveling photon has been a long-standing goal in optics, with applications in quantum information and measurement. Realizing such a detector is complicated by the fact that photon-photon interactions are typically very weak. At microwave frequencies, very strong effective photon-photon interactions in a waveguide have recently been demonstrated. Here we show how this type of interaction can be used to realize a quantum nondemolition measurement of a single propagating microwave photon. The scheme we propose uses a chain of solid-state three-level systems (transmons) cascaded through circulators which suppress photon backscattering. Our theoretical analysis shows that microwave-photon detection with fidelity around 90% can be realized with existing technologies.