Mechanisms of development of multimorbidity in the elderly.
In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K-AKT-mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation ("inflammaging"). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted.


Ribbon networks for modeling navigable paths of autonomous agents in virtual environments.
This paper presents the Environment Description Framework (EDF) for modeling complex networks of intersecting roads and pathways in virtual environments. EDF represents information about the layout of streets and sidewalks, the rules that govern behavior on roads and walkways, and the locations of agents with respect to navigable structures. The framework serves as the substrate on which behavior programs for autonomous vehicles and pedestrians are built. Pathways are modeled as ribbons in space. The ribbon structure provides a natural coordinate frame for defining the local geometry of navigable surfaces. EDF includes a powerful runtime interface supported by robust and efficient code for locating objects on the ribbon network, for mapping between Cartesian and ribbon coordinates, and for determining behavioral constraints imposed by the environment.


Improved automated monitoring and new analysis algorithm for circadian phototaxis rhythms in Chlamydomonas.
Automated monitoring of circadian rhythms is an efficient way of gaining insight into oscillation parameters like period and phase for the underlying pacemaker of the circadian clock. Measurement of the circadian rhythm of phototaxis (swimming towards light) exhibited by the green alga Chlamydomonas reinhardtii has been automated by directing a narrow and dim light beam through a culture at regular intervals and determining the decrease in light transmittance due to the accumulation of cells in the beam. In this study, the monitoring process was optimized by constructing a new computer-controlled measuring machine that limits the test beam to wavelengths reported to be specific for phototaxis and by choosing an algal strain, which does not need background illumination between test light cycles for proper expression of the rhythm. As a result, period and phase of the rhythm are now unaffected by the time a culture is placed into the machine. Analysis of the rhythm data was also optimized through a new algorithm, whose robustness was demonstrated using virtual rhythms with various noises. The algorithm differs in particular from other reported algorithms by maximizing the fit of the data to a sinusoidal curve that dampens exponentially. The algorithm was also used to confirm the reproducibility of rhythm monitoring by the machine. Machine and algorithm can now be used for a multitude of circadian clock studies that require unambiguous period and phase determinations such as light pulse experiments to identify the photoreceptor(s) that reset the circadian clock in C. reinhardtii.


Comparison of two red-cell transfusion strategies after pediatric cardiac surgery: a subgroup analysis.
To determine the impact of a restrictive vs. a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome in children post cardiac surgery. The optimal transfusion threshold after cardiac surgery in children is unknown. Randomized, controlled trial. Tertiary pediatric intensive care units. Participants are a subgroup of pediatric patients post cardiac surgery from the TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units) study. Exclusion criteria specific to the cardiac surgery subgroup included: age <28 days and patients remaining cyanotic. Critically ill children with a hemoglobin < or = 95 g/L within 7 days of pediatric intensive care unit admission were randomized to receive prestorage leukocyte-reduced red-cell transfusion if their hemoglobin dropped either <70 g/L (restrictive) or 95 g/L (liberal). Postoperative cardiac patients (n = 125) from seven centers were enrolled. The restrictive (n = 63) and liberal (n = 62) groups were similar at baseline in age (mean +/- standard deviation = 31.4 +/- 38.1 mos vs. 26.4 +/- 39.1 mos), surgical procedure, severity of illness (Pediatric Risk of Mortality score = 3.4 +/- 3.2 vs. 3.2 +/- 3.2), multiple organ dysfunction syndrome (46% vs. 44%), mechanical ventilation (62% vs. 60%), and hemoglobin (83 vs. 80 g/L). Mean hemoglobin remained 21 g/L lower in the restrictive group after randomization. No significant difference was found in new or progressive multiple organ dysfunction syndrome (primary outcome) in the restrictive group vs. liberal group (12.7% vs. 6.5%; p = .36), pediatric intensive care unit length of stay (7.0 +/- 5.0 days vs. 7.4 +/- 6.4 days) or 28-day mortality (3.2% vs. 3.2%). In this subgroup analysis of cardiac surgery patients, a restrictive red-cell transfusion strategy, as compared with a liberal one, was not associated with any significant difference in new or progressive multiple organ dysfunction syndrome, but this evidence is not definitive.


Growth inhibition of human melanoma cells in nude mice by antisense strategies to the type 1 insulin-like growth factor receptor.
The growth of human melanoma cells FO-1 in nude mice is strongly inhibited or even abrogated when the cells are stably transfected with a plasmid expressing an antisense RNA to the insulin-like growth factor 1 receptor (IGF-1R) RNA, which causes a marked reduction in the number of IGF-1 receptors. When a tumor arises after a long delay in nude mice, it can be shown that the tumor cells have lost the expression plasmid and that the number of IGF-1 receptors has returned to wild-type levels. The antisense effect is even more remarkable, since the growth of FO-1 melanoma cells in monolayers is not affected by the expression of the antisense RNA. Inhibition of tumorigenesis was also evident when FO-1 melanoma cells were treated with antisense oligodeoxynucleotides to the IGF-1R RNA prior to injection into nude mice. These results confirm in human cells that the IGF-1R plays a dominant role in transformation and tumorigenesis and that its effect on tumorigenesis is more profound than its effect on mitogenesis.


Early Holocene human remains from the Argentinean Pampas: additional evidence for distinctive cranial morphology of early South Americans.
The cranial morphology of Early Holocene American human samples is characterized by a long and narrow cranial vault, whereas more recent samples exhibit a shorter and wider cranial vault. Two hypotheses have been proposed to account for the morphological differences between early and late-American samples: (a) the migratory hypothesis that suggests that the morphological variation between early and late American samples was the result of a variable number of migratory waves; and (b) the local diversification hypothesis, that is, the morphological differences between early and late American samples were mainly generated by local, random (genetic drift), and nonrandom factors (selection and phenotypic plasticity). We present the first craniometric study of three early skulls from the Argentinean Pampas, dated ∼8,000 cal. years BP (Arroyo Seco 2, Chocorí, and La Tigra), and one associated with mega-faunal remains (Fontezuelas skull). In addition, we studied several Late Holocene samples. We show that the skulls from the Argentinean Pampas are morphologically similar to other Early Holocene American skulls (i.e., Lagoa Santa from Brazil, Tequendama, Checua, and Aguazuque from Colombia, Lauricocha from Peru, and early Mexicans) that exhibit long and narrow cranial vaults. These samples differ from the Late Holocene American samples that exhibit a shorter and wider cranial vault. Our results underscore the important differences in cranial morphology between early and late-American samples. However, we emphasize the need for further studies to discuss alternative hypotheses regarding such differences.


Effect of blocking tactile information from the fingertips on adaptation and execution of grip forces to friction at the grasping surface.
Adaptation of fingertip forces to friction at the grasping surface is necessary to prevent use of inadequate or excessive grip forces. In the current study we investigated the effect of blocking tactile information from the fingertips noninvasively on the adaptation and efficiency of grip forces to surface friction during precision grasp. Ten neurologically intact subjects grasped and lifted an instrumented grip device with 18 different frictional surfaces under three conditions: with bare hands or with a thin layer of plastic (Tegaderm) or an additional layer of foam affixed to the fingertips. The coefficient of friction at the finger-object interface of each surface was obtained for each subject with bare hands and Tegaderm by measuring the slip ratio (grip force/load force) at the moment of slip. We found that the foam layer reduced sensibility for two-point discrimination and pressure sensitivity at the fingertips, but Tegaderm did not. However, Tegaderm reduced static, but not dynamic, tactile discrimination. Adaptation of fingertip grip forces to surface friction measured by the rate of change of peak grip force, and grip force efficiency measured by the grip-load force ratio at lift, showed a proportional relationship with bare hands but were impaired with Tegaderm and foam. Activation of muscles engaged in precision grip also varied with the frictional surface with bare hands but not with Tegaderm and foam. The results suggest that sensitivity for static tactile discrimination is necessary for feedforward and feedback control of grip forces and for adaptive modulation of muscle activity during precision grasp.


Can sodium valproate improve learning in children with epileptiform bursts but without clinical seizures?
This study aimed to determine whether sodium valproate (VPA) improves cognitive performance and behaviour in children with learning and behavioural problems associated with electrographic epileptiform discharges but without clinical seizures. A randomized, double-blind, single-crossover trial was carried out with VPA or placebo on eight participants with different learning and behaviour problems. Participants also underwent neuropsychological testing under video EEG and the parent and teacher Behaviour Check List (CBCL; Achenbach 1991a, b) during each treatment phase. Clinically none of the children improved on VPA. On formal testing children were more distractable, had increased delay in response time, and showed lower memory scores while on VPA. In addition, parents reported higher internalizing scores on the CBCL while children were on VPA. Our data do not support the use of VPA in similar patients.


Commissioning and dosimetric characteristics of TrueBeam system: composite data of three TrueBeam machines.
A TrueBeam linear accelerator (TB-LINAC) is designed to deliver traditionally flattened and flattening-filter-free (FFF) beams. Although it has been widely adopted in many clinics for patient treatment, limited information is available related to commissioning of this type of machine. In this work, commissioning data of three units were measured, and multiunit comparison was presented to provide valuable insights and reliable evaluations on the characteristics of the new treatment system. The TB-LINAC is equipped with newly designed waveguide, carousel assembly, monitoring control, and integrated imaging systems. Each machine in this study has 4, 6, 8, 10, 15 MV flattened photon beams, and 6 MV and 10 MV FFF photon beams as well as 6, 9, 12, 16, 20, and 22 MeV electron beams. Dosimetric characteristics of the three new TB-LINAC treatment units are systematically measured for commissioning. High-resolution diode detectors and ion chambers were used to measure dosimetric data for a range of field sizes from 10 × 10 to 400 × 400 mm(2). The composite dosimetric data of the three units are presented in this work. The commissioning of intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), image-guided radiation therapy, and gating systems are also illustrated. Critical considerations of P(ion) of FFF photon beams and small field dosimetric measurements were investigated. The authors found all PDDs and profiles matched well among the three machines. Beam data were quantitatively compared and combined through average to yield composite beam data. The discrepancies among the machines were quantified using standard deviation (SD). The mean SD of the PDDs among the three units is 0.12%, and the mean SD of the profiles is 0.40% for 10 MV FFF open fields. The variations of P(ion) of the chamber CC13 is 1.2 ± 0.1% under 6 MV FFF and 2.0 ± 0.5% under 10 MV FFF from dmax to the 18 cm-off-axis point at 35 cm depth under 40 × 40 cm(2). The mean penumbra of crossplane flattened photon beams at collimator angle of 0° is measured from 5.88 ± 0.09 to 5.99 ± 0.13 mm from 4 to 15 MV at 10 cm depth of 100 × 100 mm(2). The mean penumbra of crossplane beams at collimator angle of 0° is measured as 3.70 ± 0.21 and 4.83 ± 0.04 mm for 6 MV FFF and 10 MV FFF, respectively, at 10 cm depth with a field size of 5 × 5 cm(2). The end-to-end test procedures of both IMRT and VMAT were performed for various energy modes. The mean ion chamber measurements of three units showed less than 2% between measurement and calculation; the mean MultiCube ICA measurements demonstrated over 90% pixels passing gamma analysis (3%, 3 mm, 5% threshold). The imaging dosimetric data of KV planar imaging and CBCT demonstrated improved consistency with vendor specifications and dose reduction for certain imaging protocols. The gated output verification showed a discrepancy of 0.05% or less between gating radiation delivery and nongating radiation delivery. The commissioning data indicated good consistency among the three TB-LINAC units. The commissioning data provided us valuable insights and reliable evaluations on the characteristics of the new treatment system. The systematically measured data might be useful for future reference.


Focal Palatitis (Previously Focal Palatine Erosions) in Captive Cheetahs (Acinonyx jubatus).
Focal palatine erosion (FPE) is a misleading term that is used in the literature to describe inflammatory lesions associated with depressions of the palatal mucosa in cheetah. Cheetahs have large cheek teeth and these depressions are formed to accommodate them. Previously FPE was only described as a mandibular molar tooth malocclusion on the hard palate due to suspected rotation and super eruption of the mandibular molar teeth of cheetahs aged 18 months and older. Two hundred and fifty six cheetahs (135 male, 121 female), originating from two independent facilities, had their oral cavities evaluated as part of an annual health visit over a decade. Ninety-nine cheetahs were seen once, 59 cheetahs were seen twice, 33 were seen three times, 43 on four occasions, 16 on five occasions, 5 on six occasions, and 1 cheetah was seen seven times. Apart from these clinical cases a prospective study on 5 cheetah cubs (3 male and 2 female) was conducted to document their skull development and mandibular molar tooth eruption over a period of 25 months. Of the 261 cheetahs observed none developed rotation or super eruption of their mandibular molar teeth. The term FPE is a misnomer as these inflammatory lesions were found in palatal depressions opposing any of the cusps of all of the cheetah mandibular cheek teeth. It consisted mainly of deep ulcerations, inflammation and oedema and also micro abscess formation. In severe cases oro-nasal fistulas were present. Of all the depressions present on the cheetah's palate, the large one palatal to the 4th maxillary premolar tooth was most commonly affected. In the five cubs evaluated prospectively, focal palatitis was evident from the 7 month evaluation, before all the permanent teeth erupted. Conservative treatment of the inflamed depressions by removing the foreign material through curettage and copious flushing reduced the grade of the inflammation when observed on follow-up. Focal palatine erosion is an incorrect term used to describe focal palatitis that occurs randomly in cheetahs. This focal palatitis is often associated with foreign material trapped in the palatal depressions. Conservative management is sufficient to treat these animals without odontoplasties.


Continuous Ropivacaine Subfascial Wound Infusion Compared With Intrathecal Morphine for Postcesarean Analgesia: A Prospective, Randomized Controlled, Double-Blind Study.
After cesarean delivery, postoperative pain management allows early rehabilitation and helps prevent postpartum depression and chronic pain. Our present prospective, randomized controlled, double-blind study assessed the duration and effect of intrathecal analgesia and continuous ropivacaine wound infiltration versus a control group after cesarean delivery. The primary outcome was analgesia duration, defined as time to first morphine request. Secondary outcomes were cumulative postoperative morphine consumption, number of patients who did not require IV morphine, incidence of adverse effects, and time to first ambulation. A total of 192 full-term parturients undergoing elective cesarean delivery were randomly allocated into 3 groups (control, morphine, and catheter). All patients received spinal anesthesia with 10 mg bupivacaine 0.5% hyperbaric bupivacaine (2 mL) + 5 μg of sufentanil (1 mL) and a multiholed catheter inserted into the wound. In the control group, NaCl 0.9% was administered intrathecally (0.1 mL) and through the catheter. The morphine group received 100 μg morphine (0.1 mL) intrathecally and NaCl 0.9% infused through the wound catheter. The catheter group received 0.1 mL NaCl 0.9% intrathecally and ropivacaine 0.2% infused in the catheter. Each patient received a 15-mL bolus of the dedicated solution through the catheter, which was connected to an elastomeric pump infusor delivering the same solution at a rate of 10 mL/h for 30 hours. All patients also received multimodal analgesia including acetaminophen and diclofenac. Analgesia duration was defined as the time from spinal injection (T0) to first IV morphine requirement (T1) administered via a patient-controlled IV analgesia pump. Statistical data analyses included use of the Kruskal-Wallis rank-sum test followed by the post hoc Tukey test and χ test. The duration of postoperative analgesia was increased with intrathecal morphine (380 minutes; 215-1527) and ropivacaine wound infusion (351 minutes; 227-594) compared with the control (247 minutes; 182-338) with effect sizes of 0.171 (0.043-0.293) for morphine versus control and 0.164 (0.052-0.271) for catheter versus control. There was no difference between the morphine group and catheter group (effect size, 0.007; -0.118 to 0.132). Cumulative postoperative morphine consumption was also significantly lower in the morphine group and catheter group compared with the control group. The incidence of adverse effects did not differ between groups. After elective cesarean delivery, 100 μg intrathecal morphine and ropivacaine wound infusion both increased the duration and effect of postcesarean analgesia without increased incidence of side effects.


Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice.
The worldwide prevalence of type 2 diabetes (T2D), which is caused by a combination of environmental and genetic factors, is increasing. With regard to genetic factors, variations in the gene encoding Cdk5 regulatory associated protein 1-like 1 (Cdkal1) have been associated with an impaired insulin response and increased risk of T2D across different ethnic populations, but the molecular function of this protein has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons. Mice with pancreatic β cell-specific KO of Cdkal1 (referred to herein as β cell KO mice) showed pancreatic islet hypertrophy, a decrease in insulin secretion, and impaired blood glucose control. In Cdkal1-deficient β cells, misreading of Lys codon in proinsulin occurred, resulting in a reduction of glucose-stimulated proinsulin synthesis. Moreover, expression of ER stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Further, the β cell KO mice were hypersensitive to high fat diet-induced ER stress. These findings suggest that glucose-stimulated translation of proinsulin may require fully modified tRNA(Lys)(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.


Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease.
The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction. These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.


Acute vasospasm following transcallosal resection of a xanthogranulomatous colloid cyst of the 3rd ventricle.
We present the first case of a 57 year old man who developed severe, acute vasospasm following transcallosal resection of an unusual, xanthogranulomatous colloid cyst. The 16 year history of growth of this cyst may have resulted in its unusual pathology, and the subsequent vasospastic reaction to its excision. We discuss the potential pathological relationship between the inflammatory nature of the cyst, chemical meningitis and vasospasm, and what this implies about vasospasm in general. The severe, life-threatening vasospasm affected all four major vessels and required aggressive management by endovascular injection of nimodipine and angioplasty, with good recovery. The case illustrates a previously undescribed sequel of surgery for this condition, demonstrates an effective treatment and offers possible insights into the pathogenesis of vasospasm.


Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists.
Breast cancer resistance protein (BCRP), an ATP-binding cassette transporter, confers resistance to a series of anticancer agents such as SN-38, mitoxantrone, and topotecan. In a previous study, we found that estrogens reverse drug resistance of BCRP-expressing cells. In this study, estrogen antagonists, estrogen agonists, and their derivatives were evaluated for BCRP-reversing activity. First, compounds were tested for effects on the cellular accumulation of topotecan in BCRP-transduced K562 cells (K562/BCRP). Next, these compounds were examined for their ability to reverse SN-38 and mitoxantrone resistance in K562/BCRP cells. Among commercially available estrogen antagonists and agonists tested, diethylstilbestrol showed the strongest BCRP-reversing activity. Diethylstilbestrol increased the cellular accumulation of topotecan and reversed drug resistance in K562/BCRP cells but showed marginal or no effect in parental K562 cells. The reversal activities of estrone and diethylstilbestrol were more prominent for mitoxantrone than for SN-38. Tamoxifen and toremifene were also found to enhance topotecan uptake in K562/BCRP cells. Next, various tamoxifen derivatives were screened for anti-BCRP activity. In the first cycle of screening with 14 compounds, TAG-11 showed the strongest effect. In the second cycle of screening of 25 TAG-11-related compounds, TAG-139 showed the strongest effect. Reversal of SN-38 and mitoxantrone resistance in K562/BCRP cells by TAG-139 was 5-fold stronger than that by estrone. Dose-dependent characteristics of drug resistance reversal with estrone and TAG-139 were very similar, suggesting that estrone and tamoxifen derivatives interact with the same drug-binding site of BCRP. Derivatives of antiestrogens that exhibit no other biological effects promise to be useful in overcoming BCRP-mediated drug resistance.


Subthalamic nucleus local field potential activity helps encode motor effort rather than force in parkinsonism.
Local field potential (LFP) recordings from patients with deep brain stimulation electrodes in the basal ganglia have suggested that frequency-specific activities correlate with force or effort, but previous studies have not been able to disambiguate the two. Here, we dissociated effort from actual force generated by contrasting the force generation of different fingers while recording LFP activity from the subthalamic nucleus (STN) in patients with Parkinson's disease who had undergone functional surgery. Patients were studied while on their normal dopaminergic medication. We investigated the relationship between frequency-specific oscillatory activity in the STN and voluntary flexion of either the index or little finger at different effort levels. At each tested effort level (10%, 25%, and 40% of the maximal voluntary contraction force of each individual finger), the index finger generated larger force than the little finger. Movement-related suppression of beta-band power in the STN LFP was significantly modulated by effort, but not by which finger was used, suggesting that the beta suppression in the STN LFP during sustained contraction serves as a proxy for effort. The absolute force scaled with beta power suppression, but with the scaling determined by the maximal voluntary contraction force of the motor effector. Our results argue against the hypothesis that the basal ganglia are directly involved in the parameterization of force during movement and support a role of the STN in the control of motor effort to be attributed to a response.


Arbovirus investigations in Argentina, 1977-1980. III. Identification and characterization of viruses isolated, including new subtypes of western and Venezuelan equine encephalitis viruses and four new bunyaviruses (Las Maloyas, Resistencia, Barranqueras, and Antequera).
Forty viruses isolated from mosquitoes between 1977 and 1980 in Argentina have been identified and characterized. Nineteen strains of VEE virus, identical by neutralization (N) tests, were shown by hemagglutination-inhibition tests with anti-E2 glycoprotein sera to represent a new subtype VI of the VEE complex. RNA oligonucleotide fingerprints of this virus were distinct from subtype I viruses. The virus was not lethal for English short-haired guinea pigs, indicating that it is probably not equine-virulent. Three strains of a member of the WEE virus complex were shown to differ by N tests in 1 direction from prototype WEE virus. The new WEE subtype was also found to be distinct by RNA oligonucleotide mapping. Its vector relationships indicate that it is an enzootic virus, and it has not been associated with equine disease. A new member of the Anopheles A serogroup was identified, shown to be most closely related to Lukuni and Col An 57389 viruses, and given the name Las Maloyas virus. A strain of Para virus (Bunyaviridae, Bunyavirus) was identified. Six isolates, representing 3 new viruses morphologically resembling bunyaviruses are described; the names Antequera, Barranqueras, and Resistencia are proposed for these agents, which were all isolated from Culex (Melanoconion) delpontei in Chaco Province. No serologic relationships between these viruses and other bunyaviruses were found. Since they are antigenically interrelated, they form a new (Antequera) serogroup. Eight Gamboa serogroup viruses and 2 strains of St. Louis encephalitis virus were also identified.


Can we achieve health information for all by 2015?
Universal access to information for health professionals is a prerequisite for meeting the Millennium Development Goals and achieving Health for All. However, despite the promises of the information revolution, and some successful initiatives, there is little if any evidence that the majority of health professionals in the developing world are any better informed than they were 10 years ago. Lack of access to information remains a major barrier to knowledge-based health care in developing countries. The development of reliable, relevant, usable information can be represented as a system that requires cooperation among a wide range of professionals including health-care providers, policy makers, researchers, publishers, information professionals, indexers, and systematic reviewers. The system is not working because it is poorly understood, unmanaged, and under-resourced. This Public Health article proposes that WHO takes the lead in championing the goal of "Universal access to essential health-care information by 2015" or "Health Information for All". Strategies for achieving universal access include funding for research into barriers to use of information, evaluation and replication of successful initiatives, support for interdisciplinary networks, information cycles, and communities of practice, and the formation of national policies on health information.


Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis.
There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF.


[Long-term continuous positive airway pressure (CPAP) use in obstructive sleep apnea].
The use of CPAP is the conventional therapy for the Obstructive Sleep Apnea Syndrome (OSAS). To establish the proportion of OSAS patients with CPAP indication who use it in the long-term and to determine predictive factors of adherence. Structured survey through personal interview or phone call, applied to all patients who had polisomnographically documented OSAS and CPAP titration at the Pontificia Universidad Católica de Chile Sleep Disorders Center between January 1998 and November 2001. Patients were divided in "Permanent Users" (Group I) and "Non Users" (Group II). Of 440 patients that fulfilled inclusion criteria, 162 (32.8%) answered the survey. Seventy percent (114/162) of these patients had used CPAP and 86% (98/114) continued to use it at the time of the interview, with a mean follow-up of 12.3 months (Group I 60.5% of the interviewed population). Group II included 64 patients (39.5% of the interviewed patients). Among the latter, 25% (16/64) stopped using CPAP due to intolerance, 25% (16/64) could not use it because of economical restrictions, 20.5% (13/64) preferred other therapies and 29.5% (15/64) merely refused treatment. Predictors of long-term use of CPAP were number of respiratory events (p <0.01), hypersomnolence (p <0.01) and age (p =0.03). Approximately two thirds of patients with OSAS, with an indication for CPAP, continue to use this therapy in the long term in a Chilean population. This figure is similar to other reports from abroad. It is also possible to identify predictive factors for CPAP discontinuation in this population.


On testing for genetic association in case-control studies when population allele frequencies are known.
With the emergence of Biobanks alongside large-scale genome-wide association studies (GWAS) we will soon be in the enviable situation of obtaining precise estimates of population allele frequencies for SNPs which make up the panels in standard genotyping arrays, such as those produced from Illumina and Affymetrix. For disease association studies it is well known that for rare diseases with known population minor allele frequencies (pMAFs) a case-only design is most powerful. That is, for a fixed budget the optimal procedure is to genotype only cases (affecteds). In such tests experimenters look for a divergence from allele distribution in cases from that of the known population pMAF; in order to test the null hypothesis of no association between the disease status and the allele frequency. However, what has not been previously characterized is the utility of controls (known unaffecteds) when available. In this study we consider frequentist and Bayesian statistical methods for testing for SNP genotype association when population MAFs are known and when both cases and controls are available. We demonstrate that for rare diseases the most powerful frequentist design is, somewhat counterintuitively, to actively discard the controls even though they contain information on the association. In contrast we develop a Bayesian test which uses all available information (cases and controls) and appears to exhibit uniformaly greater power than all frequentist methods we considered.


Connectivity reveals relationship of brain areas for reward-guided learning and decision making in human and monkey frontal cortex.
Reward-guided decision-making depends on a network of brain regions. Among these are the orbitofrontal and the anterior cingulate cortex. However, it is difficult to ascertain if these areas constitute anatomical and functional unities, and how these areas correspond between monkeys and humans. To address these questions we looked at connectivity profiles of these areas using resting-state functional MRI in 38 humans and 25 macaque monkeys. We sought brain regions in the macaque that resembled 10 human areas identified with decision making and brain regions in the human that resembled six macaque areas identified with decision making. We also used diffusion-weighted MRI to delineate key human orbital and medial frontal brain regions. We identified 21 different regions, many of which could be linked to particular aspects of reward-guided learning, valuation, and decision making, and in many cases we identified areas in the macaque with similar coupling profiles.


A tephritid fly mimics the territorial displays of its jumping spider predators.
The tephritid fly Zonosemata vittigera (Coquillett) has a leg-like pattern on its wings and a wing-waving display that together mimic the agonistic territorial displays of jumping spiders (Salticidae). Zonosemata flies initiate this display when stalked by jumping spiders, causing the spiders to display back and retreat. Wing transplant experiments showed that both the wing pattern and wing-waving displays are necessary for effective mimicry: Zonosemata flies with transplanted house fly wings and house flies with transplanted Zonosemata wings were attacked by jumping spiders. Similar experiments showed that this mimicry does not protect Zonosemata against nonsalticid predators. This is a novel form of sign stimulus mimicry that may occur more generally.


Generation of three different fragments of bound C3 with purified factor I or serum. II. Location of binding sites in the C3 fragments for factors B and H, complement receptors, and bovine conglutinin.
The many different recognized functions of C3 are dependent upon the ability of the activated C3 molecule both to bind covalently to protein and carbohydrate surfaces and to provide binding sites for as many as eleven different proteins. The location of the binding sites for six of these different proteins (factors B and H, complement receptors CR(1), CR(2) and CR(3) and conglutinin) was examined in the naturally occurring C3-fragments generated by C3 activation (C3b) and degradation by Factor I (iC3b, C3c, C3d,g) and trypsin (C3d). Evidence was obtained for at least four distinct binding sites in C3 for these six different C3 ligands. One binding site for B was detectable only in C3b, whereas a second binding site for H and CR(1) was detectable in both C3b and iC3b. The affinity of the binding site for H and CR(1) was charge dependent and considerably reduced in iC3b as compared to C3b. H binding to iC3b-coated sheep erythrocytes (EC3bi) was measurable only in low ionic strength buffer (4 mS). The finding that C3c-coated microspheres bound to CR(1), indicated that this second binding site was still intact in the C3c fragment. However, H binding to C3c was not examined. A third binding site in C3 for CR(2) was exposed in the d region by factor I cleavage of C3b into iC3b, and the activity of this site was unaffected by the further I cleavage of iC3b into C3d,g. Removal of the 8,000-dalton C3g fragment from C3d,g with trypsin forming C3d, resulted in reduced CR2 activity. However, because saturating amounts of monoclonal anti-C3g did not block the CR(2)-binding activity of EC3d,g, it appears unlikely that the g region of C3d,g or iC3b forms a part of the CR(2)-binding site. In addition, detergent-solubilized EC3d (C3d-OR) inhibited the CR(2)-binding activity of EC3d,g. Monocytes and neutrophils, that had been previously thought to lack CR(2) because of their inability to form EC3d rosettes, did bind EC3d,g containing greater than 5 x 10(4) C3d,g molecules per E. The finding that monocyte and neutrophil rosettes with EC3d,g were inhibited by C3d-OR, suggested that these phagocytic cells might indeed express very low numbers of CR(2), and that these CR(2) were detectable with EC3d,g and not with EC3d because C3d,g had a higher affinity for CR2 than did C3d. A fourth C3 binding site for CR(3) and conglutinin (K) was restricted to the iC3b fragment. Because of simultaneous attachment of iC3b to phagocyte CR3 and CR(3), the characteristics of iC3b binding to CR3 could only be examined with phagocytes on which the CR(1) had been blocked with anti-CR(1). Inhibition studies with EDTA and N-acetyl-D-glucosamine demonstrated a requirement for both calcium cations and carbohydrate in the binding of EC3bi to CR3 and to K. However, CR(3) differed from K in that magnesium cations were required in addition to calcium for maximum CR(3) binding activity, and NADG produced less inhibition of CR(3) activity than of K activity.


Single-solute and bisolute sorption of phenol and trichloroethylene from aqueous solution onto modified montmorillonite and application of sorption models.
The single-solute and bisolute sorption behaviour of phenol and trichloroethylene, two organic compounds with different structures, onto cetyltrimethylammonium bromide (CTAB)-montmorillonite was studied. The monolayer Langmuir model (MLM) and empirical Freundlich model (EFM) were applied to the single-solute sorption of phenol or trichloroethylene from water onto monolayer or multilayer CTAB-montmorillonite. The parameters contained in the MLM and EFM were determined for each solute by fitting to the single-solute isotherm data, and subsequently utilized in binary sorption. The extended Langmuir model (ELM) coupled with the single-solute MLM and the ideal adsorbed solution theory (IAST) coupled with the single-solute EFM were used to predict the binary sorption of phenol and trichloroethylene onto CTAB-montmorillonite. It was found that the EFM was better than the MLM at describing single-solute sorption from water onto CTAB-montmorillonite, and the IAST was better than the ELM at describing the binary sorption from water onto CTAB-montmorillonite.


The synergistic effect of layered double hydroxides with other flame retardant additives for polymer nanocomposites: a critical review.
Layered double hydroxides (LDHs) are a new type of inorganic flame retardant additive for polymer nanocomposites. Although their unique structural properties and tunable chemical compositions make them highly promising, it has been noticed that on their own, LDHs can hardly fulfill all the requirements for commercial applications. In recent years, the application of LDHs together with other synergistic additives has been proposed as a new route for obtaining highly efficient flame retardant polymer nanocomposites. It is believed that the synergistic additives can overcome the shortcomings of LDHs. As great progress has been made in this field so far, we believe that a timely review is warranted. Thus, in this contribution, the synergistic effect of LDHs with other flame retardant additives including (1) phosphorus-containing compounds, (2) graphene and carbon compounds, (3) intumescent flame retardants, (4) magnesium hydroxide, (5) borate-containing compounds, and (6) some other flame retardant compounds will be critically reviewed. For each type of additive, the synergistic mechanism with LDHs, and their performance on both flame retardancy and thermal stability will be discussed. We believe that this work will inspire and guide researchers from a wide range of backgrounds and help to pave the way for major breakthroughs in both fundamental studies and industrial applications in this field.


Epidemic dispersion of HIV and HCV in a population of co-infected Romanian injecting drug users.
Co-infections with HIV and HCV are very frequent among people who inject drugs (PWID). However, very few studies comparatively reconstructed the transmission patterns of both viruses in the same population. We have recruited 117 co-infected PWID during a recent HIV outbreak in Romania. Phylogenetic analyses were performed on HIV and HCV sequences in order to characterize and compare transmission dynamics of the two viruses. Three large HIV clusters (2 subtype F1 and one CRF14_BG) and thirteen smaller HCV transmission networks (genotypes 1a, 1b, 3a, 4a and 4d) were identified. Eighty (65%) patients were both in HIV and HCV transmission chains and 70 of those shared the same HIV and HCV cluster with at least one other patient. Molecular clock analysis indicated that all identified HIV clusters originated around 2006, while the origin of the different HCV clusters ranged between 1980 (genotype 1b) and 2011 (genotypes 3a and 4d). HCV infection preceded HIV infection in 80.3% of cases. Coincidental transmission of HIV and HCV was estimated to be rather low (19.65%) and associated with an outbreak among PWID during detention in the same penitentiary. This study has reconstructed and compared the dispersion of these two viruses in a PWID population.


Biomarker qualification pilot process at the US Food and Drug Administration.
New biomarkers of safety and efficacy are becoming powerful tools in drug development. Their application can be accelerated if a consensus can be reached about their qualification for regulatory applications. This consensus requires a review structure within the US Food and Drug Administration (FDA) that can evaluate qualification data for these biomarkers and determine whether these biomarkers can be qualified. A pilot process and corresponding Biomarker Qualification Review Team have been developed to test how the FDA can work on biomarker qualification.


Predicting bird phenology from space: satellite-derived vegetation green-up signal uncovers spatial variation in phenological synchrony between birds and their environment.
Population-level studies of how tit species (Parus spp.) track the changing phenology of their caterpillar food source have provided a model system allowing inference into how populations can adjust to changing climates, but are often limited because they implicitly assume all individuals experience similar environments. Ecologists are increasingly using satellite-derived data to quantify aspects of animals' environments, but so far studies examining phenology have generally done so at large spatial scales. Considering the scale at which individuals experience their environment is likely to be key if we are to understand the ecological and evolutionary processes acting on reproductive phenology within populations. Here, we use time series of satellite images, with a resolution of 240 m, to quantify spatial variation in vegetation green-up for a 385-ha mixed-deciduous woodland. Using data spanning 13 years, we demonstrate that annual population-level measures of the timing of peak abundance of winter moth larvae (Operophtera brumata) and the timing of egg laying in great tits (Parus major) and blue tits (Cyanistes caeruleus) is related to satellite-derived spring vegetation phenology. We go on to show that timing of local vegetation green-up significantly explained individual differences in tit reproductive phenology within the population, and that the degree of synchrony between bird and vegetation phenology showed marked spatial variation across the woodland. Areas of high oak tree (Quercus robur) and hazel (Corylus avellana) density showed the strongest match between remote-sensed vegetation phenology and reproductive phenology in both species. Marked within-population variation in the extent to which phenology of different trophic levels match suggests that more attention should be given to small-scale processes when exploring the causes and consequences of phenological matching. We discuss how use of remotely sensed data to study within-population variation could broaden the scale and scope of studies exploring phenological synchrony between organisms and their environment.


Longitudinal assessment of endothelial function in the microvasculature of mice in-vivo.
Endothelial dysfunction is associated with early development of cardiovascular disease, making longitudinal measurements desirable. We devised a protocol using laser Doppler imaging (LDI) and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess the skin microcirculation longitudinally in mice every 4 weeks for 24 weeks in two groups of C57BL/6 mice, chow versus high-cholesterol diet(known to induce endothelial dysfunction). LDI measurements were compared with vascular function (isometric tension) measured using wire myography in the tail artery in response to ACh and SNP. Microvascular responses to ACh were significantly reduced in cholesterol-fed versus chow-fed mice from week 4 onwards (P<0.005, ANOVA). Pre-treatment with N(G)-nitro-L-arginine methyl-ester-hydrochloride (L-NAME) showed a significant reduction in ACh response compared with vehicle-treated animals (P<0.05) at baseline and at 12 weeks. In cholesterol-fed mice, ACh responses were 226 ± 21 and 180 ± 21 AU (P=0.03) before and after L-NAME, respectively. A reduction in ex-vivo ACh response was detected in the tail artery in cholesterol-fed mice, and a significant correlation found between peak microvascular ACh response and maximum ACh response in the tail artery (r=0.699, P=0.017). No changes were found in SNP responses in the microvasculature or tail artery. Using this protocol, we have shown longitudinal decreases in microvascular endothelial function to cholesterol feeding. L-NAME studies confirm that the reduced vasodilatation to ACh in cholesterol-fed mice was mediated partly through reduced NO bioavailability. Wire myography of tail arteries confirmed that in-vivo measurements of microvascular function reflect ex-vivo vascular function in other beds. Longitudinal assessments of skin microvascular function in mice could provide a useful translatable model for assessing early endothelial dysfunction.


Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome.
Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging. To evaluate relationships between TL, CVR and inflammation markers in CS. In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL. Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL. TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a "low" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.


More conflict does not trigger more adjustment of cognitive control for subsequent events: a study of the bivalency effect.
Encountering a conflict triggers an adjustment of cognitive control. This adjustment of cognitive control can even affect subsequent performance. The purpose of the present study was to determine whether more conflict triggers more adjustment of cognitive control for subsequent performance. To this end, we focussed on the bivalency effect, that is, the adjustment of cognitive control following the conflict induced by bivalent stimuli (i.e., stimuli with relevant features for two tasks). In two experiments, we tested whether the amount of conflict triggered by bivalent stimuli affected the bivalency effect. Bivalent stimuli were either compatible (i.e., affording one response) or incompatible (i.e., affording two different responses). Thus, compatible bivalent stimuli involved a task conflict, whereas incompatible bivalent stimuli involved a task and a response conflict. The results showed that the bivalency effect was not affected by this manipulation. This indicates that more conflict does not trigger more adjustment of cognitive control for subsequent performance. Therefore, only the occurrence of conflict--not its amount--is determinant for cognitive control.


Prenatal HIV testing in the US-Mexico border region, 2005: the Brownsville-Matamoros Sister City Project for Women's Health.
Routine prenatal human immunodeficiency virus (HIV) screening provides a critical opportunity to diagnose HIV infection, begin chronic care, and prevent mother-to-child transmission. However, little is known about the prevalence of prenatal HIV testing in the US-Mexico border region. We explored the correlation between prenatal HIV testing and sociodemographic, health behavior, and health exposure characteristics. The study sample consisted of women who delivered live infants in 2005 in hospitals with more than 100 deliveries per year and resided in Matamoros, Tamaulipas, Mexico (n = 489), or Cameron County, Texas (n = 458). We examined univariate and bivariate distributions of HIV testing in Matamoros and Cameron County and quantified the difference in odds of HIV testing by using logistic regression. The prevalence of prenatal HIV testing varied by place of residence--57.6% in Matamoros and 94.8% in Cameron County. Women in Cameron County were significantly more likely than those in Matamoros to be tested. Marital status, education, knowledge of methods to prevent HIV transmission (adult-to-adult), discussion of HIV screening with a health care professional during prenatal care, and previous HIV testing were significantly associated with prenatal HIV testing in Matamoros, although only the latter 2 variables were significant in Cameron County. Although national policies in both the United States and Mexico recommend prenatal testing for HIV, a greater proportion of women in Cameron County were tested, compared with women in Matamoros. Efforts between Matamoros and Cameron County to improve HIV testing during pregnancy in the border region should consider correlates for testing in each community.


Dietary magnesium intake improves insulin resistance among non-diabetic individuals with metabolic syndrome participating in a dietary trial.
Many cross-sectional studies show an inverse association between dietary magnesium and insulin resistance, but few longitudinal studies examine the ability to meet the Recommended Dietary Allowance (RDA) for magnesium intake through food and its effect on insulin resistance among participants with metabolic syndrome (MetS). The dietary intervention study examined this question in 234 individuals with MetS. Magnesium intake was assessed using 24-h dietary recalls at baseline, 6, and 12 months. Fasting glucose and insulin levels were collected at each time point; and insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The relation between magnesium intake and HOMA-IR was assessed using linear mixed models adjusted for covariates. Baseline magnesium intake was 287 ± 93 mg/day (mean ± standard deviation), and HOMA-IR, fasting glucose and fasting insulin were 3.7 ± 3.5, 99 ± 13 mg/dL, and 15 ± 13 μU/mL, respectively. At baseline, 6-, and 12-months, 23.5%, 30.4%, and 27.7% met the RDA for magnesium. After multivariate adjustment, magnesium intake was inversely associated with metabolic biomarkers of insulin resistance (P < 0.01). Further, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower [odds ratio (OR): 0.29; 95% confidence interval (CI): 0.12, 0.72] in participants in the highest quartile of magnesium intake than those in the lowest quartile. For individuals meeting the RDA for magnesium, the multivariate-adjusted OR for high HOMA-IR over time was 0.37 (95% CI: 0.18, 0.77). These findings indicate that dietary magnesium intake is inadequate among non-diabetic individuals with MetS and suggest that increasing dietary magnesium to meet the RDA has a protective effect on insulin resistance.


The ecology of primate material culture.
Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The 'method of exclusion' has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture.


Under What Conditions Can Recursion Be Learned? Effects of Starting Small in Artificial Grammar Learning of Center-Embedded Structure.
It has been suggested that external and/or internal limitations paradoxically may lead to superior learning, that is, the concepts of starting small and less is more (Elman, ; Newport, ). In this paper, we explore the type of incremental ordering during training that might help learning, and what mechanism explains this facilitation. We report four artificial grammar learning experiments with human participants. In Experiments 1a and 1b we found a beneficial effect of starting small using two types of simple recursive grammars: right-branching and center-embedding, with recursive embedded clauses in fixed positions and fixed length. This effect was replicated in Experiment 2 (N = 100). In Experiment 3 and 4, we used a more complex center-embedded grammar with recursive loops in variable positions, producing strings of variable length. When participants were presented an incremental ordering of training stimuli, as in natural language, they were better able to generalize their knowledge of simple units to more complex units when the training input "grew" according to structural complexity, compared to when it "grew" according to string length. Overall, the results suggest that starting small confers an advantage for learning complex center-embedded structures when the input is organized according to structural complexity.


Stereotyping of medical disability claimants' communication behaviour by physicians: towards more focused education for social insurance physicians.
Physicians who hold medical disability assessment interviews (social insurance physicians) are probably influenced by stereotypes of claimants, especially because they have limited time available and they have to make complicated decisions. Because little is known about the influences of stereotyping on assessment interviews, the objectives of this paper were to qualitatively investigate: (1) the content of stereotypes used to classify claimants with regard to the way in which they communicate; (2) the origins of such stereotypes; (3) the advantages and disadvantages of stereotyping in assessment interviews; and (4) how social insurance physicians minimise the undesirable influences of negative stereotyping. Data were collected during three focus group meetings with social insurance physicians who hold medical disability assessment interviews with sick-listed employees (i.e. claimants). The participants also completed a questionnaire about demographic characteristics. The data were qualitatively analysed in Atlas.ti in four steps, according to the grounded theory and the principle of constant comparison. A total of 22 social insurance physicians participated. Based on their responses, a claimant's communication was classified with regard to the degree of respect and acceptance in the physician-claimant relationship, and the degree of dominance. Most of the social insurance physicians reported that they classify claimants in general groups, and use these classifications to adapt their own communication behaviour. Moreover, the social insurance physicians revealed that their stereotypes originate from information in the claimants' files and first impressions. The main advantages of stereotyping were that this provides a framework for the assessment interview, it can save time, and it is interesting to check whether the stereotype is correct. Disadvantages of stereotyping were that the stereotypes often prove incorrect, they do not give the complete picture, and the claimant's behaviour changes constantly. Social insurance physicians try to minimise the undesirable influences of stereotypes by being aware of counter transference, making formal assessments, staying neutral to the best of their ability, and being compassionate. We concluded that social insurance physicians adapt their communication style to the degree of respect and dominance of claimants in the physician-claimant relationship, but they try to minimise the undesirable influences of stereotypes in assessment interviews. It is recommended that this issue should be addressed in communication skills training.


Aggression, social cognitions, anger and sadness in bullies and victims.
The present study aimed to investigate children's social information processing (SIP) and emotions in the bullying situation, taking into account reactive and proactive aggression. More specifically, we investigated the way in which children interpret social information, which goals they select, how they evaluate their responses and which emotions they express in hypothetical situations. The participants comprised 242 Dutch children (120 girls and 122 boys; mean age: 117.2 months), who were assigned by means of peer nominations (Salmivalli, Lagerspetz, et al., 1996) to one of the following roles: bully (n=21), follower of the bully (n=38), victim (n=35), defender of the victim (n=48), outsider (n=52) and not involved (n=32). Sixteen children (including 3 bully/victims) were not given any role. The reactive and proactive aggression scale (Dodge, & Coie, 1987) was filled out by teachers in order to test the association between these types of aggression and involvement in bullying. Children were presented with ambiguous scenarios and responded to questions about attribution of intent, goal selection and emotions (anger and sadness). In addition, two questionnaires were administered to children: one assessed perceived self-efficacy in performing aggression, inhibiting aggression and using verbal persuasion skills, and the other assessed expected outcomes from behaving aggressively or prosocially. Results showed that while reactive aggression was common in bullies and victims, proactive aggression was only characteristic of bullies. Both bullies and victims, compared to the other children, scored higher on hostile interpretation, anger, retaliation and ease of aggression. Bullies and followers claimed that it was easy for them to use verbal persuasion, while victims turned out to be the saddest group. All children, irrespective of their role in the peer group, thought that aggressive as well as prosocial behavior was more likely to produce desired results from a friendly peer than from an aggressive one. Bullies and victims seem to be similar in reactive aggression, SIP, and in the expression of anger, but the motivations which lead to their behavior may be different, as well as the final outcomes of their acts.


Melanosome-autonomous regulation of size and number: the OA1 receptor sustains PMEL expression.
Little is known as to how cells ensure that organelle size and number are coordinated to correctly couple organelle biogenesis to the demands of proliferation or differentiation. OA1 is a melanosome-associated G-protein-coupled receptor involved in melanosome biogenesis during melanocyte differentiation. Cells lacking OA1 contain fewer, but larger, mature melanosomes. Here, we show that OA1 loss of function reduces both the basal expression and the α-melanocyte-stimulating hormone/cAMP-dependent induction of the microphthalmia-associated transcription factor (MITF), the master regulator of melanocyte differentiation. In turn, this leads to a significant reduction in expression of PMEL, a major melanosomal structural protein, but does not affect tyrosinase and melanin levels. In line with its pivotal role in sensing melanosome maturation, OA1 expression rescues melanosome biogenesis, activates MITF expression and thereby coordinates melanosome size and number, providing a quality control mechanism for the organelle in which resides. Thus, resident sensor receptors can activate a transcriptional cascade to specifically promote organelle biogenesis.


Workforce projections for hepato-pancreato-biliary surgery.
We wanted to determine whether current levels of fellowship training in hepato-pancreato-biliary (HPB) surgery will be sufficient to meet demand for HPB procedures in 2020. The Nationwide Inpatient Sample database for 1988 through 2003 was used to construct projections for the number of HPB procedures that will be performed in the US each year through 2020. Available workforce literature was also used to generate estimates of current and future supply of HPB subspecialists. These demand and supply estimates were then used to construct sensitivity analyses of the mean number of HPB procedures per subspecialist in 2020, depending on the degree of regionalization that exists and the number of fellowship-trained subspecialists needed to train each year to meet projected demand for HPB procedures in 2020. An estimated 16,800 HPB procedures will be performed in 2020, representing a 25% increase during the next 15 years. We estimate that 28 fellowship-trained HPB subspecialists will enter the workforce each year. If half of all HPB procedures are performed by HPB subspecialists in 2020, then the average subspecialist will perform only 14 such procedures that year. If high-volume HPB surgery is defined as 40 procedures per year, and 50% of HPB procedures are performed by high-volume surgeons in 2020, then only 15 fellows need to be trained in HPB surgery each year to meet demand in 2020. Current levels of fellowship training will result in an excess of HPB subspecialists in 2020.


Risk factors for, and prevention of, shoulder injuries in overhead sports: a systematic review with best-evidence synthesis.
To assess the evidence for risk factors and prevention measures for shoulder injuries in overhead sports. Systematic review with best-evidence synthesis. Medline (Ovid), PubMed (complementary search), Embase (Elsevier), Cochrane (Wiley), SPORTDiscus (Ebsco) and Web of Science Core Collection (Thomson Reuters), from 1 January 1990 to 15 May 2017. Randomised controlled trials, cohort studies and case-control studies on risk factors or prevention measures for shoulder injuries in overhead sports. The eligible studies were quality assessed using the Scottish Intercollegiate Guidelines Network criteria. Of 4778 studies identified, 38 were eligible for quality review and 17 met the quality criteria to be included in the evidence synthesis. One additional quality study presented a shoulder injury prevention programme. Most studies focused on baseball, lacrosse or volleyball (n=13). The risk factors examined included participation level (competition vs training) (n=10), sex (n=4), biomechanics (n=2) and external workload (n=2). The evidence for all risk factors was limited or conflicting. The effect of the prevention programme within the subgroup of uninjured players at baseline was modest and possibly lacked statistical power. All investigated potential risk factors for shoulder injury in overhead sports had limited evidence, and most were non-modifiable (eg, sex). There is also limited evidence for the effect of shoulder injury prevention measures in overhead sports. CRD42015026850.


Collective genius.
How can leaders build an organization that is capable of innovating continually over time? By creating a community that is both willing and able to innovate. To be willing, the community must share a sense of purpose, values, and rules of engagement. When Luca de Meo was Volkswagen's head of marketing communication, he fostered a sense of purpose in his team by asking its members to reflect on what being part of VW meant to them; strengthened their shared values by encouraging them to use the brand's three components-innovation, responsibility, and value-to guide their work; and built significant responsibility and autonomy into their rules of engagement. To be able, companies must generate ideas through discourse and debate; experiment quickly, reflect, and adjust; and make decisions that combine disparate and even opposing ideas. Bill Coughran, an SVP of engineering at Google, employed these capabilities both to solve the company's near-term data storage needs and to make progress toward a next-generation solution.


Mechanical recovery of dentin following remineralization in vitro--an indentation study.
This study sought to gain insights into the steps leading to remineralization and mechanical recovery of hydrated dentin. Mechanical recovery in water was hypothesized to result from effective mineral matrix binding and to occur from the innermost regions outwards due to an increase in the number of nucleation sites. Partially demineralized (0.05 M acetate, pH=5.0, 8h) dentin was remineralized using calcium and phosphate solutions of 10.1 or 9.8 degree of saturation (DS) for hydroxyapatite (pH=7.4) for 4, 8 or 24h. Remineralization used a constant solution composition approach, which allowed for a continuous mineral growth with relatively constant thermodynamic driving forces. Crystal growth rates (R) were calculated using concentrations of calcium and phosphate. Before and after de- and re-mineralization, specimens had their surface and cross-section elastic moduli measured using AFM-nanoindentation in water. DS=10.1 provided higher R and higher mechanical recovery at the surface (p<0.0001). Cross-sectional measurements showed that subsurface mechanical recovery occurred from the innermost demineralized areas gradually outwards for both groups with no statistical differences at different DS, thus suggesting that remineralization is driven by mineral growth within nucleation sites with preserved collagen fibrils. Further, mechanical recovery appeared to initially obey a heterogeneous pattern, which vanished with time. This study provides evidence of mechanical recovery of hydrated dentin after remineralization and novel insights into the steps leading to mechanical recovery of carious dentin.


Holographic dual of an Einstein-Podolsky-Rosen pair has a wormhole.
We construct the holographic dual of two colored quasiparticles in maximally supersymmetric Yang-Mills theory entangled in a color singlet Einstein-Podolsky-Rosen (EPR) pair. In the holographic dual, the entanglement is encoded in a geometry of a nontraversable wormhole on the world sheet of the flux tube connecting the pair. This gives a simple example supporting the recent claim by Maldacena and Susskind that EPR pairs and nontraversable wormholes are equivalent descriptions of the same physics.


Wilms' tumor with intravascular extension: A review article.
Intravascular extension of Wilms' tumor is a well-recognized phenomenon. Intravascular extension into the vena cava occurs in only 4-8% of patients with Wilms' tumors and intraatrial extension occurs in around 1-3% of patients. This review of the published literature in this cohort aims to summarize the findings of different case series to provide an optimum management plan. A literature search was performed and index papers were retrieved for review. The search included the following terms: Intracaval, intravascular, intraatrial and intracardiac extension of Wilms' tumor or nephroblastoma. The management of patients with intravascular tumor thrombus in Wilms' tumor is complex. A skilled multi-disciplinary team at a tertiary referral center with cardiothoracic surgery available should manage these patients. Multi-modal diagnostic and preoperative imaging are required to confirm and define the extent of the extension. Preoperative chemotherapy is advocated for all but exceptional circumstances and must be followed closely. Surgical resection should be planned according to the stage of intravascular extension with possible need for cardiopulmonary bypass and deep hypothermia with cardiac arrest if required. Surgical complications are more common in this group of patients, but outcome is comparable to those without intravascular extension, and is more closely correlated with the histological subtype then stage of intravascular extension. Operative imaging are required to confirm and define the extent of the extension.


Anticipating the future: prognostic tools as a complementary strategy to improve care for patients with febrile illnesses in resource-limited settings.
In low-income and middle-income countries, most patients with febrile illnesses present to peripheral levels of the health system where diagnostic capacity is very limited. In these contexts, accurate risk stratification can be particularly impactful, helping to guide allocation of scarce resources to ensure timely and tailored care. However, reporting of prognostic research is often imprecise and few prognostic tests or algorithms are translated into clinical practice.Here, we review the often-conflated concepts of prognosis and diagnosis, with a focus on patients with febrile illnesses. Drawing on a recent global stakeholder consultation, we apply these concepts to propose three use-cases for prognostic tools in the management of febrile illnesses in resource-limited settings: (1) guiding referrals from the community to higher-level care; (2) informing resource allocation for patients admitted to hospital and (3) identifying patients who may benefit from closer follow-up post-hospital discharge. We explore the practical implications for new technologies and reflect on the challenges and knowledge gaps that must be addressed before this approach could be incorporated into routine care settings.Our intention is that these use-cases, alongside other recent initiatives, will help to promote a harmonised yet contextualised approach for prognostic research in febrile illness. We argue that this is especially important given the heterogeneous settings in which care is often provided for patients with febrile illnesses living in low-income and middle-income countries.


Pharmacokinetics and pharmacodynamics of intravenous acetaminophen in neonates.
Effective analgesia in neonates is still hampered owing to a lack of data on pharmacokinetics and pharmacodynamics of analgesics. In this article, the consecutive steps taken to document aspects of disposition (pharmacokinetics and metabolism) and safety (hepatic tolerance, hemodynamic stability and effects on body temperature) during exposure to intravenous acetaminophen in neonates are summarized. Based on these data, dosing suggestions were formulated. However, we have to be aware that such dosing suggestions are - at present - without any validated pharmacodynamic correlates since the applicability of a fixed acetaminophen target concentration (10 mg·l(-1)) in neonates of different subpopulations remains to be documented. In addition, the number of observations in extreme preterm neonates is limited. Finally, epidemiological data suggest a link between perinatal acetaminophen exposure and an increased risk to developing asthma. Consequently, well designed and appropriately powered pharmacodynamic studies in neonates are urgently required, with specific emphasis on extreme preterm neonates.


First evaluation of the possibility of testing for drugged driving using exhaled breath sampling.
Objective: Driving under the influence of psychoactive drugs causes an increased risk for accidents. In combating this, sobriety tests at the roadside are common practice in most countries. Sampling of blood and urine for forensic investigation cannot be done at the roadside and poses practical problems associated with costs and time. An alternative specimen for roadside testing is therefore warranted and the aerosol particles in exhaled breath are one such alternative. Methods: The present study investigated how the exhaled breath sample compared with the routine legal investigations of blood and urine collected from suspects of drugged driving at 2 locations in Sweden. Exhaled breath was collected using a simple filter collection device and analyzed with state-of-the-art mass spectrometry technique. Results: The total number of cases used for this investigation was 67. In 54 of these cases (81%) the results regarding a positive or negative drug test result agreed and in 13 they disagreed. Out of these, the report from the forensic investigation of blood/urine was negative in 21 cases. In 6 of these, analytical findings were made in exhaled breath and these cases were dominated by the detection of amphetamine. In 7 cases a positive drug test from the forensic investigation was not observed in the breath sample and these cases were dominated by detection of tetrahydrocannabinol in blood. In total, 45 samples were positive with breath testing and the number of positives with established forensic methods was 46. Conclusion: The promising results from this study provide support to exhaled breath as a viable specimen for testing of drugged driving. The rapid, easy, and convenient sampling procedure offers the possibility to collect a drug test specimen at the roadside. The analytical investigation must be done in a laboratory at present because of the need for a highly sensitive instrument, which is already in use in forensic laboratories. The analytical work is not more challenging than for blood or oral fluid and should not cause an increase in cost. However, more studies need to be done before exhaled breath drug testing can be applied routinely for drugged driving investigation.


Interresponse-time punishment: a basis for shock-maintained behavior.
Lever pressing of squirrel monkeys postponed brief electric shock according to a free-operant shock-postponement procedure. Pressing also produced shock with a probability proportional to the duration of the current interresponse time in some conditions, or to the fifth ordinally-preceding interresponse time in others. These conditions provided equal frequencies and temporal distributions of response-produced shocks either contingent on or independent of the current interresponse-time duration, respectively. Shock delivered contingent on the current interresponse-time duration resulted in shorter mean interresponse times and higher overall response rates that shock delivered independent of the current interresponse time. In subsequent conditions, response-produced shocks were sufficient to maintain responding following suspension of the postponement procedure only when those shocks were contingent on the current interresponse time. Presenting shock independent of the current interresponse time, conversely, suppressed response rate and ultimately led to cessation of responding in the absence of a conjoint shock-postponement procedure. These results demonstrate interresponse-time punishment in the absence of any indirect avoidance contingencies based on overall shock-frequency reduction, and strongly support similar interpretation at the more local level of shock-frequency reduction correlated with particular interresponse times. Differential punishment of long interresponse times also provides both an a priori basis for predicting whether a schedule of shock presentation will maintain or suppress responding and a framework for interpreting many of the functional relations between overall response rate and parameters of consequent shock presentation. Finally, these results and others indicate the importance of response-consequence contiguity above and beyong any notion of noncontiguous contingency in the control of behavior.


Complementary and alternative medical therapies in multiple sclerosis--the American Academy of Neurology guidelines: a commentary.
Complementary and alternative medicine (CAM) use in individuals with multiple sclerosis (MS) is common, but its use has been limited by a lack of evidence-based guidance. In March 2014, the American Academy of Neurology published the most comprehensive literature review and evidence-based practice guidelines for CAM use in MS. The guideline author panel reviewed and classified articles according to the American Academy of Neurology therapeutic scheme, and recommendations were linked to the evidence strength. Level A recommendations were found for oral cannabis extract effectiveness in the short term for spasticity-related symptoms and pain and ineffectiveness of ginkgo biloba for cognitive function improvement in MS. Key level B recommendations included: Oral cannabis extract or a synthetic cannabis constituent, tetrahydrocannabinol (THC) is probably ineffective for objective spasticity improvement in the short term; Nabiximols oromucosal cannabinoid spray is probably effective for spasticity symptoms, pain, and urinary frequency, but probably ineffective for objective spasticity outcomes and bladder incontinence; Magnetic therapy is probably effective for fatigue reduction in MS; A low-fat diet with fish oil supplementation is probably ineffective for MS-related relapses, disability, fatigue, magnetic resonance imaging lesions, and quality of life. Several Level C recommendations were made. These included possible effectiveness of gingko biloba for fatigue; possible effectiveness of reflexology for MS-related paresthesias; possible ineffectiveness of the Cari Loder regimen for MS-related disability, symptoms, depression, and fatigue; and bee sting therapy for MS relapses, disability, fatigue, magnetic resonance imaging outcomes, and health-related quality of life. Despite the availability of studies evaluating the effects of oral cannabis in MS, the use of these formulations in United States may be limited due to a lack of standardized, commercial US Food and Drug Administration-regulated preparations. Additionally, significant concern about prominent central nervous system-related adverse effects with cannabis was emphasized in the review.


Early expression of bcl-2 protein in the adenoma-carcinoma sequence of colorectal neoplasia.
bcl-2 was originally identified as an oncogene involved in follicular lymphomas as a result of chromosomal translocation (14;18). It is now believed that bcl-2 is implicated in the regulation of cell death by inhibiting apoptosis and that its expression is not restricted to haematopoietic cells, but is also present in many epithelial and mesenchymal tissues. Recent studies have analysed the expression of this molecule in a variety of non-lymphoid malignancies including lung, breast, prostate, and nasopharyngeal carcinomas and neuroblastoma. In the present study, 50 colorectal adenomas, 10 hyperplastic polyps, and 142 carcinomas, including 25 arising from pre-existing adenomas, were examined using an antibody detecting the bcl-2 protein product. In non-neoplastic mucosa, bcl-2 was expressed in the crypt cells only, whilst the more differentiated surface epithelial cells lacked any demonstrable bcl-2. Forty-one of the 50 adenomas (82 per cent) and 48 of the 142 carcinomas were positive for bcl-2 expression. All hyperplastic polyps were negative. A reciprocal relationship was found between bcl-2 reactivity and p53 overexpression, as detected by DO7 antibody, in approximately 65 per cent of the cases. The bcl-2-positive/p53-negative subgroup showed a strong correlation (P = 0.0056) with negative lymph node status (Dukes' A and B), implying a less aggressive pathway of neoplastic transformation.


Possible role of oxygen radicals in cell transformation by diethylstilbestrol and related compounds.
Diethylstilbestrol (DES) and four derivatives, viz. tetrafluoro-DES, 3'-hydroxy-DES, Z,Z-dienestrol and hexestrol, were examined for their abilities to form superoxide radicals and to induce DNA strand breaks in the presence of horseradish peroxidase/hydrogen peroxide metabolism in a cell-free system. Furthermore, the induction of strand breaks by these compounds was tested in Syrian hamster embryo (SHE) cells in vitro. Formation of superoxide radicals could be demonstrated by reduction of nitro blue tetrazolium for DES but not for its derivatives. With isolated superhelical DNA, induction of strand breaks in the presence of Fe3+ was observed for DES, tetrafluoro-DES and 3'-hydroxy-DES, while hexestrol and Z,Z-dienestrol were ineffective. In SHE cells, alkaline elution technique showed that DNA strand breaks were induced by DES and all derivatives tested, although only at cytotoxic concentrations. It is concluded that DES, under conditions of peroxidative metabolism, can give rise to superoxide generation and DNA strand breaks, and that these events may play a role in the process of DES-induced cell transformation.


Coronavirus Disease Model to Inform Transmission-Reducing Measures and Health System Preparedness, Australia.
The ability of health systems to cope with coronavirus disease (COVID-19) cases is of major concern. In preparation, we used clinical pathway models to estimate healthcare requirements for COVID-19 patients in the context of broader public health measures in Australia. An age- and risk-stratified transmission model of COVID-19 demonstrated that an unmitigated epidemic would dramatically exceed the capacity of the health system of Australia over a prolonged period. Case isolation and contact quarantine alone are insufficient to constrain healthcare needs within feasible levels of expansion of health sector capacity. Overlaid social restrictions must be applied over the course of the epidemic to ensure systems do not become overwhelmed and essential health sector functions, including care of COVID-19 patients, can be maintained. Attention to the full pathway of clinical care is needed, along with ongoing strengthening of capacity.


Structures of the stator complex that drives rotation of the bacterial flagellum.
The bacterial flagellum is the prototypical protein nanomachine and comprises a rotating helical propeller attached to a membrane-embedded motor complex. The motor consists of a central rotor surrounded by stator units that couple ion flow across the cytoplasmic membrane to generate torque. Here, we present the structures of the stator complexes from Clostridium sporogenes, Bacillus subtilis and Vibrio mimicus, allowing interpretation of the extensive body of data on stator mechanism. The structures reveal an unexpected asymmetric A5B2 subunit assembly where the five A subunits enclose the two B subunits. Comparison to structures of other ion-driven motors indicates that this A5B2 architecture is fundamental to bacterial systems that couple energy from ion flow to generate mechanical work at a distance and suggests that such events involve rotation in the motor structures.


Unsatisfactory outcomes following unicompartmental knee arthroplasty in patients with partial thickness cartilage loss: a medium-term follow-up.
While medial unicompartmental knee arthroplasty (UKA) is indicated for patients with full-thickness cartilage loss, it is occasionally used to treat those with partial-thickness loss. The aim of this study was to investigate the five-year outcomes in a consecutive series of UKAs used in patients with partial thickness cartilage loss in the medial compartment of the knee. Between 2002 and 2014, 94 consecutive UKAs were undertaken in 90 patients with partial thickness cartilage loss and followed up independently for a mean of six years (1 to 13). These patients had partial thickness cartilage loss either on both femur and tibia (13 knees), or on either the femur or the tibia, with full thickness loss on the other surface of the joint (18 and 63 knees respectively). Using propensity score analysis, these patients were matched 1:2 based on age, gender and pre-operative Oxford Knee Score (OKS) with knees with full thickness loss on both the femur and tibia. The functional outcomes, implant survival and incidence of re-operations were assessed at one, two and five years post-operatively. A subgroup of 36 knees in 36 patients with partial thickness cartilage loss, who had pre-operative MRI scans, was assessed to identify whether there were any factors identified on MRI that predicted the outcome. Knees with partial thickness cartilage loss had significantly worse functional outcomes at one, two and five years post-operatively compared with those with full thickness loss. A quarter of knees with partial thickness loss had a fair or poor result and a fifth failed to achieve a clinically significant improvement in OKS from a baseline of four points or more; double that seen in knees with full thickness loss. Whilst there was no difference in implant survival between the groups, the rate of re-operation in knees with partial thickness loss was three times higher. Most of the re-operations (three-quarters), were arthroscopies for persistent pain. Compared with those achieving good or excellent outcomes, patients with partial thickness cartilage loss who achieved fair or poor outcomes were younger and had worse pre-operative functional scores. However, there were no other differences in the baseline demographics. MRI findings of full thickness cartilage loss, subchondral oedema, synovitis or effusion did not provide additional prognostic information. Medial UKA should be reserved for patients with full thickness cartilage loss on both the femur and tibia. Whilst some patients with partial thickness loss achieve a good result we cannot currently identify which these will be and in this situation MRI is unhelpful and misleading. Cite this article: Bone Joint J 2017;99-B:475-82.


Violence to Others, Violent Self-Victimization, and Violent Victimization by Others Among Persons With a Mental Illness.
This research examined the frequency of and characteristics associated with three forms of violence among persons with mental illness-violence directed at others, self-directed violence, and violence directed at them by others. Previously unreported data from a follow-up sample of 951 patients from the MacArthur Violence Risk Assessment Study were analyzed to characterize involvement in violence directed at others, self-directed violence, and violence directed at them by others. Most patients (58%) experienced at least one form of violence, 28% experienced at least two forms, and 7% experienced all three forms. Several diagnostic, social, and historical variables distinguished the groups. Given the substantial overlap among the three forms of violence, clinicians should routinely screen patients who report one form for the occurrence of the other two. Co-occurrence of several forms of violence may require a package of interventions with components geared to each.


Foliar Nutritional Quality Explains Patchy Browsing Damage Caused by an Invasive Mammal.
Introduced herbivores frequently inflict significant, yet patchy damage on native ecosystems through selective browsing. However, there are few instances where the underlying cause of this patchy damage has been revealed. We aimed to determine if the nutritional quality of foliage could predict the browsing preferences of an invasive mammalian herbivore, the common brushtail possum (Trichosurus vulpecula), in a temperate forest in New Zealand. We quantified the spatial and temporal variation in four key aspects of the foliar chemistry (total nitrogen, available nitrogen, in vitro dry matter digestibility and tannin effect) of 275 trees representing five native tree species. Simultaneously, we assessed the severity of browsing damage caused by possums on those trees in order to relate selective browsing to foliar nutritional quality. We found significant spatial and temporal variation in nutritional quality among individuals of each tree species examined, as well as among tree species. There was a positive relationship between the available nitrogen concentration of foliage (a measure of in vitro digestible protein) and the severity of damage caused by browsing by possums. This study highlights the importance of nutritional quality, specifically, the foliar available nitrogen concentration of individual trees, in predicting the impact of an invasive mammal. Revealing the underlying cause of patchy browsing by an invasive mammal provides new insights for conservation of native forests and targeted control of invasive herbivores in forest ecosystems.


Population similarity of enterococci and Escherichia coil in surface waters: A predictive tool to trace the sources of fecal contamination.
A biochemical fingerprinting method (the PhPlate system) was used to compare similarities between Escherichia coli and enterococci populations from surface water samples with those found in different animal species during the wet and the dry seasons in order to predict the dominant source(s) of fecal contamination in a local creek. A significant increase in the number and diversity of enterococci was observed in the creek during the wet season. Enterococci population from water samples also showed a higher population similarity with animal species than did E. coli. A higher population similarity was found between both indicator bacteria and animal species during the wet season with highest population similarities found in dogs, horses, cows and kangaroos. In contrast, a low population similarity was found for both fecal indicator bacteria from humans with water samples during the wet and the dry seasons, indicating that humans are not a major source of contamination in the studied creek. The results also indicate that the population similarity analysis of enterococci population has an advantage over E. coli in tracing the possible source(s) of contamination in the studied creek and that population similarity analysis as used in this study can be used to predict the source(s) of fecal contamination in surface waters.


Neutrino emission from the direction of the blazar TXS 0506+056 prior to the IceCube-170922A alert.
A high-energy neutrino event detected by IceCube on 22 September 2017 was coincident in direction and time with a gamma-ray flare from the blazar TXS 0506+056. Prompted by this association, we investigated 9.5 years of IceCube neutrino observations to search for excess emission at the position of the blazar. We found an excess of high-energy neutrino events, with respect to atmospheric backgrounds, at that position between September 2014 and March 2015. Allowing for time-variable flux, this constitutes 3.5σ evidence for neutrino emission from the direction of TXS 0506+056, independent of and prior to the 2017 flaring episode. This suggests that blazars are identifiable sources of the high-energy astrophysical neutrino flux.