Cost-effectiveness of Remdesivir and Dexamethasone for COVID-19 Treatment in South Africa.
Dexamethasone and remdesivir have the potential to reduce coronavirus disease 2019 (COVID)-related mortality or recovery time, but their cost-effectiveness in countries with limited intensive care resources is unknown. We projected intensive care unit (ICU) needs and capacity from August 2020 to January 2021 using the South African National COVID-19 Epi Model. We assessed the cost-effectiveness of (1) administration of dexamethasone to ventilated patients and remdesivir to nonventilated patients, (2) dexamethasone alone to both nonventilated and ventilated patients, (3) remdesivir to nonventilated patients only, and (4) dexamethasone to ventilated patients only, all relative to a scenario of standard care. We estimated costs from the health care system perspective in 2020 US dollars, deaths averted, and the incremental cost-effectiveness ratios of each scenario. Remdesivir for nonventilated patients and dexamethasone for ventilated patients was estimated to result in 408 (uncertainty range, 229-1891) deaths averted (assuming no efficacy [uncertainty range, 0%-70%] of remdesivir) compared with standard care and to save $15 million. This result was driven by the efficacy of dexamethasone and the reduction of ICU-time required for patients treated with remdesivir. The scenario of dexamethasone alone for nonventilated and ventilated patients requires an additional $159 000 and averts 689 [uncertainty range, 330-1118] deaths, resulting in $231 per death averted, relative to standard care. The use of remdesivir for nonventilated patients and dexamethasone for ventilated patients is likely to be cost-saving compared with standard care by reducing ICU days. Further efforts to improve recovery time with remdesivir and dexamethasone in ICUs could save lives and costs in South Africa.


Classification of veterans with post-traumatic stress disorder using visual brain evoked P3s to traumatic stimuli.
Post-traumatic stress disorder (PTSD) typically involves a re-experiencing of traumatic events. In a previous P3 study it was found that PTSD patients react both selectively and involuntarily to combat-related pictures, exhibiting augmented P3 event-related potentials and thus providing a brain activity measure. The clinical application of these findings in differentiating PTSD patients from controls was tested. Twenty Israeli combat veterans suffering from PTSD and 20 age-matched veterans without PTSD were evaluated. P3 potentials were recorded at Pz and Cz in response to visual motor-task target stimuli (pictures of domestic animals), non-target probe stimuli (combat-related pictures), and non-target irrelevant stimuli (pictures of furnishings and flowers). Using the Fisher Linear Discrimination Method the P3 measures correctly classified 90% of the PTSD patients and 85% of the controls. Visual P3s recorded in response to combat-related pictorial stimuli may introduce an efficient tool for studying higher brain activity in PTSD, complementing other behavioural and psychophysiological measurements.


Acute lung injury-induced collagen deposition is associated with elevated asymmetric dimethylarginine and arginase activity.
Evidence suggests that lung structure and function are partly maintained by a balance between the competing arginine-metabolizing enzymes arginase and nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. It is metabolized by dimethylarginine dimethylaminohydrolase 2 (DDAH-2), which is oxidant-sensitive. The mechanism that induces excess lung collagen deposition in burned patients has not yet been explored. Our objective was to investigate the role of ADMA and the arginase pathway in acute lung injury. An ovine model for burn and smoke inhalation injury was used to assess excess lung collagen deposition. Sheep were deeply anesthetized during the injury, mechanically ventilated, resuscitated with fluid, and killed after either 2 or 3 weeks. Lungs were assessed histologically and biochemically for collagen content, arginase activity, lipid peroxidation product and antioxidant concentration, and protein concentrations. Plasma was assessed for amino acid and nitrate/nitrite concentrations. Burn and inhalation injury resulted in significantly reduced pulmonary function and increased lung collagen deposition. These physiological changes were associated with significantly increased lung arginase activity, collagen synthesis precursor ornithine aminotransferase, and ornithine decarboxylase, which is associated with cell proliferation. Significant decreases in plasma nitrate/nitrite after injury were associated with increased lung ADMA concentrations and decreased DDAH-2 expression. The decreased DDAH-2 expression was associated with significantly increased lipid peroxidation product and decreased antioxidant content in the lung. These data support that excess lung collagen deposition and reduced pulmonary function in acute lung injury after burn and inhalation injury are mediated through the arginase pathway.


The role of clinical, genetic and segregation evaluation in sudden infant death.
Sudden infant death syndrome (SIDS) is the leading cause of death in the first year of life. Several arrhythmogenic genes have been associated with cardiac pathologies leading to infant sudden cardiac death (SCD). Our aim was to take advantage of next generation sequencing (NGS) technology to perform a thorough genetic analysis of a SIDS case. A SIDS case was referred to our institution after negative autopsy. We performed a genetic analysis of 104 SCD-related genes using a custom panel. Confirmed variants in index case were also analyzed in relatives. Clinical evaluation of first-degree family members was performed. Relatives did not show pathology. NGS identified seven variants. Two previously described as pathogenic. Four previously catalogued without clinical significance. The seventh variation was novel. Familial segregation showed that the index case's mother carried all same genetic variations except one, which was inherited from the father. The sister of the index case carried three variants. We believe that molecular autopsy should be included in current forensic protocols after negative autopsy. In addition to NGS technologies, familial genetic testing should be also performed to clarify potential pathogenic role of new variants and to identify genetic carriers at risk of SCD.


Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1.
Inflammation and wound healing are inextricably linked and complex processes, and are deranged in the setting of chronic, nonhealing diabetic foot ulcers (DFU). An ideal therapy for DFU should both suppress excessive inflammation while enhancing healing. We reasoned that biological simulation would clarify mechanisms and help refine therapeutic approaches to DFU. We developed an agent-based model (ABM) capable of reproducing qualitatively much of the literature data on skin wound healing, including changes in relevant cell populations (macrophages, neutrophils, fibroblasts) and their key effector cytokines (tumor necrosis factor-alpha [TNF], interleukin [IL]-1beta, IL-10, and transforming growth factor [TGF]-beta1). In this simulation, a normal healing response results in tissue damage that first increases (due to wound-induced inflammation) and then decreases as the collagen levels increase. Studies by others suggest that diabetes and DFU are characterized by elevated TNF and reduced TGF-beta1, although which of these changes is a cause and which one is an effect is unclear. Accordingly, we simulated the genesis of DFU in two ways, either by (1) increasing the rate of TNF production fourfold or (2) by decreasing the rate of TGF-beta1 production 67% based on prior literature. Both manipulations resulted in increased inflammation (elevated neutrophils, TNF, and tissue damage) and delayed healing (reduced TGF-beta1 and collagen). Our ABM reproduced the therapeutic effect of platelet-derived growth factor/platelet releasate treatment as well as DFU debridement. We next simulated the expected effect of administering (1) a neutralizing anti-TNF antibody, (2) an agent that would increase the activation of endogenous latent TGF-beta1, or (3) latent TGF-beta1 (which has a longer half-life than active TGF-beta1), and found that these therapies would have similar effects regardless of the initial assumption of the derangement that underlies DFU (elevated TNF vs. reduced TGF-beta1). In silico methods may elucidate mechanisms of and suggest therapies for aberrant skin healing.


Quality control of photosystem II: FtsH hexamers are localized near photosystem II at grana for the swift repair of damage.
The reaction center-binding D1 protein of Photosystem II is oxidatively damaged by excessive visible light or moderate heat stress. The metalloprotease FtsH has been suggested as responsible for the degradation of the D1 protein. We have analyzed the distribution and subunit structures of FtsH in spinach thylakoids and various membrane fractions derived from the thylakoids using clear native polyacrylamide gel electrophoresis and Western blot analysis. FtsH was found not only in the stroma thylakoids but also in the Photosystem II-enriched grana membranes. Monomeric, dimeric, and hexameric FtsH proteases were present as major subunit structures in thylakoids, whereas only hexameric FtsH proteases were detected in Triton X-100-solubilized Photosystem II membranes. Importantly, among the membrane fractions examined, hexameric FtsH proteases were most abundant in the Photosystem II membranes. In accordance with this finding, D1 degradation took place in the Photosystem II membranes under light stress. Sucrose density gradient centrifugation analysis of thylakoids and the Photosystem II membranes solubilized with n-dodecyl-β-d-maltoside and a chemical cross-linking study of thylakoids showed localization of FtsH near the Photosystem II light-harvesting chlorophyll-protein supercomplexes in the grana. These results suggest that part of the FtsH hexamers are juxtapositioned to PSII complexes in the grana in darkness, carrying out immediate degradation of the photodamaged D1 protein under light stress.


Cellular aspects of prion replication in vitro.
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders in mammals that are caused by unconventional agents predominantly composed of aggregated misfolded prion protein (PrP). Prions self-propagate by recruitment of host-encoded PrP into highly ordered b-sheet rich aggregates. Prion strains differ in their clinical, pathological and biochemical characteristics and are likely to be the consequence of distinct abnormal prion protein conformers that stably replicate their alternate states in the host cell. Understanding prion cell biology is fundamental for identifying potential drug targets for disease intervention. The development of permissive cell culture models has greatly enhanced our knowledge on entry, propagation and dissemination of TSE agents. However, despite extensive research, the precise mechanism of prion infection and potential strain effects remain enigmatic. This review summarizes our current knowledge of the cell biology and propagation of prions derived from cell culture experiments. We discuss recent findings on the trafficking of cellular and pathologic PrP, the potential sites of abnormal prion protein synthesis and potential co-factors involved in prion entry and propagation.


Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series.
First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.


New applications of the mathematical model of a permeation passive sampler: prediction of the effective uptake rate and storage stability.
As the applications of passive sampling in environmental analysis are increasing, it is crucial to ensure that the methods applied in the measurement of pollutant concentrations provide sufficient accuracy in compliance with existing regulations. Additionally, as with any sampling method in an analytical process, sample integrity is essential for accurate determination of contaminants and their concentrations. In a recent study, a mathematical model was developed to describe the sampling process in permeation passive samplers. The model was able to predict the significance of potential uptake rate changes during sampling. The model also predicted the distribution of the sampled analyte within the different compartments of the sampler. In the present work, the model was extended to include two practical applications. In the first part, a novel method allowing prediction of the effective uptake rate of the sampler is presented. The method accounts for changes in the uptake rate during the exposure time caused by resistance to mass transfer in the sorbent bed, allowing accurate calculation of the time weighted average concentrations. The method was proven to be successful through experimental verification that involved sampling toluene and trichloroethylene using the Waterloo Membrane Sampler (WMS). In the second part, the post-sampling storage period of analytes in the WMS was evaluated. It was found both theoretically and experimentally that analyzing the sorbent only is sufficient to quantify the analytes collected, as the amount retained in the remaining compartments of the sampler (PDMS membrane, air inside the sampler and the storage vial) is negligible after sampling. The amounts of analytes collected by the sorbent were stable over up to three-weeks of storage at room temperature. These findings establish confidence in the use of the WMS for sampling Volatile Organic Compounds (VOCs).


Molecular signature of differential virulence in natural isolates of Erwinia amylovora.
ABSTRACT Erwinia amylovora, the causal agent of fire blight, is considered to be a genetically homogeneous species based on physiological, biochemical, phylogenetic, and genetic analysis. However, E. amylovora strains exhibiting differential virulence are isolated from nature. The exopolysaccharide amylovoran and type III secretion system (T3SS) are two major yet separate virulence factors in E. amylovora. The objective of this study was to investigate whether there is a correlation between E. amylovora virulence and levels of virulence gene expression. Four wild-type strains (Ea1189, Ea273, Ea110, and CFBP1430), widely used in studies of E. amylovora pathogenesis, have been analyzed and compared. E. amylovora strains Ea273 and Ea110 elicited higher severity of disease symptoms than those of Ea1189 and CFBP1430 on apple cv. Golden Delicious and G16 apple root stock plants but not on susceptible Gala plants. In addition, Ea273 and Ea110 elicited severe hypersensitive responses within shorter periods of time at lower inoculum concentrations than those of Ea1189 and CFBP1430 on tobacco plants. Further molecular analyses have revealed that amylovoran production and expression of both amylovoran (amsG) and T3SS (dspE and hrpL) genes were significantly higher in Ea273 and Ea110 than those in Ea1189 and CFBP1430. Other phenotypes such as swarming motility in these four strains also differed significantly. These results indicate that E. amylovora strains of different origin can be divided into subgroups based on molecular signatures of virulence gene expression. Therefore, these molecular signatures may be used to differentiate E. amylovora strains, which may have taxonomical and evolutionary implications.


Diet and incident venous thromboembolism: the Iowa Women's Health Study.
Little is known about the role of diet in the development of venous thromboembolism (VTE). We explored the prospective relation of dietary patterns, food groups, and nutrients to incident VTE in older women. In 1986, Iowa women aged 55 to 69 years completed a mailed survey, including a 127-item food frequency questionnaire. These data were linked to Medicare data from 1986 to 2004, and International Classification of Diseases discharge codes were used to identify hospitalized VTE cases. Cox regression analyses evaluated relations of 2 principal components-derived dietary patterns, 11 food groups, and 6 nutrients to VTE, adjusted for age, education, smoking status, physical activity, and energy intake. Over 19 years of follow-up, 1,950 of the 37,393 women developed VTE. Women consuming alcohol daily were at 26% (95% CI 11%-38%) lower risk of VTE as compared to nonconsumers. All alcoholic beverages types were in the direction of lower risk; however, only beer and liquor were statistically significant. After basic adjustments, coffee was inversely related to VTE, and diet soda and fish positively related. However, these associations were confounded and became nonsignificant after adjustment for body mass index and diabetes. No associations were observed with consumption of 'Western' or 'Prudent' dietary patterns, fruit, vegetables, dairy, meat, refined grains, whole grains, regular soda, vitamins E, vitamin B6, vitamin B12, folate, omega-3 fatty acids, or saturated fat. In this cohort of older women, greater intake of alcohol was associated with a lower risk of incident VTE. No other independent associations were seen between diet and VTE.


A Bayesian approach for estimating typhoid fever incidence from large-scale facility-based passive surveillance data.
Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age-specific population-level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility-based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under-detection of cases. We developed a Bayesian approach that adjusts the count of reported blood-culture-positive cases for blood culture detection, blood culture collection, and healthcare seeking-and how these factors vary by age-while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision-making for typhoid prevention and control.


Genetic parameters for earnings in Quarter Horse.
In this study, we estimated the heritability (h(2)) of earnings in the Quarter Horse in order to evaluate the inclusion of this trait in breeding programs. Records from 14,754 races of 2443 horses from 1978-2009 were provided by Sorocaba Hippodrome, São Paulo, Brazil. All ancestors of the registered horses were included in the pedigree file until the 4th generation. Log-transformed performance measures (LPM) were analyzed for animals aged 2, 3, and 4 years and during their entire career. The h(2) estimates were obtained using a multi-trait model and Gibbs sampling that included the effects of sex, year of race, and animal in all analyses. Five analyses were performed: 1 in which LPM was divided by the number of prizes, 1 in which LPM was divided by the number of race starts, and 3 analyses that included the number of prizes, number of race starts, and both (LPM_cNPS) as covariates. Analysis was performed with and without inclusion of the maternal effect. Models were compared based on the deviance information criterion and LPM_cNPS including maternal effects was found to be the best model. The h(2) estimates and standard deviation obtained using model LPM_cNPS were 0.19 ± 0.08, 0.21 ± 0.08, 0.22 ± 0.09, and 0.21 ± 0.07 for earnings at 2, 3, and 4 years of age and total career, respectively. Our analyses indicate that earnings are subject to selection and can be included in breeding programs to improve the racing performance of Quarter Horses.


Phage-mediated dispersal of biofilm and distribution of bacterial virulence genes is induced by quorum sensing.
The microbiome and the phage meta-genome within the human gut are influenced by antibiotic treatments. Identifying a novel mechanism, here we demonstrate that bacteria use the universal communication molecule AI-2 to induce virulence genes and transfer them via phage release. High concentrations (i.e. 100 μM) of AI-2 promote dispersal of bacteria from already established biofilms, and is associated with release of phages capable of infecting other bacteria. Enterococcus faecalis V583ΔABC harbours 7 prophages in its genome, and a mutant deficient in one of these prophages (i.e. prophage 5) showed a greatly reduced dispersal of biofilm. Infection of a probiotic E. faecalis strain without lytic prophages with prophage 5 resulted in increased biofilm formation and also in biofilm dispersal upon induction with AI-2. Infection of the probiotic E. faecalis strain with phage-containing supernatants released through AI-2 from E. faecalis V583ΔABC resulted in a strong increase in pathogenicity of this strain. The polylysogenic probiotic strain was also more virulent in a mouse sepsis model and a rat endocarditis model. Both AI-2 and ciprofloxacin lead to phage release, indicating that conditions in the gastrointestinal tract of hospitalized patients treated with antibiotics might lead to distribution of virulence genes to apathogenic enterococci and possibly also to other commensals or even to beneficial probiotic strains.


The derivation of highly germline-competent embryonic stem cells containing NOD-derived genome.
It would be extremely advantageous to the analysis of disease mechanisms in the spontaneous mouse model of type 1 diabetes, the nonobese diabetic (NOD) strain, if genes in this strain could be modified in vivo using embryonic stem (ES) cells and homologous recombination. However, a NOD ES cell line with adequate germline transmission has not yet been reported. We report the development of highly germline-competent ES cell lines from the F1 hybrid of NOD and 129 for use in NOD gene targeting. Consequently, we developed ES cell lines derived from (NOD x 129)F1 x 129 backcross 1 mice, which were intercrossed to select for homozygosity of particular regions of NOD genome known to contain disease loci.


Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies.
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.


Determination of total leachable bisphenol A from polysulfone membranes based on multiple consecutive extractions.
The paper presents the development of a multiple consecutive extraction method enabling the determination of the total amount of bisphenol A (BPA) released from porous polysulfone (PS) membranes in a hemodialyzer or hemoconcentrator under simulated-use conditions. The levels of BPA were determined using solid phase extraction (SPE) coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS). We demonstrated that it was difficult to determine the total amount of BPA released from the PS membranes using a single extraction method with finite solvent volume because of the chemical equilibrium between the extraction solution and the polymer phase. Repeated extractions gave more accurate results than a single extraction for the determination of the total amount of leachables in porous membranes. A general equation was derived to fit the elution profile of BPA released during multiple consecutive extractions.


Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach.
Extracorporeal membrane oxygenation as a bridge to lung transplantation has traditionally been associated with substantial morbidity and mortality. A major contributor to these complications may be weakness and overall deconditioning secondary to pretransplant critical illness and immobility. In an attempt to address this issue, we developed a collaborative program to allow for active rehabilitation and physical therapy for patients requiring life support with extracorporeal membrane oxygenation before lung transplantation. An interdisciplinary team responded to an acute need to develop a mechanism for active rehabilitation and physical therapy for patients awaiting lung transplantation while being managed with extracorporeal membrane oxygenation. We describe a series of three patients who benefited from this new approach. A quaternary care pediatric intensive care unit in a children's hospital set within an 800-bed university academic hospital with an active lung transplantation program for adolescent and adult patients. PATIENTS, INTERVENTIONS, AND MAIN RESULTS: Three patients (ages 16, 20, and 24 yrs) with end-stage respiratory failure were rehabilitated while on extracorporeal membrane oxygenation awaiting lung transplantation. These patients were involved in active rehabilitation and physical therapy and, ultimately, were ambulatory on extracorporeal membrane oxygenation before successful transplantation. Following lung transplantation, the patients were liberated from mechanical ventilation, weaned to room air, transitioned out of the intensive care unit, and ambulatory less than 1 wk posttransplant. A comprehensive, multidisciplinary system can be developed to safely allow for active rehabilitation, physical therapy, and ambulation of patients being managed with extracorporeal membrane oxygenation. Such programs may lead to a decreased threshold for the utilization of extracorporeal membrane oxygenation before transplant and have the potential to improve conditioning, decrease resource utilization, and lead to better outcomes in patients who require extracorporeal membrane oxygenation before lung transplantation.


[Purinergic signals].
In the last decade evidence accumulated that nucleosides and nucleotides of both uridine and adenine can act as extracellular signaling factors. Their action is mediated by two main types of surface receptors commonly known as purinergic. P1 receptors are metabotropic and activated by adenosine, whereas receptors for nucleotides (ATP, ADP, UTP and UDP) and nucleotide-sugars (UDP-glucose and UDP-galactose) can be either metabotropic (P2Y) or ionotropic (P2X). The importance and complexity of this signaling system is evidenced by various mechanisms of nucleotide release, as well as by the ibiquitous distribution of various types of ectonucleotidases which catalyze and convert extracellular nucleotides. Up to now about twenty receptors have been cloned and found to modulate the nerve impulse, inflammatory response, insuline secretion, the regulation of the vascular tone and nociception, among other processes. In the present review we describe the main structural and pharmacological features of purinergic receptors, and analyze how the dynamic interaction between these receptors, nucleotides and nucleosides, and ectonucleotidases modulate several biological responses. Particular focus is given to platelet aggregation and thrombus formation, the immune response and the hydration of the mucosal linings of the respiratory tract.


Resilience to acute sleep deprivation is associated with attenuation of hippocampal mediated learning impairment.
Sleep deprivation is a universal issue that affects individuals in different ways. While some individuals experience a deficit in performance, others experience resiliency as they maintain high levels of physical and mental activity. Sleep loss is known to cause cognitive dysfunction in areas such as learning and memory, but little is known about neural mechanisms that contribute to resilience to this adverse effect. An existing database of a learning paradigm in sleep deprived and non-sleep deprived 16 to 18-month old C57BL/6 mice was used to identify fast learners and slow learners based on an R2 value representing the learning curve of each individual mouse. Results showed that sleep deprived mice had more slow learners compared to fast learners whereas non-sleep-deprived mice showed the opposite. Hippocampal immunohistochemistry and digital imaging analysis showed sleep deprived, fast learners expressed lower levels of monocyte chemoattractant protein-1 and histone deacetylase 2 and higher levels of synaptophysin and brain-derived neurotrophic factor compared to sleep-deprived slow learners. These observations provide evidence to suggest that sleep-deprived mice that performed well in a cognitive assay show less hippocampal mediated learning impairment and provide the rationale for further investigations into neurobiological resilience to sleep deprivation with increasing age.


JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms.
Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.


Near-perfect absorption in epsilon-near-zero structures with hyperbolic dispersion.
We investigate the interaction of polarized electromagnetic waves with hyperbolic metamaterial structures, whereby the in-plane permittivity component εx is opposite in sign to the normal component εz. We find that when the thickness of the metamaterial is smaller than the wavelength of the incident wave, hyperbolic metamaterials can absorb significantly higher amounts of electromagnetic energy compared to their conventional counterparts. We also demonstrate that for wavelengths leading to ℜ(εz) ≈ 0, near-perfect absorption arises and persists over a range of frequencies and subwavelength structure thicknesses.


Impact of MR Neurography in Patients with Chronic Cauda Equina Syndrome Presenting as Chronic Pelvic Pain and Dysfunction.
Chronic cauda equina syndrome, defined as persistent damage of the cauda equina nerve roots within the spinal canal can be a challenging diagnosis with varied presentations. MR neurography imaging is more commonly being used to evaluate the lumbosacral spine of patients suspected of having subacute or chronic cauda equina syndrome. Our aim was to evaluate the impact of lumbosacral plexus MR neurography in the diagnostic thinking and therapeutic management of patients presenting with chronic pelvic pain and dysfunction and suspected chronic cauda equina syndrome. Consecutive MR neurography lumbosacral plexus examinations at our institution were reviewed retrospectively. Relevant data collected included the following: patient demographics, clinical history, pertinent physical examination findings, preimaging diagnostic impression, prior MR imaging lumbar spine findings, MR neurography findings, postimaging diagnosis, and postimaging treatment plan. The impact of imaging on the preimaging clinical diagnosis and therapeutic management was evaluated. Of 185 studies of patients who presented with chronic pelvic pain and/or dysfunction, 23 with clinically suspected chronic cauda equina syndrome and imaging findings were included in the study (2 subjects were lost to follow-up). The mean ages were 53 ± 12 years and 53 ± 16 years for men and women, respectively. The common etiologies included arachnoiditis (n = 8), tethered cord (n = 2), and simple/Tarlov cysts (n = 3). Eighteen of 23 (78%) subjects had a change in diagnosis resulting from MR neurography findings, and 5/23 (22%) had no change. Seventeen of 21 (81%) subjects had a change in management, and 4/21 (19%) had no change. MR neurography impacts the diagnosis and therapeutic management of patients with suspected chronic cauda equina syndrome.


Distribution of cell surface saccharides on pancreatic cells. II. Lectin-labeling patterns on mature guinea pig and rat pancreatic cells.
The surface saccharide composition of collagenase-dispersed pancreatic cells from adult guinea pig and rat glands was examined by using eight lectins and their ferritin conjugates: Concanavalin A (ConA); Lens culinaris (LCL); Lotus tetragonolobus (LTL); Ricinus communis agglutinins I and II (RCA I, RCA II); Soybean agglutinin (SBA); Ulex europeus lectin (UEL); and wheat germ agglutinin (WGA). Binding studies of iodinated lectins and lectin-ferritin conjugates both revealed one population of saturable, high-affinity receptor sites on the total cell population (approximately 95% acinar cells). Electron microscopy, however, revealed differences in lectin-ferritin binding to the plasmalemma of acinar, centroacinar, and endocrine cells. Whereas acinar cells bound heavily all lectin conjugates, endocrine and centroacinar cells were densely labeled only by ConA, LCL, WGA, and RCA I, and possessed few receptors for LTL, UEL, and SBA. Endocrine and centroacinar cells could be differentiated from each other by using RCA II, which binds to centroacinar cells but not to endocrine cells. Some RCA II receptors appeared to be glycolipids because they were extracted by ethanol and chloroform-methanol in contrast to WGA receptors which resisted solvent treatment but were partly removed by papain digestion. RCA I receptors were affected by neither treatment. The apparent absence of receptors for SBA on endocrine and centroacinar cells, and for RCA II on endocrine cells, was reversed by neuraminidase digestion, which suggested masking of lectin receptors by sialic acid. The absence of LTL and UEL receptors on endocrine and centroacinar cells was not reversed by neuraminidase. We suggest that the differential lectin-binding patterns observed on acinar, centroacinar, and endocrine cells from the adult pancreas surface-carbohydrate-developmental programs expressed during morphogenesis and cytodifferentiation of the gland.


Androgens and prostate disease.
A growing body of literature has established the anabolic benefi ts of testosterone (T) therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently fi nd a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.


Studying the role of lipid rafts on protein receptor bindings with cellular automata.
It is widely accepted that lipid rafts promote receptor clustering and thereby facilitate signaling transduction. The role of lipid rafts in inducing and promoting receptor accumulation within the cell membrane has been explored by several computational and experimental studies. However, it remains unclear whether lipid rafts influence the recruitment and binding of proteins from the cytosol as well. To provide an answer to this question a spatial membrane model has been developed based on cellular automata. Our results indicate that lipid rafts indeed influence protein receptor bindings. In particular processes with slow dissociation and binding kinetics are promoted by lipid rafts, whereas fast binding processes are slightly hampered. However, the impact depends on a variety of parameters, such as the size and mobility of the lipid rafts, the induced slow down of receptors within rafts, and also the dissociation and binding kinetics of the cytosolic proteins. Thus, for any individual signaling pathway the influence of lipid rafts on protein binding might be different. To facilitate analyzing this influence given a specific pathway, our approach has been generalized into LiRaM, a modeling and simulation tool for lipid rafts models.


Nonlinear bayesian filtering for denoising of electrocardiograms acquired in a magnetic resonance environment.
ECGs are currently acquired during magnetic resonance examinations. This "hostile" environment highly distorts ECG signals, due to the high-static magnetic field, RF pulses and fast switching magnetic gradients. Specific signal processing is then required since the ECG signal is used for image synchronization with heart activity (or triggering) and for patient monitoring. A new set of two magnetic field gradient (MFG) artifact reduction methods, based on ECG and MFG artifact modelings and Bayesian filtering, is herein presented and will be called Bayesian gradient artifact reduction monitoring (BAGARRE-M) and BAGARRE-triggering. These algorithms overcome the limitations of state-of-the-art methods and enable accurate processing of very noisy ECG acquisitions during MRI. Whether for triggering or monitoring purposes, the presented methods overcome state-of-the-art techniques with both better QRS detection accuracy and signal denoising quality.


Noninvasive estimation of the arterial input function in positron emission tomography imaging of cerebral blood flow.
Positron emission tomography (PET) with (15)O-labeled water can provide reliable measurement of cerebral blood flow (CBF). Quantification of CBF requires knowledge of the arterial input function (AIF), which is usually provided by arterial blood sampling. However, arterial sampling is invasive. Moreover, the blood generally is sampled at the wrist, which does not perfectly represent the AIF of the brain, because of the effects of delay and dispersion. We developed and validated a new noninvasive method to obtain the AIF directly by PET imaging of the internal carotid artery in a region of interest (ROI) defined by coregistered high-resolution magnetic resonance angiography. An ROI centered at the petrous portion of the internal carotid artery was defined, and the AIF was estimated simultaneously with whole brain blood flow. The image-derived AIF (IDAIF) method was validated against conventional arterial sampling. The IDAIF generated highly reproducible CBF estimations, generally in good agreement with the conventional technique.


Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells.
The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion. To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors. We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion. This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.


Guinea Pig Transferrin Receptor 1 Mediates Cellular Entry of Junín Virus and Other Pathogenic New World Arenaviruses.
Several clade B New World arenaviruses (NWAs) can cause severe and often fatal hemorrhagic fever, for which preventive and therapeutic measures are severely limited. These NWAs use human transferrin receptor 1 (hTfR1) as a host cell receptor for virus entry. The most prevalent of the pathogenic NWAs is Junín virus (JUNV), the etiological agent of Argentine hemorrhagic fever. Small animal models of JUNV infection are limited because most laboratory rodent species are refractory to disease. Only guinea pigs are known to develop disease following JUNV infection, but the underlying mechanisms are not well characterized. In the present study, we demonstrate marked susceptibility of Hartley guinea pigs to uniformly lethal disease when challenged with as few as 4 PFU of the Romero strain of JUNV. In vitro, we show that infection of primary guinea pig macrophages results in greater JUNV replication compared to infection of hamster or mouse macrophages. We provide evidence that the guinea pig TfR1 (gpTfR1) is the principal receptor for JUNV, while hamster and mouse orthologs fail to support viral entry/infection of pseudotyped murine leukemia viruses expressing pathogenic NWA glycoproteins or JUNV. Together, our results indicate that gpTfR1 serves as the primary receptor for pathogenic NWAs, enhancing viral infection in guinea pigs.IMPORTANCE JUNV is one of five known NWAs that cause viral hemorrhagic fever in humans. Countermeasures against JUNV infection are limited to immunization with the Candid#1 vaccine and immune plasma, which are available only in Argentina. The gold standard small animal model for JUNV infection is the guinea pig. Here, we demonstrate high sensitivity of this species to severe JUNV infection and identify gpTfR1 as the primary receptor. Use of hTfR1 for host cell entry is a feature shared by pathogenic NWAs. Our results show that expression of gpTfR1 or hTfR1 comparably enhances JUNV virus entry/infectivity. Our findings shed light on JUNV infection in guinea pigs as a model for human disease and suggest that similar pathophysiological mechanisms related to iron sequestration during infection and regulation of TfR1 expression may be shared between humans and guinea pigs. A better understanding of the underlying disease process will guide development of new therapeutic interventions.


Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to a progressed form. Nodule-in-nodule-type HCC (progressed HCC within early HCC) represents the transition from early to progressed HCC and, therefore, is useful in molecular genetic analysis of HCC progression during multistage carcinogenesis. We compared expression profiles among 7 early components and 7 progressed components of nodule-in-nodule-type HCCs and their corresponding noncancerous liver tissues with oligonucleotide array. Of the approximately 12,600 genes that were analyzed, a set of 95 genes provided a molecular signature that distinguished between early HCC components and their noncancerous liver tissues, and a set of 92 genes distinguished between progressed and early HCC components. Of these genes, the most abundantly up-regulated gene in early HCC components (P <.001) was heat-shock protein 70 (HSP70). Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed this finding. Further immunohistochemical examination of HSP70 revealed its significant overexpression in early HCC compared with precancerous lesions (P <.001) and in progressed HCC compared with early HCC (P <.001). In conclusion, molecular signatures were clearly different in noncancerous liver tissue as compared with the early and progressed components of nodule-in-nodule-type HCC. Moreover, HSP70 could be a sensitive marker for the differential diagnosis of early HCC from precancerous lesion or noncancerous liver, a difficult distinction for pathologists due to very well differentiated histology with little atypia in early HCC.


Role of screening colonoscopy for colorectal tumors in Helicobacter pylori-related chronic gastritis with MDM2 SNP309 G/G homozygous: A prospective cross-sectional study in Thailand.
Helicobacter pylori infection is a risk factor for gastric cancer and colorectal cancer (CRC). MDM2 SNP309 G/G homozygosity is known to be the genetic background that influences the severity of inflammation in the gastric mucosa, and it corresponds to CRC development. We examined the role of screening colonoscopy in H. pylori-related chronic gastritis and the association of patients who have MDM2 SNP309 G/G homozygosity and advanced colorectal neoplasia (CRN) susceptibility. A prospective cross-sectional study was used to investigate H. pylori-related gastritis in 331 consecutive asymptomatic patients who had MDM2 SNP309 G/G homozygosity and who were enrolled from November 2014 to July 2017. The MDM2 SNP309 polymorphism was genotyped by real-time PCR hybridization probe assay. Totally, there were 331 patients with H. pylori-related gastritis, of whom 39 (8.76%) had advanced CRN. The H. pylori-positive group comprised 180 patients (54.36%). H. pylori infection was associated with advanced CRN (OR: 2.09, 95% CI: 1.56-2.80; p=0.01) and had an increased risk of advanced CRN (OR: 4.24, 95% CI: 1.76-5.21; p=0.01) after adjusting for confounding factors. Patients with H. pylori infection had a significantly increased risk of high-grade dysplasia or invasive adenocarcinoma (OR: 2.96, 95% CI: 1.48-4.17; p=0.03). Chronic gastritis patients infected with H. pylori and who had MDM2 SNP309 G/G homozygosity had an increased risk of advanced CRN, particularly high-grade dysplasia including invasive adenocarcinoma. Screening colonoscopy in these patients might benefit colorectal polyp diagnosis and prevention and early CRC treatment in the Thai population.


Influence of social class perceptions on attributions among mental health practitioners.
A vignette-based study assessed the influence of social class attributions toward a hypothetical client's difficulty. 188 licensed mental health professionals who were recruited through professional listservs completed an online survey after reviewing one of two versions of a vignette describing a hypothetical client that varied based on social class cues. As expected, this sample of licensed mental health practitioners detected social class differences based on the descriptors of the hypothetical client across the two vignettes. These perceived social class differences, however, did not impact participants' attributions toward the client for causing or solving her problems, level of Global Assessment of Functioning score ascribed to the client, or willingness to work with the client. There was no evidence that participants differentially ascribed attributions based on social class. Implications and directions for future research are provided.


Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency.
Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3-6 mg/day, n = 50) or hydrocortisone (15-30 mg/day, n = 909) were identified and grouped at a ratio of 1:3 (prednisolone:hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. Significantly higher mean ± s.d. total (6.3 ± 1.6 vs 5.4 ± 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 ± 1.4 vs 3.2 ± 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.


Thymoma-associated myasthenia gravis and LGI1-encephalitis, with nephrotic syndrome post-thymectomy.
Thymoma is associated with a wide spectrum of autoimmune paraneoplastic syndromes, though it is uncommon for multiple paraneoplastic syndromes to be present in a single individual. We report a rare case of an elderly gentleman who was found to have thymoma-associated myasthenia gravis and LGI1-encephalitis with myokymia, who presented with nephrotic syndrome (minimal change glomerulopathy) after thymectomy. The latter two paraneoplastic syndromes had manifested when prednisolone was tapered down to low dose. This case serves to remind neurologists that apart from paraneoplastic neurological manifestations, thymoma may also be associated with renal disease. Nephropathy in myasthenia patients with thymoma should be properly evaluated, as it is treatable with immunotherapy, and it may even occur post-thymectomy.


Preparing Physiotherapy Students for Clinical Placement: Student Perceptions of Low-Cost Peer Simulation. A Mixed-Methods Study.
Simulation is increasingly used in health care education, yet the organizational and financial costs can be prohibitive. This study aimed to investigate whether peer simulation is perceived by third-year undergraduate physiotherapy students as valuable for clinical placement preparation. Third-year undergraduate physiotherapy students participated in a 9-week peer simulation program, using each other as patients, and were invited to complete two surveys evaluating perceptions of the program. The program consisted of weekly patient interactions during which students were required to assess and treat a "patient" under strict simulation guidelines and in accordance with stated learning objectives. Items rated included self-perceived skills, confidence, time management, and clinical placement readiness and included collection of qualitative responses. Surveys were released at commencement and completion of the simulation program. Of 79 third-year students, 63% completed survey 1 and 66% completed survey 2. Students had high expectations of the program and these were consistently met. Peer simulation rated highly for all items, including identifying knowledge and skill deficits, and improving confidence, clinical reasoning, time management, and communication. Simulation was considered safe, supportive, engaging, and valuable for clinical placement preparation. Students identified some lack of authenticity when working with peers. Peer simulation was perceived by students as valuable in preparing them for clinical placement, despite a perceived lack of realism. These findings support the use of peer simulation as an alternative to the use of more formalized standardized patients in an undergraduate physiotherapy program. Further investigation is required to establish a detailed cost analysis of the program and to determine the amount of realism required to optimize the benefits of this promising educational strategy.


Facilitating students' reflective practice in a medical course: literature review.
Reflection and reflective practice is of increasing importance in medical education curricula. The aim of this review is to summarise the literature published around facilitating reflection in a medical course, and to answer the question : W0 hat is the current evidence regarding learning and development moments across the medical curriculum in developing students' reflective practice? A review of the literature was undertaken using defined databases and the search terms 'medical students', 'medical education', 'reflection', 'reflectFNx01' and 'medicine'. The search was limited to peer-reviewed published material in English and between the years 2001 and 2011, and included research, reviews and opinion pieces. Thirty-six relevant articles were found, identifying enhancing factors and barriers to effectively teaching reflective practice within medical curricula, relating to: The breadth of the meaning of reflection; facilitating reflection by medical educators; using written or web-based portfolios to facilitate reflection; and assessing the reflective work of students. A variety of reflective purposes was found in this literature review. Evidence indicates that, if students are unclear as to the purpose of reflection and do not see educators modelling reflective behaviours, they are likely to undervalue this important skill regardless of the associated learning and development opportunities embedded in the curriculum.


Challenges to improving the impact of worksite cancer prevention programs: comparing reach, enrollment, and attrition using active versus passive recruitment strategies.
The impact of worksite intervention studies is maximized when reach and enrollment are high and attrition is low. Differences in reach, enrollment, and retention were investigated by comparing 2 different employee recruitment methods for a home-based cancer-prevention intervention study. Twenty-two worksites (N = 10,014 employees) chose either active or passive methods to recruit employees into a home-based intervention study. Reach (e.g., number of employees who gave permission to be called at home), Enrollment (e.g., number of employees who joined the home intervention study), and Attrition (e.g., number who did not complete the 12- and 24-month follow-ups) were determined. Analysis at the cluster level assessed differences between worksites that selected active (n = 12) versus passive (n = 10) recruitment methods on key outcomes of interest. Employees recruited by passive methods had significantly higher reach (74.5% vs. 24.4% for active) but significantly lower enrollment (41% vs. 78%) and retention (54% vs. 70%) rates (all ps < .0001). Passive methods also successfully enrolled a more diverse, high-risk employee sample. Passive (vs. active) recruitment methods hold advantages for increased reach and the ability to retain a more representative employee sample. Implications of these results for the design of future worksite studies that involve multilevel recruitment methods are discussed.


Quantitative determination of Plasmodium vivax gametocytes by real-time quantitative nucleic acid sequence-based amplification in clinical samples.
Microscopic detection of Plasmodium vivax gametocytes, the sexual life stage of this malaria parasite, is insensitive because P. vivax parasitaemia is low. To detect and quantify gametocytes a more sensitive, quantitative real-time Pvs25-QT-NASBA based on Pvs25 mRNA was developed and tested in two clinical sample sets from three different continents. Pvs25-QT-NASBA is highly reproducible with low inter-assay variation and reaches sensitivity approximately 800 times higher than conventional microscopic gametocyte detection. Specificity was tested in 104 samples from P. vivax-, P. falciparum-, P. malariae-, and P. ovale-infected patients. All non-vivax samples were negative in the Pvs25-QT-NASBA; out of 74 PvS18-QT-NASBA positive samples 69% were positive in the Pvs25-QT-NASBA. In a second set of 136 P. vivax microscopically confirmed samples, gametocyte prevalence was 8%, whereas in contrast 66% were positive by Pvs25-QT-NASBA. The data suggest that the human P. vivax gametocyte reservoir is much larger when assessed by Pvs25-QT-NASBA than by microscopy.


Toward an Objective Assessment of Implementation Processes for Innovations in Health Care: Psychometric Evaluation of the Normalization Measure Development (NoMAD) Questionnaire Among Mental Health Care Professionals.
Successfully implementing eMental health (eMH) interventions in routine mental health care constitutes a major challenge. Reliable instruments to assess implementation progress are essential. The Normalization MeAsure Development (NoMAD) study developed a brief self-report questionnaire that could be helpful in measuring implementation progress. Based on the Normalization Process Theory, this instrument focuses on 4 generative mechanisms involved in implementation processes: coherence, cognitive participation, collective action, and reflexive monitoring. The aim of this study was to translate the NoMAD questionnaire to Dutch and to confirm the factor structure in Dutch mental health care settings. Dutch mental health care professionals involved in eMH implementation were invited to complete the translated NoMAD questionnaire. Confirmatory factor analysis (CFA) was conducted to verify interpretability of scale scores for 3 models: (1) the theoretical 4-factor structure, (2) a unidimensional model, and (3) a hierarchical model. Potential improvements were explored, and correlated scale scores with 3 control questions were used to assess convergent validity. A total of 262 professionals from mental health care settings in the Netherlands completed the questionnaire (female: 81.7%; mean age: 45 [SD=11]). The internal consistency of the 20-item questionnaire was acceptable (.62≤alpha≤.85). The theorized 4-factor model fitted the data slightly better in the CFA than the hierarchical model (Comparative Fit Index=0.90, Tucker Lewis Index=0.88, Root Mean Square Error of Approximation=0.10, Standardized Root Mean Square Residual=0.12, χ22=22.5, P≤.05). However, the difference is small and possibly not outweighing the practical relevance of a total score and subscale scores combined in one hierarchical model. One item was identified as weak (λCA.2=0.10). A moderate-to-strong convergent validity with 3 control questions was found for the Collective Participation scale (.47≤r≤.54, P≤.05). NoMAD's theoretical factor structure was confirmed in Dutch mental health settings to acceptable standards but with room for improvement. The hierarchical model might prove useful in increasing the practical utility of the NoMAD questionnaire by combining a total score with information on the 4 generative mechanisms. Future research should assess the predictive value and responsiveness over time and elucidate the conceptual interpretability of NoMAD in eMH implementation practices.


Psychiatric and otologic diagnoses in patients complaining of dizziness.
Dizziness is a common and disabling symptom in primary care practice, especially among the elderly. Though there are many organic causes of dizziness, the results of medical workups are negative in the majority of patients. A total of 75 patients with dizziness who were referred to a community otolaryngology practice received a structured psychiatric diagnostic interview (National Institute of Mental Health Diagnostic Interview Schedule) and questionnaires that assessed psychological distress as well as a complete otologic evaluation, including electronystagmogram. Patients with evidence of a peripheral vestibular disorder were compared with those without such evidence. While psychiatric diagnoses were present in both those with and without evidence of a peripheral vestibular disorder, those without such evidence had a greater mean number of lifetime psychiatric diagnoses as defined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, and specifically, a greater lifetime prevalence of major depression and panic disorder. This group also more frequently met criteria for somatization disorder, had more current and lifetime unexplained medical symptoms, and had more severe current depressive, anxiety, and somatic symptoms. Psychiatric diagnoses are common among patients with dizziness referred for otologic evaluation who do not show evidence of a peripheral vestibular disorder. Specific psychiatric disorders should be part of the differential diagnosis of patients who present with dizziness.


The potential impact of reducing indoor tanning on melanoma prevention and treatment costs in the United States: An economic analysis.
Indoor tanning is associated with an increased risk of melanoma. The US Food and Drug Administration proposed prohibiting indoor tanning among minors younger than 18 years. We sought to estimate the health and economic benefits of reducing indoor tanning in the United States. We used a Markov model to estimate the expected number of melanoma cases and deaths averted, life-years saved, and melanoma treatment costs saved by reducing indoor tanning. We examined 5 scenarios: restricting indoor tanning among minors younger than 18 years, and reducing the prevalence by 20%, 50%, 80%, and 100%. Restricting indoor tanning among minors younger than 18 years was estimated to prevent 61,839 melanoma cases, prevent 6735 melanoma deaths, and save $342.9 million in treatment costs over the lifetime of the 61.2 million youth age 14 years or younger in the United States. The estimated health and economic benefits increased as indoor tanning was further reduced. Limitations include the reliance on available data and not examining compliance to indoor tanning laws. Reducing indoor tanning has the potential to reduce melanoma incidence, mortality, and treatment costs. These findings help quantify and underscore the importance of continued efforts to reduce indoor tanning and prevent melanoma.


Dry eye disease: an (in)convenient truth.
The salient rise of chronic disease from the mid-twentieth century threatens to overwhelm public health systems in an increasing number of countries and is now considered an epidemic. Dry eye disease is an underappreciated disorder that bears all the hallmarks of chronic disease. Preventative health care seeks improved and sustainable patient engagement in the self-management of health to limit the progress and extent of chronic disease. Anthropogenic environments engendering lifestyles and behaviours that can be detrimental to human health, can be considered as direct or indirect threats to successful preventative health strategies. Chronic disease can be viewed as the result of physiological responses of the human body to the modern environment. The quest for an increasingly convenient, global, and disease-free lifestyle is ironically threatening to undo the gains in health and quality of life made over the last one hundred years. Considering dry eye disease as an anthropogenic chronic disease, contributions of diet (food and beverages consumed) and nutrition (extending to relationships with self, community, and nature) to development of dry eye disease are explored in this review. Evidence of environmental and behavioural instigators of chronic disease with an emphasis on production, disbursement, and preservation of food, is presented. Furthermore, evidence of traditional food practices that offer resistance to the development of chronic systemic inflammatory disorders are reviewed as an exemplar of potential strategies that can be put into practice by individuals and communities to reinstate a balanced life, community and planet.


The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2.
Ubiquitin chains of different topologies trigger distinct functional consequences, including protein degradation and reorganization of complexes. The assembly of most ubiquitin chains is promoted by E2s, yet how these enzymes achieve linkage specificity is poorly understood. We have discovered that the K11-specific Ube2S orients the donor ubiquitin through an essential noncovalent interaction that occurs in addition to the thioester bond at the E2 active site. The E2-donor ubiquitin complex transiently recognizes the acceptor ubiquitin, primarily through electrostatic interactions. The recognition of the acceptor ubiquitin surface around Lys11, but not around other lysines, generates a catalytically competent active site, which is composed of residues of both Ube2S and ubiquitin. Our studies suggest that monomeric E2s promote linkage-specific ubiquitin chain formation through substrate-assisted catalysis.


Maternal IL-6 can cause T-cell-mediated juvenile alopecia by non-scarring follicular dystrophy in mice.
Aiming to decipher immunological mechanisms of the autoimmune disorder alopecia areata (AA), we hypothesized that interleukin-6 (IL-6) might be associated with juvenile-onset AA, for which there is currently no experimental model. Upon intramuscular transgenesis to overexpress IL-6 in pregnant female C57BL/6 (B6) mice, we found that the offspring displayed an initial normal and complete juvenile hair growth cycle, but developed alopecia around postnatal day 18. This alopecia was patchy and reversible (non-scarring) and was associated with upregulation of Ulbp1 expression, the only mouse homolog of the human AA-associated ULBP3 gene. Alopecia was also associated with inflammatory infiltration of hair follicles by lymphocytes, including alpha-beta T cells, which contributed to surface hair loss. Despite these apparently shared traits with AA, lesions were dominated by follicular dystrophy that was atypical of human AA disease, sharing some traits consistent with B6 alopecia and dermatitis. Additionally, juvenile-onset alopecia was followed by complete, spontaneous recovery of surface hair, without recurrence of hair loss. Prolonging exposure to IL-6 prolonged the time to recovery, but once recovered, repeating high-dose IL-6 exposure de novo did not re-induce alopecia. These data suggest that although substantial molecular and cellular pathways may be shared, functionally similar alopecia disorders can occur via distinct pathological mechanisms.


Factors Associated With Delirium Following Electroconvulsive Therapy: A Systematic Review.
Delirium following electroconvulsive therapy (ECT) has been a clinical challenge, which, however, has not been investigated through a systematic literature review. The objective of this study was to systematically synthesize available evidence regarding factors associated with post-ECT delirium. We conducted a systematic literature search for any type of original investigations that reported risk factors of post-ECT delirium, using PubMed. The literature search identified 43 relevant articles. One study found an association between catatonic feature and increased risk of postictal delirium. Five studies reported that the presence of cerebrovascular disease, Parkinson disease, or dementia was related to higher incidence of post-ECT delirium. Incidence of post-ECT course delirium was increased with bitemporal stimulation (3 studies). One study showed that ultrabrief pulse ECT reduced reorientation time following seizure compared with brief pulse ECT. High stimulus intensity resulted in more prolonged reorientation time after ECT than lower stimulus intensity (2 studies). Longer seizure length was significantly associated with post-ECT delirium in 1 study. Eight studies that examined postictal delirium in association with medications used, including lithium, did not show any consistent finding in their relationships. Four studies showed decreased incidence of postictal delirium in those receiving dexmedetomidine. Limited evidence suggests that catatonic feature, cerebrovascular disease, Parkinson disease, dementia, bitemporal electrode placement, high stimulus intensity, or longer seizure length are associated with an increased risk of post-ECT delirium. Moreover, dexmedetomidine and ultrabrief pulse ECT seem to have preventive effects of post-ECT delirium.


Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types.
At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.


The time scale of asymptomatic transmission affects estimates of epidemic potential in the COVID-19 outbreak.
The role of asymptomatic carriers in transmission poses challenges for control of the COVID-19 pandemic. Study of asymptomatic transmission and implications for surveillance and disease burden are ongoing, but there has been little study of the implications of asymptomatic transmission on dynamics of disease. We use a mathematical framework to evaluate expected effects of asymptomatic transmission on the basic reproduction number R0 (i.e., the expected number of secondary cases generated by an average primary case in a fully susceptible population) and the fraction of new secondary cases attributable to asymptomatic individuals. If the generation-interval distribution of asymptomatic transmission differs from that of symptomatic transmission, then estimates of the basic reproduction number which do not explicitly account for asymptomatic cases may be systematically biased. Specifically, if asymptomatic cases have a shorter generation interval than symptomatic cases, R0 will be over-estimated, and if they have a longer generation interval, R0 will be under-estimated. Estimates of the realized proportion of asymptomatic transmission during the exponential phase also depend on asymptomatic generation intervals. Our analysis shows that understanding the temporal course of asymptomatic transmission can be important for assessing the importance of this route of transmission, and for disease dynamics. This provides an additional motivation for investigating both the importance and relative duration of asymptomatic transmission.


Beta S haplotypes in various world populations.
We have determined the beta S haplotypes in 709 patients with sickle cell anemia, 30 with SC disease, 91 with S-beta-thalassemia, and in 322 Hb S heterozygotes from different countries. The methodology concerned the detection of mutations in the promoter sequences of the G gamma- and A gamma-globin genes through dot blot analysis of amplified DNA with 32P-labeled probes, and an analysis of isolated Hb F by reversed phase high performance liquid chromatography to detect the presence of the A gamma T chain [A gamma 75(E19)Ile----Thr] that is characteristic for haplotype 17 (Cameroon). The results support previously published data obtained with conventional methodology that indicates that the beta S gene arose separately in different locations. The present methodology has the advantage of being relatively inexpensive and fast, allowing the collection of a vast body of data in a short period of time. It also offers the opportunity of identifying unusual beta S haplotypes that may be associated with a milder expression of the disease. The numerous blood samples obtained from many SS patients living in different countries made it possible to compare their hematological data. Such information is included (as average values) for 395 SS patients with haplotype 19/19, for 2 with haplotype 17/17, for 50 with haplotype 20/20, for 2 with haplotype 3/3, and for 37 with haplotype 31/31. Some information on haplotype characteristics of normal beta A chromosomes is also presented.


Quick and clean: Cracking sentences encoded in E. coli by LC-MS/MS, de novo sequencing, and dictionary search.
In this study, we faced the challenge of deciphering a protein that has been designed and expressed by E. coli in such a way that the amino acid sequence encodes two concatenated English sentences. The letters 'O' and 'U' in the sentence are both replaced by 'K' in the protein. The sequence cannot be found online and carried to-be-discovered modifications. With limited information in hand, to solve the challenge, we developed a workflow consisting of bottom-up proteomics, de novo sequencing and a bioinformatics pipeline for data processing and searching for frequently appearing words. We assembled a complete first question: "Have you ever wondered what the most fundamental limitations in life are?" and validated the result by sequence database search against a customized FASTA file. We also searched the spectra against an E. coli proteome database and found close to 600 endogenous, co-purified E. coli proteins and contaminants introduced during sample handling, which made the inference of the sentence very challenging. We conclude that E. coli can express English sentences, and that de novo sequencing combined with clever sequence database search strategies is a promising tool for the identification of uncharacterized proteins.


Docking studies of sulphamate inhibitors of estrone sulphatase in human carbonic anhydrase II.
We describe the docking of selected steroidal and non-steroidal estrone sulphatase inhibitors, including the Phase I clinical trial candidate 667COUMATE (6), into the active site of human carbonic anhydrase II (hCA II). The docking scores are compared with the inhibition of hCA II and show good correlation with biological activity.


Serum and urinary leptin and ghrelin in children with nephrotic syndrome.
The aim of the present study was to evaluate the serum and urinary levels of leptin and ghrelin in children with primary idiopathic nephrotic syndrome (NS), to compare these results between patients during the relapse and remission phase and to evaluate the possible role of leptin and ghrelin in the pathogenesis of NS. Forty-nine children with primary idiopathic NS (25 children with relapse and 24 children in remission), who were followed up at the Pediatric Nephrology Unit, enrolled. Twenty-eight age- and sex-matched healthy children served as controls. Serum and urinary leptin levels were determined by immunoenzymatic ELISA, and serum and urinary ghrelin levels were determined by the RIA method. The serum leptin levels were significantly lower in the children with NS during the relapse phase than in the children with NS during remission or in the controls (1.42±0.34 ng/dl and 3.60±0.70 ng/ml; p<0.01, 1.42±0.34 ng/ml and 5.27±4.67 ng/ml; p<0.001, respectively). The urinary leptin excretion levels were significantly higher in the relapse group than in the controls (0.40±0.11 ng/ml and 0.12±0.06 ng/ml, p<0.01, respectively). The serum ghrelin levels were similar between the study groups (p>0.05). The urinary ghrelin excretion levels were significantly higher in the relapse group than in the remission group and the controls (965.0 pg/ml [93-3711] and 679.7 pg/ml [93-3783], p<0.05; 965.0 pg/ml [93-3711] and 387.7 pg/ml [114-1214], p<0.001, respectively). The urinary ghrelin levels were also significantly higher in the remission group than in the controls (679.7 pg/ml [93-3783] and 387.7 pg/ml [114-1214]), p<0.01, respectively). The serum leptin levels were positively correlated with the serum albumin levels (r=0.440, p<0.05) and were negatively correlated with the serum triglyceride levels during the relapse phase. The urinary leptin and ghrelin levels were positively correlated with proteinuria in the relapse group. We propose that leptin plays a role in the pathophysiology of NS and is associated with proteinuria, hypoproteinemia and hyperlipidemia. The significant urinary excretion of ghrelin in children with NS is possibly due to underlying pathophysiological changes, and normal serum ghrelin levels might be associated with an unknown compensatory mechanism.


Bullying participant roles and gender as predictors of bystander intervention.
Although the importance of peer bystanders in bullying has been recognized, there are few studies that examine the phenomenon in relation to Latané and Darley's (1970) classic Bystander Intervention Model, which states that there are five stages of bystander intervention: (i) notice the event; (ii) interpret the event as an emergency that requires assistance; (iii) accept responsibility for intervening; (iv) know how to intervene or provide help; and (v) implement intervention decisions. This study examined preliminary evidence of reliability and validity of the Bystander Intervention Model in Bullying (Nickerson, Aloe, Livingston, & Feeley, 2014), and the extent to which bullying role behavior (bullying, assisting, victimization, defending, and outsider behavior) and gender predicted each step of the model with a sample of 299 middle school students. Results of a Confirmatory Factor Analysis supported a five-factor structure of the measure corresponding to the steps of the model. There was evidence of convergent validity and Cronbach alpha for each subscale exceeded .75. In addition, students who reported defending their peers were more likely to also engage in all five steps of the bystander intervention model, while victims were more likely to notice events, and outsiders were less likely to intervene. Gender differences and gender interactions were also found. Aggr. Behav. 43:281-290, 2017. © 2016 Wiley Periodicals, Inc.


Identification of Linear and Nonlinear Sensory Processing Circuits from Spiking Neuron Data.
Inferring mathematical models of sensory processing systems directly from input-output observations, while making the fewest assumptions about the model equations and the types of measurements available, is still a major issue in computational neuroscience. This letter introduces two new approaches for identifying sensory circuit models consisting of linear and nonlinear filters in series with spiking neuron models, based only on the sampled analog input to the filter and the recorded spike train output of the spiking neuron. For an ideal integrate-and-fire neuron model, the first algorithm can identify the spiking neuron parameters as well as the structure and parameters of an arbitrary nonlinear filter connected to it. The second algorithm can identify the parameters of the more general leaky integrate-and-fire spiking neuron model, as well as the parameters of an arbitrary linear filter connected to it. Numerical studies involving simulated and real experimental recordings are used to demonstrate the applicability and evaluate the performance of the proposed algorithms.


Socioeconomic inequalities in alcohol related cancer mortality among men: to what extent do they differ between Western European populations?
We aim to study socioeconomic inequalities in alcohol related cancers mortality [upper aerodigestive tract (UADT) (oral cavity, pharynx, larynx, oesophagus and liver)] in men and to investigate whether the contribution of these cancers to socioeconomic inequalities in cancer mortality differs within Western Europe. We used longitudinal mortality datasets, including causes of death. Data were collected during the 1990s among men aged 30-74 years in 13 European populations [Madrid, the Basque region, Barcelona, Turin, Switzerland (German and Latin part), France, Belgium (Walloon and Flemish part, Brussels), Norway, Sweden, Finland]. Socioeconomic status was measured using the educational level declared at the census at the beginning of the follow-up period. We conducted Poisson regression analyses and used both relative [Relative index of inequality (RII)] and absolute (mortality rates difference) measures of inequality. For UADT cancers, the RII's were above 3.5 in France, Switzerland (both parts) and Turin whereas for liver cancer they were the highest (around 2.5) in Madrid, France and Turin. The contribution of alcohol related cancer to socioeconomic inequalities in cancer mortality was 29-36% in France and the Spanish populations, 17-23% in Switzerland and Turin, and 5-15% in Belgium and the Nordic countries. We did not observe any correlation between mortality rates differences for lung and UADT cancers, confirming that the pattern found for UADT cancers is not only due to smoking. This study suggests that alcohol use substantially influences socioeconomic inequalities in male cancer mortality in France, Spain and Switzerland but not in the Nordic countries and nor in Belgium.


The genome of Eimeria falciformis--reduction and specialization in a single host apicomplexan parasite.
The phylum Apicomplexa comprises important unicellular human parasites such as Toxoplasma and Plasmodium. Eimeria is the largest and most diverse genus of apicomplexan parasites and some species of the genus are the causative agent of coccidiosis, a disease economically devastating in poultry. We report a complete genome sequence of the mouse parasite Eimeria falciformis. We assembled and annotated the genome sequence to study host-parasite interactions in this understudied genus in a model organism host. The genome of E. falciformis is 44 Mb in size and contains 5,879 predicted protein coding genes. Comparative analysis of E. falciformis with Toxoplasma gondii shows an emergence and diversification of gene families associated with motility and invasion mainly at the level of the Coccidia. Many rhoptry kinases, among them important virulence factors in T. gondii, are absent from the E. falciformis genome. Surface antigens are divergent between Eimeria species. Comparisons with T. gondii showed differences between genes involved in metabolism, N-glycan and GPI-anchor synthesis. E. falciformis possesses a reduced set of transmembrane transporters and we suggest an altered mode of iron uptake in the genus Eimeria. Reduced diversity of genes required for host-parasite interaction and transmembrane transport allow hypotheses on host adaptation and specialization of a single host parasite. The E. falciformis genome sequence sheds light on the evolution of the Coccidia and helps to identify determinants of host-parasite interaction critical for drug and vaccine development.


Serum 25-hydroxyvitamin d level and influenza vaccine immunogenicity in children and adolescents.
Vaccination is an important strategy in the prevention of influenza, but immunologic response to vaccination can vary widely. Recent studies have shown an association between serum 25-hydroxyvitamin D (25[OH]D) levels and immune function. The purpose of this study was to determine if serum 25(OH)D level correlates with influenza vaccine immunogenicity in children and adolescents. We conducted a prospective cohort study of children age 3 to 15 years of age vaccinated with trivalent influenza vaccine (A/Brisbane/59/2007[H1N1]-like virus, A/Brisbane/10/2007 [H3N2]-like virus and B/Florida/4/2006-like virus) in Hutterite communities in Alberta, Saskatchewan and Manitoba. Serum 25(OH)D levels were measured at baseline and immunogenicity was assessed using hemagluttination inhibition (HAI) titers done at baseline and 3-5 weeks post vaccination. Logistic regression was used to assess the relationship between serum 25(OH)D level as both a continuous and dichotomous variable and seroprotection, seroconversion, fold increase in geometric mean titer (GMT) and post vaccination titer. A total of 391 children and adolescents were included in the study and 221 (57% had post-vaccination HAI titers. The median serum 25(OH)D level was 61.0 nmol/L (Interquartile range [IQR] 50.0, 71.0). No relationship was found between serum 25(OH)D level and seroprotection (post-vaccination titer ≥ 40 and ≥ 320) or seroconversion (post-vaccination titer ≥ 40 for participants with pre-vaccine titer <10 or four-fold rise in post-vaccination titer for those with a pre-vaccine titer ≥ 10). Serum 25(OH)D level was not associated with influenza vaccine immunogenicity in otherwise healthy children and adolescents. Other strategies to enhance influenza vaccine response should continue to be evaluated in this population. The role of serum 25(OH)D level in vaccine responsiveness in other populations, especially those hyporesponsive to influenza vaccination, requires further study.


Candida albicans iron acquisition within the host.
As a commensal and opportunistic pathogen, Candida albicans possesses a range of determinants that contribute to survival, persistence and virulence. Among this repertoire of fitness and virulence attributes are iron acquisition factors and pathways, which allow fungal cells to gain this essential mineral in the iron-poor environment of the host. The aim of this review is to present the strategies used by C. albicans to exploit host iron reservoirs and their impact on C. albicans pathogenicity. Because iron in the human host is mostly linked to host proteins, pathogens such as C. albicans must possess mechanisms to gain iron from these proteins. Here, we introduce the most important groups of human proteins, including haemoglobin, transferrin, lactoferrin and ferritin, which contain iron and that are potential iron sources for invading microorganisms. We then summarize and discuss the known and proposed strategies by which C. albicans exploits or may exploit iron from host proteins and compare these with strategies from other pathogenic microorganisms.


Detection of epigenetic changes using ANOVA with spatially varying coefficients.
Identification of genome-wide epigenetic changes, the stable changes in gene function without a change in DNA sequence, under various conditions plays an important role in biomedical research. High-throughput epigenetic experiments are useful tools to measure genome-wide epigenetic changes, but the measured intensity levels from these high-resolution genome-wide epigenetic profiling data are often spatially correlated with high noise levels. In addition, it is challenging to detect genome-wide epigenetic changes across multiple conditions, so efficient statistical methodology development is needed for this purpose. In this study, we consider ANOVA models with spatially varying coefficients, combined with a hierarchical Bayesian approach, to explicitly model spatial correlation caused by location-dependent biological effects (i.e., epigenetic changes) and borrow strength among neighboring probes to compare epigenetic changes across multiple conditions. Through simulation studies and applications in drug addiction and depression datasets, we find that our approach compares favorably with competing methods; it is more efficient in estimation and more effective in detecting epigenetic changes. In addition, it can provide biologically meaningful results.


Do we need core sets of fibromyalgia domains? The assessment of fibromyalgia (and other rheumatic disorders) in clinical practice.
An OMERACT consensus process recommended domains for investigation in fibromyalgia (FM) clinical trials. We used patient data to investigate variable importance in the determination of patient global and health-related quality of life (HRQOL) in FM and non-FM patients to determine whether variables were valued differently in FM compared with non-FM states. We used ACR 2010 diagnostic FM criteria modified for epidemiological and clinical research to identify patients with rheumatoid arthritis (RA; N = 5884) with and without FM, and also characterized previously diagnosed patients with FM (N = 808) as to current criteria status. We measured variable importance by multivariable regression, decomposing regression variance by averaging over model orderings. We examined the distributions of key variables in the various disorders, and the distributions as a function of a FM severity index (fibromyalgianess). Out of 9 measures, pain, Health Assessment Questionnaire disability index, and fatigue explained more than 50% of explainable variance (50.49%-56.59%). Explained variance was similar across all disorders and diagnostic groups. In addition, the SF-36 physical component summary score varied across disorders as a function of fibromyalgianess. The main determinants of global severity and HRQOL in FM are pain, function, and fatigue. But these variables are also the main determinants in RA and other rheumatic diseases. The content and impact of FM, whether measured by discrete variables or a fibromyalgianess scale, seems to be independent of diagnosis. These data argue for a common set of variables rather than disease-specific variables. Clinical use is supported and enhanced by simple measures.


Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese.
Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.