Predator identity influences the effect of habitat management on nest predation.
Predation is the leading cause of nest failure for many passerines and considerable effort is devoted to identifying the habitat characteristics and management practices that influence nest loss. The habitat components associated with nest loss are strongly influenced by the ecology of nest predators and differ among predator species as a result. Nevertheless, there is a tendency to generalize about the effects of habitat features and management on nest failure without considering how resulting patterns are influenced by nest predators. We examined how predator-specific patterns of nest loss differed among predators and in response to grassland management with fire and grazing by cattle (Bos taurus). We used video cameras to monitor and identify predators at nests of the Grasshopper Sparrow (Ammodramus savannarum), a species of conservation concern throughout its range. We observed predation by 15 different species that differed in their response to management and the habitat characteristics associated with nests they preyed on. Losses to mammals and snakes were more likely at nests with greater amounts of litter cover and tall fescue (Schedonorus phoenix). Mammals were less likely to prey on nests surrounded by greater forb cover. Nest predation by snakes was lower in burned areas, whereas predation by mammals and Brown-headed Cowbirds (Molothrus ater) was unaffected by the use of fire. Neither vegetation density at the nest, nor landscape context was related to nest loss by any predator taxon. Although there were many similarities, we identified important differences in the species composing the nest predator community between our. study and other published research. These differences are likely to be responsible for geographic variation in the influence of habitat features and management actions on nest success. Our results demonstrate the need for natural resource managers to incorporate knowledge of local nest predators and their ecology when developing management prescriptions aimed at enhancing the reproductive success of songbirds.


Branchial osteogenetic neoplasm in barbel Barbus barbus plebejus.
A branchial osteogenetic neoplasm affecting a barbel Barbus barbus plebejus (Valenciennes, 1829) is described. The osteoblasts' pleomorphism, the lack of a well-developed and complete separation, the presence of eccentric, terminal proliferative edges infiltrating the lining tissues and the abundant tumour matrix suggest a histopathological diagnosis of a 'productive osteoblastic osteosarcoma'. The occurrence of eosinophilic granule cells (EGCs) scattered among neoplastic tissue is discussed in relation to the neoplastic growth and the inflammatory reaction, with reference to recent discoveries in mammalian mast cell biology.


Bruising on ostrich carcasses and the implications on the microbiology and losses in utilizable meat when removing them post-evisceration or post-chilling.
Bruising on ostrich carcasses reduces meat yield. These bruises are usually removed as part of the primary meat inspection, performed directly after evisceration. Three separate studies were conducted to determine the advantages and disadvantages of removing the bruises at primary meat inspection or after overnight cooling of the ostrich carcasses (0-4 degrees C). The bruised areas were also investigated to determine their frequency and distribution and to establish the most obvious causes and possible preventative measures. The neck bruises represented 52.58% of all bruises; the high side railings of the transport vehicles being the most probable cause. Large and multiple bruising were probably from the trampling of birds lying down. It was established that trimming bruises on warm carcasses caused higher total aerobic viable counts on the trimmed surfaces than cold trimming. Cold trimming together with better management of trimming practices also led to a decrease in meat yield losses.


Quantitative and functional characterization of the hyper-conserved protein of Prochlorococcus and marine Synechococcus.
A large fraction of any bacterial genome consists of hypothetical protein-coding open reading frames (ORFs). While most of these ORFs are present only in one or a few sequenced genomes, a few are conserved, often across large phylogenetic distances. Such conservation provides clues to likely uncharacterized cellular functions that need to be elucidated. Marine cyanobacteria from the Prochlorococcus/marine Synechococcus clade are dominant bacteria in oceanic waters and are significant contributors to global primary production. A Hyper Conserved Protein (PSHCP) of unknown function is 100% conserved at the amino acid level in genomes of Prochlorococcus/marine Synechococcus, but lacks homologs outside of this clade. In this study we investigated Prochlorococcus marinus strains MED4 and MIT 9313 and Synechococcus sp. strain WH 8102 for the transcription of the PSHCP gene using RT-Q-PCR, for the presence of the protein product through quantitative immunoblotting, and for the protein's binding partners in a pull down assay. Significant transcription of the gene was detected in all strains. The PSHCP protein content varied between 8±1 fmol and 26±9 fmol per ug total protein, depending on the strain. The 50 S ribosomal protein L2, the Photosystem I protein PsaD and the Ycf48-like protein were found associated with the PSHCP protein in all strains and not appreciably or at all in control experiments. We hypothesize that PSHCP is a protein associated with the ribosome, and is possibly involved in photosystem assembly.


Polyelectrolyte Based Sensors as Key to Achieve Quantitative Electronic Tongues: Detection of Triclosan on Aqueous Environmental Matrices.
Triclosan (TCS) is a bacteriostatic used in household items that promotes antimicrobial resistance and endocrine disruption effects both to humans and biota, raising health concerns. In this sense, new devices for its continuous monitoring in complex matrices are needed. In this work, sensors, based on polyelectrolyte layer-by-layer (LbL) films prepared onto gold interdigitated electrodes (IDE), were studied. An electronic tongue array, composed of (polyethyleneimine (PEI)/polysodium 4-styrenesulfonate (PSS))5 and (poly(allylamine hydrochloride/graphene oxide)5 LbL films together with gold IDE without coating were used to detect TCS concentrations (10-15-10-5 M). Electrical impedance spectroscopy was used as means of transduction and the obtained data was analyzed by principal component analysis (PCA). The electronic tongue was tested in deionized water, mineral water and wastewater matrices showing its ability to (1) distinguish between TCS doped and non-doped solutions and (2) sort out the TCS range of concentrations. Regarding film stability, strong polyelectrolytes, as (PEI/PSS)n, presented more firmness and no significant desorption when immersed in wastewater. Finally, the PCA data of gold IDE and (PEI/PSS)5 sensors, for the mineral water and wastewater matrices, respectively, showed the ability to distinguish both matrices. A sensitivity value of 0.19 ± 0.02 per decade to TCS concentration and a resolution of 0.13 pM were found through the PCA second principal component.


Fortuitous diagnosis of "full stomach" made by using ultrasonographic examination of the antrum in two elective patients.
We report two cases of patients presenting for elective surgery, in whom significant gastric contents were identified by performing fortuitous ultrasound examination of their antral area. The first patient presented for a day-case surgery scheduled under regional anesthesia. With his consent, ultrasound examination of the antral area was by chance performed within the context of training for this technique, showing significant solid contents in the stomach. The patient admitted that he had not respected preoperative fasting. The second patient was scheduled for an elective ophthalmologic surgery. Ultrasound examination of the antrum showed that the antrum was dilated, with significant solid and liquid gastric contents. This case may be related to a strongly delayed gastric emptying. These two cases demonstrate that some elective patients may present with significant gastric contents exposing them to the risk of pulmonary aspiration in the case of general anesthesia.


Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients.
As the population ages, the number of injured elderly is increasing. We sought to determine if low skeletal muscle mass adversely affected outcome in elderly patients following trauma. Patients ≥ 65 years of age with an admission abdominal computed tomography scan and requiring intensive care unit (ICU) stay at a Level I trauma center in 2009-2010 were reviewed. Muscle cross-sectional area at the 3rd lumbar vertebra was quantified and muscle index, a normalized measure of muscle mass, was calculated and related to clinical parameters including ventilator-free days, ICU-free days, and mortality. Using previously established sex-specific, muscle index cut-points, patients were then categorized as sarcopenic or non-sarcopenic and differences in clinical outcomes between these two groups were also compared. We also examined muscle index as a continuous variable relative to the same clinical outcomes. There were 149 severely injured elderly patients (median age 79 years) enrolled in this study of which 71% were sarcopenic. Of the patients who were sarcopenic, 9% were underweight, 44% normal weight, and 47% overweight/obese as per body mass index (BMI) classifications. The overall mortality rate was 27% and univariate analysis demonstrated higher mortality among those who were sarcopenic (32% vs. 14%, P = 0.018). After controlling for age, sex, and injury severity, multiple logistic regression demonstrated that increased muscle index was significantly associated with decreased mortality (OR per unit muscle index = 0.93, 95% CI: 0.875-0.997, P = 0.025). In addition, multivariate linear regression showed that sarcopenia, but not muscle index, was associated with decreased ventilator-free (P = 0.004) and ICU-free days (P = 0.002). Neither BMI, serum albumin nor total adipose tissue on admission were indicative of survival, ventilator-free or ICU-free days. Sarcopenia is highly prevalent in the elderly population with traumatic injuries. Traditional measures of nutritional assessment, such as BMI and serum albumin, do not accurately predict outcome in the injured elderly. Sarcopenia, however, represents a potential new predictor for mortality, discharge disposition, and ICU utilization. Measurement of muscularity allows for the early identification of at-risk patients who may benefit from aggressive and multidisciplinary nutritional and rehabilitative strategies.


Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines.
Patients with metastatic testis tumors are generally curable using chemotherapy, whereas those with disseminated bladder carcinomas are not. We have compared levels of the nuclear enzyme topoisomerase II in three testis (SuSa, 833K, and GH) and three bladder (RT4, RT112, and HT1376) cancer cell lines which differ in their sensitivity to chemotherapeutic agents. The testis cell lines were more sensitive than the bladder lines to three drugs whose cytotoxicity is mediated in part by inhibiting topoisomerase II: amsacrine; Adriamycin; and etoposide (VP16). The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells. The level of topoisomerase II-mediated DNA strand breakage in vitro, measured by filter trapping of amsacrine-induced protein:DNA cross-links, was similarly higher in nuclear extracts from the testis than the bladder cells. Western blot analysis showed a generally higher level of topoisomerase II protein in testis than in bladder cell nuclear extracts. Topoisomerase II protein expression broadly correlated with drug-induced strand breakage in both protein extracts and whole cells, but not with population doubling time. However, despite a 2- to 20-fold increased sensitivity to the different topoisomerase II inhibitors, the testis line 833K had a less than 2-fold higher level of topoisomerase II protein than that of the bladder line RT4. These results indicate that the level of expression of topoisomerase II is an important determinant of the relative chemosensitivity of testis and bladder tumor cell lines, but that additional factors must contribute to the extreme chemosensitivity of testis cells.


Multiplicative synaptic normalization and a nonlinear Hebb rule underlie a neurotrophic model of competitive synaptic plasticity.
Synaptic normalization is used to enforce competitive dynamics in many models of developmental synaptic plasticity. In linear and semilinear Hebbian models, multiplicative synaptic normalization fails to segregate afferents whose activity patterns are positively correlated. To achieve this, the biologically problematic device of subtractive synaptic normalization must be used instead. Our own model of competition for neurotrophic support, which can segregate positively correlated afferents, was developed in part in an attempt to overcome these problems by removing the need for synaptic normalization altogether. However, we now show that the dynamics of our model decompose into two decoupled subspaces, with competitive dynamics being implemented in one of them through a nonlinear Hebb rule and multiplicative synaptic normalization. This normalization is "emergent" rather than imposed. We argue that these observations permit biologically plausible forms of synaptic normalization to be viewed as abstract and general descriptions of the underlying biology in certain scaleless models of synaptic plasticity.


Countries influence the trade-off between crop yields and nitrogen pollution.
National institutions and policies could provide powerful levers to steer the global food system towards higher agricultural production and lower environmental impact. However, causal evidence of countries' influence is scarce. Using global geospatial datasets and a regression discontinuity design, we provide causal quantifications of the way crop yield gaps, nitrogen pollution and nitrogen pollution per crop yield are influenced by country-level factors, such as institutions and policies. We find that countries influence nitrogen pollution much more than crop yields and there is only a small trade-off between reducing nitrogen pollution and increasing yields. Overall, countries that cause 35% less nitrogen pollution than their neighbours only show a 1% larger yield gap (the difference between attainable and attained yields). Explanations of which countries cause the most pollution relative to their crop yields include economic development, population size, institutional quality and foreign financial flows to land resources, as well as countries' overall agricultural intensity and share in the economy. Our findings suggest that many national governments have an impressive capacity to reduce global nitrogen pollution without having to sacrifice much agricultural production.


Mortality of non-participants in cervical screening: Register-based cohort study.
The selective uptake of screening by healthy participants and its impact on the evaluation of screening effectiveness in non-randomized studies have been discussed, but hardly studied. We quantified excess mortality among cervical screening non-participants compared to participants. Based on Danish healthcare registers, we determined women's participation in cervical screening in 1990-1993 (one screening round) and 1990-1997 (two screening rounds). Women were followed until end of 2010. We computed hazard ratios (HR) comparing non-participants' and participants' risk of death, and analyzed the impact of age, calendar period of screening evaluation, screening intensity, length of follow-up and cause of death. After one screening round, the 17-year HR of death in non-participants was 1.61 (95% CI: 1.59-1.63), with an increasing trend over calendar time. After two rounds, regular non-participants had a HR of 2.09 (95% CI: 2.05-2.14) compared to regular participants. The HR for human papillomavirus (HPV)-related cancers other than cervical cancer was 3.80 (95% CI: 2.67-5.41). Younger women, whose coverage rates were higher, had higher all-cause mortality HRs. Women screened more frequently than recommended had the same mortality as those screened as recommended. Acute illness did not seem to be a major reason for non-participation, as the excess risk of death was not higher in the first years following screening evaluation. Non-participants in cervical screening had substantially higher all-cause mortality than participants, and a particularly increased risk of HPV-related causes of death. These results indicate that improper control for the selective uptake of cervical screening may result in overestimating its effectiveness.


Withdrawing Versus Withholding Freedoms: Nudging and the Case of Tobacco Control.
Is it a stronger interference with people's freedom to withdraw options they currently have than to withhold similar options they do not have? Drawing on recent theorizing about sociopolitical freedom, this article identifies considerations that often make this the case for public policy. However, when applied to tobacco control, these considerations are shown to give us at best only very weak freedom-based reason to prioritize the status quo. This supports a popular argument for so-called "endgame" tobacco control measures: If we believe that cigarettes would and should be withheld from entering markets in hypothetical scenarios in which they do not yet exist, then we also have reason to seek their abolition in situations, such as ours, in which cigarettes do exist-if necessary by banning their sale. The same considerations are then used to disarm objections that have recently been raised to using nudges in public policy.


A Framework for Evaluating Vendor Procurement in a Digital Health Project.
The eHealth Centre of Excellence, a Waterloo, Ontario-based organization that advances and promotes digital health initiatives in clinical care, developed and assessed an innovative evaluation procurement framework. The purpose of the framework was to assess and support long-term vendor-organization procurement partnerships to develop, improve and expand electronic referral (eReferral) solutions. The framework focused on six criteria: the quality of the eReferral solution, its implementation, the service provided, the extent of training and knowledge transfer, the quality of the vendor's team and the vendor's project experience. These domains were further defined by components and key performance indicators unique to the eReferral solution to accommodate the stakeholders' specified needs as well as change management challenges to create value for users and organizations in long-term relationships. The evaluation used both qualitative and quantitative methodologies. The framework used data from three sources: (1) the System Coordinated Access program and vendor team experience surveys that focused on the six criteria mentioned earlier; (2) key stakeholder interviews that focused on system quality, user satisfaction and perception of net benefits; and (3) a vendor scorecard that focused on deliverables and efficiencies. Vendor procurement should be viewed not as a process that ends when a vendor is selected but rather as a continuing and evolving relationship. Evaluation should assess the ability and willingness of vendors to support stakeholders and meet their needs, stimulate new ideas and adapt to changing environments and expanding systems. The model enabled recording of factors necessary for successful outcomes and provided a strategy to help select vendors for successful long-term partnerships.


Perfusion-cultured bovine anterior segments as an ex vivo model for studying glucocorticoid-induced ocular hypertension and glaucoma.
To determine whether perfusion-cultured bovine anterior segments would be a suitable model for glaucoma research. Fresh bovine eyes were dissected and sealed on a custom-made acrylic dish with an O-ring. Perfusion medium was infused by a syringe pump at a constant infusion rate of 5 μL/min. After intraocular pressure (IOP) was stable, bovine eyes were perfused with medium containing either a vehicle control (0.1% ethanol [ETH]) or dexamethasone (DEX) for up to 7 days. IOP was recorded by a pressure transducer and a computerized system. Perfusion medium was collected for Western immunoblot analysis of myocilin (MYOC). The morphology of the bovine trabecular meshwork after perfusion culture was similar to that of freshly dissected, nonperfused bovine eyes. Treatment with DEX elevated IOP in some bovine eyes, whereas others showed little change. The authors analyzed the data from 18 ETH-treated control eyes and defined 2.82 mm Hg as the threshold of ocular hypertension (OHT), which equals mean pressure change + 2× SD. Approximately 40% (12/29) of the bovine eyes were DEX responders, which is very close to the DEX-responsive rates observed in human and monkey eyes. Western blot data showed that DEX treatment induced the expression of the DEX-inducible gene MYOC only in the perfusion-cultured anterior segments with DEX-induced OHT. OHT can be induced by DEX in perfusion-cultured bovine anterior segments. This is a fast, convenient, affordable, and reliable model for studying DEX-induced OHT and the mechanisms of trabecular outflow.


SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer.
Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/- mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer.


Carvedilol improves glucose tolerance and insulin sensitivity in treatment of adrenergic overdrive in high fat diet-induced obesity in mice.
Catecholamine excess reflecting an adrenergic overdrive of the sympathetic nervous system (SNS) has been proposed to link to hyperleptinemia in obesity and may contribute to the development of metabolic disorders. However, relationship between the catecholamine level and plasma leptin in obesity has not yet been investigated. Moreover, whether pharmacological blockade of the adrenergic overdrive in obesity by the third-generation beta-blocker agents such as carvedilol could help to prevent metabolic disorders is controversial and remains to be determined. Using the high fat diet (HFD)-induced obese mouse model, we found that basal plasma norepinephrine, the principal catecholamine as an index of SNS activity, was persistently elevated and highly correlated with plasma leptin concentration during obesity development. Targeting the adrenergic overdrive from this chronic norepinephrine excess in HFD-induced obesity with carvedilol, a third-generation beta-blocker with vasodilating action, blunted the HFD-induced hepatic glucose over-production by suppressing the induction of gluconeogenic enzymes, and enhanced the muscular insulin signaling pathway. Furthermore, carvedilol treatment in HFD-induced obese mice decreased the enlargement of white adipose tissue and improved the glucose tolerance and insulin sensitivity without affecting body weight and blood glucose levels. Our results suggested that catecholamine excess in obesity might directly link to the hyperleptinemic condition and the therapeutic targeting of chronic adrenergic overdrive in obesity with carvedilol might be helpful to attenuate obesity-related metabolic disorders.


Healthcare access: A sequence-sensitive approach.
It is widely accepted that healthcare-seeking behaviour is neither limited to nor terminated by access to one single healthcare provider. Yet the sequential conceptualisation of healthcare-seeking processes has not diffused into quantitative research, which continues to analyse healthcare access as a "one-off" event. The ensuing lack of understanding healthcare behaviour is problematic in light of the immense burden of premature death especially in low- and middle-income countries. This paper presents an alternative approach. Based on a novel survey instrument, we analyse original survey data from rural India and China that contain 119 unique healthcare pathways among 637 respondents. We offer three applications of how such sequential data can be analysed to enhance our understanding of people's health behaviour. First, descriptive analysis of sequential data enables more a comprehensive representation of people's health behaviours, for example the time spent in various healthcare activities, common healthcare pathways across different groups, or shifts in healthcare provider access during a typical illness. Second, by analysing the effect of mobile technology on healthcare-seeking process characteristics, we demonstrate that conventional, sequence-insensitive indicators are potentially inconsistent and misleading approximations when compared to a more precise, sequence-sensitive measure. Third, we describe how sequential data enable transparent and flexible evaluations of people's healthcare behaviour. The example of a sequence-insensitive evaluation suggests that household wealth has no statistical link to an illustrative "ideal" form of public healthcare utilisation. In contrast, sequence-sensitive evaluations demonstrate that household wealth is associated with an increased likelihood of bypassing referral processes and approaching unregulated and costly informal and private practitioners before accessing a public clinic. Sequential data therefore do not only reveal otherwise neglected locational idiosyncrasies, but they also yield deeper insights into the drivers of people's health behaviours compared to a conventional approach to "access to healthcare."


miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain.
microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory-promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD.


A new twist on old ideas: how sitting reorients crawlers.
Traditionally, crawling and sitting are considered distinct motor behaviors with different postures and functions. Ten- to 12-month-old infants were observed in the laboratory or in their homes while being coaxed to crawl continuously over long, straight walkways (Study 1; N = 20) and during spontaneous crawling during free play (Study 2; N = 20). In every context, infants stopped crawling to sit 3-6 times per minute. Transitions from crawling to sitting frequently turned infants' bodies away from the direction of heading; subsequent transitions back to crawling were offset by as much as 180° from the original direction of heading. Apparently, body reorientations result from the biomechanics of transitioning between crawling and sitting. Findings indicate that sustained, linear crawling is likely an epiphenomenon of how gait is studied in standard paradigms. Postural transitions between crawling and sitting are ubiquitous and can represent a functional unit of action. These transitions and the accompanying body reorientations likely have cascading effects for infants' exploration, visual perception, and spatial cognition.


Design for an aberration-corrected concave grating for a mid-infrared long-slit spectrometer.
A new design for an aberration-corrected concave grating for the spectral region near 10 microm is presented. It was designed for use in the ground-based astronomical medium-resolution (lambda/Dlambda approximately 100) Mid-Infrared Camera and Spectrometer (MICS). It provides a flat focal plane for a wide spectral range (7.5-13.5 microm) with small aberrations, permitting efficient long-slit observations in the mid-infrared region. It permits a simple design of the spectrometer without collimator and camera mirrors, which is quite advantageous for cryogenic instruments. The grating has variable spacing grooves to reduce aberrations. In addition, the grating surface figure is designed to be toroidal and in the direction perpendicular to the grooves, aspherical, to suppress the aberrations further over a wide spectral range. The angle of the grooves is also varied to yield better efficiency near the blaze angle. The grating was fabricated by high-quality ultraprecision machining, which made these features possible. Test observations confirmed that the designed spectral resolution was achieved.


Differentiated patterns of cognitive impairment 12 months after severe and moderate traumatic brain injury.
To assess cognitive function at 12 months after moderate and severe traumatic brain injury (TBI) separately, as well as improvement from 3 to 12 months and relationship to global outcome. Cognitive function among patients with moderate (n = 30, Glasgow Coma Scale score (GCS) 9-3) and severe traumatic brain injury (n = 20, GCS score ≤ 8), recruited from an unselected neurosurgical cohort, all with MRI performed in the early phase were assessed with a neuropsychological test battery and Glasgow Outcome Scale Extended. Healthy volunteers (n = 47) matched for age, gender and years of education served as controls. Executive function was reduced at 12-months post-injury in patients with both moderate and severe TBI. However, motor function, processing speed and memory were reduced only among patients with severe TBI. Both patients with moderate and severe TBI improved their processing speed and visual memory. Patients with moderate TBI also improved motor function, while patients with severe TBI also improved executive function. Differentiating between patients with moderate and severe TBI yields a more accurate description of cognitive deficits and their improvement over time. Further, executive dysfunction and attention problems affected the ability to resume independent living and employment regardless of injury severity and age.


A randomized controlled trial of acupressure as an adjunctive therapy to sodium valproate on the prevention of chronic migraine with aura.
The primary objective of the present study was to evaluate the efficacy and safety of using acupressure as an adjunctive therapy to sodium valproate (SV) combined with acupressure (ASV) on the prevention of chronic migraine with aura (CMA). A total of 98 patients with CMA were randomly divided into an intervention group and a control group, with 49 patients in each group. The patients in the intervention group received ASV, while the participants in the control group received SV alone. The primary outcome was measured by the numeric rating scale (NRS). The secondary outcomes including frequency of migraine attacks, the times of using analgesics, and quality of life, measured by the short-form 36 Health Survey Scale (SF-36) score. In addition, adverse events (AEs) were also recorded throughout the trial. The outcomes were measured at the end of the 8-week treatment, and 4-week follow-up. After the 8-week treatment and 4-week follow-up, ASV efficacy was not greater than that of SV alone regarding pain relief, as measured using the NRS, and frequency of migraine attacks, consumption of analgesics, and quality of life, as measured using the SF-36. However, ASV can significantly reduce the nausea when compared with SV (P = .04). The present results indicate that ASV can decrease migraine-related nausea during treatment, but cannot relieve pain or enhance quality of life in patients with CMA.


Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments.
Edward Jenner and his contemporaries believed that his variolae vaccinae originated in horses and molecular analyses show that modern vaccinia virus (VACV) strains share common ancestry with horsepox virus (HPXV). Given concerns relating to the toxicity of modern VACV vaccines, we asked whether an HPXV-based vaccine might provide a superior alternative. Since HPXV may be extinct and the only specimen of HPXV that has been identified is unavailable for investigation, we explored whether HPXV could be obtained by large-scale gene synthesis. Ten large (10-30 kb) fragments of DNA were synthesized based on the HPXV sequence along with two 157 nt VACV terminal sequences, and were recombined into a live synthetic chimeric HPXV (scHPXV) in cells infected with Shope fibroma virus (SFV). Sequencing of the 212 kbp scHPXV confirmed it encoded a faithful copy of the input DNA. We believe this is the first complete synthesis of a poxvirus using synthetic biology approaches. This scHPXV produced smaller plaques, produced less extracellular virus and exhibited less virulence in mice than VACV, but still provided vaccine protection against a lethal VACV challenge. Collectively, these findings support further development of scHPXV as a novel replication-proficient smallpox vaccine.


The consequences of nuclear transfer for mammalian foetal development and offspring survival. A mitochondrial DNA perspective.
The introduction of nuclear transfer (NT) and other technologies that involve embryo reconstruction require us to reinvestigate patterns of mitochondrial DNA (mtDNA) transmission, transcription and replication. MtDNA is a 16.6 kb genome located within each mitochondrion. The number of mitochondria and mtDNA copies per organelle is specific to each cell type. MtDNA is normally transmitted through the oocyte to the offspring. However, reconstructed oocytes often transmit both recipient oocyte mtDNA and mtDNA associated with the donor nucleus. We argue that the transmission of two populations of mtDNA may have implications for offspring survival as only one allele might be actively transcribed. This could result in the offspring phenotypically exhibiting mtDNA depletion-type syndromes. A similar occurrence could arise when nucleo-cytoplasmic interactions fail to regulate mtDNA transcription and replication, especially as the initiation of mtDNA replication post-implantation is a key developmental event. Furthermore, failure of the donor somatic nucleus to be reprogrammed could result in the early initiation of replication and the loss of cellular mtDNA specificity. We suggest investigations should be conducted to enhance our understanding of nucleo-cytoplasmic interactions in order to improve NT efficiency.


Melanoma after laser therapy of pigmented lesions--circumstances and outcome.
The use of laser therapy in the treatment of pigmented lesions is a controversial issue as it can delay melanoma diagnosis and may negatively impact mortality. Few cases of melanoma after laser therapy have been reported. It is still unknown whether melanoma can be induced by lasers. We discuss the outcomes of twelve patients presenting with melanoma subsequent to previous treatment with laser. In four patients, a skin biopsy was performed before laser treatment. Histology was re-evaluated by a panel of experienced dermatopathologists and analyzed in the context of clinical and photo-optical data. There was evidence for pathological misdiagnosis in two cases. The other two cases initially presented with non-suspicious features before laser treatment and were clearly diagnosed as melanoma thereafter, opening the possibility of melanoma induction by laser treatment. Most patients were female and presented with facial lesions. Three patients have already died of melanoma and two are in stage IV, showing progressive disease with distant metastases. Laser therapy is a common treatment for pigmented lesions, increasing the risk of delayed melanoma diagnosis. This prevents appropriate and timely therapy, and may therefore lead to a fatal outcome. A careful examination of all pigmented lesions using surface microscopy and representative biopsies in combination with a close follow-up is recommended.


Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.
It has been reported that among drugs with mixed actions on central nervous system monoamine systems, increased serotonergic activity is associated with decreased potency as a reinforcer. The present experiment was designed to examine this relationship for amphetamine analogs that varied in serotonin releasing potency and to evaluate whether serotonergic actions can affect reinforcing efficacy. Compounds PAL 313 and 314 are para- and meta-methylamphetamine, respectively. PAL 303 and 353 are para- and meta-fluoroamphetamine, respectively. All compounds had similar potencies as in vitro releasers of dopamine (DA) and norepinephrine (NE) but differed in potency for 5-hydroxytryptamine (serotonin) (5-HT) release [EC(50) (nanomolar) PAL 313 = 53.4; PAL 314 = 218; PAL 303 = 939; PAL 353 = 1937]. When made available to rhesus monkeys (Macaca mulatta)(n = 4) for self-administration under a fixed-ratio 25 schedule, all were positive reinforcers with biphasic dose-response functions (0.003-1.0 mg/kg) and were equipotent. PAL 313 was self-administered at a lower rate than the other compounds, which were indistinguishable. Under a progressive-ratio schedule (n = 5), all drugs were positive reinforcers. Dose-response functions increased to a maximum or were biphasic (0.01-1.0 mg/kg), and drugs were equipotent. At maximum, PAL 313 maintained less responding than other PAL drugs, which maintained similar maxima. Thus, all compounds were positive reinforcers under both schedules, consistent with their potent DA actions. Responding was lower when 5-HT potency was higher and comparable with DA and NE potency. The results suggest that the mechanism for this effect involves a decrease in reinforcing potency and efficacy among monoamine releasing agents when 5-HT releasing potency is increased relative to DA.


Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study.
This study examined baseline correlates of substance use in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness project. Approximately 60% of the sample was found to use substances, including 37% with current evidence of substance use disorders. Users (with and without substance use disorders), compared with nonusers, were significantly more likely to be male, be African-American, have lower educational attainment, have a recent period of homelessness, report more childhood conduct problems, have a history of major depression, have lower negative symptom and higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. Individuals with comorbid substance use disorders were significantly more likely to be male, report more childhood conduct problems, have higher positive symptom scores on the Positive and Negative Syndrome Scale, and have a recent illness exacerbation. These analyses suggest that substance use disorders in schizophrenia are especially common among men with a history of childhood conduct disorder problems and that childhood conduct disorder problems are potent risk factors for substance use disorders in schizophrenia.


Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.
We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.


Aggression Replacement Training for Violent Young Men in a Forensic Psychiatric Outpatient Clinic.
The effects of Aggression Replacement Training (ART) were explored in a group of Dutch violent young men aged 16 to 21 years, who were obliged by the court to follow a treatment program in a forensic psychiatric outpatient clinic. To evaluate the training, patients completed a set of self-report questionnaires at three moments in time: at intake/before a waiting period, after the waiting period/before the training, and after the training. During the waiting period, the patients did not change on most measures, although they displayed a significant increase in anger. The patients who completed the therapy scored significantly lower on psychopathy than the patients who dropped out. The training produced significant decreases in physical aggression and social anxiety and showed trends toward a decline in self-reported hostility, general aggression, and anger. After the training, the patients scored comparably with a reference group on measures of hostility and aggressive behavior. Altogether, these results provide tentative support for the efficacy of the ART for violent young men referred to forensic psychiatric outpatient settings.


Impact of chronic obstructive pulmonary disease on morbidity and mortality after myocardial infarction.
To gain a better understanding of the impact of chronic obstructive pulmonary disease (COPD) on long-term mortality in patients with myocardial infarction (MI) and identify areas where the clinical care for these patients may be improved. Patients hospitalised for MI between 2005 and 2010 were identified from the nationwide Swedish SWEDEHEART registry. Patients with MI and a prior COPD hospital discharge diagnosis were compared to patients with MI without a prior COPD hospital discharge diagnosis for the primary endpoint of all-cause mortality at 1 year after MI. Secondary endpoints included rates of reinfarction, new-onset stroke, new-onset bleeding and new-onset heart failure at 1 year. A total of 81 191 MI patients were included, of which 4867 (6%) had a COPD hospital discharge diagnosis at baseline. Patients with COPD showed a significantly higher unadjusted 1-year mortality (24.6 vs 13.8%) as well as a higher rate of reinfarction, new-onset bleeding and new-onset heart failure post-MI. After adjustment for potential confounders, including comorbidities and treatment, the patients with COPD still showed a significantly higher 1-year mortality (HR 1.14, 95% CI 1.07 to 1.21) as well as a higher rate of new-onset heart failure (HR 1.35, 95% CI 1.24 to 1.47), whereas no significant association between COPD and myocardial reinfarction or new-onset bleeding remained. In this nationwide contemporary study, patients with COPD frequently had an atypical presentation, less often underwent revascularisation and less often received guideline-recommended secondary preventive medications of established benefit. Prior COPD was associated with a higher 1-year mortality and a higher risk of subsequent new-onset heart failure after MI. The association seems to be mainly explained by differences in background characteristics, comorbidities and treatment, although a minor part might be explained by COPD in itself. Improved in-hospital MI treatment and post-MI secondary prevention according to the guidelines may lower the mortality in this high-risk population.


The Perils of Integrating Wellness and Safety and Health and the Possibility of a Worker-Oriented Alternative.
In response to the article by Michael B. Lax, MD entitled "The perils of integrating wellness and safety and health and the possibility of a worker-oriented alternative," the National Institute for Occupational Safety and Health (NIOSH) provides updated information on the current focus and priorities and addresses concerns raised regarding the Total Worker Health® initiative. Many of the concerns and criticisms in the report echo those NIOSH publicly shares on a regular basis. The theory and practice of Total Worker Health (TWH) continues to evolve in response to valuable stakeholder input like that provided by Dr. Lax. In 2015, NIOSH updated the TWH concept to emphasize the main focus of TWH is the primacy of traditional health protection which prioritizes employer responsibilities for the organization of work over individual worker health behaviors. NIOSH acknowledges the past lack of "fit" between theory and practice in some publications of TWH-funded grantees as Dr. Lax points out. NIOSH is hopeful that the solicitation of new research, which is now underway, will clarify the work-centered priorities for TWH-funded research. Based on input from Dr. Lax and other stakeholders, NIOSH looks forward to contributing more effectively to protecting and promoting worker safety and health in the new twenty-first century world of work.


Sociodemographic and health related factors associated with poor mental health in midlife Australian women.
To examine associations between poor mental health and sociodemographic, psychosocial and health related variables in midlife Australian women. The random population-based sample comprised 13,961 Australian women aged 45-50 years who participated in the baseline postal survey for the Australian Longitudinal Study on Women's Health, conducted in 1996. The outcome measure, poor mental health status, was measured by the Mental Health Index (MH) of the SF-36. Sociodemographic factors associated with poor mental health were low educational levels, being unemployed or engaged solely in home duties, and non-English speaking background (European). Health related factors independently associated with poor mental health were having five or more visits to the doctor in the past year, menopausal status (surgical and peri-menopausal), less exercise, and smoking 20 or more cigarettes per day. Among psychosocial variables, low satisfaction with partner or close relationships, low perceived social support outside family, and more life-events over the past 12 months were independently associated. The findings suggest a number of areas in which preventive interventions could be strengthened to improve quality of life among mid-aged women. These include policy changes to promote and support more education and employment opportunities for women before they reach midlife, increase understanding of the link between health risk behaviours and psychological well-being, and provide counselling services to improve women's relational and psychosocial circumstances.


Trabecular bone density of the proximal tibia as it relates to failure of a total knee replacement.
The relationship between post-operative bone density and subsequent failure of total knee replacement (TKR) is not known. This retrospective study aimed to determine the relationship between bone density and failure, both overall and according to failure mechanism. All 54 aseptic failures occurring in 50 patients from 7760 consecutive primary cemented TKRs between 1983 and 2004 were matched with non-failing TKRs, and 47 failures in 44 patients involved tibial failures with the matching characteristics of age (65.1 for failed and 69.8 for non-failed), gender (70.2% female), diagnosis (93.6% OA), date of operation, bilaterality, pre-operative alignment (0.4 and 0.3 respectively), and body mass index (30.2 and 30.0 respectively). In each case, the density of bone beneath the tibial component was assessed at each follow-up interval using standardised, calibrated radiographs. Failing knees were compared with controls both overall and, as a subgroup analysis, by failure mechanism. Knees were compared with controls using univariable linear regression. Significant and continuous elevation in tibial density was found in knees that eventually failed by medial collapse (p < 0.001) and progressive radiolucency (p < 0.001) compared with controls, particularly in the medial region of the tibia. Knees failing due to ligamentous instability demonstrated an initial decline in density (p = 0.0152) followed by a non-decreasing density over time (p = 0.034 for equivalence). Non-failing knees reported a decline in density similar to that reported previously using dual-energy x-ray absorptiometry (DEXA). Differences between failing and non-failing knees were observable as early as two months following surgery. This tool may be used to identify patients at risk of failure following TKR, but more validation work is needed.


Promoter efficiency depends upon intragenic sequences.
Experiments concerning gene transcription in Xenopus oocytes have revealed that the efficiency of the HSV-TK promoter is dependent upon the nature of the attached gene sequences. Transcriptional efficiency of the TK promoter when attached to its own gene was 30-fold higher than that observed when the promoter was attached either to an avian keratin gene or to the chicken histone H2B gene. Furthermore, attachment of the keratin gene promoter to the TK gene resulted in a 20-fold increase in keratin promoter efficiency. It was found by subsequent experiments that the TK gene is able to exert a stimulatory influence upon attached promoter sequences. This cis effect was shown to be independent of orientation but dependent upon the distance between the DNA sequences involved.


Aortic valve replacement with on-pump beating heart technique.
The aim of this study was to assess the efficacy and applicability of on-pump beating heart aortic valve replacement with retrograde coronary sinus (CS) warm blood perfusion. The prospective study included 14 consecutive patients who underwent aortic valve replacement with mechanical prosthesis using retrograde CS perfusion. The operative variables and early outcome of this procedure are presented. Retrograde CS perfusion and venting the heart from the pulmonary vein provided good visualization of the operative field and performance of the operations without any difficulty. Partial oxygen pressures of CS perfusion blood and the returning blood from the coronary ostia were 288.5 +/- 34.4 and 39.6 +/- 4.6 mmHg, respectively. Postoperative peak creatine kinase-MB and troponin T values were mean 77.0 +/- 63.6 IU/L and mean 0.8 +/- 0.7 ng/mL, respectively. No mortality or major complication was observed and all the patients were discharged from the hospital in good condition. On-pump beating heart aortic valve replacement with retrograde CS warm blood perfusion is a good surgical option, and has the advantage of maintaining physiologic condition of the heart throughout the procedure.


Excited-state intramolecular proton transfer in a bioactive flavonoid provides fluorescence observables for recognizing its engagement with target proteins.
A benzothiophene-substituted chromenone with promising activity against Leishmania and Trypanosoma species exhibits peculiar fluorescence properties useful for identifying its complexes with target proteins in the microorganism proteomes. The emission spectra, anisotropy and time profiles of this flavonoid strongly change when moving from the free to the protein-bound forms. The same two types of emission are observed in organic solvents and their mixtures with water, with the relative band intensities depending on the solvent ability to establish hydrogen bonds with the solute. The regular emission prevails in protic solvents, while in aprotic solvents the anomalously red-shifted emission occurs from a zwitterionic tautomeric form, produced in the excited state by proton transfer within the intramolecularly H-bonded form. This interpretation finds support from an experimental and theoretical investigation of the conformational preferences of this compound in the ground and lowest excited state, with a focus on the relative twisting about the chromenone-benzothiophene interconnecting bond. An analysis of the absorption and emission spectra and of the photophysical properties of the two emitting tautomers highlights the relevance of the local microenvironment, particularly of the intra- and intermolecular hydrogen bonds in which this bioactive compound is involved, in determining both its steady-state and time-resolved fluorescence behaviour.


RPGR gene therapy presents challenges in cloning the coding sequence.
Introduction: Currently, there are three Phase I/II clinical trials based on gene therapy ongoing to test different AAV.RPGR or deleted RPGR vectors on patients affected by X-linked retinitis pigmentosa. These three vectors differ in the adeno-associated viral (AAV) vector capsid used, and the coding sequences: two contain codon optimized versions of RPGR which give the full-length protein, whilst the third uses a wild-type sequence that contains a large deletion encoding part of the functional domain of the RPGR protein.Areas covered: This review approaches the different studies that have led to the initiation of three different clinical trials for RPGR related X-linked retinitis pigmentosa.Expert opinion: The development of a gene therapy vector to deliver a normal copy of the RPGR gene into the photoreceptors has presented a challenge for the scientific community. The instability of its sequence and the fact that its function is not well understood can lead to the production of a nonfunctional or deleterious protein for the human retina. Since the RPGR protein undergoes post-translational glutamylation in the protein domain that may be particularly affected by gene instability, a functional assay of glutamylation is essential to verify the correct coding sequence.


UniChem: extension of InChI-based compound mapping to salt, connectivity and stereochemistry layers.
UniChem is a low-maintenance, fast and freely available compound identifier mapping service, recently made available on the Internet. Until now, the criterion of molecular equivalence within UniChem has been on the basis of complete identity between Standard InChIs. However, a limitation of this approach is that stereoisomers, isotopes and salts of otherwise identical molecules are not considered as related. Here, we describe how we have exploited the layered structural representation of the Standard InChI to create new functionality within UniChem that integrates these related molecular forms. The service, called 'Connectivity Search' allows molecules to be first matched on the basis of complete identity between the connectivity layer of their corresponding Standard InChIs, and the remaining layers then compared to highlight stereochemical and isotopic differences. Parsing of Standard InChI sub-layers permits mixtures and salts to also be included in this integration process. Implementation of these enhancements required simple modifications to the schema, loader and web application, but none of which have changed the original UniChem functionality or services. The scope of queries may be varied using a variety of easily configurable options, and the output is annotated to assist the user to filter, sort and understand the difference between query and retrieved structures. A RESTful web service output may be easily processed programmatically to allow developers to present the data in whatever form they believe their users will require, or to define their own level of molecular equivalence for their resource, albeit within the constraint of identical connectivity.


Use of the CRISPR-Cas9 System in Drosophila Cultured Cells to Introduce Fluorescent Tags into Endogenous Genes.
The CRISPR-Cas9 system makes it possible to cause double-strand breaks in specific regions, inducing repair. In the presence of a donor construct, repair can involve insertion or 'knock-in' of an exogenous cassette. One common application of knock-in technology is to generate cell lines expressing fluorescently tagged endogenous proteins. The standard approach relies on production of a donor plasmid with ∼500 to 1000 bp of homology on either side of an insertion cassette that contains the fluorescent protein open reading frame (ORF). We present two alternative methods for knock-in of fluorescent protein ORFs into Cas9-expressing Drosophila S2R+ cultured cells, the single-stranded DNA (ssDNA) Drop-In method and the CRISPaint universal donor method. Both methods eliminate the need to clone a large plasmid donor for each target. We discuss the advantages and limitations of the standard, ssDNA Drop-In, and CRISPaint methods for fluorescent protein tagging in Drosophila cultured cells. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Knock-in into Cas9-positive S2R+ cells using the ssDNA Drop-In approach Basic Protocol 2: Knock-in into Cas9-positive S2R+ cells by homology-independent insertion of universal donor plasmids that provide mNeonGreen (CRISPaint method) Support Protocol 1: sgRNA design and cloning Support Protocol 2: ssDNA donor synthesis Support Protocol 3: Transfection using Effectene Support Protocol 4: Electroporation of S2R+-MT::Cas9 Drosophila cells Support Protocol 5: Single-cell isolation of fluorescent cells using FACS.


Integrator or coincidence detector --- what shapes the relation of stimulus synchrony and the operational mode of a neuron?
The operational mode of a neuron (i.e., whether a neuron is an integrator or a coincidence detector) is in part determined by the degree of synchrony in the firing of its pre-synaptic neural population. More specifically, it is determined by the degree of synchrony that causes the neuron to fire. In this paper, we investigate the relationship between the input and the operational mode. We compare the response-relevant input synchrony, which measures the operational mode and can be determined using a membrane potential slope-based measure [7], with the spike time distance of the spike trains driving the neuron, which measures spike train synchrony and can be determined using the multivariate SPIKE-distance metric [10]. We discover that the relationship between the two measures changes substantially based on the values of the parameters of the input (firing rate and number of spike trains) and the parameters of the post-synaptic neuron (synaptic weight, membrane leak time constant and spike threshold). More importantly, we determine how the parameters interact to shape the synchrony-operational mode relationship. Our results indicate that the amount of depolarisation caused by a highly synchronous volley of input spikes, is the most influential factor in defining the relationship between input synchrony and operational mode. This is defined by the number of input spikes and the membrane potential depolarisation caused per spike, compared to the spike threshold.


The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues.
Ryanodine receptors (RyRs) are intracellular calcium release channels that participate in controlling cytosolic calcium levels. At variance with the probably ubiquitous inositol 1,4,5-trisphosphate-operated calcium channels (1,4,5-trisphosphate receptors), RyRs have been mainly regarded as the calcium release channels controlling skeletal and cardiac muscle contraction. Increasing evidence has recently suggested that RyRs may be more widely expressed, but this has never been extensively examined. Therefore, we cloned three cDNAs corresponding to murine RyR homologues to carry a comprehensive analysis of their expression in murine tissues. Here, we report that the three genes are expressed in almost all tissues analyzed, where tissue-specific patterns of expression were observed. In the uterus and vas deferens, expression of RyR3 was localized to the smooth muscle component of these organs. In the testis, expression of RyR1 and RyR3 was detected in germ cells. RyR mRNAs were also detected in in vitro-cultured cell lines. RyR1, RyR2, and RyR3 mRNA were detected in the cerebrum and in the cerebellum. In situ analysis revealed a cell type-specific pattern of expression in the different regions of the central nervous system. The differential expression of the three ryanodine receptor genes in the central nervous system was also confirmed using specific antibodies against the respective proteins. This widespread pattern of expression suggests that RyRs may participate in the regulation of intracellular calcium homeostasis in a range of cells wider than previously recognized.


Comparison of commercial enzyme immunoassay kits with plaque reduction neutralization test for detection of measles virus antibody.
Four commercially available enzyme immunoassay (EIA) kits were evaluated in comparison with the plaque reduction neutralization (PRN) test for detection of measles virus antibody. The EIA kits, Enzygnost (Behring), Diamedix, Vidas (bioMerieux Vitek), and Measlestat (Biowhittaker), were assessed with two PRN cutoff titers: a PRN titer of 8, the lowest detectable antibody level by the PRN test under the test conditions, and a titer of 120, which has been shown to be the minimum protective antibody titer. At a PRN cutoff titer of 8, the sensitivity was 88.2, 91.1, 74.6, and 69.8% for Behring, Diamedix, Vidas, and Biowhittaker EIA tests, respectively, with negative predictive values ranging from 22.7 to 45.5%. The specificity was 93.8% for Diamedix and 100% for the rest. At a PRN cutoff titer of 120, the sensitivity and specificity, respectively, were 100 and 90.7% (Behring), 98.2 and 58.8% (Diamedix), 90.6 and 94.5% (Vidas), and 85.7 and 96.4% (Biowhittaker). At this PRN cutoff titer, the negative predictive values of all EIA tests improved considerably, ranging from 70.7 to 100%. The EIA results showed an excellent association with PRN results when the PRN titers of the test samples were either < 8 or > 1,052. Discrepancies occurred especially when testing samples having PRN titers in the range of 8 to 120, indicating lack of sensitivity of the EIA tests in detecting measles virus antibody at low levels. Maternally derived measles virus antibody at this level has been shown to interfere with measles vaccine response in children and hence has implications from the standpoint of measles immunization. The ready availability, ease of operation, and rapid turnaround time are strong plus points of the EIA kits, and they could be useful in a clinical laboratory setting for routine application, but they may have limited use in vaccine-related studies and seroepidemiological surveys.


Predictive wavefront control for adaptive optics with arbitrary control loop delays.
We present a modification of the closed-loop state space model for adaptive optics control that allows delays that are a noninteger multiple of the system frame rate. We derive the new forms of the predictive Fourier control Kalman filters for arbitrary delays and show that they are linear combinations of the whole-frame delay terms. This structure of the controller is independent of the delay. System stability margins and residual error variance both transition gracefully between integer-frame delays.


Estimation of the proportion of feed protein digested in the small intestine of cattle consuming wet corn gluten feed.
The objectives of this study were to expand the database and determine the intestinal digestibility of rumen undegradable protein (dRUP) of common dairy feeds and to determine the effects of feeding 37.9% wet corn gluten feed on these estimates. Two ruminally and duodenally fistulated steers were assigned randomly to a crossover design with 4-wk periods. The mobile bag technique was used to determine rumen undegradable protein (RUP), dRUP, total tract digestible protein, and total tract digestible dry matter of alfalfa hay, brome hay, alfalfa haylage, corn silage, whole cottonseed, soybean meal, soyhulls, ground corn, nonenzymatically browned soybean meal, and dried distillers grains. There was no consistent effect of diet on RUP, dRUP, total tract digestible protein, and total tract digestible dry matter. The RUP (% of crude protein) ranged from 5.97% for alfalfa haylage to 75.6% for nonenzymatically browned soybean meal. The dRUP ranged from 15.3% for alfalfa haylage to 96.5% for nonenzymatically browned soybean meal. The dRUP for alfalfa hay (33.9%), brome hay (39.1%), alfalfa haylage (15.5%), and corn silage (19.9%) were lower than National Research Council reported values. The higher dRUP of the nonenzymatically browned soybean meal is reflective of more total protein reaching the small intestine. The large range in dRUP was not reflected in total tract digestible protein (% of crude protein), with corn silage being the lowest at 85.2% and nonenzymatically browned soybean meal the highest at 97.9%. In this study, diet had little effect on intestinal digestibility of protein or dry matter.


Generalized buneman pruning for inferring the most parsimonious multi-state phylogeny.
Accurate reconstruction of phylogenies remains a key challenge in evolutionary biology. Most biologically plausible formulations of the problem are formally NP-hard, with no known efficient solution. The standard in practice are fast heuristic methods that are empirically known to work very well in general, but can yield results arbitrarily far from optimal. Practical exact methods, which yield exponential worst-case running times but generally much better times in practice, provide an important alternative. We report progress in this direction by introducing a provably optimal method for the weighted multi-state maximum parsimony phylogeny problem. The method is based on generalizing the notion of the Buneman graph, a construction key to efficient exact methods for binary sequences, so as to apply to sequences with arbitrary finite numbers of states with arbitrary state transition weights. We implement an integer linear programming (ILP) method for the multi-state problem using this generalized Buneman graph and demonstrate that the resulting method is able to solve data sets that are intractable by prior exact methods in run times comparable with popular heuristics. We further show on a collection of less difficult problem instances that the ILP method leads to large reductions in average-case run times relative to leading heuristics on moderately hard problems. Our work provides the first method for provably optimal maximum parsimony phylogeny inference that is practical for multi-state data sets of more than a few characters.


Exposure of the oesophagus in breast cancer radiotherapy: A systematic review of oesophagus doses published 2010-2020.
Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently. A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques. In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range <0.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques. Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today.


Platelet count and total and cause-specific mortality in the Women's Health Initiative.
We used data from the Women's Health Initiative to examine the association of platelet count with total mortality, coronary heart disease (CHD) mortality, cancer mortality, and non-CHD/noncancer mortality. Platelet count was measured at baseline in 159,746 postmenopausal women and again in year 3 in 75,339 participants. Participants were followed for a median of 15.9 years. Cox proportional hazards models were used to estimate the relative mortality hazards associated with deciles of baseline platelet count and of the mean of baseline + year 3 platelet count. Low and high deciles of both baseline and mean platelet count were positively associated with total mortality, CHD mortality, cancer mortality, and non-CHD/noncancer mortality. The association was robust and was not affected by adjustment for a number of potential confounding factors, exclusion of women with comorbidity, or allowance for reverse causality. Low- and high-platelet counts were associated with all four outcomes in never smokers, former smokers, and current smokers. In this large study of postmenopausal women, both low- and high-platelet counts were associated with total and cause-specific mortality.


Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependant high-affinity choline transporter.
SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.


Search for resonant second generation slepton production at the Fermilab Tevatron.
We present a search for supersymmetry in the R-parity violating resonant production and decay of smuons and muon sneutrinos in the channels mu-->chi(1)(0)mu, mu-->chi(2,3,4)(0)mu, and nu(mu)-->chi(1,2)(+/-)mu. We analyzed 0.38 fb(-1) of integrated luminosity collected between April 2002 and August 2004 with the D0 detector at the Fermilab Tevatron Collider. The observed number of events is in agreement with the standard model expectation, and we calculate 95% C.L. limits on the slepton production cross section times branching fraction to gaugino plus muon, as a function of slepton and gaugino masses. In the framework of minimal supergravity, we set limits on the coupling parameter lambda(211)('), extending significantly previous results obtained in Run I of the Tevatron and at the CERN LEP collider.


Safer Design - Composable EHRs and Mechanisms for Safety.
As the deployment of health information technology progresses, issues of usability and safety, including the possibility of technology-induced errors have come to the fore. Increased complexity of care delivery models and emergent conditions such as the Ebola scare in the US point to the difficulty of design that allows for human cognitive limits while meeting complex needs. We previously described a modular composable approach to health information systems, which gives the end-user some control of design and allows for creation of systems meeting myriad and varied needs. Here we discuss how the different drag/drop interaction paradigm has implications for health IT safety via several mechanisms. These include display fragmentation and the need to changeably prioritize information elements, interruptions, fit to tasks and contexts, and rapid changeability allowing low-cost readjustments when lack of fit is found.


Regulation of the Amount of Starch in Plant Tissues by ADP Glucose Pyrophosphorylase.
Starch, a major storage metabolite in plants, positively affects the agricultural yield of a number of crops. Its biosynthetic reactions use adenosine diphosphate glucose (ADPGlc) as a substrate; ADPGlc pyrophosphorylase, the enzyme involved in ADPGlc formation, is regulated by allosteric effectors. Evidence that this plastidial enzyme catalyzes a rate-limiting reaction in starch biosynthesis was derived by expression in plants of a gene that encodes a regulatory variant of this enzyme. Allosteric regulation was demonstrated to be the major physiological mechanism that controls starch biosynthesis. Thus, plant and bacterial systems for starch and glycogen biosynthesis are similar and distinct from yeast and mammalian systems, wherein glycogen synthase has been demonstrated to be the rate-limiting regulatory step.


A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy.
A kindred affected with fish eye disease (FED) from Oklahoma is reported. Two probands with corneal opacification had mean levels of high-density lipoprotein (HDL) cholesterol (C), apolipoprotein (apo) A-I, and apoA-I in very large alpha-1 HDL particles that were 9%, 17%, and 5% of normal, whereas their parents and 1 sibling had values that were 61%, 77%, and 72% of normal. The probands had no detectable lipoprotein-X, and had mean low-density lipoprotein cholesterol (LDL-C) and triglyceride levels that were elevated. Their mean lecithin cholesterol acyltransferase (LCAT) activities, cholesterol esterification rates, and free cholesterol levels were 8%, 42%, and 258% of normal, whereas their parents and 1 sibling had values that were 55%, 49%, and 114% of normal. The defect was due to 1 common variant in the LCAT gene in exon 1: c101t causing a proline34leucine substitution and a novel mutation c1177t causing a threonine37methionine substitution, with the former variant being found in the father and 1 sibling, and the latter mutation being found in the mother, and both mutations being present in the 2 probands. FED is distinguished from familial LCAT deficiency (FLD) by the lack of anemia, splenomegaly, and renal insufficiency as well as normal or increased LDL-C. Both FLD and FED cases have marked HDL deficiency and corneal opacification, and FED cases may have premature coronary heart disease in contrast to FLD cases. Therapy, using presently available agents, in FED should be to optimize LDL-C levels, and 1 proband responded well to statin therapy. The investigational use of human recombinant LCAT as an enzyme source is ongoing.


They know!-Do they? A qualitative study of residents and relatives views on advance care planning, end-of-life care, and decision-making in nursing homes.
Residents living in long-term care facilities are a vulnerable population. For many residents, a nursing home is their place of death. Palliative care and end-of-life decisions are important components of their care provision. To study the views of cognitively able residents and relatives on advance care planning, end-of-life care, and decision-making in nursing homes. A qualitative study with in-depth interviews with nursing home residents and focus group interviews with relatives of nursing home residents. Analysis is based on interpretive description. In total, 43 informants from nine nursing homes participated in the study (25 nursing home residents and 18 relatives). All included residents had capacity to provide informed consent and lived in long-term care. The main findings of this study were the differing views about decision-making and advance care planning of residents and relatives. Residents do trust relatives and staff to make important decisions for them. The relatives are in contrast insecure about the residents' wishes and experience decision-making as a burden. The majority of the residents had not participated in advance care planning. None of the residents stated challenges connected to end-of-life care or mentioned the wish for euthanasia. Although most residents seem to be satisfied with decision-making and end-of life care, there is a need for systematic advance care planning. Advance care planning could help to explore future wishes for care and ease decision-making for the relatives, physicians, and staff and should be offered to all cognitively able nursing homes residents.


AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia.
AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein show that sustained endoplasmic reticulum (ER) stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp- and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further upregulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also show that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical proapoptotic versus prosurvival effects of AMPK activation.


Bayesian spatial modelling and the significance of agricultural land use to scrub typhus infection in Taiwan.
Scrub typhus is transmitted by the larval stage of trombiculid mites. Environmental factors, including land cover and land use, are known to influence breeding and survival of trombiculid mites and, thus, also the spatial heterogeneity of scrub typhus risk. Here, a spatially autoregressive modelling framework was applied to scrub typhus incidence data from Taiwan, covering the period 2003 to 2011, to provide increased understanding of the spatial pattern of scrub typhus risk and the environmental and socioeconomic factors contributing to this pattern. A clear spatial pattern in scrub typhus incidence was observed within Taiwan, and incidence was found to be significantly correlated with several land cover classes, temperature, elevation, normalized difference vegetation index, rainfall, population density, average income and the proportion of the population that work in agriculture. The final multivariate regression model included statistically significant correlations between scrub typhus incidence and average income (negatively correlated), the proportion of land that contained mosaics of cropland and vegetation (positively correlated) and elevation (positively correlated). These results highlight the importance of land cover on scrub typhus incidence: mosaics of cropland and vegetation represent a transitional land cover type which can provide favourable habitats for rodents and, therefore, trombiculid mites. In Taiwan, these transitional land cover areas tend to occur in less populated and mountainous areas, following the frontier establishment and subsequent partial abandonment of agricultural cultivation, due to demographic and socioeconomic changes. Future land use policy decision-making should ensure that potential public health outcomes, such as modified risk of scrub typhus, are considered.


Non-Suicidal Self-Injury and Interpersonal Violence in Suicide Attempters.
The current study compared characteristics of suicidal behavior and interpersonal violence in suicide attempters with and without a history of non-suicidal self-injury (NSSI). A total of 100 suicide attempters were assessed with Karolinska Interpersonal Violence Scale (KIVS) and Karolinska Suicide History Interview concerning interpersonal violence and NSSI. There was a high degree of comorbid NSSI in suicide attempters (44%). Suicide attempters with NSSI-history reported more interpersonal violence as adults and more severe suicidal behavior compared to suicide attempters without NSSI. Comorbid NSSI was related to severity of suicidal behavior in a gender specific manner. Comorbid NSSI in suicide attempters may increase suicide and violence risk.


Development of an Anisotropically Organized Brain dECM Hydrogel-Based 3D Neuronal Culture Platform for Recapitulating the Brain Microenvironment in Vivo.
To mimic the brain tissue microenvironment in vitro, the biological and structural properties of the utilized system must be similar to those of the native brain in the microenvironment in vivo. To promote the bioactive (biological) properties of matrix hydrogels, we used the decellularized extracellular matrix (dECM) of porcine brain, which was found to enhance neuronal differentiation/outgrowth and neuron-to-brain dECM interactions. To implement the desired structural properties, we aligned microfibrils within a composite hydrogel mixed with the brain dECM and collagen I, with or without encapsulated neurons, by the stretching and releasing of a hydrogel-based chip. We then tested the ability of the aligned brain dECM hydrogel-based three-dimensional (3D) culture platform to mimic the in vivo brain microenvironment. We found that dECM-containing gels harbored brain-derived ECM proteins, including collagen I, collagen IV, laminin, and various cytokines, and that neurons incubated in these gels exhibited enhanced neurite outgrowth and development compared to those incubated in collagen gel (dECM 0 mg/mL). We evaluated the surface morphology and mechanical properties of the hydrogel with and without the brain dECM and found that their encapsulated neurons showed similar levels of cell viability. We then used a mechanical process to align the composite dECM hydrogel, conferring the desired structural properties to our system. Together, our results suggest that our newly developed brain dECM-based 3D culture platform could potentially be further developed for use in drug screening.


Embryonal carcinoma and the basement membrane glycoproteins laminin and entactin.
The mouse embryonal carcinoma lines PCC4-F and F9 have played important roles in the isolation and characterization of the two ubiquitous basement membrane proteins, laminin and entactin. The contributions of these cells to our work on extracellular matrices are briefly summarized. The in vitro differentiation of PCC4-F gives rise to a multiplicity of cell types. Two of these cell types have been propagated as cell lines. One of these, M1536-B3, synthesizes and deposits copious quantities of extracellular matrix glycoproteins, which led to the initial discovery and characterization of laminin and entactin. In addition, M1536-B3 provides a model system for analyzing the assembly of laminin and the laminin-entactin complex and for manipulating extracellular matrix structure and composition. The other cell line, 4CQ, synthesizes a matrix consisting of fibronectin and entactin. F9 cells differentiate to endodermal cells in response to retinoic acid and dibutyryl cyclic AMP (Strickland and Mahdavi, Cell 15: 393-402, 1978). The differentiated cells synthesize basement membrane components and provided the probes for the cDNA cloning of entactin and the three chains of laminin. The F9 cells have been widely employed to examine the regulation of expression of the laminin and entactin genes.


Periodic dielectric structures for light-trapping in InGaAs/GaAs quantum well solar cells.
We study dielectric diffraction gratings for light-trapping in quantum well solar cells and compare their performance with plasmonic and Lambertian light-trapping structures. The optimum structural parameters are identified for symmetric uni-periodic, symmetric bi-periodic and asymmetric bi-periodic gratings. The enhancement in short-circuit current density from the quantum well region with respect to a reference cell with no diffraction grating is calculated. The ratio of this enhancement to the maximum achievable enhancement (i.e. no transmission losses) is 33%, 75% and 74%, respectively for these structures. The optimum asymmetric and symmetric bi-periodic structures perform closest to Lambertian light-trapping, while all three optimum grating structures outperform optimum plasmonic light-trapping. We show that the short-circuit current density from the quantum well region is further enhanced by incorporating a rear reflector.


Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer.
Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.


A 20-year prospective longitudinal MRI study on cervical spine after whiplash injury: Follow-up of a cross-sectional study.
Some patients suffer from long-lasting symptoms after whiplash injury. However, there are few reports on the long-term changes in the cervical spine after whiplash injury using imaging tests. The purpose of this longitudinal study was to determine the changes on MRI of the cervical spine 20 years after whiplash injury, and to examine the relationships between changes in the cervical spine on MRI and changes in related clinical symptoms. Eighty-one subjects finally participated in this study (follow-up rate 16%). The mean follow-up duration was 21.7 years. All subjects filled out a questionnaire about their clinical symptoms. The MRI findings were assessed using numerical grading system applied in the original study. Statistic analyses were used to investigate whether the progression of each MRI finding was associated with the severity of neck pain, stiff shoulders, dizziness and tinnitus. All subjects had complained of some clinical symptoms in the original study: 71 had neck pain, 53 stiff shoulders, and others. In the present study, 66 subjects (81.5%) complained of some clinical symptoms: 57 had stiff shoulders, 20 neck pain, and others. The progression of degeneration on MRI was observed in 95% of the subjects, with C4/5 and 5/6 being the most frequently involved levels. Changes in the severity of neck pain, stiff shoulders, dizziness and tinnitus over 20 years were not significantly associated with the progression of degenerative changes in the cervical spine on MRI. Twenty years after whiplash injury, 95% of the subjects showed a progression of degeneration in the cervical spine. The progression of the intervertebral disc degeneration in the cervical spine on MRI after whiplash injury was not significantly associated with changes in the severity of related clinical symptoms, indicating that the degenerative changes on MRI may reflect the physiological aging process rather than post-traumatic sequelae.


Use of Non-Cancer Medications in New Zealand Women at the Diagnosis of Primary Invasive Breast Cancer: Prevalence, Associated Factors and Effects on Survival.
Assessing the use of multiple medications in cancer patients is crucial as such use may affect cancer outcomes. This study reports the prevalence of non-cancer medication use at breast cancer diagnosis, its associated factors, and its effect on survival. We identified all women diagnosed with primary invasive breast cancer between 1 January 2007 and 31 December 2016, from four population-based breast cancer registries, in Auckland, Waikato, Wellington, and Christchurch, New Zealand. Through linkage to the pharmaceutical records, we obtained information on non-cancer medications that were dispensed for a minimum of 90 days' supply between one year before cancer diagnosis and first cancer treatment. We performed ordered logistic regressions to identify associated factors and Cox regressions to investigate its effect on patient survival. Of 14,485 patients, 52% were dispensed at least one drug (mean-1.3 drugs; maximum-13 drugs), with a higher prevalence observed in patients who were older, treated at a public facility, more economically deprived, and screen-detected. The use of 2-3 drugs showed a reduced non-breast cancer mortality (HR = 0.75, 95%CI = 0.60-0.92) in previously hospitalised patients, with other groups showing non-significant associations when adjusted for confounding factors. Drug use was not associated with changes in breast cancer-specific mortality. Non-cancer medication use at breast cancer diagnosis was common in New Zealand, more prevalent in older and disadvantaged women, and showed no effect on breast cancer-specific mortality, but a reduction in other cause mortality with the use of 2-3 drugs.


Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance.
Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2(-/-) mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2(-/-) mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2(-/-) mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.


Convergence of backward-error-propagation learning in photorefractive crystals.
We analytically determine that the backward-error-propagation learning algorithm has a well-defined region of convergence in neural learning-parameter space for two classes of photorefractive-based optical neural-network architectures. The first class uses electric-field amplitude encoding of signals and weights in a fully coherent system, whereas the second class uses intensity encoding of signals and weights in an incoherent/coherent system. Under typical assumptions on the grating formation in photorefractive materials used in adaptive optical interconnections, we compute weight updates for both classes of architectures. Using these weight updates, we derive a set of conditions that are sufficient for such a network to operate within the region of convergence. The results are verified empirically by simulations of the xor sample problem. The computed weight updates for both classes of architectures contain two neural learning parameters: a learning-rate coefficient and a weight-decay coefficient. We show that these learning parameters are directly related to two important design parameters: system gain and exposure energy. The system gain determines the ratio of the learning-rate parameter to decay-rate parameter, and the exposure energy determines the size of the decay-rate parameter. We conclude that convergence is guaranteed (assuming no spurious local minima in the error function) by using a sufficiently high gain and a sufficiently low exposure energy per weight update.