Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge.
Very-low birthweight (VLBW, <1500 g) infants comprise about 1%-1.4% of all births in high-income countries. Every year, about 3000 VLBW babies in Australia and New Zealand receive intensive care. Many die or else survive with severe brain injury, retinopathy, late-onset sepsis or necrotising enterocolitis (NEC), each of which carries substantial risk of disability. This trial tests whether adding bovine lactoferrin (bLF) to feeds in VLBW infants improves (1) survival to hospital discharge free from brain injury, late-onset sepsis, NEC and treated retinopathy of prematurity (primary composite end point); (2) each component of the primary composite end point and (3) time to reach full enteral feeds, number of blood transfusions, chronic lung disease and length of hospital stay. It includes a cost-effectiveness analysis of bLF in improving survival free from major morbidity, and evaluates the effect of bLF on survival and developmental outcomes at 24 to 36 months corrected gestational age.This is a multicentre, two-arm, randomised trial comparing the treatment group receiving bLF added to breast milk or formula milk daily (up to 250 mg/kg/day bLF) versus the control group receiving no bLF supplementation. The intervention is administered until 34 completed weeks corrected gestation or for 2 weeks, whichever is longer, or until discharge home, if earlier. The target sample size of 1500 participants yields 85% power, at the two-sided 5% level significance, to detect a difference in proportions meeting the primary outcome assuming the true probability is 74% in controls and 80.5% in the bLF group. This protocol was approved by Northern Sydney Local Human Research Ethics Committee in January 2017 (Version 2.0, Reference 1003-118M) and other relevant ethics committees. The findings of the trial will be disseminated through peer-reviewed journals and conference presentations. ACTRN12611000247976; Pre-results.


Operational Insights Into Mosquito Control Disaster Response in Coastal North Carolina: Experiences With the Federal Emergency Management Agency After Hurricane Florence.
Preparation for post-hurricane mosquito control is essential for an effective emergency response to protect public health and promote recovery efforts. Effective pre-hurricane planning includes laying the groundwork for a successful reimbursement application to the Federal Emergency Management Agency. The critical and overlapping need to sustain funding for mosquito control programs is highlighted here in the context of both normal and emergency responses. Community support is an integral component of an effective integrated pest management program and is established over time with appropriate communication and engagement. Experienced mosquito control operators who are familiar with treatment areas are an essential component of successful operations. Here, practical advice is provided to plan, prepare, and implement a successful ground- and aerial-based mosquito control response.


Partisans without Constraint: Political Polarization and Trends in American Public Opinion.
Public opinion polarization is here conceived as a process of alignment along multiple lines of potential disagreement and measured as growing constraint in individuals' preferences. Using NES data from 1972 to 2004, the authors model trends in issue partisanship-the correlation of issue attitudes with party identification-and issue alignment-the correlation between pairs of issues-and find a substantive increase in issue partisanship, but little evidence of issue alignment. The findings suggest that opinion changes correspond more to a resorting of party labels among voters than to greater constraint on issue attitudes: since parties are more polarized, they are now better at sorting individuals along ideological lines. Levels of constraint vary across population subgroups: strong partisans and wealthier and politically sophisticated voters have grown more coherent in their beliefs. The authors discuss the consequences of partisan realignment and group sorting on the political process and potential deviations from the classic pluralistic account of American politics.


Preventing recurrent homelessness among mentally ill men: a "critical time" intervention after discharge from a shelter.
This study examined a strategy to prevent homelessness among individuals with severe mental illness by providing a bridge between institutional and community care. Ninety-six men with severe mental illness who were entering community housing from a shelter institution were randomized to receive 9 months of a "critical time" intervention plus usual services or usual services only. The primary analysis compared the mean number of homeless nights for the two groups during the 18-month follow-up period. To elucidate time trends, survival curves were used. Over the 18-month follow-up period, the average number of homeless nights was 30 for the critical time intervention group and 91 for the usual services group. Survival curves showed that after the 9-month period of active intervention, the difference between the two groups did not diminish. Strategies that focus on a critical time of transition may contribute to the prevention of recurrent homelessness among individuals with mental illness, even after the period of active intervention.


Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain.
Ketamine has demonstrated usefulness as an analgesic to treat nonresponsive neuropathic pain; however, it is not widely administered to outpatients due to fear of such side effects as hallucinations and other cognitive disturbances. This retrospective chart review is the first research to study the safety and efficacy of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in noncancer outpatients. Thirteen outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point verbal analog score (VAS), 11 of 13 patients (85%) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The results demonstrate that ketamine may provide a reasonable alternative treatment for nonresponsive neuropathic pain in ambulatory outpatients.


Evidence from 18S ribosomal RNA sequences that lampreys and hagfishes form a natural group.
Lampreys and hagfishes (cyclostomes) traditionally were considered to be a natural (monophyletic) group. Recently, the consensus of opinion, based largely on morphological analyses, has shifted to a view that lampreys are more closely related to jawed vertebrates (gnathostomes) than to hagfishes. Phylogenetic comparisons of 18S ribosomal RNA sequences from two hagfishes, two lampreys, a tunicate, a lancelet, and a number of gnathostomes support the monophyly of the cyclostomes. These data force a reassessment of several features of early vertebrate evolution.


Dynamics of suspended sediment borne persistent organic pollutants in a large regulated Mediterranean river (Ebro, NE Spain).
Mediterranean rivers are characterized by highly variable hydrological regimes that are strongly dependent on the seasonal rainfall. Sediment transport is closely related to the occurrence of flash-floods capable to deliver enough kinetic energy to mobilize the bed and channel sediments. Contaminants accumulated in the sediments are likely to be mobilized as well during such events. However, whereas there are many studies characterizing contaminants in steady sediments, those devoted to the transport dynamics of suspended-sediment borne pollution are lacking. Here we examined the occurrence and transport of persistent organic microcontaminants present in the circulating suspended sediments during a controlled flushing flow in the low part of the River Ebro (NE Spain) 12 km downstream of a well-known contaminated hot-spot associated to a nearby chloro-alkali industry. Polycyclic aromatic hydrocarbons (PAHs) and semi-volatile organochlorine pollutants (DDT and related compounds, DDX; polychlorinated byphenils, PCBs; and other organochlorine compound, OCs) were measured in the particulate material by GC-MS and GC-MS/MS, using previously developed analytical methods. The concentration levels observed were compared to previously reported values in steady sediments in the same river and discussed on a regulatory perspective. Hydrographs and sedigraphs recorded showed a peak-flow of 1,300 m(3)s(-1) and a corresponding peak of suspended sediments of 315 mg L(-1). Combination of flow discharge, suspended sediments and pollutants' concentrations data allowed for quantifying the mass flows (mass per unit of time) and setting the load budgets (weight amount) of the different pollutants transported by the river during the monitored event. Mean mass-flows and total load values found were 20.2 mg s(-1) (400 g) for PAHs, 38 mg s(-1) (940 g) for DDX, 44 mg s(-1) (1,038 g) for PCBs and 8 mg s(-1) (200 g) for OCs. The dynamic pattern behavior of PAHs differs substantially to that of organochlorine pollutants, thus reflecting different pollution origins.


Long-term consequences of kidney donation.
The long-term renal consequences of kidney donation by a living donor are attracting increased appropriate interest. The overall evidence suggests that living kidney donors have survival similar to that of nondonors and that their risk of end-stage renal disease (ESRD) is not increased. Previous studies have included relatively small numbers of donors and a brief follow-up period. We ascertained the vital status and lifetime risk of ESRD in 3698 kidney donors who donated kidneys during the period from 1963 through 2007; from 2003 through 2007, we also measured the glomerular filtration rate (GFR) and urinary albumin excretion and assessed the prevalence of hypertension, general health status, and quality of life in 255 donors. The survival of kidney donors was similar to that of controls who were matched for age, sex, and race or ethnic group. ESRD developed in 11 donors, a rate of 180 cases per million persons per year, as compared with a rate of 268 per million per year in the general population. At a mean (+/-SD) of 12.2+/-9.2 years after donation, 85.5% of the subgroup of 255 donors had a GFR of 60 ml per minute per 1.73 m(2) of body-surface area or higher, 32.1% had hypertension, and 12.7% had albuminuria. Older age and higher body-mass index, but not a longer time since donation, were associated with both a GFR that was lower than 60 ml per minute per 1.73 m(2) and hypertension. A longer time since donation, however, was independently associated with albuminuria. Most donors had quality-of-life scores that were better than population norms, and the prevalence of coexisting conditions was similar to that among controls from the National Health and Nutrition Examination Survey (NHANES) who were matched for age, sex, race or ethnic group, and body-mass index. Survival and the risk of ESRD in carefully screened kidney donors appear to be similar to those in the general population. Most donors who were studied had a preserved GFR, normal albumin excretion, and an excellent quality of life.


Evaluation of water uptake and mechanical properties of blended polymer films for preparing gas-generated multiple-unit floating drug delivery systems.
Among various strategies of gastroretentive drug delivery systems (DDSs) developed to prolong the gastric residence time and to increase the overall bioavailability, effervescent multiple-unit floating DDSs (muFDDSs) were studied here. These systems consist of drug (losartan)- and effervescent (sodium bicarbonate)-containing pellets coated with a blended polymeric membrane, which was a mixture of gastrointestinal tract (GIT)-soluble and GIT-insoluble polymers. The addition of GIT-soluble polymers, such as hydroxypropyl methylcellulose, polyethylene glycol (PEG) 6000, PEG 600, and Kollicoat® IR, greatly increased the water uptake ability of the GIT-insoluble polymers (Eudragit® NE, RS, and RL; Surelease®; and Kollicoat® SR) and caused them to immediately initiate the effervescent reaction and float, but the hydrated films should also be impermeable to the generated CO(2) to maintain floatation and sufficiently flexible to withstand the pressure of carbon dioxide to avoid rupturing. The study demonstrated that the water uptake ability and mechanical properties could be applied as screening tools during the development of effervescent muFDDSs. The optimized system of SRT(5)P600(5) (i.e., a mixture of 5% Kollicoat® SR and 5% PEG 600) with a 20% coating level began to completely float within 15 min and maintained its buoyancy over a period of 12 h with a sustained-release effect.


Genome-wide analysis of day/night DNA methylation differences in Populus nigra.
DNA methylation is an important mechanism of epigenetic modification. Methylation changes during stress responses and developmental processes have been well studied; however, their role in plant adaptation to the day/night cycle is poorly understood. In this study, we detected global methylation patterns in leaves of the black poplar Populus nigra 'N46' at 8:00 and 24:00 by methylated DNA immunoprecipitation sequencing (MeDIP-seq). We found 10,027 and 10,242 genes to be methylated in the 8:00 and 24:00 samples, respectively. The methylated genes appeared to be involved in multiple biological processes, molecular functions, and cellular components, suggesting important roles for DNA methylation in poplar cells. Comparing the 8:00 and 24:00 samples, only 440 differentially methylated regions (DMRs) overlapped with genic regions, including 193 hyper- and 247 hypo-methylated DMRs, and may influence the expression of 137 downstream genes. Most hyper-methylated genes were associated with transferase activity, kinase activity, and phosphotransferase activity, whereas most hypo-methylated genes were associated with protein binding, ATP binding, and adenyl ribonucleotide binding, suggesting that different biological processes were activated during the day and night. Our results indicated that methylated genes were prevalent in the poplar genome, but that only a few of these participated in diurnal gene expression regulation.


EUS liver assessment using contrast agents and elastography.
Transabdominal-US is the first-line imaging modality used to assess the whole liver parenchyma and vascularization; EUS assessment of the liver is incomplete and is not sufficient to rule out the presence of focal liver lesions. On the other hand, due the high diagnostic yield in detecting very small (< 1 cm) lesions, EUS is considered complementary to radiological imaging techniques for the investigation of liver parenchyma. Scarce data are available regarding the investigation of liver parenchyma using both EUS-elastography (EUS-E) and CH-EUS. The aim of this review is to evaluate the clinical role of image enhancement techniques, namely EUS-E and contrast harmonic-EUS (CH-EUS), for the evaluation liver diseases. Despite a potential interest for the application of EUS-E in the assessment of liver diseases, available evidence relegates this technique only to research areas, such as the differential diagnosis between benign and malignant focal liver lesions and the quantification of liver fibrosis in diffuse parenchymal diseases. With the future introduction of EUS shear-wave elastography, interesting data can be obtained for the assessment of liver fibrosis during real-time EUS evaluation. The usefulness of CH-EUS for the evaluation of liver disease is limited by the intrinsic EUS ability to explore only the left lobe and a small part of the right lobe. CH-EUS could be used to increase the diagnostic ability of EUS for the detection and characterization of small lesions and for guiding tissue sampling. Targeting EUS-guided treatments with either EUS-E or CH-EUS might represent potential future applications.


The role of lycopene and its derivatives in the regulation of transcription systems: implications for cancer prevention.
Evidence from epidemiologic studies has suggested that carotenoids, and lycopene in particular, decrease the risk of cancer: however, not all studies support this view. To gain insight into the molecular mechanisms whereby lycopene and other carotenoids may exert their chemoprotective effects, we and others performed a series of studies that used a large panel of cancer cell lines of different lineages and animal models of human cancer. In this review we address some of the mechanisms proposed for the cancer-preventive activity of tomato lycopene, focusing on the induction of the antioxidant response element transcription system and the inhibition of the transcriptional activity of sex hormones, such as estrogens and androgens, and the activity of growth factors, such as insulin-like growth factor. We also considered the modulation by lycopene of the transcription factors peroxisome proliferator-activated receptor, retinoid X receptor, liver X receptor, and activating protein-1. The ligands and the phytonutrient regulators of these transcription systems contain electrophilic active groups, whereas lycopene and nonxanthophylic carotenoids are devoid of them. Thus, we suggest that at least some of the cellular effects of carotenoids are mediated through their derivatives formed either by chemical oxidation or by enzymatic cleavage inside the cells. This review highlights findings that pertain to this exciting avenue of research, which is currently under intense scrutiny in several laboratories worldwide.


Record-linkage studies of the coexistence of epilepsy and bipolar disorder.
Interest is growing in a possible link between epilepsy and bipolar disorder (BPD). We used two large datasets of hospital admission data to determine whether epilepsy and BPD occur together in the same individuals more commonly than expected. We undertook retrospective cohort studies using the Oxford Record Linkage Study (ORLS) and English national linked Hospital Episode Statistics. We constructed a cohort of people in each dataset admitted with epilepsy (without prior admission for BPD), and a control cohort (without prior admission for BPD), and compared their subsequent admission rates for BPD. Conversely, we constructed a cohort of people in each dataset admitted with BPD and a control cohort (both without prior admission for epilepsy), and compared their subsequent admission rates for epilepsy. In the epilepsy cohort, compared with the control cohort, the rate ratio (RR) for BPD was significantly high at 3.0 (95 % confidence interval 1.7-5.1) in the ORLS and 3.6 (3.3-3.9) in the all-England dataset. In the BPD cohort, the RR for epilepsy was 2.2 (1.2-3.7) in the ORLS and 4.2 (4.0-4.4) in the all-England cohort. We found no significant differences between RRs for males and females. Epilepsy and BPD occur together in individuals more frequently than expected by chance.


In utero exposure to valproate increases the risk of isolated cleft palate.
Orofacial clefting (OFC) has been described in infants exposed to valproic acid (VPA) prenatally, but often no distinction is made between cleft lip and palate (CLP) and isolated cleft palate (ICP). This distinction is important as these conditions have different management implications and the distinction has implications too for understanding the teratogenic mechanisms. We searched EMBASE, Medline and Web of Science for observational studies describing OFC in association with VPA exposure. Searches for similarly exposed patients referred to a regional genetic centre and those recorded in the UK Epilepsy and Pregnancy Register (UKEPR) were undertaken. Cleft type and, where available, VPA doses prescribed were recorded. A total of 4459 cases of VPA exposure were reported in the literature in nine separate studies with 50 cases of OFC, the majority of which did not differentiate the cleft type. Eight patients ascertained through the regional genetic centre had ICP. Thirteen cases of OFC occurred in 1282 VPA monotherapy-exposed pregnancies in the UKEPR; nine had ICP and four had CLP, representing an 11.3-fold and 3.5-fold increase risk in ICP and CLP, respectively, over general population risk. Doses ranged from 200 to 2500 mg VPA daily with 73% of monotherapy ICP cases from the local cohort and UKEPR occurring at doses over 1000 mg. ICP is the predominant cleft type seen in prenatal VPA exposure. Parents should be counselled appropriately and infants should undergo review after delivery for ICP. Pregnancy registers collecting information on congenital anomalies should make the distinction between CLP and ICP as the risk differs across the two conditions.


Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis.
The fact that Fat-1 transgenic mice producing n-3 polyunsaturated fatty acids via overexpressed 3-desaturase significantly mitigated Helicobacter pylori (H. pylori)-associated gastric tumorigenesis through rejuvenation of chronic atrophic gastritis (CAG) led us to study whether dietary intake of walnut plentiful of n-3 PUFAs can be nutritional intervention to prevent H. pylori-associated gastric cancer. In our model that H. pylori-initiated, high salt diet-promoted gastric carcinogenesis, pellet diet containing 100 mg/kg and 200 mg/kg walnut was administered up to 36 weeks. As results, control mice (24 weeks) developed significant chronic CAG, in which dietary walnuts significantly ameliorated chronic atrophic gastritis. Expressions of COX-2/PGE2/NF-κB/c-Jun, elevated in 24 weeks control group, were all significantly decreased with walnut (p<0.01). Tumor suppressive enzyme, 15-PGDH, was significantly preserved with walnut. Control mice (36 weeks) all developed significant tumors accompanied with severe CAG. However, significantly decreased tumorigenesis was noted in group treated with walnuts, in which expressions of COX-2/PGE2/NF-κB/IL-6/STAT3, all elevated in 36 weeks control group, were significantly decreased with walnut. Defensive proteins including HO-1, Nrf2, and SOCS-1 were significantly increased in walnut group. Proliferative index as marked with Ki-67 and PCNA was significantly regulated with walnut relevant to 15-PGDH preservation. Conclusively, walnut can be an anticipating nutritional intervention against H. pylori.


Role of Mesenchymal Stem Cells in Dermal Repair in Burns and Diabetic Wounds.
In this review we explore stem cell function in wounds that are resistant to healing, such as burn injuries and diabetic wounds. Diabetic ulcers are of interest due to their remarkable resistance to heal; severe thermal burns are addressed due to critical need for effective therapies for the prevention shock and improvement in scarring. Cell-based therapy utilizing mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are currently being investigated as a therapeutic avenue for both chronic diabetic ulcers and severe thermal burns. The clinical utility of stem cells, in particular MSCs, in caring for these types of injuries is primarily based on repairing and replacing cellular substrates, attenuation of inflammation, increasing angiogenesis, and enhancing migration of reparative cells. MSCs are sought after due to their unique ability to initiate different wound-healing programs, depending on the environmental milieu. Thus, this review aims to highlight the properties of MSCs, including their characterization, immunogenicity, and function in the context of dermal repair and regeneration in severe burns and diabetic wounds. Additionally, relevant clinical and pre-clinical studies illustrating the impact of allogeneic and autologous sources of MSCs on therapeutic efficacy are reviewed. Insight into the properties of MSCs and the dramatic host-to-MSC interactions within these pathological states may lead to the development of effective strategies for improving outcomes in impaired wounds.


Bird use of organic apple orchards: Frugivory, pest control and implications for production.
As the largest terrestrial biomes, crop and pasturelands can have very large positive or negative impacts on biodiversity and human well-being. Understanding how animals use and impact agroecosystems is important for making informed decisions that achieve conservation and production outcomes. Yet, few studies examine the tradeoffs associated with wildlife in agricultural systems. We examined bird use of organic apple orchards as well as how birds influence fruit production positively through control of an economically important insect pest (codling moth (Cydia pomonella)) and negatively through fruit damage. We conducted transect surveys, observed bird frugivory and assessed bird and insect damage with an exclosure experiment in small organic farms in western Colorado. We found that organic apple orchards in this region provide habitat for a large number of both human-adapted and human-sensitive species and that the species in orchards were relatively similar to adjacent hedgerow habitats. Habitat use did not vary as a function of orchard characteristics, and apple damage by both birds and C. pomonella was consistent within and across apple blocks that varied in size. A small subset of bird species was observed foraging on apples yet the effect of birds as agents of fruit damage appeared rather minor and birds did not reduce C. pomonella damage. Our results demonstrate that organic apple orchards have the potential to provide habitat for diverse bird communities, including species typically sensitive to human activities, with little apparent effect on production.


A simple strategy for robust preparation and characterisation of hydrogels derived from chitosan and amino functional monomers for biomedical applications.
Molecular interactions of amino functional (AF) monomers with chitosan (CS) lead to the formation of external stimuli responsive hydrogels (HGs). These have the potential to produce biomaterials with novel properties by a simple blending approach. Six independent AF monomers such as diethylenetriamine (DETA), bis(3-aminopropyl)amine (BAPA), 3,3'-diamino-N-methyldipropyleamine (DAMPA), hexamethylenediamine (HMDA), N,N-dimethylethylamine (DMEA) and diethylamine (DEA) with distinct functional groups and chain lengths were designed to form stable HGs at physiological pH. Such AF monomers are able to form HGs within a short time (in the range from 10 to 19 seconds) by physically interacting with CS. This is an alternative to the covalently crosslinking reaction process, providing cost effective HG biomaterials. HG complexes were characterized by rheometry, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. The interaction between AF monomers and the CS polymer has been discussed and the results have been confirmed by FTIR analysis. The storage modulus (G'), loss modulus (G'') and complex viscosity (η*) were evaluated for all HGs using a rheometer, and the ratios of CS and the particular AF monomer were optimized for stable HG formation. The swelling ratio was evaluated using a simple method and was found to be directly related to the structure of the AF monomer, pH and temperature. These HGs were utilised for encapsulation, and the release of active molecules (e.g., reactive red 120 (RR120) as a model compound) was measured at low pH 5.5, physiological pH 7.4 and high pH 9.5. The cell viability and cellular compatibility of the HGs were evaluated in vitro cell culture, demonstrating that all the five different types of HGs support cellular compatibility, attachment and growth. The physical mixing of AF monomers with CS is expedited for the development of new bespoke economically viable biomaterials.


Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent.
The target molecule of pemphigus autoantibodies is a transmembrane desmosomal component, desmoglein 3 (Dsg3) in pemphigus vulgaris (PV) and Dsg1 in pemphigus foliaceus (PF). In this study, we examined the effects of calcium and glycosylation on the anti-genicity of the pemphigus antigens and on the generation of conformational epitopes. We used recombinant baculovirus proteins, PVIg and PFIg, which are considered to reflect accurately the native conformation of the extracellular domain of their respective proteins Dsg3 and Dsg1. These baculoproteins could immunoadsorb heterogeneous autoantibodies from the corresponding sera of PV and PF patients, completely blocking indirect immunofluorescence staining of normal human skin. Chelating calcium from the solution containing the baculoproteins using ethylenediaminetetraacetic acid (EDTA) or ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) abolished immunoadsorption by both PVIg and PFIg; however, immunoadsorption by the baculoproteins was restored after dialysis against 1 mM calcium. Nonglycosylated forms of both baculoproteins produced in the presence of tunicamycin retained their immunoadsorptive ability. Furthermore, immunoadsorption by the baculo-proteins was prevented irreversibly by treatment with low pH, high pH, and boiling, but not with the non-ionic detergent Nonidet P-40. These findings indicate that formation of the conformational epitopes on the pemphigus antigens is dependent on calcium but independent of glycosylation, and provide direct evidence that calcium plays an important role in determining the antigenic properties of the pemphigus antigens.


Hepatic responses to dietary stress in zinc- and metallothionein-deficient mice.
Metallothionein (MT) and zinc are both reported to be protective against oxidative and inflammatory stress and may also influence energy metabolism. The role of MT in regulating intracellular labile zinc, thus influencing zinc (Zn)-modulated protein activity, may be a key factor in the response to stress and other metabolic challenges. The objective of this study was to investigate the influence of dietary zinc intake and MT on hepatic responses to a pro-oxidant stress and energy challenge in the form of a high dietary intake of linoleic acid, an omega-6 polyunsaturated fatty acid. Male MT-null (KO) and wild-type (WT) mice, aged 16 weeks, were given semisynthetic diets containing 16% fat and either 5 (marginally zinc-deficient [ZD]) or 35 (zinc-adequate [ZA]) mg Zn/kg. For comparison, separate groups of KO and WT mice were given a rodent chow diet containing 3.36% fat and 86.6 mg Zn/kg. After 4 months on these diets, the body weights of all mice were equal, but liver size, weight, and lipid content were much greater in the animals that consumed semisynthetic diets compared to the chow diet. The increase in liver size was significantly lower in ZA but not ZD KO mice, compared with WT mice. Principally, MT appears to affect the diet-induced increase in liver tissue but it also influences the concentration of hepatic lipid. Plasma levels of C-reactive protein (CRP), a marker of inflammation, were increased by zinc deficiency in WT mice, suggesting that marginal zinc deficiency is proinflammatory. CRP was unaffected by zinc deficiency in KO mice, indicating a role for MT in modulating the influence of zinc. Neither zinc nor MT deficiency affects the level of soluble liver proteins, as determined using two-dimensional (2D) gel proteomics. This study highlights the close association between zinc and MT in the manifestation of stress responses.


Lumbar Disc Surgery with Epidural Anesthesia: Review of 700 Cases.
Lumbar disc surgery can be performed under general anesthesia or regional anesthesia methods. There are long-standing discussions between neurosurgeons, orthopedic surgeons and anesthesiologists concerning the use of epidural anesthesia in lumbar surgery. The results of this study's 700 lumbar disc surgery cases operated with epidural anesthesia in our clinic between September 2006 and December 2011 will contribute to these discussions. This study included 700 patients underwent lumbar disc surgery with epidural anesthesia, which consisted of 388 males (55%) and 312 females (45%). Forty-two of these cases had recurrence disc herniation and only 11 of 42 cases were operated in our department. Eleven of 700 cases had dural injury and were repaired intraoperatively by primary sutures and tissue sealants. Infection of the incision site developed in six patients, who healed with appropriate antibiotic treatment with no problems. In addition to those 700 cases, 22 patients received general anesthesia in which we started with epidural anesthesia. Microdiscectomies were performed in 578 of 700 cases, and open surgery in 122 cases. This study showed that epidural anesthesia seems more advantageous for some patients since it does not have some of the risks that general anesthesia bears.


Responding to the crisis in sub-Saharan Africa: the role of nutrition.
In the chapter dealing with education and health, the report of the influential Commission for Africa prioritises basic health systems, HIV/AIDS, malaria and tuberculosis. In contrast, nutrition is given less than half a page and is reduced to parasite control and micronutrient support. Such neglect of nutrition is hard to understand in the context of increasing hunger and malnutrition across the continent. Sub-Saharan Africa is the only region in the world where the proportion of underweight children has stagnated and the absolute numbers have actually increased in the last decade. It has been pointed out that if current trends continue sub-Saharan Africa will achieve the Millennium Development Goal for child mortality around 2115 - one century after the target date. Quite clearly those concerned with nutrition need to more powerfully advocate the role of nutrition in lifting Africa out of the spiral of poverty. The present paper argues that to achieve this requires an understanding not just of the critical role of nutrition for health and development (both individual and national), but also of how recent global changes are interacting with changes in food production and supply, other determinants of maternal and child health, and the role and capacity of the state to tackle malnutrition in Africa. It concludes by suggesting some responses that nutritionists could now be making.


Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: results from the CHARM study.
We determined the effects of adalimumab maintenance treatment on the risks of hospitalization and surgery in Crohn's disease (CD). A total of 778 patients with CD were randomized to placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly, all after an 80-mg/40-mg adalimumab induction regimen. All-cause and CD-related hospitalizations and major CD-related surgeries were compared between the placebo and adalimumab groups (every other week, weekly, and both combined) using Kaplan-Meier analysis and Cox proportional hazard models. Both 3- and 12-month hospitalization risks were significantly lower for patients who received adalimumab. Hazard ratios for all-cause hospitalization were 0.45, 0.36, and 0.40 for the adalimumab every other week, weekly, and combined groups, respectively (all P < .01 vs placebo). Hazard ratios for CD-related hospitalization were 0.50, 0.34, and 0.42, respectively (all P < .05). Cox model estimates demonstrated adalimumab every other week and weekly maintenance therapies were associated with 52% and 60% relative reductions in 12-month, all-cause hospitalization risk, and 48% and 64% reductions in 12-month risk of CD-related hospitalization. The combined adalimumab group was associated with 56% reductions in both all-cause and CD-related hospitalization risks. Fewer CD-related surgeries occurred in the adalimumab every other week, weekly, and combined groups compared with placebo (0.4, 0.8, and 0.6 vs 3.8 per 100 patients; all P < .05). Patients with moderate-to-severe CD treated with adalimumab had lower 1-year risks of hospitalization and surgery than placebo patients.


Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes.
Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.


Cumulative effects of transcranial direct current stimulation on EEG oscillations and attention/working memory during subacute neurorehabilitation of traumatic brain injury.
To investigate in a randomized, double-blind design, cumulative effects of anodal tDCS on EEG oscillations and neuropsychological tests among patients with traumatic brain injury (TBI) undergoing subacute neurorehabilitation. Twenty-six patients were randomly assigned to active (n=13) or sham (n=13) tDCS groups. EEGs were recorded at 6 different time points, assessing both immediate and cumulative effects of tDCS on EEG oscillations. Twenty minute sessions of 1mA anodal stimulation to the left dorsolateral prefrontal cortex (F3, cathode placed at right supraorbital site, Fp2), were provided on 10 consecutive days. Neuropsychological tests were administered before and after the series of tDCS sessions. Theta was significantly reduced for active tDCS patients following the first tDCS session. Delta decreased and alpha increased, both significantly, for the active tDCS group after 10 consecutive tDCS sessions. No significant changes were seen for sham group. Decreases in delta were significantly correlated with improved performance on neuropsychological tests for the active tDCS group to far greater degree than for the sham group. Participants in the active tDCS group who had excess slow EEG activity in their initial recordings showed greater improvement on neuropsychological tests than other groups. Results suggest that 10 anodal tDCS sessions may beneficially modulate regulation of cortical excitability for patients with TBI. EEG-guided tDCS warrants further investigation as a potential intervention for TBI during subacute neurorehabilitation.


Cardiovascular Disease Risk Factors Profile Among Australian Vegetarian and Nonvegetarian Teenagers.
Atherosclerosis develops over a long period of time and often begins in childhood. The goal of this study was to make a cross-sectional assessment of the pattern of cardiovascular disease risk factors among Australian vegetarian (n = 49) and nonvegetarian (n = 639) 14- to 17-year-old participants from New South Wales, Australia. Vegetarians had statistically significant lower mean total (4.05 vs 4.4 mmol/L;P < .001) and low-density lipoprotein (LDL) cholesterol (2.18 vs 2.55 mmol/L; P < .001) and lower incidence of abnormal total and LDL cholesterol (31.1% vs 46.2%, P = .036, having total cholesterol ≥4.4 mmol/L and 13.3% vs 29.6%, P = .021, having LDL cholesterol ≥2.84 mmol/L). Vegetarians had a higher diastolic BP (72.0 vs 69.7 mm Hg; P = .038). No statistically significant difference was found in other risk factors including high-density lipoprotein cholesterol (P = .83), triglycerides (P = .601), systolic blood pressure (P = .727), body mass index (P = .159), plasma glucose (P = .09), C-reactive protein (P = .527), or homocysteine (P = .45). The prevalence rate with 3 or more risk factors was 12.2% among vegetarians and 13.9% among nonvegetarians (P = .156). The high percentage of abnormal total cholesterol in both diet groups and, in addition, LDL cholesterol in nonvegetarians is a cause of concern and underlines the need for lifestyle change.


Radiation injury is a potentially serious complication to fluoroscopically-guided complex interventions.
Radiation-induced injury to skin is an infrequent but potentially serious complication to complex fluoroscopically-guided interventional procedures. Due to a lack of experience with such injuries, the medical community has found fluoroscopically-induced injuries difficult to diagnose. Injuries have occurred globally in many countries. Serious injuries most frequently occur on the back but have also occurred on the neck, buttocks and anterior of the chest. Severities of injuries range from skin rashes and epilation to necrosis of the skin and its underlying structures. This article reviews the characteristics of these injuries and some actions that can be taken to reduce their likelihood or seriousness.


Do exercise and self-management interventions benefit patients with osteoarthritis of the knee? A metaanalytic review.
Osteoarthritis (OA) is the most prevalent health condition among seniors and it causes significant pain and disability. We assessed the influence of patient education and exercise regimens on the well-being of patients with knee OA. A metaanalysis was conducted on 16 studies reporting exercise and/or self-management interventions for patients with knee OA. The effects on physical and psychological well-being were assessed immediately after the interventions. Compared to control conditions, exercise regimens led to improvement in physical health (by self-report and direct measures) and in overall impact of OA. Perceived psychological health remained unchanged by the exercise programs. Although the effect sizes for the self-management programs were significant for psychological outcomes and for the overall effect of OA, there was a significant difference between self-management and control groups only in psychological outcomes. Overall, both patient education and exercise regimens had a modest, yet clinically important, influence on patients' well-being.


Modeling the anti-cyberbullying preferences of university students: Adaptive choice-based conjoint analysis.
Adaptive choice-based conjoint analysis was used to study the anti-cyberbullying program preferences of 1,004 university students. More than 60% reported involvement in cyberbullying as witnesses (45.7%), victims (5.7%), perpetrator-victims (4.9%), or perpetrators (4.5%). Men were more likely to report involvement as perpetrators and perpetrator-victims than were women. Students recommended advertisements featuring famous people who emphasized the impact of cyberbullying on victims. They preferred a comprehensive approach teaching skills to prevent cyberbullying, encouraging students to report incidents, enabling anonymous online reporting, and terminating the internet privileges of students involved as perpetrators. Those who cyberbully were least likely, and victims of cyberbullying were most likely, to support an approach combining prevention and consequences. Simulations introducing mandatory reporting, suspensions, or police charges predicted a substantial reduction in the support of uninvolved students, witnesses, victims, and perpetrators.


Ethanol induction of CYP2A5: permissive role for CYP2E1.
CYP2A5 metabolizes xenobiotics and activates hepatocarcinogens, and induction occurs in response to hepatic damage and cellular stress. We evaluated whether ethanol can elevate CYP2A5 and whether CYP2E1 plays a role in the ethanol induction of CYP2A5. Wild-type (WT), CYP2E1 knockout (KO), and CYP2E1 knockin (KI) mice were fed ethanol for 3 weeks. Ethanol increased CYP2E1 and CYP2A5 protein and activity in WT mice but not in the KO mice. Induction of CYP2A5 (and CYP2E1) was restored in the KI mice. Ethanol induction of CYP2A5 occurred only after CYP2E1 was first induced. Immunohistochemical staining revealed that CYP2E1 and CYP2A5 colocalize to the same zones in the liver. Ethanol also elevated CYP2A5 mRNA levels in WT and KI mice but not in KO mice. Induction of CYP2A5 by cadmium was partially decreased in KO mice compared with WT or KI mice. Ethanol elevated CYP2A4 mRNA levels in all mice although the extent of induction was lowest in the KO mice. In summary, ethanol elevated mouse hepatic CYP2A5 levels, which may be of toxicological significance because CYP2A5 metabolizes nicotine and other drugs and activates hepatocarcinogens. Induction of CYP2A5 by ethanol is potentiated by the induction of CYP2E1. We speculate that ethanol induction of CYP2E1 followed by increases in reactive oxygen species and activation of Nrf2 are important steps in the mechanism by which ethanol induces CYP2A5. The possibility that induction of CYP2E1 is permissive for the induction of CYP2A5 may reflect a new contribution by CYP2E1 to the actions of ethanol.


Outcomes of Genitourinary Injury in U.S. Iraq and Afghanistan War Veterans Receiving Care from the Veterans Health Administration.
In the recent conflicts, unprecedented numbers of US service personnel have survived with genitourinary (GU) injury, but few reports have focused on outcomes of these injuries. Outcomes of combat-related GU injury were investigated in wounded US male veterans of Operations Enduring/Iraqi Freedom and New Dawn receiving Veterans Health Administration (VHA) care. Department of Defense Trauma Registry (DoDTR) data for male service members injured in theater were linked with VHA electronic health records (EHRs) for veterans who received VHA care at least once from October 2001 through September 2011. Abbreviated Injury Scale scores and International Classification of Diseases-9th Revision-Clinical Modification codes were used to identify GU injuries, severity, and outcomes. Wounded veterans with vs. without GU injury were compared. A total of 12,923 injured veterans were found in both databases; 591 (4.6%) had a GU injury diagnosis in the DoDTR; 18 (3.0% of 591) had a GU injury diagnosis in VHA EHRs. Of the 591 with GU injury, 179 (30.3%) had at least one severe GU injury. The prevalence of both urinary symptoms (6.3% vs. 3.1%; p < 0.0001) and sexual dysfunction (13.5% vs. 7.1%; p < 0.0001) was higher among those with vs. without GU injury, respectively. Traumatic brain injury prevalence was also higher (48.0 % vs. 40.0%; p < 0.0001); post-traumatic stress disorder prevalence was similar between the two groups (51.6% vs. 50.6%). We identified an opportunity to improve the diagnosis and coordination of care for veterans with GU injury. Routine screening and better documentation upon transfer from DoD to VHA care should be implemented to alert multi-specialty care teams to provide care for the urinary, sexual, fertility, and psychological health problems of these patients.


p63 expression in assessment of bronchioloalveolar proliferations of the lung.
Discrimination of well-differentiated pulmonary adenocarcinoma from reactive bronchioloalveolar epithelium can be difficult on routine histology, especially with small biopsies. Ancillary studies to help in this distinction are desirable. p63, a p53-homologous nuclear protein, is a marker of reserve cells of the bronchus and terminal lobular unit. In this study, 33 cases of adenocarcinoma (20 open lung and 13 transbronchial/percutaneous biopsies) and 43 cases of benign lungs with fibrosis and metaplasia (22 open lung and 21 transbronchial/percutaneous biopsies) were studied for nuclear p63 expression by immunohistochemistry (Dako, Carpinteria, CA, USA). Five additional cases each of atypical adenomatous hyperplasia and adenosquamous carcinoma and three cases of squamous carcinoma (all open lung biopsies) were also stained. The diagnostic categories of benign lung conditions were usual interstitial pneumonia, parenchymal scar, cryptogenic organizing pneumonia and diffuse alveolar damage. In neoplastic cases, p63 positivity was calculated as percentage of all tumor cells examined. In areas of normal lung, p63 decorated the reserve cells of large and small airways and occasional cells of the distal lobular unit. In fibrotic reactive processes, an interrupted but distinct pattern of nuclear staining was present in all cases, with staining of basal cells of the airways as well as bronchiolar- and squamous-metaplastic epithelium (43/43, 100%). p63 immunoreactivity was less uniform in areas of acute lung injury within these cases. One adenocarcinoma and two cases of atypical adenomatous hyperplasia showed strong immunoreactivity (>80%), while three adenocarcinomas highlighted only rare tumor nuclei (<5% of tumor cells). Morphologic areas where p63 immunostaining was not helpful included the junction of normal lung and lepidic growth of adenocarcinoma, and retrograde spread of adenocarcinoma into small airways. Our results highlight the differential expression of p63 across various bronchioloalveolar lesions. Moreover, p63 may be helpful in distinguishing reactive from neoplastic glandular proliferations in the lung.


Classification of human genomic regions based on experimentally determined binding sites of more than 100 transcription-related factors.
Transcription factors function by binding different classes of regulatory elements. The Encyclopedia of DNA Elements (ENCODE) project has recently produced binding data for more than 100 transcription factors from about 500 ChIP-seq experiments in multiple cell types. While this large amount of data creates a valuable resource, it is nonetheless overwhelmingly complex and simultaneously incomplete since it covers only a small fraction of all human transcription factors. As part of the consortium effort in providing a concise abstraction of the data for facilitating various types of downstream analyses, we constructed statistical models that capture the genomic features of three paired types of regions by machine-learning methods: firstly, regions with active or inactive binding; secondly, those with extremely high or low degrees of co-binding, termed HOT and LOT regions; and finally, regulatory modules proximal or distal to genes. From the distal regulatory modules, we developed computational pipelines to identify potential enhancers, many of which were validated experimentally. We further associated the predicted enhancers with potential target transcripts and the transcription factors involved. For HOT regions, we found a significant fraction of transcription factor binding without clear sequence motifs and showed that this observation could be related to strong DNA accessibility of these regions. Overall, the three pairs of regions exhibit intricate differences in chromosomal locations, chromatin features, factors that bind them, and cell-type specificity. Our machine learning approach enables us to identify features potentially general to all transcription factors, including those not included in the data.


Loss of methyl-CpG-binding domain protein 2 enhances endothelial angiogenesis and protects mice against hind-limb ischemic injury.
Despite intensive investigation, how DNA methylation influences endothelial function remains poorly understood. We used methyl-CpG-binding domain protein 2 (MBD2), an interpreter for DNA methylome-encoded information, to dissect the impact of DNA methylation on endothelial function in both physiological and pathophysiological states. Human umbilical vein endothelial cells under normal conditions express moderate levels of MBD2, but knockdown of MBD2 by siRNA significantly enhanced angiogenesis and provided protection against H(2)O(2)-induced apoptosis. Remarkably, Mbd2(-/-) mice were protected against hind-limb ischemia evidenced by the significant improvement in perfusion recovery, along with increased capillary and arteriole formation. Loss of MBD2 activated endothelial survival and proangiogenic signals downstream of vascular endothelial growth factor signaling characterized by an increase in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 expression, along with enhanced extracellular signal-regulated kinase 1/2 activation and BCL-2 expression. Mechanistic studies confirmed the methylation of CpG elements in the eNOS and vascular endothelial growth factor receptor 2 promoter. MBD2 binds to these methylated CpG elements and suppresses eNOS promoter activity. On ischemic insult, key endothelial genes such as eNOS and vascular endothelial growth factor receptor 2 undergo a DNA methylation turnover, and MBD2 interprets the changes of DNA methylation to suppress their expressions. Moreover, MBD2 modulation of eNOS expression is likely confined to endothelial cells because nonendothelial cells such as splenocytes fail to express eNOS after loss of MBD2. We provided direct evidence supporting that DNA methylation regulates endothelial function, which forms the molecular basis for understanding how environmental insults (epigenetic factor) affect the genome to modify disease susceptibility. Because MBD2 itself does not affect the methylation of DNA and is dispensable for normal physiology in mice, it could be a viable epigenetic target for modulating endothelial function in disease states.


[Genetics of dilated cardiomyopathy].
Dilated cardiomyopathy is one of the leading causes of heart failure and a primary cause for heart transplantation in patients below the age of 40 years. Despite major advances in diagnostic procedures such as examination of myocardial biopsies, the etiology remains unknown in many patients. Chronic inflammation or myocarditis and chronic alcohol abuse are considered two main etiologic factors in dilated cardiomyopathy. A third causal factor, namely genetic transmission of the disease, is at least as common as myocardial inflammation or toxic damage. Several prospective studies of relatives of patients with dilated cardiomyopathy proved that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is the disease inherited as an X-chromosomal trait. Autosomal recessive and mitochondrial transmission is rare. The penetrance is highly variable and age dependent. Many relatives of patients with DCM show only minor cardiac abnormalities and it is unknown whether they progress to full cardiomyopathy in later life. Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene. Certain mutations in lamin A/C cause conduction system disease and dilated cardiomyopathy, whereas other mutations cause in addition skeletal muscle myopathy. Dystrophin mutations are the cause of the rare X-linked dilated cardiomyopathy without skeletal muscle involvement and a progressive course in young men. Other mutations in the dystrophin gene, mainly deletions, are the cause of the muscular dystrophy Becker and Duchenne which also present with dilated cardiomyopathy. Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities. The infantile X-linked DCM is caused by mutations of the tafazzin gene. The onset of the disease is typically within the first year of life and death occurs usually in childhood. Most patients may in addition be characterized by skeletal myopathy, short stature, neutropenia and abnormal mitochondria, also referred to as Barth syndrome. Knowledge of the DCM disease genes led to the new hypothesis that dilated cardiomyopathy is a disease of the myocardial force generation or force transmission. Many more disease loci are known but the responsible disease genes are not yet identified. Better understanding of the expression and function of disease genes may eventually result in new diagnostic and therapeutic tools in order to improve the prognosis of this severe disorder.


A Method to Form Smooth Films of Liquid Metal Supported by Elastomeric Substrate.
Several methods are proposed to manipulate and pattern liquid metal films into elastic conductors but all lack precise control over the film thickness and roughness, thereby limiting its uniformity, stability, and reproducibility. Here, an approach relying solely on wetting phenomena is proposed to produce smooth film of liquid gallium (Ga) on extended surface areas with controlled thickness and electrical properties. The surface chemistry and topography of silicone rubber (poly(dimethylsiloxane)) is engineered with microstructured pillars and gold precoating layer to produce Ga superlyophilic substrates. Physical vapor deposition of Ga on such substrates leads to the formation of smooth and homogeneous films by imbibition of the surface topography rather than coalescence and formation of Ga drops. By capillarity, Ga accumulates in between the pillars up to their top surface, forming a smooth film with a root mean square roughness (Rq) smaller than 100 nm. The wetting conditions and electromechanical properties of the resulting films are compared based on the selection of the microtexture patterns and a model of the film sheet resistance as a function of the texture geometrical parameters is established.


Leading multiple teams: average and relative external leadership influences on team empowerment and effectiveness.
External leaders continue to be an important source of influence even when teams are empowered, but it is not always clear how they do so. Extending research on structurally empowered teams, we recognize that teams' external leaders are often responsible for multiple teams. We adopt a multilevel approach to model external leader influences at both the team level and the external leader level of analysis. In doing so, we distinguish the influence of general external leader behaviors (i.e., average external leadership) from those that are directed differently toward the teams that they lead (i.e., relative external leadership). Analysis of data collected from 451 individuals, in 101 teams, reporting to 25 external leaders, revealed that both relative and average external leadership related positively to team empowerment. In turn, team empowerment related positively to team performance and member job satisfaction. However, while the indirect effects were all positive, we found that relative external leadership was not directly related to team performance, and average external leadership evidenced a significant negative direct influence. Additionally, relative external leadership exhibited a significant direct positive influence on member job satisfaction as anticipated, whereas average external leadership did not. These findings attest to the value in distinguishing external leaders' behaviors that are exhibited consistently versus differentially across empowered teams. Implications and future directions for the study and management of external leaders overseeing multiple teams are discussed.


Evidence of influenza a virus RNA in siberian lake ice.
Influenza A virus infects a large proportion of the human population annually, sometimes leading to the deaths of millions. The biotic cycles of infection are well characterized in the literature, including in studies of populations of humans, poultry, swine, and migratory waterfowl. However, there are few studies of abiotic reservoirs for this virus. Here, we report the preservation of influenza A virus genes in ice and water from high-latitude lakes that are visited by large numbers of migratory birds. The lakes are along the migratory flight paths of birds flying into Asia, North America, Europe, and Africa. The data suggest that influenza A virus, deposited as the birds begin their autumn migration, can be preserved in lake ice. As birds return in the spring, the ice melts, releasing the viruses. Therefore, temporal gene flow is facilitated between the viruses shed during the previous year and the viruses newly acquired by birds during winter months spent in the south. Above the Arctic Circle, the cycles of entrapment in the ice and release by melting can be variable in length, because some ice persists for several years, decades, or longer. This type of temporal gene flow might be a feature common to viruses that can survive entrapment in environmental ice and snow.


Identifying appropriate outcomes to help evaluate the impact of the Canadian Guideline for Safe and Effective Use of Opioids for Non-Cancer Pain.
The Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain (COG) was developed in response to increasing rates of opioid-related hospital visits and deaths in Canada, and uncertain benefits of opioids for chronic non-cancer pain (CNCP). Following publication, we developed a list of evaluable outcomes to assess the impact of this guideline on practice and patient outcomes. A working group at the National Pain Centre at McMaster University used a modified Delphi process to construct a list of clinical and patient outcomes important in assessing the uptake and application of the COG. An advisory group then reviewed this list to determine the relevance and feasibility of each outcome, and identified potential data sources. This feedback was reviewed by the National Faculty for the Guideline, and a National Advisory Group that included the creators of the COG, resulting in the final list of 5 priority outcomes. Five outcomes were judged clinically important and feasible to measure: 1) Effects of opioids for CNCP on quality of life, 2) Assessment of patient's risk of addiction before starting opioid therapy, 3) Monitoring patients on opioid therapy for aberrant drug-related behaviour, 4) Mortality rates associated with prescription opioid overdose and 5) Use of treatment agreements with patients before initiating opioid therapy for CNCP. Data sources for these outcomes included patient's medical charts, e-Opioid Manager, prescription monitoring programs and administrative databases. Measuring the impact of best practice guidelines is infrequently done. Future research should consider capturing the five outcomes identified in this study to evaluate the impact of the COG in promoting evidence-based use of opioids for CNCP.


Acute hypotension associated with leucocyte depletion filters during cell salvaged blood transfusion.
Summary Intra-operative cell salvage is used in more than 75% of NHS hospitals in the United Kingdom and is a safe and cost effective alternative to allogenic blood transfusion. We report a case of acute hypotension during reinfusion of cell salvaged blood through a leucocyte depletion filter that occurred during a caesarean section. We review the literature of hypotension associated with the use of bedside leucocyte depletion filters.


Full inactivation of human influenza virus by high hydrostatic pressure preserves virus structure and membrane fusion while conferring protection to mice against infection.
Whole inactivated vaccines (WIVs) possess greater immunogenicity than split or subunit vaccines, and recent studies have demonstrated that WIVs with preserved fusogenic activity are more protective than non-fusogenic WIVs. In this work, we describe the inactivation of human influenza virus X-31 by high hydrostatic pressure (HHP) and analyze the effects on the structure by spectroscopic measurements, light scattering, and electron microscopy. We also investigated the effects of HHP on the glycoprotein activity and fusogenic activity of the viral particles. The electron microscopy data showed pore formation on the viral envelope, but the general morphology was preserved, and small variations were seen in the particle structure. The activity of hemagglutinin (HA) during the process of binding and fusion was affected in a time-dependent manner, but neuraminidase (NA) activity was not affected. Infectious activity ceased after 3 hours of pressurization, and mice were protected from infection after being vaccinated. Our results revealed full viral inactivation with overall preservation of viral structure and maintenance of fusogenic activity, thereby conferring protection against infection. A strong response consisting of serum immunoglobulin IgG1, IgG2a, and serum and mucosal IgA was also detected after vaccination. Thus, our data strongly suggest that applying hydrostatic pressure may be an effective method for developing new vaccines against influenza A as well as other viruses.


SU-E-I-53: Optimal KVp for Image Quality and Noise in Iodine Contrast in Head CTA.
For brain CT perfusion it is well established that 80 kVp is optimal. Although neuro-CT angiography is somewhat similar, emphasis is on the detection of aneurysms and related vascular pathologies throughout the brain. Thus it is necessary to visualize small and large blood vessels with contrast material, as well as form multi-planar views and 3D images, so image quality and noise in addition to contrast are important for thin slices. A study was initiated to determine the optimal kVp for neuro-CTA. A customized version of a commercial head phantom (CIRS 007TE-27 medium adult head CT dose phantom) was purchased to facilitate quantitative measurements with iodinated contrast material, contrast for white and gray matter, and to maintain the ability to perform dosimetry. The customization consisted of adding four 25 mm holes, 35 mm from the center arranged at 45 degree angles from the center, with solid rods equivalent with brain, white, and gray matter, as well as four fillable vials were included for study of contrast agents. Dosimetry measurements were carried out with standard pencil chamber and with 0.6 cc ionization chamber. For study of the optimal kVp for a head CTA, the vials were filled with four different concentrations of contrast, approximating low to medium concentrations that would be expected in such a study. The standard CTA protocol was followed, 64 × 0.625, pitch 0.53, rotation speed 0.5 second, and CTDIvol was kept constant for each kVp. The best contrast was observed at 80 kVp; however, in order to achieve noise in CTA low enough to be clinically useful there may be issues with tube current capability for a clinical technique. Clinical investigation is underway. The best balance of contrast and noise currently possible will be achieved at 100 kVp in a clinical scan.


Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Support for an excess methylation hypothesis for parkinsonism.
The major symptoms of Parkinson's disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal dopaminergic terminals. Norepinephrine, serotonin, and melanin pigments are also decreased and cholinergic activity is increased. The cause of PD is unknown. Increased methylation reactions may play a role in the etiology of PD, because it has been observed recently that the CNS administration of S-adenosyl-L-methionine (SAM), the methyl donor, caused tremors, hypokinesia, and rigidity; symptoms that resemble those that occur in PD. Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly, L-DOPA, the most effective drug used to treat PD, reacts avidly with SAM. So methylation may be important in PD; an idea that is of particular interest because methylation reactions increase in aging, the symptoms of PD are strikingly similar to the neurological and functional changes seen in advanced aging, and PD is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration. To know this, the effects of an increase in methylation in the brain were studied by injecting SAM into the lateral ventricle of rats. The injection of SAM caused neuronal degeneration, noted by a loss of neurons, gliosis, and increased silver reactive fibers in the SN. The degeneration was accompanied with a decrease in SN tyrosine hydroxylase (TH) immunoreactivity, and degeneration of TH-containing fibers. At the injection site in the lateral ventricle it appears that SAM caused a weakening or dissolution of the intercellular substances; observed as a disruption of the ependymal cell layer and the adjacent caudate tissues. SAM may also cause brain atrophy; evidenced by the dilation of the cerebral ventricle. Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.


Dysexecutive Symptoms in Primary Progressive Aphasia: Beyond Diagnostic Criteria.
Primary progressive aphasia (PPA) is a heterogeneous neurodegenerative condition in which the most prominent clinical feature is language difficulties. Other cognitive domains have been described to remain unaffected at the early stages of the disease and, therefore, excluded from diagnostic criteria. However, we show in this article that executive function (EF) disorders may be present in the 3 variants (nonfluent/agrammatic, logopenic, and semantic) of PPA. We also illustrate changes in language and EF by means of a 3-year behavioral and neuroimaging longitudinal study of a patient suffering from the semantic variant of PPA. This review provides an update on current knowledge of PPA, suggesting that dysexecutive symptoms may be encountered in the 3 PPA variants, in their early phases and/or in more advanced stages, when atrophy extends to adjacent brain areas.


Use of nanocellulose in printed electronics: a review.
Since the last decade, interest in cellulose nanomaterials known as nanocellulose has been growing. Nanocellulose has various applications ranging from composite reinforcement to rheological modifiers. Recently, nanocellulose has been shown to have great potential in flexible printed electronics applications. The property of nanocellulose to form self-standing thermally stable films has been exploited for producing transparent and smooth substrates for printed electronics. However, other than substrates, the field of printed electronics involves the use of inks, various processing methods and the production of flexible electronic devices. This review aims at providing an overview of the use and potential of nanocellulose throughout the printed electronics field.


Association of µ-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis.
Previous studies have suggested that the effect of naltrexone in patients with alcohol dependence may be moderated by genetic factors. In particular, the possession of the G allele of the A118G polymorphism of the µ-opioid receptor gene (OPRM1) has been associated with a better response to naltrexone, although controversial results have been reported. The aim of this paper is to combine previous findings by means of a systematic review and a meta-analysis. We retrieved studies on the relationship between A118G polymorphism in OPRM1 gene and response to treatment with naltrexone in patients with alcohol dependence by means of electronic database search. A meta-analysis was conducted using a random-effects model. Calculations of odds ratio (OR) and their confidence intervals (CI) and tests for heterogeneity of the results have been performed. Six previous studies have analyzed the role of A118G polymorphism in response to naltrexone for alcohol dependence. After meta-analysis, we found that naltrexone-treated patients carrying the G allele had lower relapse rates than those who were homozygous for the A allele (OR: 2.02, 95% CI 1.26-3.22; P = 0.003). There were no differences in abstinence rates. Our results support the fact that the G allele of A118G polymorphism of OPRM1 moderates the effect of naltrexone in patients with alcohol dependence. This genetic marker may therefore identify a subgroup of individuals more likely to respond to this treatment.


Touch as an interpersonal emotion regulation process in couples' daily lives: the mediating role of psychological intimacy.
Interpersonal touch seems to promote physical health through its effects on stress-sensitive parameters. However, less is known about the psychological effects of touch. The present study investigates associations between touch and romantic partners' affective state in daily life. We hypothesized that this association is established by promoting the recipient's experience of intimacy. Both partners of 102 dating couples completed an electronic diary 4 times a day during 1 week. Multilevel analyses revealed that touch was associated with enhanced affect in the partner. This association was mediated by the partner's psychological intimacy. Touch was also associated with intimacy and positive affect in the actor. Finally, participants who were touched more often during the diary study week reported better psychological well-being 6 months later. This study provides evidence that intimate partners benefit from touch on a psychological level, conveying a sense of strengthened bonds between them that enhances affect and well-being.


The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells.
Epithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated. A vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-β1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-β1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-β1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-β1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05). This study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in tubular epithelial cells.


A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis.
An increased level of dihydrouridine in tRNA(Phe) was found in human malignant tissues nearly three decades ago, but its biological significance in carcinogenesis has remained unclear. Through analysis of genome-wide gene-expression profiles among non-small cell lung carcinomas (NSCLC), we identified overexpression of a novel human gene, termed hDUS2, encoding a protein that shared structural features with tRNA-dihydrouridine synthases (DUS). The deduced 493-amino-acid sequence showed 39% homology to the dihydrouridine synthase 2 enzyme (Dus2) of Saccharomyces cerevisiae and contained a conserved double-strand RNA-binding motif (DSRM). We found that hDUS2 protein had tRNA-DUS activity and that it physically interacted with EPRS, a glutamyl-prolyl tRNA synthetase, and was likely to enhance translational efficiencies. A small interfering RNA against hDUS2 transfected into NSCLC cells suppressed expression of the gene, reduced the amount of dihydrouridine in tRNA molecules, and suppressed growth. Immunohistochemical analysis showed significant association between higher levels of hDUS2 in tumors and poorer prognosis of lung cancer patients. Our data imply that up-regulation of hDUS2 is a relatively common feature of pulmonary carcinogenesis and that selective suppression of hDUS2 enzyme activity and/or inhibition of formation of the hDUS2-tRNA synthetase complex could be a promising therapeutic strategy for treatment of many lung cancers.


Military veterans and canine assistance for post-traumatic stress disorder: A narrative review of the literature.
Veterans with post-traumatic stress disorder (PTSD) are a vulnerable population at high risk for depression, isolation, and suicide. A substantial body of anecdotal evidence exists supporting the use of canines as an effective adjunct treatment for this population. However, a comprehensive review of its use based on scientific literature has thus far not been conducted. A narrative literature review was conducted to examine the current state of the science on canine assistance for veterans diagnosed with PTSD in order to synthesize current empirical knowledge on the subject. Articles were retrieved among the small body of recent literature using computerized database searches. Inclusion criteria included peer-reviewed journal publications published through October 1st, 2015. Only originally published articles that examined the outcomes of canine assistance on veterans with PTSD were examined. Additionally, each included article was specific to veterans, dogs, and, PTSD in combination rather than article that discuss the concepts separately. Exclusion criteria included symposia and conference material, dissertations, media articles, and no mention of canines as a treatment modality. 563 articles were retrieved; 6 met the criteria. When evaluating data, information and themes were extracted into an Excel table; this table was employed in the synthesis of information into manuscript form. The following themes were explored within the selected publications: What is Canine Assistance; Why Use Canine Assistance for PTSD in Veterans; Concerns; and Future Directions. The literature endorsed canine assistance for PTSD in veterans as a promising modality. Authors also raised concerns about lack of protocols, cost and availability barriers, and animal welfare calling for additional, rigorous research to advance its use as a treatment for veterans with PTSD. PTSD continues to pose significant psychological, health, and welfare challenges to veterans and the multi-disciplinary providers who treat them. Analysis of this literature should expand knowledge and outline future directions for healthcare professions and improve health and wellness for veterans with PTSD through the use of canine assistance.


Computed tomographic evaluation of anatomic and pathologic variations in the feline nasal septum and paranasal sinuses.
The purpose of this study was to compare the prevalence of nasal septal deviation and variations of the paranasal sinuses in normal and diseased cats. Prevalence of nasal septal deviation was 86.7%, 68.4%, and 71.4% in cats with rhinitis, neoplasia, and normal cats, respectively, with no statistically significant difference (P = 0.244). There was a statistically significant difference (P = 0.01) in the magnitude of nasal septal deviation between cats with and cats without nasal disease, using a cutoff value of 1 mm for maximum distance of deviation from midline. There was a statistically significant difference (P = 0.019) between cats with rhinitis and neoplasia when comparing the presence of a mass (7.7% and 53.8%, respectively), but not when comparing for lysis of the septum. Deviation of the frontal sinus septum occurred in 27.7% of all cats, while the sphenoid septum was oblique and eccentric in 96.6% of all cats. The mean length of the frontal sinus was longer in male cats than female cats. The presence of nasal septal deviation alone cannot be used as a criterion to diagnose nasal disease, but cats with rhinitis or neoplasia have more marked deviation than normal cats. The presence of a mass and lysis of the septum were only seen in cats with nasal disease and a mass is more likely to be seen with neoplasia than rhinitis. Male cats have a longer frontal sinus than female cats. Almost all cats have an oblique, eccentric sphenoid septum.


Identification of Microbial Profile of Koji Using Single Molecule, Real-Time Sequencing Technology.
Koji is a kind of Japanese traditional fermented starter that has been used for centuries. Many fermented foods are made from koji, such as sake, miso, and soy sauce. This study used the single molecule real-time sequencing technology (SMRT) to investigate the bacterial and fungal microbiota of 3 Japanese koji samples. After SMRT analysis, a total of 39121 high-quality sequences were generated, including 14354 bacterial and 24767 fungal sequence reads. The high-quality gene sequences were assigned to 5 bacterial and 2 fungal plyla, dominated by Proteobacteria and Ascomycota, respectively. At the genus level, Ochrobactrum and Wickerhamomyces were the most abundant bacterial and fungal genera, respectively. The predominant bacterial and fungal species were Ochrobactrum lupini and Wickerhamomyces anomalus, respectively. Our study profiled the microbiota composition of 3 Japanese koji samples to the species level precision. The results may be useful for further development of traditional fermented products, especially optimization of koji preparation. Meanwhile, this study has demonstrated that SMRT is a robust tool for analyzing the microbial composition in food samples.


Ultrasound Based Planning and Navigation for Non-Anatomical Liver Resections - An Ex-Vivo Study.
Goal: Non-anatomical resections of liver tumors can be very challenging as the surgeon cannot use anatomical landmarks on the liver surface or in the ultrasound image for guidance. This makes it difficult to achieve negative resection margins (R0) and still preserve as much healthy liver tissue as possible. Even though image-guided surgery systems have been introduced to overcome this challenge, they are still rarely used due to their inaccuracy, time-effort and complexity in usage and setup. Methods: We have developed a novel approach, which allows us to create an intra-operative resection plan using navigated ultrasound. First, the surface is scanned using a navigated ultrasound, followed by tumor segmentation on a midsection ultrasound image. Based on this information, the navigation system calculates an optimal resection strategy and displays it along with the tracked surgical instruments. In this study, this approach was evaluated by three experienced hepatobiliary surgeons on ex-vivo porcine models. Results: Using this technique, an R0 resection could be achieved in 22 out of 23 (95.7% R0 resection rate) cases with a median resection margin of 5.9 mm (IQR 3.5-7.7 mm). The resection margin between operators 1, 2 and 3 was 7.8 mm, 4.15 mm and 5.1 mm respectively (p = 0.054). Conclusions: This approach could represent a useful tool for intra-operative guidance in non-anatomical resection alongside conventional ultrasound guidance. However, instructions and training are essential especially if the operator has not used an image-guidance system before.


Highly Active Antiretroviral Therapy (HAART)-Related Hypertriglyceridemia Is Associated With Failure of Recovery of CD14lowCD16+ Monocyte Subsets in AIDS Patients.
As cellular reservoirs, CD16 monocyte subsets play important roles in the progression of HIV infection. Previous studies have shown that highly active antiretroviral therapy (HAART) reduced the percentages of CD14CD16 monocyte subsets, but did not recover the percentages of CD14CD16 subsets. Eighty-four chronic HIV-infected, HAART-naïve individuals and 55 HIV-negative subjects (31 without hyperlipidemia and 24 with hypertriglyceridemia) were enrolled. Plasma HIV-1 RNA levels, CD4 T-cell counts, triglycerides, total cholesterol, high-density lipoprotein, and low-density lipoprotein were followed up for 48 weeks during HAART treatment in the longitudinal study. We found that mild hypertriglyceridemia in HIV-negative subjects and HIV-infected patients, naïve to HAART, did not affect the percentage of monocyte subsets. However, a failure of CD14CD16 subset recovery was observed in patients with HAART-related hypertriglyceridemia at 48 weeks. Thus, HAART-related hypertriglyceridemia altered homeostasis of monocyte subsets to antiviral therapy, which might further affect immune reconstitution.


Assessment of laboratory quality in urine drug testing. A proficiency testing pilot study.
As part of a program to develop accreditation guidelines for urine drug testing laboratories, a pilot study for proficiency testing was conducted. Fifty civilian, commercial laboratories were included on a voluntary basis. Drug-free urine specimens were collected and either fortified with commonly abused drugs at concentrations comparable to casual use or submitted unfortified to participating laboratories as blanks. Samples were submitted on both an open and blind basis to the laboratories. Laboratory performance on open proficiency testing was comparable with that reported in existing proficiency testing programs. Blind proficiency testing produced less accurate results in terms of apparent false-negatives, but significant difficulties were evident in carrying out blind testing and in comparing its results with those of open testing. Specific problems have been identified to guide future programs.


Contribution of demographic and behavioral factors on the changing incidence rates of oropharyngeal and oral cavity cancers in northern California.
It is unknown to what extent patient demographics, smoking, and alcohol use have contributed to changes in oropharyngeal and oral cavity cancer incidence rates. We performed a cohort study of Kaiser Permanente health plan members, ages 20 to 89, for years 1995-2010 (n = 2.2 million annual members). Poisson Regression models estimated calendar trends in cancer rates both adjusted for and stratified by age, sex, smoking, and alcohol abuse history. We identified 1,383 human papillomavirus (HPV)-related and 1,344 HPV-unrelated oral cavity and oropharyngeal cancer cases. With adjustment for age and sex, HPV-related cancer incidence rates increased 3.8% per year (P < 0.001) between 1995 and 2010, whereas rates for HPV-unrelated cancers decreased 2.4% per year (P < 0.001). For years 2007 to 2010, with additional adjustment for smoking and alcohol abuse, results were nonsignificant, but similar in magnitude. The increasing rates for HPV-related cancers were more prominent among nonsmokers (+14.5%) compared with smokers (-2.5%; P-interaction = 0.058). The decreased rates for HPV-unrelated sites were more prominent among those ≥ 60 years (-11.0%) compared with those <60 years (+16.8%; P-interaction = 0.006), among smokers (-9.7%) compared with nonsmokers (+8.4%; P-interaction = 0.055), and among those with an alcohol abuse history (-20.4%) compared with those without a history (+5.8%; P-interaction = 0.009). The observed increasing HPV-related cancer rates are most evident among nonsmokers, whereas the decreasing HPV-unrelated cancer rates are least evident among younger individuals, nonsmokers, and those without an alcohol abuse history. Continued vigilance for oropharyngeal and oral cavity cancer is warranted, including among those without traditional risk factors such as smoking and alcohol abuse.


From START to FINISH: the influence of osmotic stress on the cell cycle.
The cell cycle is a sequence of biochemical events that are controlled by complex but robust molecular machinery. This enables cells to achieve accurate self-reproduction under a broad range of different conditions. Environmental changes are transmitted by molecular signalling networks, which coordinate their action with the cell cycle. The cell cycle process and its responses to environmental stresses arise from intertwined nonlinear interactions among large numbers of simpler components. Yet, understanding of how these pieces fit together into a coherent whole requires a systems biology approach. Here, we present a novel mathematical model that describes the influence of osmotic stress on the entire cell cycle of S. cerevisiae for the first time. Our model incorporates all recently known and several proposed interactions between the osmotic stress response pathway and the cell cycle. This model unveils the mechanisms that emerge as a consequence of the interaction between the cell cycle and stress response networks. Furthermore, it characterises the role of individual components. Moreover, it predicts different phenotypical responses for cells depending on the phase of cells at the onset of the stress. The key predictions of the model are: (i) exposure of cells to osmotic stress during the late S and the early G2/M phase can induce DNA re-replication before cell division occurs, (ii) cells stressed at the late G2/M phase display accelerated exit from mitosis and arrest in the next cell cycle, (iii) osmotic stress delays the G1-to-S and G2-to-M transitions in a dose dependent manner, whereas it accelerates the M-to-G1 transition independently of the stress dose and (iv) the Hog MAPK network compensates the role of the MEN network during cell division of MEN mutant cells. These model predictions are supported by independent experiments in S. cerevisiae and, moreover, have recently been observed in other eukaryotes.


Survey design in orthopaedic surgery: getting surgeons to respond.
We provide an overview of survey design and implementation strategies in orthopaedic surgery. Health-care surveys are vital for obtaining information on the beliefs, patterns of practice, attitudes, and behaviors of orthopaedic surgeons. It is important to obtain a high response rate from administered surveys to reduce bias due to nonresponse. Researchers should follow the guidelines provided by this review to increase the response rate of orthopaedic surgeons to surveys. When designing these surveys, the researcher must consider length, format, and aesthetics. In addition, the types of questions that are included, the wording of these questions, and the order in which the questions are presented within the survey need to be carefully considered. Surveys can be administered by telephone, mail, facsimile (fax), and electronically by e-mail or Internet. The use of a mixed-mode method is recommended to improve the response rate. To increase the response rate to surveys that are directed at health professionals, a number of strategies have been suggested, including using cover letters, personalizing the cover letter and survey package, pretesting the cover letter and survey, contacting the surgeons prior to administration of the survey, contacting the surgeons multiple times, using stamped return envelopes in mail surveys, using appropriate survey packaging styles, providing incentives, and ensuring that the orthopaedic surgeon recognizes the sender of the survey. The costs associated with each administration method are briefly discussed, and ethical considerations are reviewed.


Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study.
Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20-60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926. Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16-30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77-0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50-0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80-0·88; p<0·001), and full lockdowns (0·57, 0·54-0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include protected elective surgical pathways and long-term investment in surge capacity for acute care during public health emergencies to protect elective staff and services. National Institute for Health Research Global Health Research Unit, Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, Medtronic, Sarcoma UK, The Urology Foundation, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.


Malaria vector bionomics in Taita-Taveta County, coastal Kenya.
Estimation of the composition and densities of mosquito species populations is crucial for monitoring the epidemiology of mosquito-borne diseases and provide information on local vectors to public health officials and policy-makers. The aim of this study was to evaluate malaria vector bionomics in ecologically distinct sites in Taita-Taveta County, Kenya. Adult mosquitoes were collected using backpack aspirators and paired indoor/outdoor CDC light traps in 10 randomly selected households in six villages with distinct ecologies over a study period of 3 years. All Anopheles mosquitoes were morphotyped, and sibling species of Anopheles gambiae sensu lato (An. gambiae s.l.) were identified and separated by PCR analysis of extracted ribosomal DNA. All female anophelines were tested for sporozoite infectivity, with engorged females screened for blood-meal sources using the enzyme-linked immunosorbent assay technique. A subsample of those testing positive and those testing negative for Plasmodium in the ELISA were subjected to PCR assay. A total of eight different Anopheles species were collected both indoors and outdoors. Anopheles gambiae s.l. (82.6%, n = 5252) was the predominant species sensu lato, followed by Anopheles coustani sensu lato (An. coustani s.l.; (10.5%, n = 666) and Anopheles funestus sensu lato (An. funestus s.l.; 5.6%, n = 357). A subset of 683 mosquito samples representing An. gambiae s.l. (n = 580, approx. 11.0%) and An. funestus s.l. (n = 103, approx. 28.9%) were identified by molecular diagnostic assays into sibling species. The An. gambiae s.l. complex was composed of Anopheles arabiensis (62.5%, n = 363/580), An. gambiae sensu stricto (An. gambiae s.s.; 0.7%, n = 4/580), Anopheles merus (0.7%, n = 4/580) and Anopheles quadriannulatus (0.2%, n = 1/580), with the remaining samples (35.5%, n = 206/580) unamplified. Anopheles funestus s.l. was composed of An. rivulorum (14.6%, n = 15/103) and An. leesoni (11.6%, n = 12/103); the remaining samples were unamplified (73.8%, n = 76/103). A total of 981 samples were subjected to PCR analysis for malaria parasite detection; of these 16 (1.6%) were confirmed to be positive for Plasmodium falciparum. The overall human blood index was 0.13 (32/238). Anopheles gambiae, An. funestus and An. coustani are key malaria vectors in the Taveta region of Kenya, showing concurrent indoor and outdoor transmission. All of the vectors tested showed a higher propensity for bovine and goat blood than for human blood.