Genome-wide transcriptomic analysis of intestinal tissue to assess the impact of nutrition and a secondary nematode challenge in lactating rats.
Gastrointestinal nematode infection is a major challenge to the health and welfare of mammals. Although mammals eventually acquire immunity to nematodes, this breaks down around parturition, which renders periparturient mammals susceptible to re-infection and an infection source for their offspring. Nutrient supplementation reduces the extent of periparturient parasitism, but the underlying mechanisms remain unclear. Here, we use a genome wide approach to assess the effects of protein supplementation on gene expression in the small intestine of periparturient rats following nematode re-infection. The use of a rat whole genome expression microarray (Affymetrix Gene 1.0ST) showed significant differential regulation of 91 genes in the small intestine of lactating rats, re-infected with Nippostrongylus brasiliensis compared to controls; affected functions included immune cell trafficking, cell-mediated responses and antigen presentation. Genes with a previously described role in immune response to nematodes, such as mast cell proteases, and intelectin, and others newly associated with nematode expulsion, such as anterior gradient homolog 2 were identified. Protein supplementation resulted in significant differential regulation of 64 genes; affected functions included protein synthesis, cellular function and maintenance. It increased cell metabolism, evident from the high number of non-coding RNA and the increased synthesis of ribosomal proteins. It regulated immune responses, through T-cell activation and proliferation. The up-regulation of transcription factor forkhead box P1 in unsupplemented, parasitised hosts may be indicative of a delayed immune response in these animals. This study provides the first evidence for nutritional regulation of genes related to immunity to nematodes at the site of parasitism, during expulsion. Additionally it reveals genes induced following secondary parasite challenge in lactating mammals, not previously associated with parasite expulsion. This work is a first step towards defining disease predisposition, identifying markers for nutritional imbalance and developing sustainable measures for parasite control in domestic mammals.


Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum.
Bullosis diabeticorum is a rare presentation of cutaneous manifestation most commonly affecting the lower limbs in patients with diabetes. The appearance, often as insidious as its resolution, is characterized by tense blisters on the skin surfaces of the lower limbs and the feet. The cause still remains unclear, but it may relate to microangiopathy and neuropathy. In this report, we present a case of a 64-year-old male with multiple episodes of blistering in the left lateral lower limb after a traumatic fall who was subsequently diagnosed with type 2 diabetes mellitus. The patient had a history of poorly controlled blood glucose and subsequently developed vasculopathy and peripheral neuropathy. Despite appropriate glycemic control and antibiotics therapy, the patient developed recurrent bullosis diabeticorum on five separate occasions during a 2-year span from 2005 to 2007. Building on our success with ischemic diabetic foot, we used bone marrow mesenchymal stem cell (BMMSC) transplantation therapy for bullosis diabeticorum. After a 9-month treatment, this patient developed another episode of cellulitis in the same lower limb which was successfully treated with antibacterial therapy. It is interesting that the patient reported no recurrence in the next 10-year follow-up span. This study demonstrates that bullosis diabeticorum could appear even before the onset of diabetes, and vascular insufficiency predisposes to the occurrence of bullosis diabeticorum. Our findings suggest that autologous BMMSC transplantation therapy may be an effective measure for recurrent bullosis diabeticorum; however, this will require further investigation to be conclusive. Early identification of diabetes and its complications and appropriate treatment may improve clinical outcomes and prevent lower limb amputation. ClinicalTrials.gov Identifier: NCT00955669 . Registered on August 10, 2009.


The pharmacokinetics of long-acting antipsychotic medications.
The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, long-acting iloperidone, long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed.


Update of AAPM Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations.
Since publication of the American Association of Physicists in Medicine (AAPM) Task Group No. 43 Report in 1995 (TG-43), both the utilization of permanent source implantation and the number of low-energy interstitial brachytherapy source models commercially available have dramatically increased. In addition, the National Institute of Standards and Technology has introduced a new primary standard of air-kerma strength, and the brachytherapy dosimetry literature has grown substantially, documenting both improved dosimetry methodologies and dosimetric characterization of particular source models. In response to these advances, the AAPM Low-energy Interstitial Brachytherapy Dosimetry subcommittee (LIBD) herein presents an update of the TG-43 protocol for calculation of dose-rate distributions around photon-emitting brachytherapy sources. The updated protocol (TG-43U1) includes (a) a revised definition of air-kerma strength; (b) elimination of apparent activity for specification of source strength; (c) elimination of the anisotropy constant in favor of the distance-dependent one-dimensional anisotropy function; (d) guidance on extrapolating tabulated TG-43 parameters to longer and shorter distances; and (e) correction for minor inconsistencies and omissions in the original protocol and its implementation. Among the corrections are consistent guidelines for use of point- and line-source geometry functions. In addition, this report recommends a unified approach to comparing reference dose distributions derived from different investigators to develop a single critically evaluated consensus dataset as well as guidelines for performing and describing future theoretical and experimental single-source dosimetry studies. Finally, the report includes consensus datasets, in the form of dose-rate constants, radial dose functions, and one-dimensional (1D) and two-dimensional (2D) anisotropy functions, for all low-energy brachytherapy source models that met the AAPM dosimetric prerequisites [Med. Phys. 25, 2269 (1998)] as of July 15, 2001. These include the following 125I sources: Amersham Health models 6702 and 6711, Best Medical model 2301, North American Scientific Inc. (NASI) model MED3631-A/M, Bebig/Theragenics model I25.S06, and the Imagyn Medical Technologies Inc. isostar model IS-12501. The 103Pd sources included are the Theragenics Corporation model 200 and NASI model MED3633. The AAPM recommends that the revised dose-calculation protocol and revised source-specific dose-rate distributions be adopted by all end users for clinical treatment planning of low energy brachytherapy interstitial sources. Depending upon the dose-calculation protocol and parameters currently used by individual physicists, adoption of this protocol may result in changes to patient dose calculations. These changes should be carefully evaluated and reviewed with the radiation oncologist preceding implementation of the current protocol.


Oesophageal atresia.
Oesophageal atresia (EA) is a congenital abnormality of the oesophagus that is caused by incomplete embryonic compartmentalization of the foregut. EA commonly occurs with a tracheo-oesophageal fistula (TEF). Associated birth defects or anomalies, such as VACTERL association, trisomy 18 or 21 and CHARGE syndrome, occur in the majority of patients born with EA. Although several studies have revealed signalling pathways and genes potentially involved in the development of EA, our understanding of the pathophysiology of EA lags behind the improvements in surgical and clinical care of patients born with this anomaly. EA is treated surgically to restore the oesophageal interruption and, if present, ligate and divide the TEF. Survival is now ~90% in those born with EA with severe associated anomalies and even higher in those born with EA alone. Despite these achievements, long-term gastrointestinal and respiratory complications and comorbidities in patients born with EA are common and lead to decreased quality of life. Oesophageal motility disorders are probably ubiquitous in patients after undergoing EA repair and often underlie these complications and comorbidities. The implementation of several new diagnostic and screening tools in clinical care, including high-resolution impedance manometry, pH-multichannel intraluminal impedance testing and disease-specific quality of life questionnaires now provide better insight into these problems and may contribute to better long-term outcomes in the future.


Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside.
Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).


Evaluation of a mobile phone telemonitoring system for glycaemic control in patients with diabetes.
We conducted a randomized controlled trial using mobile health technology in an ethnically diverse sample of 137 patients with complicated diabetes. Patients in the intervention group (n = 72) were trained to measure their blood glucose with a sensor which transmitted the readings to a mobile phone via a Bluetooth wireless link. Clinicians were then able to examine and respond to the readings which were viewed with a web-based application. Patients in the control arm of the study (n = 65) did not transmit their readings and received care with their usual doctor in the outpatient and/or primary care setting. The mean follow-up period was 9 months in each group. The default rate was higher in the patients in the intervention arm due to technical problems. In an intention-to-treat analysis there were no differences in HbA(1c) between the intervention and control groups. In a sub-group analysis of the patients who completed the study, the telemonitoring group had a lower HbA(1c) than those in the control group: 7.76% and 8.40%, respectively (P = 0.06).


Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth.
Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH <7.10, base excess ≤12 mmol/L, and 5-min Apgar score <7). All deliveries were planned vaginal, but 51 neonates were born by emergency cesarean section. Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress.


Prostratin and 12-O-tetradecanoylphorbol 13-acetate are potent and selective inhibitors of Chikungunya virus replication.
A chemical study of the Vietnamese plant species Trigonostemon howii led to the isolation of a new tigliane-type diterpenoid, trigowiin A (1), along with several known coumarins and phenylpropanoids. The planar structure and the relative configuration of compound 1 were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Trigowiin A (1) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Since the structure of compound 1 is closely related to those of well-known tigliane diterpenoids such as prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13-acetate (TPA) (4), and 4α-TPA (5), the antiviral activity of the latter compounds was also evaluated against CHIKV, as well as in virus-cell-based assays of two additional members of the genus Alphavirus (Sindbis virus, SINV, and Semliki forest virus, SFV). Whereas prostratin inhibited CHIKV replication with a moderate EC(50) of 2.6 μM and a selectivity index (SI) approximating 30, compound 4 proved to be an extremely potent inhibitor, with an EC(50) of ∼3 nM and a SI near 2000. Interestingly, no or very little activity was observed on the replication of SINV and SFV.


Prevalence of antibodies to West Nile virus and other arboviruses among Crested Caracaras (Caracara cheriway) in Florida.
We documented the antibody prevalence to three arboviruses, St. Louis encephalitis virus (SLEV), eastern equine encephalitis virus (EEEV), and West Nile virus (WNV), in Crested Caracaras (Caracara cheriway; n = 80) in Florida from 2007 to 2008. Antibody prevalence to WNV was higher (9%) than for the other viruses. Most seropositive birds were adults (< or =3 yr of age), with 55% of adults testing positive for antibodies to at least one virus. Adults were significantly more likely to have antibodies to WNV than nonadults (P<0.001). Prevalence of SLEV and EEEV antibodies among Crested Caracaras was 3% for each virus, and three adult caracaras had indistinguishable anti-flavivirus antibodies. The susceptibility of Crested Caracaras to adverse effects of WNV, SLEV, or EEEV infection remains unknown; however, we observed that some free-ranging individuals survived infection and successfully fledged young. Knowledge of arboviral infection among Florida's Crested Caracara, which is both state and federally threatened, is valuable considering increasing pressure on this population from rapid and extensive habitat alterations.


Food hypersensitivity among adult patients: epidemiological and clinical aspects.
Food hypersensitivity (FH) is lesser frequent among adult patients than in childhood. Foods implicated in hypersensitivity reactions vary with sociocultural and diet habits from a geographic place to other. We studied 142 adult patients sensitized to foods, among 7698 patients visited at our Outpatient Clinic. Hundred and twenty patients referred clinical symptoms after consumption of one or more foods consistently. From the latest, 107 patients (89.2%) were atopics (92 of them sensitizes to dust mites) and 54 (45%) referred atopic familiar background. Most frequent recorded symptoms were: urticaria/angioedema 84 cases (70%), oral syndrome 65 (54%), asthma 48 (37%) and anaphylaxis 33 patients (27.5%). Shellfish sensitization occurred in 50 patients, fresh fruits in 33 and nuts in 29 cases. Shrimp (48 patients), squid (33), kiwi (14), papaya (14), avocado (13) and banana (12 cases) were the most frequent causes of FH. Significant statistical association between foods and inhalants was observed for fresh fruits and latex (p < 0.001), fresh fruits and pollens (p < 0.01), and shellfish and Blatta germanica (p < 0.001). Prevalence of FH among patients at our Area is around 1.6%. Tropical fruits, as other kind of fruits, seem to share common IgE-epitopes to pollens. High prevalence of shellfish and cockroach hypersensitivity could be more easily developed by previous domestic mites sensitization.


Modeling of the suprachiasmatic nucleus based on reduced molecular clock mechanisms.
One of the physiological substrates of circadian rhythms is known to be located in the suprachiasmatic nucleus (SCN), which unilaterally contains up to 10,000 or more pacemaker cells. Specific molecular clock mechanisms are working within each cell. Here, in order to prevent complexity explosion in understanding the dynamics of SCN, the molecular clock mechanisms are modeled in a reduced form preserving their dynamical characteristics. The reduced cellular models are coupled by diffusions of activating and suppressing agents so as to construct the whole SCN model. The resulting spatial patterns of entrainment are studied under varied diffusion constants. The simulation results suggest validity of reduction of the molecular dynamics as well as usefulness of the strategy employed to model the hierarchical biological system.


Long-run effects of gestation during the Dutch Hunger Winter famine on labor market and hospitalization outcomes.
The Dutch Hunger Winter (1944/45) is the most-studied famine in the literature on long-run effects of malnutrition in utero. Its temporal and spatial demarcations are clear, it was severe, it was not anticipated, and nutritional conditions in society were favorable and stable before and after the famine. This is the first study to analyze effects of in utero exposure on labor market outcomes and hospitalization late in life, and the first to use register data covering the full Dutch population to examine long-run effects of this famine. We provide results of famine exposure by sub-interval of gestation. We find a significantly negative effect of exposure during the first trimester of gestation on employment outcomes 53 or more years after birth. Hospitalization rates in the years before retirement are higher after middle or late gestational exposure.


Plasma insulin levels predict atherosclerotic lesion burden in obese hyperlipidemic mice.
Despite a clear association between obesity, insulin resistance and atherosclerosis in humans, to date, no animal models have been described in which insulin resistance is associated with atherosclerotic lesion burden. Using two mouse models of obesity-induced hyperlipidemia:leptin deficient (ob/ob) mice on an apolipoprotein E deficient (apoE-/-) or low density lipoprotein receptor deficient (LDLR-/-) background, we sought to determine metabolic parameters most closely associated with atherosclerotic lesion burden. Total plasma cholesterol (TC) levels in ob/ob;apoE-/- mice and ob/ob;LDLR-/- mice were indistinguishable (682+/-48 versus 663+/-16, respectively). Analysis of lipoprotein profiles showed that cholesterol was carried primarily on VLDL in the ob/ob;apoE-/- mice and on LDL in the ob/ob;LDLR-/- mice. Plasma triglycerides (TG) were 55% lower (P<0.001), non-esterified fatty acids (NEFA) were 1.5-fold higher (P<0.01), and insulin levels were 1.7-fold higher (NS) in ob/ob;apoE-/- mice compared to ob/ob;LDLR-/- mice. Other parameters such as body weight, fat pad weight, and glucose levels were not different between the groups. Aortic sinus lesion area of ob/ob;apoE-/- mice was increased 3.2-fold above ob/ob;LDLR-/- mice (102,455+/-8565 microm2/section versus 31,750+/-4478 microm2/section, P<0.001). Lesions in ob/ob;apoE-/- mice were also more complex as evidenced by a 7.7-fold increase in collagen content (P<0.001). Atherosclerotic lesion area was positively correlated with body weight (P<0.005), NEFA (P=0.007), and insulin (P=0.002) levels in the ob/ob;LDLR-/- mice and with insulin (P=0.014) in the ob/ob;apoE-/- mice. In contrast, lesion burden was neither associated with TC and TG, nor with individual lipoprotein pools, in either animal model. These data provide a direct demonstration of the pathophysiologic relevance of hyperinsulinemia, NEFA, and increased body weight to atherosclerotic lesion formation.


TLR15 is unique to avian and reptilian lineages and recognizes a yeast-derived agonist.
The TLRs represent a family of pattern recognition receptors critical in the induction of vertebrate immune responses. Between 10 and 13 different TLR genes can be identified in each vertebrate species, with many represented as orthologous genes in different species. The agonist specificity of orthologous TLR is also highly conserved. In contrast, TLR15 can only be identified in avian and reptilian genomes, suggesting that this receptor arose ~320 million years ago after divergence of the bird/reptile and mammalian lineages. Transfection of a constitutively active form of chicken TLR15 led to NF-κB activation in HEK293 cells and induced cytokine mRNA upregulation in chicken cell lines. Full-length TLR15 mediated NF-κB induction in response to lysates from yeast, but not those derived from viral or bacterial pathogens, or a panel of well-characterized TLR agonists. TLR15 responses were induced by whole-cell lysates derived from Candida albicans, Saccharomyces cerevisiae, and Schizosaccharomyces pombe, but not zymosan preparations from S. cerevisiae. The ability of yeast lysate to activate TLR15-dependent NF-κB pathways (in transfection assays) or stimulate IL-1β mRNA upregulation in chicken macrophages was abrogated by heat inactivation or pre-exposure of the lysate to PMSF. Identification of yeast as an agonist source for TLR15 provides a functional framework for consideration of this TLR within the context of pattern recognition receptor evolution and may impact on the development of novel adjuvants.


The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse.
The role of intestinal microbiota in the development and function of host physiology is of high interest, especially with respect to the nervous system. While strong evidence has accrued that intestinal bacteria alter host nervous system function, mechanisms by which this occurs have remained elusive. For this reason, we have carried out experiments examining the electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system (ENS) in germ-free (GF) mice compared with specific pathogen-free (SPF) control mice and adult germ-free mice that have been conventionalized (CONV-GF) with intestinal bacteria. Segments of jejunum from 8 to 12 week old GF, SPF, and CONV-GF mice were dissected to expose the myenteric plexus. Intracellular recordings in current-clamp mode were made by impaling cells with sharp microelectrodes. Action potential (AP) shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured. In GF mice, excitability was decreased in myenteric afterhyperpolarization (AH) neurons as measured by a lower resting membrane potential and by the number of APs generated at 2× threshold. The post AP slow afterhyperpolarization (sAHP) was prolonged for GF compared with SPF and CONV-GF animals. Passive membrane characteristics were also altered in GF mice by a decrease in input resistance. Here, we report the novel finding that commensal intestinal microbiota are necessary for normal excitability of gut sensory neurons and thus provide a potential mechanism for the transfer of information between the microbiota and nervous system.


Disentangling trophic interactions inside a Caribbean marine reserve.
Recent empirical studies have demonstrated that human activities such as fishing can strongly affect the natural capital and services provided by tropical seascapes. However, policies to mitigate anthropogenic impacts can also alter food web structure and interactions, regardless of whether the regulations are aimed at single or multiple species, with possible unexpected consequences for the ecosystems and their associated services. Complex community response to management interventions have been highlighted in the Caribbean, where, contrary to predictions from linear food chain models, a reduction in fishing intensity through the establishment of a marine reserve has led to greater biomass of herbivorous fish inside the reserve, despite an increased abundance of large predatory piscivores. This positive multi-trophic response, where both predators and prey benefit from protection, highlights the need to take an integrated approach that considers how numerous factors control species coexistence in both fished and unfished systems. In order to understand these complex relationships, we developed a general model to examine the trade-offs between fishing pressure and trophic control on reef fish communities, including an exploration of top-down and bottom-up effects. We then validated the general model predictions by parameterizing the model for a reef system in the Bahamas in order to tease apart the wide range of species responses to reserves in the Caribbean. Combining the development of general theory and site-specific models parameterized with field data reveals the underlying driving forces in these communities and enables us to make better predictions about possible population and community responses to different management schemes.


Building the evidence base for population-level interventions: barriers and opportunities.
Population-level interventions focused on policy, systems, and environmental change strategies are increasingly being used to affect and improve the health of populations. At the same time, emphasis on implementing evidence-based public health practices and programming is increasing, particularly at the federal level. Valuing strategies in the population health domain without the benefit of demonstrated efficacy through highly rigorous methods introduces an inherent tension between planning and acting on the best evidence available, waiting for more rigorous evidence to emerge, as well as exploring innovative ways to evaluate and model evidence-based strategies. This article describes the creation of a resource that helps public health practitioners use current evidence for strategic decision making while building the evidence base for population-level interventions. The resource addresses topics of current discussion in the field of evaluating population-level interventions, including the tension between internal and external validity, the need to include measures of health equity, and the balance between fidelity to the intervention and adaptation to the community context. The resource is intended to advance development of evidence in the field by providing practitioners, project managers, and evaluators with a practical guide for using, reviewing, and adding to the existing evidence base.


The four principles: can they be measured and do they predict ethical decision making?
The four principles of Beauchamp and Childress--autonomy, non-maleficence, beneficence and justice--have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care. This study tests whether these principles can be quantitatively measured on an individual level, and then subsequently if they are used in the decision making process when individuals are faced with ethical dilemmas. The Analytic Hierarchy Process was used as a tool for the measurement of the principles. Four scenarios, which involved conflicts between the medical ethical principles, were presented to participants who then made judgments about the ethicality of the action in the scenario, and their intentions to act in the same manner if they were in the situation. Individual preferences for these medical ethical principles can be measured using the Analytic Hierarchy Process. This technique provides a useful tool in which to highlight individual medical ethical values. On average, individuals have a significant preference for non-maleficence over the other principles, however, and perhaps counter-intuitively, this preference does not seem to relate to applied ethical judgements in specific ethical dilemmas. People state they value these medical ethical principles but they do not actually seem to use them directly in the decision making process. The reasons for this are explained through the lack of a behavioural model to account for the relevant situational factors not captured by the principles. The limitations of the principles in predicting ethical decision making are discussed.


Gene-for-gene defense of wheat against the Hessian fly lacks a classical oxidative burst.
Genetic similarities between plant interactions with microbial pathogens and wheat interactions with Hessian fly larvae prompted us to investigate defense and counterdefense mechanisms. Plant oxidative burst, a rapid increase in the levels of active oxygen species (AOS) within the initial 24 h of an interaction with pathogens, commonly is associated with defenses that are triggered by gene-for-gene recognition events similar to those involving wheat and Hessian fly larvae. RNAs encoded by Hessian fly superoxide dismutase (SOD) and catalase (CAT) genes, involved in detoxification of AOS, increased in first-instar larvae during both compatible and incompatible interactions. However, mRNA levels of a wheat NADPH oxidase (NOX) gene that generates superoxide (O2-) did not increase. In addition, inhibiting wheat NOX enzyme with diphenyleneiodonium did not result in increased survival of avirulent larvae. However, nitro blue tetrazolium staining indicated that basal levels of O2- are present in both uninfested and infested wheat tissue. mRNA encoded by wheat genes involved in detoxification of the cellular environment, SOD, CAT, and glutathione-S-transferase did not increase in abundance. Histochemical staining with 3,3-diaminobenzidine revealed no increases in wheat hydrogen peroxide (H2O2) during infestation that were correlated with the changes in larval SOD and CAT mRNA. However, treatment with 2',7'-dichlorofluorescin demonstrated the presence of basal levels of H2O2 in the elongation zone of both infested and uninfested plants. The accumulation of a wheat flavanone 3-hydroxylase mRNA did show some parallels with larval gene mRNA profiles. These results suggested that larvae encounter stresses imposed by mechanisms other than an oxidative burst in wheat seedlings.


Combining an evolution-guided clustering algorithm and haplotype-based LRT in family association studies.
With the completion of the international HapMap project, many studies have been conducted to investigate the association between complex diseases and haplotype variants. Such haplotype-based association studies, however, often face two difficulties; one is the large number of haplotype configurations in the chromosome region under study, and the other is the ambiguity in haplotype phase when only genotype data are observed. The latter complexity may be handled based on an EM algorithm with family data incorporated, whereas the former can be more problematic, especially when haplotypes of rare frequencies are involved. Here based on family data we propose to cluster long haplotypes of linked SNPs in a biological sense, so that the number of haplotypes can be reduced and the power of statistical tests of association can be increased. In this paper we employ family genotype data and combine a clustering scheme with a likelihood ratio statistic to test the association between quantitative phenotypes and haplotype variants. Haplotypes are first grouped based on their evolutionary closeness to establish a set containing core haplotypes. Then, we construct for each family the transmission and non-transmission phase in terms of these core haplotypes, taking into account simultaneously the phase ambiguity as weights. The likelihood ratio test (LRT) is next conducted with these weighted and clustered haplotypes to test for association with disease. This combination of evolution-guided haplotype clustering and weighted assignment in LRT is able, via its core-coding system, to incorporate into analysis both haplotype phase ambiguity and transmission uncertainty. Simulation studies show that this proposed procedure is more informative and powerful than three family-based association tests, FAMHAP, FBAT, and an LRT with a group consisting exclusively of rare haplotypes. The proposed procedure takes into account the uncertainty in phase determination and in transmission, utilizes the evolutionary information contained in haplotypes, reduces the dimension in haplotype space and the degrees of freedom in tests, and performs better in association studies. This evolution-guided clustering procedure is particularly useful for long haplotypes containing linked SNPs, and is applicable to other haplotype-based association tests. This procedure is now implemented in R and is free for download.


Cumulative risk assessment of the intake of organophosphorus and carbamate pesticides in the Danish diet.
The aim of the study is to evaluate the potential cumulative effects of organophosphorus and carbamate pesticides that act through a common mechanism of toxicity, and to assess the long- and short-term risks for the Danish population. The intake estimates are based on dietary intake data collected in the Danish nation-wide food consumption survey in 1995. The pesticide data are based on the Danish pesticide residue-monitoring programme from 1996-2001. The amount of 35 organophosphorus pesticides and carbamates were included in the cumulative risk assessment. Processing factors, such as reduction of pesticide levels by rinsing and peeling, were applied in the exposure assessment. The "Toxicity Equivalence Factor" (TEF) approach was used to normalise the toxicity of the different organophosphorus and carbamate pesticides. Cumulative chronic exposure of organophosphorus and carbamates pesticides via fruit, vegetables and cereals is for adults 0.8-2% of the Acceptable Daily Intake (ADI) in chlorpyrifos equivalents, and 0.03-11% of the ADI in methamidophos equivalents; and for children 2-5% of the ADI in the chlorpyrifos equivalents, and 0.07-27% of the ADI in methamidophos equivalents. Neither Acute Reference Dose (ARfD) nor ADI was exceeded for any of the compounds studied. The results indicate that the Danish population is neither exposed to any cumulative chronic risk, nor at risk of acute exposure, from consumption of organophosphorus and carbamate pesticides from fruit, vegetables and cereals.


STEM: a tool for the analysis of short time series gene expression data.
Time series microarray experiments are widely used to study dynamical biological processes. Due to the cost of microarray experiments, and also in some cases the limited availability of biological material, about 80% of microarray time series experiments are short (3-8 time points). Previously short time series gene expression data has been mainly analyzed using more general gene expression analysis tools not designed for the unique challenges and opportunities inherent in short time series gene expression data. We introduce the Short Time-series Expression Miner (STEM) the first software program specifically designed for the analysis of short time series microarray gene expression data. STEM implements unique methods to cluster, compare, and visualize such data. STEM also supports efficient and statistically rigorous biological interpretations of short time series data through its integration with the Gene Ontology. The unique algorithms STEM implements to cluster and compare short time series gene expression data combined with its visualization capabilities and integration with the Gene Ontology should make STEM useful in the analysis of data from a significant portion of all microarray studies. STEM is available for download for free to academic and non-profit users at http://www.cs.cmu.edu/~jernst/stem.


Beyond arctic and alpine: the influence of winter climate on temperate ecosystems.
Winter climate is expected to change under future climate scenarios, yet the majority of winter ecology research is focused in cold-climate ecosystems. In many temperate systems, it is unclear how winter climate relates to biotic responses during the growing season. The objective of this study was to examine how winter weather relates to plant and animal communities in a variety of terrestrial ecosystems ranging from warm deserts to alpine tundra. Specifically, we examined the association between winter weather and plant phenology, plant species richness, consumer abundance, and consumer richness in 11 terrestrial ecosystems associated with the U.S. Long-Term Ecological Research (LTER) Network. To varying degrees, winter precipitation and temperature were correlated with all biotic response variables. Bud break was tightly aligned with end of winter temperatures. For half the sites, winter weather was a better predictor of plant species richness than growing season weather. Warmer winters were correlated with lower consumer abundances in both temperate and alpine systems. Our findings suggest winter weather may have a strong influence on biotic activity during the growing season and should be considered in future studies investigating the effects of climate change on both alpine and temperate systems.


The Microbial Genomes Atlas (MiGA) webserver: taxonomic and gene diversity analysis of Archaea and Bacteria at the whole genome level.
The small subunit ribosomal RNA gene (16S rRNA) has been successfully used to catalogue and study the diversity of prokaryotic species and communities but it offers limited resolution at the species and finer levels, and cannot represent the whole-genome diversity and fluidity. To overcome these limitations, we introduced the Microbial Genomes Atlas (MiGA), a webserver that allows the classification of an unknown query genomic sequence, complete or partial, against all taxonomically classified taxa with available genome sequences, as well as comparisons to other related genomes including uncultivated ones, based on the genome-aggregate Average Nucleotide and Amino Acid Identity (ANI/AAI) concepts. MiGA integrates best practices in sequence quality trimming and assembly and allows input to be raw reads or assemblies from isolate genomes, single-cell sequences, and metagenome-assembled genomes (MAGs). Further, MiGA can take as input hundreds of closely related genomes of the same or closely related species (a so-called 'Clade Project') to assess their gene content diversity and evolutionary relationships, and calculate important clade properties such as the pangenome and core gene sets. Therefore, MiGA is expected to facilitate a range of genome-based taxonomic and diversity studies, and quality assessment across environmental and clinical settings. MiGA is available at http://microbial-genomes.org/.


Chemoprevention of head and neck cancer with green tea polyphenols.
Recently, squamous cell carcinoma of the head and neck chemoprevention research has made major advances with novel clinical trial designs suited for the purpose, use of biomarkers to identify high-risk patients, and the emergence of numerous molecularly targeted agents and natural dietary compounds. Among many natural compounds, green tea polyphenols, particularly (-)-epigallocatechin-3-gallate (EGCG), possess remarkable potential as chemopreventive agents. EGCG modulates several key molecular signaling pathways at multiple levels and has synergistic or additive effects when combined with many other natural or synthetic compounds. This review will provide an update of the potential of green tea polyphenols, particularly EGCG, for the chemoprevention of squamous cell carcinoma of the head and neck.


Variability of bronchodilator response and effects of inhaled corticosteroid treatment in obstructive airways disease. Dutch CNSLD Study Group.
In the day to day care of obstructive airways diseases (asthma and chronic obstructive pulmonary disease) important decisions such as disease classification and choice of therapy are based on assessment of the bronchodilator response. However, surprisingly little is known of the long term course of the bronchodilator response in patients with obstructive airways disease. Data from a multicentre trial were used in which 274 patients aged 18-60 years with airways obstruction were selected with PC20 < 8 mg/ml and FEV1 < 95% CI of predicted. FEV1 was measured before and 20 minutes after 1000 micrograms terbutaline and 40 minutes after an additional 80 micrograms ipratropium bromide. Data were analysed from 185 patients who were followed up for 21 months (five measurements). Four different expressions of bronchodilator response (BDR) were examined for change under long term therapy, long term variability, and prognostic value in predicting response to inhaled corticosteroids. There was a significant reduction in BDR of 117 ml after three months of treatment with a beta 2 agonist plus a corticosteroid (BA + CS), but not after bronchodilators only. Significant reductions with BA + CS were also found in BDR as a percentage of initial FEV1, and in BDR as a percentage of predicted FEV1. Bronchodilator tests were quite variable (SD 186 ml or 11% of initial value) and less than half of the patients could consistently be classified as "irreversible" with recommended cutoff levels. The bronchodilator response at the start of the study proved to be a poor predictor of improvement in FEV1 under BA + CS treatment (correct prediction 60%). Bronchodilator responses decrease substantially with inhaled corticosteroid therapy, and within subject variability is considerable both in asthma and chronic obstructive pulmonary disease. Dichotomous decisions on whether patients are "irreversible" according to any single bronchodilator measurement should therefore be made with great caution. The bronchodilator response cannot be used accurately as a predictor of response to inhaled corticosteroids in obstructive airways disease.


Branch Atheromatous Disease: A Clinically Meaningful, Yet Unproven Concept.
In 1989, Louis Caplan first used the term branch atheromatous disease (BAD) to describe an occlusion or stenosis at the origin of a deep penetrating artery of the brain, associated with a microatheroma or a junctional plaque, and leading to an internal capsule or pontine small infarct. BAD remained an understudied concept for decades. In recent years, the increasing diffusion of high-resolution magnetic resonance imaging (HRMRI) techniques brought new attention to the BAD debate. We have reviewed clinical studies dealing with BAD-related stroke checking whether a univocal definition of BAD existed, as well as to what extent were consistently associated clinical and imaging features reported. We conducted a search of the available literature published up to October 20, 2015 via PubMed using the following search terms: 'branch atheromatous disease,' 'intracranial branch atheromatous disease,' 'cerebral branch atheromatous disease,' combined with 'stroke.' Forty-six articles were included. We found discrepant definitions and a large variation among clinical features reported in BAD-related stroke patients: among others, a consistent association between BAD and any specific vascular risk factor profile was not detected. Despite this, early neurological deterioration (END) was consistently reported to occur frequently in such patients, although no clear-cut rate range or specific predictor or mechanism of progression was established. In a majority of the studies reporting imaging data, BAD diagnosis was not based on the selective site or type of arterial walls changes, but was inferred based on the vascular territory, size and/or shape of the ischemic lesion. Following the concept that these changes are seated proximally along the perforator artery, differently from to lipohyalinosis changes located distally, the consequent ischemic lesion was hypothesized to be larger in BAD than in lacunar infarcts. However, across reviewed studies, there was little consistency on the dimensional cutoff used to define BAD-related infarcts. In the last few years, a still limited number of studies using HRMRI techniques is providing preliminary proofs that atheromatous changes causing selective remodeling in the parent vessel and extending through the proximal segment of perforating vessel may subtend BAD. Our literature search showed the lack of a clear-cut definition of BAD, although BAD-related strokes were consistently considered a high risk of END. The use of high-resolution imaging techniques in the assessment of small subcortical strokes may represent the cornerstone in the perspective to better delimiting the boundaries of BAD as a nosological entity.


An Asian origin for a 10,000-year-old domesticated plant in the Americas.
New genetic and archaeological approaches have substantially improved our understanding of the transition to agriculture, a major turning point in human history that began 10,000-5,000 years ago with the independent domestication of plants and animals in eight world regions. In the Americas, however, understanding the initial domestication of New World species has long been complicated by the early presence of an African enigma, the bottle gourd (Lagenaria siceraria). Indigenous to Africa, it reached East Asia by 9,000-8,000 before present (B.P.) and had a broad New World distribution by 8,000 B.P. Here we integrate genetic and archaeological approaches to address a set of long-standing core questions regarding the introduction of the bottle gourd into the Americas. Did it reach the New World directly from Africa or through Asia? Was it transported by humans or ocean currents? Was it wild or domesticated upon arrival? Fruit rind thickness values and accelerator mass spectrometer radiocarbon dating of archaeological specimens indicate that the bottle gourd was present in the Americas as a domesticated plant by 10,000 B.P., placing it among the earliest domesticates in the New World. Ancient DNA sequence analysis of archaeological bottle gourd specimens and comparison with modern Asian and African landraces identify Asia as the source of its introduction. We suggest that the bottle gourd and the dog, two "utility" species, were domesticated long before any food crops or livestock species, and that both were brought to the Americas by Paleoindian populations as they colonized the New World.


The intersection of youth masculinities, decreasing homophobia and class: an ethnography.
This article examines the emergence of progressive attitudes toward homosexuality among working-class boys in a sixth form in the south of England to develop an intersectional analysis of class, youth masculinities and decreasing homophobia. Drawing on three months of ethnographic data collection, I find that working-class male youth intellectualize pro-gay attitudes and that homophobic language is almost entirely absent from the setting. I document the presence of homosocial tactility, as well as the valuing of friendship and emotional closeness. However, these behaviours are less pronounced than documented among middle-class boys, and I use these findings to advance understanding of how class influences the development of inclusive attitudes and behaviours. Inclusive masculinity theory is used to understand these findings, refining the theory and extending it to a new demographic.


Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy.
The profound hypogonadism due to androgen deprivation therapy for prostate cancer results in complications such as sexual dysfunction, poor quality of life, vasomotor symptoms and altered cognition. Since estrogen is associated with cardiovascular risks, phytoestrogens are being increasingly evaluated as a potential treatment for these adverse effects. We evaluated the effects of high dose isoflavones, equivalent to that consumed by Asian populations, on the aforementioned consequences of androgen deprivation therapy. A total of 33 men undergoing androgen deprivation therapy for prostate cancer were enrolled in this randomized, double-blind, placebo controlled, 12-week pilot trial. Participants were randomly assigned to receive 20 gm soy protein containing 160 mg total isoflavones (17) vs taste matched placebo, that is 20 gm whole milk protein (16). The study was performed at a tertiary care center in the United States. At baseline the groups were well matched in demographic parameters, sleep quality, cognition and overall quality of life. However, men in the isoflavone group had a higher baseline prevalence of hot flashes and poor intercourse satisfaction compared to those on placebo. At 12 weeks there were no significant differences between the 2 groups in any outcome measure. This pilot study of high dose isoflavones in androgen deprived men showed no significant improvement in cognition, vasomotor symptoms or any other aspect of quality of life measures compared to placebo. Future studies should use variable doses of isoflavones for a longer period before ruling out beneficial isoflavone effects in this population.


Born too soon in a resource-limited setting: A 10-year mixed methods review of a special care baby unit for refugees and migrants on the Myanmar-Thailand border.
Preterm birth is a major public health concern with the largest burden of morbidity and mortality falling within low- and middle-income countries (LMIC). This sequential explanatory mixed methods study was conducted in special care baby units (SCBUs) serving migrants and refugees along the Myanmar-Thailand border. It included a retrospective medical records review, qualitative interviews with mothers receiving care within SCBUs, and focus group discussions with health workers. Changes in neonatal mortality and four clinical outcomes were described. A mix of ethnographic phenomenology and implementation frameworks focused on cultural aspects, the lived experience of participants, and implementation outcomes related to SCBU care. From 2008-2017, mortality was reduced by 68% and 53% in very (EGA 28-32 weeks) and moderate (EGA 33-36 weeks) preterm neonates, respectively. Median SCBU stay was longer in very compared to moderate preterm neonates: 35 (IQR 22, 48 days) vs. 10 days (IQR 5, 16). Duration of treatments was also longer in very preterm neonates: nasogastric feeding lasted 82% (IQR 74, 89) vs. 61% (IQR 40, 76) of the stay, and oxygen therapy was used a median of 14 (IQR 7, 27) vs. 2 (IQR 1, 6) days respectively. Nine interviews were conducted with mothers currently receiving care in the SCBU and four focus group discussions with a total of 27 local SCBU staff. Analysis corroborated quantitative analysis of newborn care services in this setting and incorporated pertinent implementation constructs including coverage, acceptability, appropriateness, feasibility, and fidelity. Coverage, acceptability, and appropriateness were often overlapping outcomes of interest highlighting financial issues prior to or while admitted to the SCBU and social issues and support systems adversely impacting SCBU stays. Interview and FGD findings highlight the barriers in this resource-limited setting as they impact the feasibility and fidelity of providing evidence-based SCBU care that often required adaptation to fit the financial and environmental constraints imposed by this setting. This study provides an in-depth look at the nature of providing preterm neonatal interventions in a SCBU for a vulnerable population in a resource-limited setting. These findings support implementation of basic evidence-based interventions for preterm and newborn care globally, particularly in LMICs.


Advances in topical glaucoma therapy.
Significant advances have recently been achieved in the development of topical glaucoma medications. The primary advantage of a topical preparation is the reduced incidence of adverse systemic effects attributable to a given drug compared to its systemically administered counterpart. However, the strong protective barrier of the eye forces topical ophthalmic preparations to be highly concentrated and in some cases, they have the potential to produce unwanted systemic effects, particularly in smaller animals. Oral carbonic anhydrase inhibitors are commonly associated with adverse effects in both humans and animals. Two recently developed topical carbonic anhydrase inhibitors, dorzolamide and brinzolamide, have shown promise in reducing intraocular pressure in animals and systemic side effects are apparently limited with their use. The topical alpha2-agonist apraclonidine, on the other hand, effectively reduces intraocular pressure in cats and dogs, but in its currently available form is likely to induce unwanted systemic effects. Latanoprost is a topical prostaglandin F2alpha analog that has proven effective in reducing intraocular pressure in dogs and horses, but while systemic side effects have not yet been reported, this topical preparation may exacerbate pre-existing or concurrent ocular inflammatory disease.


Neural correlates of transitive and intransitive action imitation: an investigation using voxel-based morphometry.
The ability to reproduce visually presented actions has been studied through neuropsychological observations of patients with ideomotor apraxia. These studies include attempts to understand the neural basis of action reproduction based on lesion-symptom mapping in different patient groups. While there is a convergence of evidence that areas in the parietal and frontal lobes within the left hemisphere are involved in the imitation of a variety of actions, questions remain about whether the results generalize beyond the imitation of tool use and whether the presence of a strong grasp component of the action is critical. Here we used voxel-based lesion-symptom mapping to assess the neural substrates of imitating meaningful (familiar, MF) and meaningless (unfamiliar, ML) tool-related (transitive) and non-tool related (intransitive) actions. The analysis showed that the left parietal cortex was involved in the imitation of transitive gestures, regardless of whether they were meaningful or not. In addition there was poor reproduction of meaningless actions (both transitive and intransitive) following damage of the right frontal cortex. These findings suggest a role of right frontal regions in processing of unfamiliar actions.


Paleomagnetic study of antarctic deep-sea cores.
The magnetic inclinations and inten sities of about 650 samples from seven deepsea cores taken in the Antarctic were measured on a spinner magnetometer. This series of measurements provided a magnetic stratigraphy, based on zones of normally or reversally polar ized specimens for each core, which was then correlated with the magnetic stra tigraphy of Cox et al. (1). One core (V16-134) gave a continuous record of the paleomagnetic field back to about 3.5 million years. When selected samples were subject ed to alternatingfield demagnetization, most were found to have an unstable component that was removed by fields of 150 oersteds; all samples from two cores were partially demagnetized in a field of 150 oersteds. The average inclination in these two cores was then in good agreement with the average inclination of the ambient field for the latitude of the core site. It was also found that the intensities of the samples decreased at the points of reversal; this finding is to be expected if, as has been postulated by the dynamo theory, the intensity of the dipole field decreases to zero and builds again with opposite polarity. We believe that the magnetiza tion of the cores results from the pres ence of detrital magnetite, although other magnetic minerals also may be present. Four faunal zones (, X, , and ) have been recognized in these Antarctic cores on the basis of upward sequential disappearance of Radiolaria. The faunal boundaries and reversals consistently have the same relations to one another, indicating that they are both timedependent phenomena. Using previously determined times of reversal, one may date the following events in the cores: 1) Radiolarian faunal boundaries:-X, 2 million years; X-, 0.7 million years; -, 0.4 to 0.5 million years. These dates are in good agreement with ages previously extrapolated from radio metric dates. 2) Initiation of Antarctic diatom ooze deposition, approximately 2.0 mil-lion years ago. 3) First occurrence of ice- rafted detritus, approximately 2.5 million years ago. One can also calculate rates of sedi mentation, which vary in the cores studied from 1.1 to about 8.0 millimeters per 1000 years. Sedimentation rates for the Indian Ocean cores are higher than for the Bellingshausen Sea cores. The near coincidence of faunal changes and reversals in the cores suggests but does not prove a causal relation. We conclude from this study that paleomagnetic stratigraphy is a unique method for correlating and dating deep sea cores, and that future work with such cores may provide a complete or nearly complete record of the history of the earth's magnetic field beyond 4 million years.


Factors affecting activities of daily living, physical balance, and prosthesis adjustment in non-traumatic lower limb amputees.
This study aims to identify the factors affecting the activities of daily living, balance, and prosthesis satisfaction in patients with non-traumatic lower limb amputation (LLA). This cross-sectional study included a total of 195 patients (120 males, 75 females; mean age 65.9±11.6 years; range, 40 to 90 years) who underwent LLA between January 2009 and April 2017. All patients were evaluated in terms of age, sex, amputation etiology, side, level, comorbidity, length of hospital stay, prosthesis adjustment, ambulation level, functional outcome, and complications. Prosthesis adjustment, physical balance ability, and daily living activities were assessed using the Turkish versions of the Trinity Amputation and Prosthesis Experience Scales (TAPES), Berg Balance Scale (BBS), and Nottingham Extended Activities of Daily Living Scale (NEADLS), respectively. There was no significant difference between male and female patients in terms of prosthesis and amputation adaptation, physical balance, and activities of daily living. The BBS, TAPES, and NEADLS scores were lower in the patients aged over 65 years (p<0.001, p<0.001, and p<0.001, respectively). Prosthesis and amputation adaptation, physical balance, and daily living activities were also worse in this age group. Transfemoral amputees had lower BBS, TAPES, and NEADLS scores than the transtibial amputees (p=0.009, p=0.020, and p=0.004, respectively). Prosthesis and amputation adaptation, physical balance, and daily living activities were worse in the transfemoral amputees. Age and amputation level affect physical balance, prosthesis satisfaction, and daily living activities after non-traumatic LLA. Therefore, orthopedic surgeons and physical therapists should conduct a multidisciplinary evaluation, particularly in patients aged over 65 years and in transfemoral amputees to improve outcomes.


The relationships between Internet addiction, subjective vitality, and subjective happiness.
The aim of the present study is to examine the relationships between Internet addiction, subjective vitality, and subjective happiness. The participants were 328 university students who completed a questionnaire package that included the Online Cognition Scale, the Subjective Vitality Scale, and the Subjective Happiness Scale. According to the results, subjective vitality and subjective happiness were negatively predicted by Internet addiction. On the other hand, subjective happiness was positively predicted by subjective vitality. In addition, subjective vitality mediated the relationship between Internet addiction and subjective happiness. Results were discussed in light of the literature.


Identification of individual prokaryotic cells by using enzyme-labeled, rRNA-targeted oligonucleotide probes.
A method to microscopically detect and identify individual cells of members of the domains Bacteria and Archaea is presented. rRNA-targeted oligonucleotides were 5' end labeled with the enzyme horseradish peroxidase and used for whole-cell hybridization. Specifically bound probe was visualized by the enzymatic formation of an intracellular precipitate from the substrate diaminobenzidine. Permeation of the enzyme-labeled probe into whole fixed cells of gram-negative bacteria required their pretreatment with lysozyme-EDTA, whereas permeability of some archaebacterial cells was improved by addition of detergent to the hybridization buffer. Hitherto we had not achieved penetration of enzyme-labeled probe into gram-positive bacteria and yeast cells. This method should be a valuable tool for identification of suitable prokaryotic cells in environments with elevated background fluorescence or in situations in which an epifluorescence microscope is not available.


Distinct strains of Toxoplasma gondii feature divergent transcriptomes regardless of developmental stage.
Using high through-put RNA sequencing, we assayed the transcriptomes of three different strains of Toxoplasma gondii representing three common genotypes under both in vitro tachyzoite and in vitro bradyzoite-inducing alkaline stress culture conditions. Strikingly, the differences in transcriptional profiles between the strains, RH, PLK, and CTG, is much greater than differences between tachyzoites and alkaline stressed in vitro bradyzoites. With an FDR of 10%, we identified 241 genes differentially expressed between CTG tachyzoites and in vitro bradyzoites, including 5 putative AP2 transcription factors. We also observed a close association between cell cycle regulated genes and differentiation. By Gene Set Enrichment Analysis (GSEA), there are a number of KEGG pathways associated with the in vitro bradyzoite transcriptomes of PLK and CTG, including pyrimidine metabolism and DNA replication. These functions are likely associated with cell-cycle arrest. When comparing mRNA levels between strains, we identified 1,526 genes that were differentially expressed regardless of culture-condition as well as 846 differentially expressed only in bradyzoites and 542 differentially expressed only in tachyzoites between at least two strains. Using GSEA, we identified that ribosomal proteins were expressed at significantly higher levels in the CTG strain than in either the RH or PLK strains. This association holds true regardless of life cycle stage.


Characterization of microbiologically influenced corrosion by comprehensive metagenomic analysis of an inland oil field.
Corrosion in pipelines and reservoir tanks in oil plants is a serious problem in the global energy industry because it causes substantial economic losses associated with frequent part replacement and can lead to potential damage to entire crude oil fields. Previous studies revealed that corrosion is mainly caused by microbial activities in a process currently termed microbiologically influenced corrosion or biocorrosion. Identifying the bacteria responsible for biocorrosion is crucial for its suppression. In this study, we analyzed the microbial communities present at corrosion sites in oil plant pipelines using comparative metagenomic analysis along with bioinformatics and statistics. We analyzed the microbial communities in pipelines in an oil field in which groundwater is used as injection water. We collected samples from four different facilities in the oil field. Metagenomic analysis revealed that the microbial community structures greatly differed even among samples from the same facility. Treatments such as biocide administration and demineralization at each location in the pipeline may have independently affected the microbial community structure. The results indicated that microbial inspection throughout the pipeline network is essential to prevent biocorrosion at industrial plants. By identifying the bacterial species responsible for biocorrosion, this study provides bacterial indicators to detect and classify biocorrosion. Furthermore, these species may serve as biomarkers to detect biocorrosion at an early stage. Then, appropriate management such as treatment with suitable biocides can be performed immediately and appropriately. Thus, our study will serve as a platform for obtaining microbial information related to biocorrosion to enable the development of a practical approach to prevent its occurrence.


Urinary incontinence in women: study of surgical practice in France.
To assess the number and the types of surgical intervention for urinary incontinence among women in France. We are assuming that techniques by suburethral sling (SUS) have replaced Burch colposuspension. Using French hospital discharge data from the 2009 medical information system program (PMSI), we analyzed with regard to three relatively homogeneous diagnosis-related groups of patients (DRG) comprising the majority of stress urinary incontinence surgical interventions (cervicocystopexy, repair of the female genital apparatus, and hysterectomy) the detailed distribution of the different operations indexed in that information system. More than 42,000 cervicocystopexies (42,223) were carried out in France in 2009, and a SUS was used in 92% of the procedures (n=38,929). In 58% of the cases (n=24,387) this surgery was the only one, and in the others, it was associated with static pelvic intervention in 25% of the cases (n=10,741) or with a hysterectomy in 16% (n=6671). When a cervicocystopexy was the only operation performed, the average age of the women was 56.5 years and the average stay in hospital was 12.9 days. Fifty-seven percent of the cervicocystopexies by SUS (n=24,037) were carried out in private sector. Mean durations of stay were significantly shorter in the private sector than in the public sector for the diagnosis-related groups undergoing cervicocystopexy or repair of the female genital apparatus. In 2009, 10 years after its introduction in France, the suburethral sling is used in the overwhelming majority of cervicocystopexies in France. Among an estimated 4,000,000 incontinent women in France in 2009, this surgery was undergone by approximately 1% of them each year.


The clinical utility of tumor mutational burden in non-small cell lung cancer.
Despite advances made during the last two decades, lung cancer remains the leading cause of cancer-related death worldwide. Recently, immune checkpoint inhibitors (ICIs) became available for the treatment of advanced non-small cell lung cancer (NSCLC) patients. Although ICIs showed a survival advantage in comparison with chemotherapy in the second and first-line setting, overall response rate is only around 20% and a large proportion of patients will undergo disease progression within the first weeks of treatment. For this reason, there is a need for biomarkers to predict the efficacy of ICIs in NSCLC and to identify patients who will benefit from ICIs. The first biomarker developed was programmed cell death ligand 1 (PD-L1) expression. However, the predictive role of PD-L1 expression varied from one clinical trial to another, due to the multiple assays used, with different antibodies, different platforms, and different thresholds. Moreover, PD-L1 expression is highly heterogeneous. For these reasons, PD-L1 expression alone is not a good biomarker to predict the efficacy of ICIs and there is a need for the identification of other biomarkers. Tumor mutational burden (TMB) is defined as the number of mutations per DNA megabases. It was first assessed as a biomarker for ICI based on the observation of successful immune checkpoint inhibition in solid tumors with high TMB such as NSCLC, melanoma or bladder cancer. Pre-clinical data suggested that the association between TMB and ICIs efficacy could be explained by the creation of neoantigens induced by mutations acquisition, increasing tumor immunogenicity and response to ICIs. Preliminary observations of TMB role as a predictive biomarker for the efficacy of ICIs in patients with advanced NSCLC led to the assessment of TMB clinical utility in phase III clinical trials. This review reports the clinical features and prognostic role of TMB in NSCLC. This review also focuses on TMB predictive role for the treatment of NSCLC patients with single-agent programmed cell death 1 (PD-1) and PD-L1 inhibitors such as pembrolizumab, nivolumab and atezolizumab or ICIs combination.


Pulmonary embolism in cancer patients.
Pulmonary embolism (PE) is rare in the Indian population and is under-reported in patients with malignancy. We studied the clinical profile and outcome of patients with PE and cancer in the Indian population. Data of cancer patients with PE, admitted in a tertiary cancer centre, was analyzed. The prevalence of PE was calculated as the number of patients with PE per 10,000 hospital admissions. The demographic data, details of cancer, co-morbidities, details of PE, and treatment given for PE and their outcomes were recorded and analyzed. There were 56,425 hospital admissions in the study period. The prevalence of PE was 6.4 per 10,000 hospital admissions .Thirty-six cancer patients were diagnosed to have PE. In females, gynecological malignancies (36.84%) and in males gastrointestinal, head and neck cancers, and hematological malignancies were the most common sites (17.7% each). PE was associated with DVT in 41.7%. Dyspnea was the most common presenting symptom. Five patients (13.88%) were asymptomatic and were incidentally detected to have PE . The most common echocardiographic finding was right ventricular dysfunction (55.55%). Mortality among the treated patients was 22% (7 / 31) and in untreated patients it was 80% (4 / 5). The factors that had an impact on a three-month survival were, the presence of massive PE (P = 0.019) and the presence of RV dysfunction at presentation (P = 0.005). The prevalence of PE and mortality due to PE is high in cancer patients. Risk stratification for venous thromboembolism (VTE) should be done in all cancer patients and thromboprophylaxis should be optimally used.


Endoscopic findings in a cohort of newly diagnosed gastroesophageal reflux disease patients registered in a UK primary care database.
Gastroesophageal reflux disease (GERD) may be accompanied by erosive complications that are diagnosed by endoscopy. This study aimed to describe the characteristics of patients newly diagnosed with GERD who are referred for endoscopy, and the factors associated with esophageal endoscopic findings. The study included patients aged 2-79 years with a first recorded diagnosis of GERD in 1996, as identified in a previous cohort study in the UK General Practice Research database. The rate and results of endoscopy were recorded. Unconditional logistic regression analysis was used to estimate the odds ratios and 95% confidence intervals for the relationship between a range of factors and endoscopy and its findings. Of the 7159 patients with a new GERD diagnosis, 805 (11%) underwent endoscopy close to the time of first consultation for GERD. Endoscopic findings indicative of esophageal damage were recorded in 73% of these patients. Esophageal endoscopic findings were significantly more likely in males, older patients, and individuals with a history of peptic ulcer disease or gastrointestinal bleeding. Use of acid-suppressive drugs, particularly proton pump inhibitors, was inversely associated with erosive endoscopic findings. Patients with erosive endoscopic findings were more likely to start a new course of treatment with a proton pump inhibitor. In conclusion, relatively few patients are referred for endoscopy close to the first consultation for GERD and the majority of these individuals have esophageal findings. Male gender, increasing age and a history of bleeding were risk factors for esophageal complications.


Hydrodynamics and propulsion mechanism of self-propelled catalytic micromotors: model and experiment.
The hydrodynamic behavior and propulsion mechanism of self-propelled micromotors are studied theoretically and experimentally. A hydrodynamic model to describe bubble growth and detachment is proposed to investigate the mechanism of a self-propelled conical tubular catalytic micromotor considering bubble geometric asymmetry and buoyancy force. The growth force caused by the growth of the bubble surface against the fluid is the driving force for micromotor motion. Also, the buoyancy force plays a primary role in bubble detachment. The effect of geometrical parameters on the micromotor velocity and drag force is presented. The bubble radius ratio is investigated for different micromotor radii to determine its hydrodynamic behavior during bubble ejection. The average micromotor velocity is found to be strongly dependent on the semi-cone angle, expelling frequency and bubble radius ratio. The semi-cone angle has a significant effect on the expelling frequency for conical tubular micromotors. The predicted results are compared to already existing experimental data for cylindrical micromotors (semi-cone angle δ = 0°) and conical micromotors. A good agreement is found between the theoretical calculation and experimental results. This model provides a profound explanation for the propulsion mechanism of a catalytic micromotor and can be used to optimize the micromotor design for its biomedical and environmental applications.


Tea flavonoids for bone health: from animals to humans.
Osteoporosis is a skeletal disease characterized by a deterioration of bone mass and bone quality that predisposes an individual to a higher risk of fragility fractures. Emerging evidence has shown that the risk for low bone mass and osteoporosis-related fractures can be reduced by nutritional approaches aiming to improve bone microstructure, bone mineral density, and strength. Tea and its flavonoids, especially those of black tea and green tea, have been suggested to protect against bone loss and to reduce risk of fracture, due to tea's antioxidant and anti-inflammatory properties. Based on the results of animal studies, moderate intake of tea has shown to benefit bone health as shown by mitigation of bone loss and microstructural deterioration as well as improvement of bone strength and quality. Epidemiological studies have reported positive, insignificant, and negative impacts on bone mineral density at multiple skeletal sites and risk of fracture in humans with habitual tea consumption. There are limited human clinical trials that objectively and quantitatively assessed tea consumption and bone efficacy using validated outcome measures in a population at high risk for osteoporosis, along with safety monitoring approach. This review summarizes the current state of knowledge of laboratory animal research, epidemiological observational studies, and clinical trials assessing the skeletal effects of tea and its active flavonoids, along with discussion of relevant future directions in translational research.


Compounds affecting mosquito oviposition: structure-activity relationships and concentration effects.
Evidence is reviewed for a dose-dependent reversal of response in mosquito oviposition, in which a compound that attracts or stimulates oviposition may repel or deter oviposition at a higher concentration. On the basis of a review of structure-activity relationships in compounds affecting mosquito oviposition, 5 hexanoic acid derivatives were selected for field tests with Aedes aegypti ssp. formosus in Kenya. Egg counts were increased most by methyl hexanoic acid and 5-methyl-2-hexanone, and the presence or absence of a methyl branch affected egg numbers more than the difference between a carbonyl and a carboxylic acid functional group. Hexanoic acid increased egg counts at low release rates, but decreased them at higher release rates.


Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles.
The influence of various structural patterns in a series of novel bi- and tricyclic N-heterocycles on the activity against Leishmania major and Leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. Both quinolines and tetrahydrooxazinoindoles (TOI) proved to have significant antileishmanial activities, while substituted indoles were inactive. We have also showed that a chloroquine analogue induces Leishmania killing by modulating macrophage activation.


A review on recent developments in electrochemical hydrogen peroxide synthesis with a critical assessment of perspectives and strategies.
Electrochemical hydrogen peroxide synthesis using two-electron oxygen electrochemistry is an intriguing alternative to currently dominating environmentally unfriendly and potentially hazardous anthraquinone process and noble metals catalysed direct synthesis. Electrocatalytic two-electron oxygen reduction reaction (ORR) and water oxidation reaction (WOR) are the source of electrochemical hydrogen peroxide generation. Various electrocatalysts have been used for the same and were characterized using several electroanalytical, chemical, spectroscopic and chromatographic tools. Though there have been a few reviews summarizing the recent developments in this field, none of them have unified the approaches in catalysts' design, criticized the ambiguities and flaws in the methods of evaluation, and emphasized the role of electrolyte engineering. Hence, we dedicated this review to discuss the recent trends in the catalysts' design, performance optimization, evaluation perspectives and their appropriateness and opportunities with electrolyte engineering. In addition, particularized discussions on fundamental oxygen electrochemistry, additional methods for precise screening, and the role of solution chemistry of synthesized hydrogen peroxide are also presented. Thus, this review discloses the state-of-the-art in an unpresented view highlighting the challenges, opportunities, and alternative perspectives.


Using SMOG 2 to Simulate Complex Biomolecular Assemblies.
Over the last 20 years, the application of structure-based (Gō-like) models has ranged from protein folding with coarse-grained models to all-atom representations of large-scale molecular assemblies. While there are many variants that may be employed, the common feature of these models is that some (or all) of the stabilizing energetic interactions are defined based on the knowledge of a particular experimentally obtained conformation. With the generality of this approach, there was a need for a versatile computational platform for designing and implementing this class of models. To this end, the SMOG 2 software package provides an easy-to-use interface, where the user has full control of the model parameters. This software allows the user to edit XML-formatted files in order to provide definitions of new structure-based models. SMOG 2 reads these "template" files and maps the interactions onto specific structures, which are provided in PDB format. The force field files produced by SMOG 2 may then be used to perform simulations with a variety of popular molecular dynamics suites. In this chapter, we describe some of the key features of the SMOG 2 package, while providing examples and strategies for applying these techniques to complex (often large-scale) molecular assemblies, such as the ribosome.


Hepatitis C: prevalence and common genotypes among ethnic groups in Jeddah, Saudi Arabia.
The presence of antibodies to hepatitis C virus (HCV) was examined using a third-generation ELISA in 3,350 serum samples obtained from patients visiting different outpatient clinics, preoperative patients, and women visiting for ante-natal care at the Dr. Fakeeh hospital in Jeddah, Saudi Arabia from January to September 1998. The population included mainly Saudis, Egyptians, and Yemenis, and patients from other Middle East and Asian countries. The prevalence of HCV infection was 5.87% among Saudis, 22.54% among Egyptians, and 2.12% among Yemenis. The prevalence among patients from other Middle East and Asian countries were 3.38% and 4.98%, respectively. The overall prevalence among the studied group was 6.75%. Genotyping of isolates from Saudi Arabia showed that the prevalences of types 4, la, 1b, and 2 were 45.9%, 40.6%, 10.85%, and 2.7%, respectively. Genotyping of isolates from Egypt showed that type 4 was the major type among Egyptians (91.6%), while types 1a and 1b each had prevalences of 4.2%.


Hospital work environment, nurse staffing and missed care in Chile: A cross-sectional observational study.
To characterise the problem of missed nursing care in Chilean hospitals and to test associations with hospital organisational variables. Missed nursing care is a common problem in different countries, but it has not been studied in Chile. Multihospital cross-sectional study (Supplementary file 1: STROBE guideline). Study population of 45 adult high-complexity hospitals and 1853 registered nurses (RN) working on medical-surgical units. Primary data were collected through a nurse survey. Nurses reported, out of a list of nursing care activities, the ones left undone during their last shift. The main independent variables were the work environment, measured through the Practice Environment Scale of the Nursing Work Index, patient-to-nurse ratios and RN skillmix. Adjusted logistic regression analyses were used to test associations, accounting for clustering of nurses working in the same hospital. The hospital response rate was 88.9% and, for nurses, 88.1%. The mean patient-to-nurse ratio was 14.5 (range 6-23). The average skillmix was 31% RN. Eighty-six percent of nurses missed at least one activity. The activities most frequently missed included patient education, comforting patients and surveillance. The adjusted model showed a significant association between the work environment, staffing ratios and missed care. The RN skillmix was not associated. Missed care is highly prevalent problem in Chilean hospitals. Clinical activities were the least missed. It is necessary to improve work environments and reduce the number of patients per nurse to improve the safety and quality of care. The study results are relevant since they provide new data to Chile. Better work environments and adequate human resources are modifiable factors that can be addressed from a managerial perspective, with low-cost strategies to effectively reduce missed care and improve safety and quality.


Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study.
Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH). This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate. The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT. pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.


A regulator of a G protein signalling (RGS) gene, cag8, from the insect-pathogenic fungus Metarhizium anisopliae is involved in conidiation, virulence and hydrophobin synthesis.
Regulators of the G protein signalling (RGS) pathway have been implicated in the control of a diverse array of cellular functions, including conidiation in filamentous fungi. However, the regulatory processes involved in conidiation in insect-pathogenic fungi are poorly understood. Since conidia are the infective propagules in these fungi, an understanding of the regulatory processes involved in conidiation is essential to the development of an effective biocontrol fungus. Here, the cloning and characterization of an RGS protein gene, cag8 (conidiation-associated gene), from the insect-pathogenic fungus Metarhizium anisopliae is reported. Phylogenetic analysis showed that CAG8 was orthologous to the RGS protein FlbA from Aspergillus nidulans. Complementation of A. nidulans DeltaflbA, which cannot conidiate, with M. anisopliae cag8 restored conidiation. Gene disruption of cag8 in M. anisopliae resulted in the lack of conidia on agar plates and on infected insects, reduced mycelial growth, decreased virulence, lysis during growth in liquid medium as well as lack of pigmentation and irregularly shaped blastospores. Transcript levels of ssgA (hydrophobin-encoding gene) were markedly reduced in a Deltacag8 strain, while pr1A (subtilisin-like protease) transcription was unaffected. These results suggest that cag8 is involved in the modulation of conidiation, virulence and hydrophobin synthesis in M. anisopliae.


Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.
Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies related to oxygen deficiency. Since increased HIF-1 expression correlates with advanced disease stage, increased angiogenesis and poor prognosis, HIF-1 and its signaling pathway have become targets for cancer chemotherapy. In this study, we identified noscapine to be a novel small molecule inhibitor of the HIF-1 pathway based on its structure-function relation-ships with HIF-1 pathway inhibitors belonging to the benzylisoquinoline class of plant metabolites and/or to microtubule binding agents. We demonstrate that noscapine treatment of human glioma U87MG and T98G cell lines exposed to the hypoxic mimetic agent, CoCl2, inhibits hypoxia-mediated HIF-1alpha expression and transcriptional activity as measured by decreased secretion of VEGF, a HIF-1 target gene. Inhibition of hypoxia-mediated HIF-1alpha expression was due, in part, to its ability to inhibit accumulation of HIF-1alpha in the nucleus and target it for degradation via the proteasome. One mechanism of action of microtubule binding agents is their antiangiogenic activity associated with disruption of endothelial tubule formation. We show that noscapine has similar properties in vitro. Thus, noscapine may possess novel antiangiogenic activity associated with two broad mechanisms of action: first, by decreasing HIF-1alpha expression in hypoxic tumor cells, upregulation of target genes, such as VEGF, would be decreased concomitant with its associated angiogenic activity; second, by inhibiting endothelial cells from forming blood vessels in response to VEGF stimulation, it may limit the process of neo-vascularization, correlating with antitumor activity in vivo. For more than 75 years, noscapine has traditionally been used as an oral cough suppressant with no known toxic side effects in man. Thus, the studies reported here have found a novel function for an old drug. Given its low toxicity profile, its demonstrated antitumor activity in several animal models of cancer and its potential to inhibit the HIF-1 pathway, noscapine should be considered as an antiangiogenic chemotherapy for glioma.


Impact of Workplace Climate on Burnout Among Critical Care Nurses in the Veterans Health Administration.
Burnout is a maladaptive response to work-related stress that is associated with negative consequences for patients, clinicians, and the health care system. Critical care nurses are at especially high risk for burnout. Previous studies of burnout have used survey methods that simultaneously measure risk factors and outcomes of burnout, potentially introducing common method bias. To evaluate the frequency of burnout and individual and organizational characteristics associated with burnout among critical care nurses across a national integrated health care system using data from an annual survey and methods that avoid common method bias. A 2017 survey of 2352 critical care nurses from 94 sites. Site-level workplace climate was assessed using 2016 survey data from 2191 critical care nurses. Overall, one-third of nurses reported burnout, which varied significantly across sites. In multilevel analysis, workplace climate was the strongest predictor of burnout (odds ratio [OR], 2.20; 95% CI, 1.50-3.22). Other significant variables were overall hospital quality (OR, 1.44; 95% CI, 1.05-1.99), urban location (OR, 1.93; 95% CI, 1.09-3.42), and nurse tenure (OR, 2.11; 95% CI, 1.44-3.10). In secondary multivariable analyses, workplace climate subthemes of perceptions of workload and staffing, supervisors and senior leadership, culture of teamwork, and patient experience were each significantly associated with burnout. Drivers of burnout are varied, yet interventions frequently target only the individual. Results of this study suggest that in efforts to reduce burnout, emphasis should be placed on improving local workplace climate.


Role of Pure Technetium Chemistry: Are There Still Links to Applications in Imaging?
The discovery and development of new 99mTc-based radiopharmaceuticals or labeled drugs in general is based on innovative, pure chemistry and subsequent, application-targeted research. This was the case for all currently clinically applied imaging agents. Most of them were market-introduced some 20 years ago, and the few more recent ones are based on even older chemistry, albeit technetium chemistry has made substantial progress over the last 20 years. This progress though is not mirrored by new molecular imaging agents and is even accompanied by a steady decrease in the number of groups active in pure and applied technetium chemistry, a contrast to the trends in most other fields in which d-elements play a central role. The decrease in research with technetium has been partly counterbalanced by a strong increase of research activities with homologous, cold rhenium compounds for therapy, disclosing in the future eventually a quite unique opportunity for theranostics. This Viewpoint analyzes the pathways that led to radiopharmaceuticals in the past and their underlying fundamental contributions. It attempts to tackle the question of why new chemistry still does not lead to new imaging agents, i.e., the question of whether pure technetium chemistry is still needed at all.


A qualitative investigation of the roles and perspectives of older patients with advanced cancer and their family caregivers in managing pain in the home.
Pain in advanced cancer is complex and multifaceted. In older patients comorbidities and age-related functional decline add to the difficulties in managing cancer pain. The current emphasis on care in the community, and preference by patients with life-limiting disease to receive care in the home, has meant that patients and their family caregivers have become increasingly responsible for the day-to-day management of cancer pain. An appreciation of patients' and caregivers' roles and perspectives managing pain is, therefore, fundamental to addressing cancer pain in this setting. Consequently, we sought to explore and describe their perspectives and roles. A qualitative descriptive approach was used. Semi-structured interviews were conducted with a purposeful sample of patient- family caregiver dyads. Participants included 18 patients aged 65 years and over, with advanced cancer, receiving palliative care at home, and 15 family caregivers. The interview data were analysed using thematic analyses. Strategies were used to establish rigour. Two main themes were identified. The first theme, "Communicating the pain", represented pain assessment and incorporated four subthemes in which participants described: their roles in pain assessment, the identification and expression of pain, and the communication of pain between patients and caregivers. The second theme, "Finding a solution", comprised of four subthemes that reflected participants' roles and approaches in controlling pain; as well as their beliefs about cancer pain control, experience with side effects, and perspectives on the goals of treatment. The findings support other studies in identifying knowledge and attitudinal barriers to pain control; while adding to the literature by highlighting practical and relational barriers faced by older patients and their family caregivers. Health care professionals can do much to address the barriers identified by: correcting misconceptions regarding cancer pain, facilitating the communication of pain within dyads, and ensuring that patients and family caregivers have the knowledge, skills, and ability to assess and implement pain treatment strategies. This support needs to be individually tailored to meet the ongoing needs of both members of the dyad so that the shared goals of pain management are accomplished.