Survival and years of life lost in different age cohorts of patients with multiple myeloma.
To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients > or = age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age > or = 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients > or = age 80 years. Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age > or = 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.


Serum Vascular Endothelial Growth Factor-A as a Prognostic Biomarker for Epithelial Ovarian Cancer.
Bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, has recently been proven to be effective for the treatment of epithelial ovarian cancer (EOC). Thus, interest in VEGF-A has increased. There are few reports on concomitant detection of both ligands and its soluble receptors in serum samples, and the significance of serum VEGF-A in EOC is unclear, unlike the situation with tissue samples. We conducted the present study to explore the levels of serum VEGF family and its receptors and to evaluate their utility as prognostic biomarkers. A total of 128 patients with EOC, who were consecutively treated at Tottori University Hospital between 2006 and 2012, were included. Blood samples were collected before initial surgery. Serum concentrations of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assay. We also examined the mRNA and protein expression of VEGF-A in tumor tissue from 30 cases by real-time reverse transcription polymerase chain reaction and immunohistochemistry. The levels of VEGF-A in patients with stage III/IV disease were significantly higher than those with stage I/II disease (P = 0.0036). On the other hand, the level of VEGFR-2 in stage III/IV was significantly lower than that in stage I/II (P = 0.0026). With the cutoff value of VEGF/VEGFRs at the median level, the overall survival (OS) for patients with high VEGF-A levels was significantly lower than those with low levels (P = 0.015). Patients with high VEGFR-2 levels showed better prognosis than those with low VEGFR-2 levels (P = 0.023). Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage and serum VEGF-A were independent prognostic factors for OS [hazard ratio 2.01, 95% confidence interval (1.13-3.63), P = 0.017]. There was no significant correlation between mRNA or protein expression and serum levels of VEGF-A. Serum VEGF-A is an independent prognostic factor for OS in patients with EOC, implying that serum VEGF-A is a prognostic biomarker for EOC. Further study to validate the data is needed.


Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches.
Cyclin-dependent kinase 1 (Cdk1) kinase dephosphorylation and activation by Cdc25 phosphatase are essential for mitotic entry. Activated Cdk1 phosphorylates Cdc25 and other substrates, further activating Cdc25 to form a positive feedback loop that drives the abrupt G2/mitosis switch. Conversely, mitotic exit requires Cdk1 inactivation and reversal of Cdk1 substrate phosphorylation. This dephosphorylation is mediated, in part, by Clp1/Cdc14, a Cdk1-antagonizing phosphatase, which reverses Cdk1 phosphorylation of itself, Cdc25, and other Cdk1 substrates. Thus, Cdc25 phosphoregulation is essential for proper G2-M transition, and its contributions to cell cycle control have been modeled based on studies using Xenopus and human cell extracts. Because cell extract systems only approximate in vivo conditions where proteins interact within dynamic cellular environments, here, we use Schizosaccharomyces pombe to characterize, both experimentally and mathematically, the in vivo contributions of Cdk1-mediated phosphorylation of Cdc25 to the mitotic transition. Through comprehensive mapping of Cdk1 phosphosites on Cdc25 and characterization of phosphomutants, we show that Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the precision of mitotic entry, and unvarying cell length but not Cdc25 localization or abundance. We propose a mathematical model that explains Cdc25 regulation by Cdk1 through a distributive and disordered phosphorylation mechanism that ultrasensitively activates Cdc25. We also show that Clp1/Cdc14 dephosphorylation of Cdk1 sites on Cdc25 controls the proper timing of cell division, a mechanism that is likely due to the double negative feedback loop between Clp1/Cdc14 and Cdc25 that controls the abruptness of the mitotic exit switch.


Using Death Certificates to Explore Changes in Alcohol-Related Mortality in the United States, 1999 to 2017.
Alcohol consumption, alcohol-related emergency department visits, and hospitalizations have all increased in the last 2 decades, particularly among women and people middle-aged and older. The purpose of this study was to explore data from death certificates to assess whether parallel changes in alcohol-related mortality occurred in the United States in recent years. U.S. mortality data from the National Center for Health Statistics were analyzed to estimate the annual number and rate of alcohol-related deaths by age, sex, race, and ethnicity between 1999 and 2017 among people aged 16+. Mortality data contained details from all death certificates filed nationally. For each death, an underlying cause and up to 20 multiple or contributing causes were indicated. Deaths were identified as alcohol-related if an alcohol-induced cause was listed as either an underlying or multiple cause. Joinpoint analyses were performed to assess temporal trends. The number of alcohol-related deaths per year among people aged 16+ doubled from 35,914 to 72,558, and the rate increased 50.9% from 16.9 to 25.5 per 100,000. Nearly 1 million alcohol-related deaths (944,880) were recorded between 1999 and 2017. In 2017, 2.6% of roughly 2.8 million deaths in the United States involved alcohol. Nearly half of alcohol-related deaths resulted from liver disease (30.7%; 22,245) or overdoses on alcohol alone or with other drugs (17.9%; 12,954). Rates of alcohol-related deaths were highest among males, people in age-groups spanning 45 to 74 years, and among non-Hispanic (NH) American Indians or Alaska Natives. Rates increased for all age-groups except 16 to 20 and 75+ and for all racial and ethnic groups except for initial decreases among Hispanic males and NH Blacks followed by increases. The largest annual increase occurred among NH White females. Rates of acute alcohol-related deaths increased more for people aged 55 to 64, but rates of chronic alcohol-related deaths, which accounted for the majority of alcohol-related deaths, increased more for younger adults aged 25 to 34. Death certificates suggest that alcohol-related mortality increased in the United States between 1999 and 2017. Given previous reports that death certificates often fail to indicate the contribution of alcohol, the scope of alcohol-related mortality in the United States is likely higher than suggested from death certificates alone. Findings confirm an increasing burden of alcohol on public health and support the need for improving surveillance of alcohol-involved mortality.


Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology.
Carbonyl groups are frequently found in endogenous or xenobiotic compounds. Reactive carbonyls, formed during lipid peroxidation or food processing, and xenobiotic quinones are able to covalently modify DNA or amino acids. They can also promote oxidative stress, the products of which are thought to be an important initiating factor in degenerative diseases or cancer. Carbonyl groups are reduced by an array of distinct NADPH-dependent enzymes, belonging to several oxidoreductase families. These reductases often show broad and overlapping substrate specificities and some well-characterized members, e.g., carbonyl reductase (CBR1) or NADPH-quinone reductase (NQO1) have protective roles toward xenobiotic carbonyls and quinones because metabolic reduction leads to less toxic products, which can be further metabolized and excreted. This review summarizes the current knowledge on structure and function relationships of the major human and mammalian carbonyl reductases identified.


Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle.
Centrosome duplication involves the formation of a single procentriole next to each centriole, once per cell cycle. The mechanisms governing procentriole formation and those restricting its occurrence to one event per centriole are poorly understood. Here, we show that HsSAS-6 is necessary for procentriole formation and that it localizes asymmetrically next to the centriole at the onset of procentriole formation. HsSAS-6 levels oscillate during the cell cycle, with the protein being degraded in mitosis and starting to accumulate again at the end of the following G1. Our findings indicate that APC(Cdh1) targets HsSAS-6 for degradation by the 26S proteasome. Importantly, we demonstrate that increased HsSAS-6 levels promote formation of more than one procentriole per centriole. Therefore, regulated HsSAS-6 levels normally ensure that each centriole seeds the formation of a single procentriole per cell cycle, thus playing a fundamental role in driving the centrosome duplication cycle and ensuring genome integrity.


Phase II clinical trial of carboplatin and docetaxel in patients with metastatic ovarian cancer: active combination with low incidence of peripheral neuropathy.
During the past 2 decades there have been chemotherapeutic advances in the management of patients with advanced epithelial ovarian cancer. Nevertheless, new drug combinations aimed at increasing response and survival and decreasing toxicities are under investigation. The aim of this phase II study is to determine the feasibility, efficacy and toxicity of docetaxel at a dose of 75 mg/m2 in combination with Carboplatin at an area under the curve (AUC) of 6, as first line treatment in patients with advanced ovarian cancer. 37 patients with stage III-IV epithelial ovarian cancer were entered, and are currently evaluable for response and toxicity. Treatment was well tolerated. The most common grade III and IV toxicities were leukopenia and neutropenia. The incidence of febrile neutropenia was 16.2%. Grade II and III sensory peripheral neuropathy occurred in 8.1% of patients. Peripheral neuropathy resolved in two patients and persisted for more than 10 months in one patient. An overall clinical response of 89% was documented (95% CI 74.5% to 96.9%). Carboplatin and docetaxel administered according to our protocol is an effective alternative to other existing platinum-taxane based combinations. This treatment is associated with low incidence of sensory peripheral neuropathy, which is generally associated with better patient compliance and quality of life.


Near infrared harvesting dye-sensitized solar cells enabled by rare-earth upconversion materials.
Dye-sensitized solar cells (DSSCs) have been deemed as promising alternatives to silicon solar cells for the conversion of clean sunlight energy into electricity. A major limitation to their conversion efficiency is their inability to utilize light in the infrared (IR) spectral range, which constitutes almost half the energy of the sun's radiation. This fact has elicited motivations and endeavors to extend the response wavelength of DSSCs to the IR range. Photon upconversion through rare-earth ions constitutes one of the most promising approaches toward the goal of converting near-IR (NIR) or IR light into visible or ultraviolet light, where DSSCs typically have high sensitivity. In the present review, we summarize recent progress based on the utilization of various upconversion materials and device structures to improve the performance of dye-sensitized solar cells.


Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway.
Allopregnanolone, a neurosteroid whose levels rise throughout gestation, putatively stabilizes antenatal mood. The present study aimed to investigate associations of plasma allopregnanolone to antenatal depressive symptoms, as well as to genetic and obstetric factors. Allopregnanolone plasma levels from 284 pregnant women were measured around gestational week 18. Haplotype tag single nucleotide polymorphisms in the aldo-keto reductase family 1, members C2 and C4 (AKR1C2, AKR1C4), and steroid 5 alpha-reductase 1 and 2 (SRD5A1, and SRD5A2) genes were genotyped in a larger sample of pregnant women (n=1351). The Edinburgh Postnatal Depression Scale (EPDS) was administered via web-questionnaires in gestational weeks 17 and 32. Demographic and obstetric data was retrieved from web-questionnaires and medical records. There was no association between allopregnanolone levels and depressive symptoms. Furthermore, no associations between allopregnanolone level and synthesis pathway genotypes were found after accounting for multiple comparisons. However, exploratory analyses suggested that the women who were homozygous for the minor allele of the AKR1C2 polymorphism rs1937863 had nominally lower allopregnanolone levels and lower depression scores in gestational week 17, but also the highest increase in depression scores between week 17 and 32. Additionally, higher body mass index was associated with lower allopregnanolone levels. The results do not support second trimester plasma allopregnanolone as a mood stabilizing factor. However, we speculate that AKR1C2 variation may alter the susceptibility to depressive symptoms through effects on central allopregnanolone synthesis. Another implication of this study is that the relationship between neuroactive steroids and obesity in pregnancy deserves to be investigated.


Attenuated modulation of brain activity accompanies emotion regulation deficits in alexithymia.
The personality trait alexithymia has been associated with deficits in emotion regulation; nevertheless, experimental investigations on this research question are sparse. We investigated reappraisal as one emotion regulation strategy in 44 healthy participants with high (HDA) versus low (LDA) degrees of alexithymia. High density EEG and spatiotemporal current density reconstruction were used to characterize the time course of emotion regulation and to identify brain regions involved. Main results were that reappraisal was accompanied by reduced arousal and significant amplitude reduction of P3 and slow wave in the LDA group only. In contrast to the LDA group, reappraisal was not associated with an increase of activation in fusiform gyrus and inferior temporal gyrus in the HDA group. We demonstrate profound deficits in emotion regulation, which might contribute to everyday problems of social functioning in alexithymia.


First asymmetric total synthesis of aspergillide D.
The first asymmetric total synthesis of a 16-membered macrolide, aspergillide D, is described. The chiral centers of the acid are derived from d-ribose and the alcohol subunit from 1,8-octane diol through Sharpless kinetic resolution, respectively. The other key reactions include Yamaguchi esterification, ring-closing metathesis reaction, and Shiina macrolactonization to construct the fully functionalized macrocycle.


Adaptation of cognitive function to hypoglycemia in healthy men.
Antecedent hypoglycemia reduces hypoglycemic counterregulation and symptoms, thereby provoking the hypoglycemia unawareness syndrome. The effects of antecedent hypoglycemia on hypoglycemia-induced cognitive dysfunction are less well established. To determine whether antecedent hypoglycemia also reduces hypoglycemic cognitive dysfunction, we performed stepwise hypoglycemic clamp experiments (4.1, 3.6, 3.1, and 2.6 mmol/l) during a 6-h period in 30 young healthy men. A total of 15 subjects additionally received a 2.5-h antecedent hypoglycemic clamp (3.1 mmol/l) on the preceding day (prior-hypo group), whereas the other 15 subjects did not (control group). Cognitive function was assessed by auditory-evoked brain potentials (AEBPs) and reaction time during a vigilance task and short-term memory recall. Tests were performed during the stepwise hypoglycemic clamp at baseline and at each hypoglycemic plateau. In both groups, performance on all measures of cognitive function deteriorated during stepwise hypoglycemia (all P < 0.01). However, after antecedent hypoglycemia, the hypoglycemia-induced decrease in the amplitude of the P3 of the AEBP was distinctly reduced compared with the control condition (P < 0.05). Also, short-term memory performance was less impaired in the prior-hypo group than in the control group (P < 0.005), and a minor hypoglycemic impairment of reaction time (P < 0.05) was evident in the prior-hypo group. Data provide evidence that a single episode of mild antecedent hypoglycemia (3.1 mmol/l) attenuates several aspects of cognitive dysfunction during subsequent hypoglycemia 18-24 h later.


Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)?
The outbreak of a novel corona Virus Disease 2019 (COVID-19) in the city of Wuhan, China has resulted in more than 1.7 million laboratory confirmed cases all over the world. Recent studies showed that SARS-CoV-2 was likely originated from bats, but its intermediate hosts are still largely unknown. In this study, we assembled the complete genome of a coronavirus identified in 3 sick Malayan pangolins. The molecular and phylogenetic analyses showed that this pangolin coronavirus (pangolin-CoV-2020) is genetically related to the SARS-CoV-2 as well as a group of bat coronaviruses but do not support the SARS-CoV-2 emerged directly from the pangolin-CoV-2020. Our study suggests that pangolins are natural hosts of Betacoronaviruses. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. In addition to conservation of wildlife, minimizing the exposures of humans to wildlife will be important to reduce the spillover risks of coronaviruses from wild animals to humans.


Comparative genomics of vertebrate Fox cluster loci.
Vertebrate genomes contain numerous duplicate genes, many of which are organised into paralagous regions indicating duplication of linked groups of genes. Comparison of genomic organisation in different lineages can often allow the evolutionary history of such regions to be traced. A classic example of this is the Hox genes, where the presence of a single continuous Hox cluster in amphioxus and four vertebrate clusters has allowed the genomic evolution of this region to be established. Fox transcription factors of the C, F, L1 and Q1 classes are also organised in clusters in both amphioxus and humans. However in contrast to the Hox genes, only two clusters of paralogous Fox genes have so far been identified in the Human genome and the organisation in other vertebrates is unknown. To uncover the evolutionary history of the Fox clusters, we report on the comparative genomics of these loci. We demonstrate two further paralogous regions in the Human genome, and identify orthologous regions in mammalian, chicken, frog and teleost genomes, timing the duplications to before the separation of the actinopterygian and sarcopterygian lineages. An additional Fox class, FoxS, was also found to reside in this duplicated genomic region. Comparison of loci identifies the pattern of gene duplication, loss and cluster break up through multiple lineages, and suggests FoxS1 is a likely remnant of Fox cluster duplication.


Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors.
The authors' goals were to determine whether baseline dopamine activity contributes to response to methylphenidate and to assess the pattern of metabolic responses associated with enhanced dopamine activity. They used positron emission tomography with 2-deoxy-2[18F]fluoro-D-glucose to evaluate the effects of two sequential doses of methylphenidate on brain metabolism in 15 healthy subjects. Dopamine D2 receptor availability was measured with [11C]raclopride to evaluate its relation to methylphenidate-induced metabolic changes. Methylphenidate increased brain metabolism in six subjects, decreased it in two, and did not change it in seven; however, it consistently increased cerebellar metabolism. Methylphenidate significantly increased "relative" (region relative to the whole brain) metabolism in the cerebellum and decreased it in the basal ganglia. Regional metabolic changes in the cerebellum and the frontal and temporal cortices were significantly correlated with D2 availability. Frontal and temporal metabolism were increased in subjects with high D2 receptors and decreased in subjects with low D2 receptors. Methylphenidate induced variable changes in brain metabolism, but it consistently increased cerebellar metabolism. It also induced a significant reduction in relative metabolism in the basal ganglia. The significant association between metabolic changes in the frontal and temporal cortices and in the cerebellum and D2 receptors suggests that methylphenidate's metabolic effects in these brain regions are due in part to dopamine changes and that differences in D2 receptors may be one of the mechanisms accounting for the variability in response to methylphenidate.


First medical contact and physicians' opinion after the implementation of an electronic record system.
Hospitals implement electronic medical record systems (EMRSs) that are intended to support medical and nursing staff in their daily work. Evolution toward more computerization seems inescapable. Nevertheless, this evolution introduced new problems of organization. This before-and-after observational study evaluated the door-to-first-medical-contact (FMC) times before and after the introduction of EMRS. A satisfaction questionnaire, administered after the "after" period, measured clinicians' satisfaction concerning computerization in routine clinical use. The following 5 questions were asked: Do you spare time in your note taking with EMRS? Do you spare time in the medical care that you provide to the patients with EMRS? Does EMRS improve the quality of medical care for your patients? Are you satisfied with the EMRS implementation? Would you prefer a return to handwritten records? Results showed an increase in door-to-FMC time induced by EMRS and a lower triage capacity. In the satisfaction questionnaire, clinicians reported minimal satisfaction but refused to return to handwritten records. The increase in door-to-FMC time may be explained by the improved quantity/quality of data and by the many interruptions due to the software. Medical reorganization was requested after the installation of the EMRS.


Neuropsychological evidence of an integrated visuotactile representation of peripersonal space in humans.
Current interpretations of extinction suggest that the disorder is due to an unbalanced competition between ipsilesional and contralesional representations of space. The question addressed in this study is whether the competition between left and right representations of space in one sensory modality (i.e., touch) can be reduced or exacerbated by the activation of an intact spatial representation in a different modality that is functionally linked to the damaged representation (i.e., vision). This hypothesis was tested in 10 right-hemisphere lesioned patients who suffered from reliable tactile extinction. We found that a visual stimulus presented near the patient"s ipsilesional hand (i.e., visual peripersonal space) inhibited the processing of a tactile stimulus delivered on the contralesional hand (cross-modal visuotactile extinction) to the same extent as did an ipsilesional tactile stimulation (unimodal tactile extinction). It was also found that a visual stimulus presented near the contralesional hand improved the detection of a tactile stimulus applied to the same hand. In striking contrast, less modulatory effects of vision on touch perception were observed when a visual stimulus was presented far from the space immediately around the patient"s hand (i.e., extrapersonal space). This study clearly demonstrates the existence of a visual peripersonal space centered on the hand in humans and its modulatory effects on tactile perception. These findings are explained by referring to the activity of bimodal neurons in premotor and parietal cortex of macaque, which have tactile receptive fields on the hand and corresponding visual receptive fields in the space immediately adjacent to the tactile fields.


American College of Sports Medicine. Position Stand. Physical activity, physical fitness, and hypertension.
Hypertension is present in epidemic proportions in adults of industrialized societies and is associated with a markedly increased risk of developing numerous cardiovascular pathologies. There is a continuing debate as to the efficacy of aggressive pharmacological therapy in individuals with mild to moderate elevations in blood pressure. This has led to a search for nonpharmacological therapies, such as exercise training, for these individuals. The available evidence indicates that endurance exercise training by individuals at high risk for developing hypertension will reduce the rise in blood pressure that occurs with time. Thus, it is the position of the American College of Sports Medicine that endurance exercise training is recommended as a nonpharmacological strategy to reduce the incidence of hypertension in susceptible individuals. A large number of studies indicate that endurance exercise training will elicit a 10 mm Hg average reduction in both systolic and diastolic blood pressures in individuals with mild essential hypertension (blood pressures 140-180/90-105 mm Hg). Endurance exercise training also has the capacity to improve other risk factors for cardiovascular disease in hypertensive individuals. Endurance exercise training appears to elicit even greater reductions in blood pressure in patients with secondary hypertension due to renal dysfunction. The mode (large muscle activities), frequency (3-5 d.wk-1), duration (20-60 min), and intensity (50-85% of maximal oxygen uptake) of the exercise recommended to achieve this effect are generally the same as those prescribed for developing and maintaining cardiovascular fitness in healthy adults. Exercise training at somewhat lower intensities (40-70% VO2max) appears to lower blood pressure as much, or more, than exercise at higher intensities, which may be important in specific hypertensive populations. Physically active and fit individuals with hypertension have markedly lower rates of mortality than sedentary, unfit hypertensive individuals. Thus, it seems reasonable to recommend exercise as the initial treatment strategy for individuals with mild to moderate essential hypertension. A follow-up period should assess the efficacy of the patient's exercise program, and adjunct therapies should be implemented according to the individual patient's blood pressure and CAD risk factor goals. Individuals with more marked elevations in blood pressure (> 180/105 mm Hg) should add endurance exercise training to their treatment regimen only after initiating pharmacologic therapy. Resistive, or strength, exercise training is not recommended to lower blood pressure in individuals with hypertension when done as their only form of exercise training.(ABSTRACT TRUNCATED AT 400 WORDS)


Sympatry or syntopy? Investigating drivers of distribution and co-occurrence for two imperiled sea turtle species in Gulf of Mexico neritic waters.
Animals co-occurring in a region (sympatry) may use the same habitat (syntopy) within that region. A central aim in ecology is determining what factors drive species distributions (i.e., abiotic conditions, dispersal limitations, and/or biotic interactions). Assessing the degree of biotic interactions can be difficult for species with wide ranges at sea. This study investigated the spatial ecology of two sea turtle species that forage on benthic invertebrates in neritic GoM waters: Kemp's ridleys (Lepidochelys kempii) and loggerheads (Caretta caretta). We used satellite tracking and modeled behavioral modes, then calculated individual home ranges, compared foraging areas, and determined extent of co-occurrence. Using six environmental variables and principal component analysis, we assessed similarity of chosen foraging sites. We predicted foraging location (eco-region) based on species, nesting site, and turtle size. For 127 turtles (64 Kemp's ridleys, 63 loggerheads) tracked from 1989 to 2013, foraging home ranges were nine to ten times larger for Kemp's ridleys than for loggerheads. Species intersected off all U.S. coasts and the Yucatán Peninsula, but co-occurrence areas were small compared to species' distributions. Kemp's ridley foraging home ranges were concentrated in the northern GoM, whereas those for loggerheads were concentrated in the eastern GoM. The two species were different in all habitat variables compared (latitude, longitude, distance to shore, net primary production, mean sea surface temperature, and bathymetry). Nesting site was the single dominant variable that dictated foraging ecoregion. Although Kemp's ridleys and loggerheads may compete for resources, the separation in foraging areas, significant differences in environmental conditions, and importance of nesting location on ecoregion selection (i.e., dispersal ability) indicate that adult females of these species do not interact greatly during foraging and that dispersal and environmental factors more strongly determine their distributions. These species show sympatry in this region but evidence for syntopy was rare.


Identifying the Need for Good Practices in Health Technology Assessment: Summary of the ISPOR HTA Council Working Group Report on Good Practices in HTA.
The systematic use of evidence to inform healthcare decisions, particularly health technology assessment (HTA), has gained increased recognition. HTA has become a standard policy tool for informing decision makers who must manage the entry and use of pharmaceuticals, medical devices, and other technologies (including complex interventions) within health systems, for example, through reimbursement and pricing. Despite increasing attention to HTA activities, there has been no attempt to comprehensively synthesize good practices or emerging good practices to support population-based decision-making in recent years. After the identification of some good practices through the release of the ISPOR Guidelines Index in 2013, the ISPOR HTA Council identified a need to more thoroughly review existing guidance. The purpose of this effort was to create a basis for capacity building, education, and improved consistency in approaches to HTA-informed decision-making. Our findings suggest that although many good practices have been developed in areas of assessment and some other key aspects of defining HTA processes, there are also many areas where good practices are lacking. This includes good practices in defining the organizational aspects of HTA, the use of deliberative processes, and measuring the impact of HTA. The extent to which these good practices are used and applied by HTA bodies is beyond the scope of this report, but may be of interest to future researchers.


Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration.
To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.


Exposure to chemicals and radiation during childhood and risk for cancer later in life.
Many chemical carcinogens are in food, water, air, household products, and personal care products. Although genetic susceptibility is an important factor in how an individual responds to exposure to a carcinogen, heritable genetic factors alone account for only a minor portion of cancer rates. We review the evidence that early life exposure to carcinogenic chemicals and ionizing radiation results in elevations in cancer later in life. Because cells are rapidly dividing and organ systems are developing during childhood and adolescence, exposure to carcinogens during these early life stages is a major risk factor for cancer later in life. Because young people have many expected years of life, the clinical manifestations of cancers caused by carcinogens have more time in which to develop during characteristically long latency periods. Many chemical carcinogens persist in the body for decades and increase risk for all types of cancers. Carcinogens may act via mutagenic, nonmutagenic, or epigenetic mechanisms and may also result from disruption of endocrine systems. The problem is magnified by the fact that many chemical carcinogens have become an integral part of our food and water supply and are in air and the general environment. The early life onset of a lifelong exposure to mixtures of multiple environmental chemical carcinogens and radiation contributes significantly to the etiology of cancer in later life.


Brief Mindfulness Meditation Induces Gray Matter Changes in a Brain Hub.
Previous studies suggest that the practice of long-term (months to years) mindfulness meditation induces structural plasticity in gray matter. However, it remains unknown whether short-term (<30 days) mindfulness meditation in novices could induce similar structural changes. Our previous randomized controlled trials (RCTs) identified white matter changes surrounding the anterior cingulate cortex (ACC) and the posterior cingulate cortex (PCC) within 2 to 4 weeks, following 5-10 h of mindfulness training. Furthermore, these changes were correlated with emotional states in healthy adults. The PCC is a key hub in the functional anatomy implicated in meditation and other perspectival processes. In this longitudinal study using a randomized design, we therefore examined the effect of a 10 h of mindfulness training, the Integrative Body-Mind Training (IBMT) on gray matter volume of the PCC compared to an active control-relaxation training (RT). We found that brief IBMT increased ventral PCC volume and that baseline temperamental trait-an index of individual differences was associated with a reduction in training-induced gray matter increases. Our findings indicate that brief mindfulness meditation induces gray matter plasticity, suggesting that structural changes in ventral PCC-a key hub associated with self-awareness, emotion, cognition, and aging-may have important implications for protecting against mood-related disorders and aging-related cognitive declines.


Advanced competencies mapping of critical care nursing: a qualitative research in two Intensive Care Units.
Nowadays, in Italy, the nursing profession has suffered important changes in response to the needs of citizens' health and to improve the quality of the health service in the country. At the basis of this development there is an increase of the nurses' knowledge, competencies and responsibilities. Currently, the presence of nurses who have followed post-basic training paths, and the subsequent acquisition of advanced clinical knowledge and specializations, has made it essential for the presence of competencies mappings for each specialty, also to differentiate them from general care nurses. The objective is to get a mapping of nurse's individual competencies working in critical care, to analyze the context of the Parma Hospital and comparing it with the Lebanon Heart Hospital in Lebanon. The survey has been done through a series of interviews involving some of the hospital staff, in order to collect opinions about the ICU nurses' competencies. What emerged from the data allowed us to get a list of important abilities, competencies, character traits and intensive care nurse activities. Italians and Lebanese nurses appear to be prepared from a technical point of view, with a desire for improvement through specializations, masters and enabling courses in advanced health maneuvers. By respondents nurses can seize a strong desire for professional improvement. At the end of our research we were able to draw a list of different individual competencies, behavioral and moral characteristics. The nurse figure has a high potential and large professional improvement prospects, if more taken into account by the health system.


A six-item short-form survey for measuring headache impact: the HIT-6.
Migraine and other severe headaches can cause suffering and reduce functioning and productivity. Patients are the best source of information about such impact. To develop a new short form (HIT-6) for assessing the impact of headaches that has broad content coverage but is brief as well as reliable and valid enough to use in screening and monitoring patients in clinical research and practice. HIT-6 items were selected from an existing item pool of 54 items and from 35 items suggested by clinicians. Items were selected and modified based on content validity, item response theory (IRT) information functions, item internal consistency, distributions of scores, clinical validity, and linguistic analyses. The HIT-6 was evaluated in an Internet-based survey of headache sufferers (n = 1103) who were members of America Online (AOL). After 14 days, 540 participated in a follow-up survey. HIT-6 covers six content categories represented in widely used surveys of headache impact. Internal consistency, alternate forms, and test-retest reliability estimates of HIT-6 were 0.89, 0.90, and 0.80, respectively. Individual patient score confidence intervals (95%) of app. +/-5 were observed for 88% of all respondents. In tests of validity in discriminating across diagnostic and headache severity groups, relative validity (RV) coefficients of 0.82 and 1.00 were observed for HIT-6, in comparison with the Total Score. Patient-level classifications based in HIT-6 were accurate 88.7% of the time at the recommended cut-off score for a probability of migraine diagnosis. HIT-6 was responsive to self-reported changes in headache impact. The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.


The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells.
Aminoacyl tRNA synthetases--enzymes that catalyze the first step of protein synthesis--in mammalian cells are now known to have expanded functions, including activities in signal transduction pathways, such as those for angiogenesis and inflammation. The native synthetases themselves are procytokines, having no signal transduction activities. After alternative splicing or natural proteolysis, specific fragments that are potent cytokines and that interact with specific receptors on cell surfaces are released. In this manner, a natural fragment of human tyrosyl tRNA synthetase (TyrRS), mini-TyrRS, has been shown to act as a proangiogenic cytokine. The mechanistic basis for the action of mini-TyrRS in angiogenesis has yet to be established. Here, we show that mini-TyrRS is exported from endothelial cells when they are treated with tumor necrosis factor-alpha. Mini-TyrRS binds to vascular endothelial cells and activates an array of angiogenic signal transduction pathways. Mini-TyrRS-induced angiogenesis requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/Flk-1/KDR). Mini-TyrRS stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. Transactivation of VEGFR2 and downstream angiogenesis require an intact Glu-Leu-Arg (ELR) motif in mini-TyrRS, which is important for its cytokine activity. These studies therefore suggest a mechanism by which mini-TyrRS induces angiogenesis in endothelial cells and provide further insight into the role of mini-TyrRS as a link between translation and angiogenesis.


Measuring axial length of the eye from magnetic resonance brain imaging.
Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size. We measured axial length, a geometric parameter describing eye size from T2-weighted brain MRI scans using three different image analysis software packages (Mango, ITK and Carestream) and compared results to biometry measurements from a specialized ophthalmic instrument (IOLMaster 500) as the reference standard. Ninety-three healthy research participants of mean age 51.0 ± SD 5.4 years were analyzed. The level of agreement between the MRI-derived measurements and the reference standard was described by mean differences as follows, Mango - 0.8 mm; ITK - 0.5 mm; and Carestream - 0.1 mm (upper/lower 95% limits of agreement across the three tools ranged from 0.9 mm to - 2.6 mm). Inter-rater reproducibility was between - 0.03 mm and 0.45 mm (ICC 0.65 to 0.93). Intra-rater repeatability was between 0.0 mm and - 0.2 mm (ICC 0.90 to 0.95). We demonstrate that axial measurements of the eye derived from brain MRI are within 3.5% of the reference standard globe length of 24.1 mm. However, the limits of agreement could be considered clinically significant. Axial length of the eye obtained from MRI is not a replacement for the precision of biometry, but in the absence of biometry it could provide sufficient accuracy to act as a proxy. We recommend measuring eye axial length from MRI in studies that do not have biometry but use retinal imaging to study neurodegenerative changes so as to control for differing eye size across individuals.


From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production.
As a young medical resident, I encountered a patient suffering from spontaneous coronary vasospasm and was puzzled by these dramatic alterations in vasomotion. This encounter piqued my interest in understanding the drivers of vascular reactivity. In a paper published in the JCI, my colleagues and I revealed a role for superoxide production in the vascular dysfunction associated with hypercholesterolemia. Subsequent work by our group and others has unveiled complex associations between ROS generation and vascular disease.


Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate.
By its antioxidant effect, molecular hydrogen gas (H2) was reported to protect organs from tissue damage induced by ischemia reperfusion. To evaluate its anti-inflammatory effects, we established a mouse model of human inflammatory bowel disease (IBD) by supplying mice with water containing (1) dextran sodium sulfate (DSS) (5%), (2) DSS (5%) and H2, or (3) H2 only ad libitum up to 7 days. At day-7, DSS-induced pathogenic outcomes including, loss of body weight, increase of colitis score, pathogenic shortening of colon length, elevated level of IL-12, TNF-alpha and IL-1beta in colon lesion, were significantly suppressed by the addition of H2 to DSS solution. Histological analysis also revealed that the DSS-mediated colonic tissue destruction accompanied by macrophage infiltration was remarkably suppressed by H2. Therefore, the present study indicated that H2 can prevent the development of DSS-induced colitis in mice.


The Functional Influence of Breast Implant Outer Shell Morphology on Bacterial Attachment and Growth.
The introduction of texture to the outer shell of breast implants was aimed at increasing tissue incorporation and reducing capsular contracture. It has also been shown that textured surfaces promote a higher growth of bacteria and are linked to the development of breast implant-associated anaplastic large cell lymphoma. The authors aimed to measure the surface area and surface roughness of 11 available implants. In addition, the authors aimed to subject these implant shells to an in vitro bacterial attachment assay with four bacterial pathogens (Staphylococcus epidermidis, S. aureus, Pseudomonas aeruginosa, and Ralstonia pickettii) and study the relationship among surface area, surface roughness, and bacterial growth. Surface area measurement showed grouping of implants into high, intermediate, low, and minimal. Surface roughness showed a correlation with surface area. The in vitro assay showed a significant linear relationship between surface area and bacterial attachment/growth. The high surface area/roughness implant texture grew significantly more bacteria at 24 hours, whereas the minimal surface area/roughness implant textures grew significantly fewer bacteria of all types at 24 hours. For implants with intermediate and low surface areas, some species differences were observed, indicating possible affinity of specific bacterial species to surface morphology. Implant shells should be reclassified using surface area/roughness into four categories (high, intermediate, low, and minimal). This classification is superior to the use of descriptive terms such as macrotexture, microtexture, and nanotexture, which are not well correlated with objective measurement and/or functional outcomes.


Combining atlas-based parcellation of regional brain data acquired across scanners at 1.5 T and 3.0 T field strengths.
Longitudinal brain morphometric studies designed for data acquisition at a single MRI field strength can be seriously limited by system replacements from lower to higher field strength. Merging data across field strengths has not been endorsed for a variety of reasons, yet the ability to combine such data would broaden longitudinal investigations. To determine whether structural T1-weighted MRI data acquired across MR field strengths could be merged, parcellations of archival SPGR data acquired in 114 individuals at 1.5 T and at 3.0 T within 3 weeks of each other were compared. The first set of analyses examined 1) the correspondence between regional tissue volumes derived from data collected at 1.5 T and 3.0 T and 2) whether there were systematic differences for which a correction factor could be determined and applied to improve measurement agreement. Comparability of regional volume determination at 1.5 T and 3.0 T was assessed with intraclass correlation (ICC) computed on volumes derived from the automated and unsupervised SRI24 atlas registration and parcellation method. A second set of analyses measured the reliability of the registration and quantification using the same approach on longitudinal data acquired in 69 healthy adults at a single field strength, 1.5 T, at an interval < 2 years. The mainstay of the analyses was based on the SRI24 method; to examine the potential of merging data across field strengths and across image analysis packages, a secondary set of analyses used FreeSurfer instead of the SRI24 method. For both methods, a regression-based linear correction function significantly improved correspondence. The results indicated high correspondence between most selected cortical, subcortical, and CSF-filled spaces; correspondence was lowest in the globus pallidus, a region rich in iron, which in turn has a considerable field-dependent effect on signal intensity. Thus, the application of a regression-based correction function that improved the correspondence in regional volume estimations argues well for the proposition that selected T1-weighted regional anatomical brain data can be reliably combined across 1.5 T and 3.0 T field strengths with the application of an appropriate correction procedure.


Workers' compensation claims for occupational tuberculosis in South African health workers: Outcomes and workers' experiences.
Given the elevated risk of tuberculosis (TB), including drug-resistant disease, experienced by health workers in South Africa (SA), effective workers' compensation for occupational TB is a legal right and an essential social benefit. To investigate the experience of the workers' compensation system among health workers who suffered from TB while working in public service facilities in Western Cape Province, SA. In this case series with a qualitative component, 300 claims for occupational TB in health workers were sampled from the provincial health department database of claims submitted. Claim status for each case was ascertained. An attempt was made to contact each health worker for a telephonic interview consisting of both closed- and open-ended (qualitative) questions. Fifty-one interviews were completed. In nearly half of the cases, there was no record of claim status on the state Compensation Fund website. Of the 51 interviewees, only one had received all the compensation benefits for their particular claim circumstances. Health workers' experience of having their cases reported for compensation purposes was marred by perception of poor communication and administration. The experience of contracting TB was further characterised by surprise, perceptions of stigma, financial burden and ongoing ill-health. Affected health workers' experience of the workers' compensation system was mostly negative, adding to the burden of being ill with TB. Education of management and clinicians, improvement in communication, and timeous and regular checking of claim status and of payment of applicable compensation are required at the provincial level. Dedicated facility-based occupational health units are needed, with a staff complement of knowledgeable persons trusted by their colleagues. However, the effectiveness of the system is ultimately dependent on the ability of the Compensation Fund to register and display claims timeously and administer compensation expeditiously.


Multilaboratory comparison of hepatitis C virus viral load assays.
We report a multilaboratory evaluation of hepatitis C virus (HCV) viral load assays to determine their linear range, reproducibility, subtype detection, and agreement. A panel of HCV RNA samples ranging in nominal concentration from 1.0 to 7.0 log10 IU/ml was constructed by diluting a clinical specimen (genotype 1b). Replicates of the panel were tested in multiple laboratories using the Abbott TaqMan analyte-specific reagent (Abbott reverse transcription-PCR [RT-PCR]), Roche TaqMan RUO (Roche RT-PCR), Roche Amplicor Monitor HCV 2.0 (Roche Monitor), and Bayer VERSANT HCV RNA 3.0 (Bayer bDNA) assays. Bayer bDNA-negative specimens were tested reflexively using the Bayer VERSANT HCV RNA qualitative assay (Bayer TMA). Abbott RT-PCR and Roche RT-PCR detected all 28 replicates with a concentration of 1.0 log10 IU/ml and were linear to 7.0 log10 IU/ml. Roche Monitor and Bayer bDNA detected 27 out of 28 and 13 out of 28 replicates, respectively, of 3.0 log10 IU/ml. Bayer TMA detected all seven replicates with 1.0 log10 IU/ml. Bayer bDNA was the most reproducible of the four assays. The mean viral load values for panel members in the linear ranges of the assays were within 0.5 log10 for the different tests. Eighty-nine clinical specimens of various genotypes (1 through 4) were tested in the Bayer bDNA, Abbott RT-PCR, and Roche RT-PCR assays. For Abbott RT-PCR, mean viral load values were 0.61 to 0.96 log10 greater than the values for Bayer bDNA assay for samples with genotype 1, 2, or 3 samples and 0.08 log10 greater for genotype 4 specimens. The Roche RT-PCR assay gave mean viral load values that were 0.28 to 0.82 log10 greater than those obtained with the Bayer bDNA assay for genotype 1, 2, and 3 samples. However, for genotype 4 samples the mean viral load value obtained with the Roche RT-PCR assay was, on average, 0.15 log10 lower than that of the Bayer bDNA. Based on these data, we conclude that the sensitivity and linear range of the Abbott and Roche RT-PCR assays enable them to be used for HCV diagnostics and therapeutic monitoring. However, the differences in the viral load values obtained with the different assays underscore the importance of using one assay when monitoring response to therapy.


Analysis of secreted aspartic proteinases from Candida albicans: purification and characterization of individual Sap1, Sap2 and Sap3 isoenzymes.
The recently discovered secreted aspartic proteinase multi-gene (SAP) family in Candida albicans has complicated assessment of proteolytic activity as a factor in the onset and development of Candida infections. Differential expression of the SAP genes under various conditions, as well as possible variation in the properties of the individual isoenzymes, have consequences for immunological detection, for targeted drug design and possibly for pathogenicity. It is therefore important to be able to monitor Sap isoenzyme profiles in different strains of C. albicans cultures, and to know the biochemical properties of each isoenzyme. We have employed a simple purification protocol based on strong anion exchange chromatography for the direct analysis of C. albicans Sap isoenzymes from culture filtrates, as well as recovery of individual Sap1, Sap2 and Sap3 products. In the case of Sap1, this involved development of an overexpression system using the pEMBLyex4 vector transformed into Saccharomyces cerevisiae. The C. albicans strains ATCC 10231 and 10261 were shown to produce different ratios of Sap2 and Sap3 under the same conditions. Analysis of all three purified proteins by gel electrophoresis, immunoblotting and proteinase assays which were designed to evaluate pH dependence, thermal stability and substrate specificity revealed similar but distinct properties for each isoenzyme. Although Sap3 was shown to be antigenically more similar to Sap2 than was Sap1, it was less similar in terms of thermal stability and activity at low pH, being more stable and more active.


The Dental Solid Waste Management in Different Categories of Dental Laboratories in Abha City, Saudi Arabia.
To study the awareness, attitude, practice and facilities among the different categories of dental laboratories in Abha city. A total of 80 dental technicians were surveyed in the study. The dental laboratories included in the study were teaching institute (Group I), Government Hospital (Group II), Private Dental Clinic (Group III) and Independent laboratory (Group IV). The pre-tested anonymous questionnaire was used to understand knowledge, attitude, facilities, practice and orientation regarding biomedical waste management. The knowledge of biomedical waste categories, colour coding and segregation was better among Group I (55-65%) and Group II (65-75%). The lowest standard of waste disposal was practiced at Group IV (15-20%) and Group III (25-35%). The availability of disposal facilities was poor at Group IV. The continuous education on biomedical waste management lacked in all the Groups. The significant improvement in disposal facilities was required at Group III and Group IV laboratories. All dental technicians were in need of regular training of biomedical waste management. The dental laboratories are an integral part of dental practice. The dental laboratories are actively involved in the generation, handling and disposal of biomedical waste. Hence, it is important to assess the biomedical waste management knowledge, attitude, facilities and practice among different categories of dental laboratories.


A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic aetiology with obesity.
Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking. We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects. We identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years. This large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.


Applications of Machine Learning in Real-Life Digital Health Interventions: Review of the Literature.
Machine learning has attracted considerable research interest toward developing smart digital health interventions. These interventions have the potential to revolutionize health care and lead to substantial outcomes for patients and medical professionals. Our objective was to review the literature on applications of machine learning in real-life digital health interventions, aiming to improve the understanding of researchers, clinicians, engineers, and policy makers in developing robust and impactful data-driven interventions in the health care domain. We searched the PubMed and Scopus bibliographic databases with terms related to machine learning, to identify real-life studies of digital health interventions incorporating machine learning algorithms. We grouped those interventions according to their target (ie, target condition), study design, number of enrolled participants, follow-up duration, primary outcome and whether this had been statistically significant, machine learning algorithms used in the intervention, and outcome of the algorithms (eg, prediction). Our literature search identified 8 interventions incorporating machine learning in a real-life research setting, of which 3 (37%) were evaluated in a randomized controlled trial and 5 (63%) in a pilot or experimental single-group study. The interventions targeted depression prediction and management, speech recognition for people with speech disabilities, self-efficacy for weight loss, detection of changes in biopsychosocial condition of patients with multiple morbidity, stress management, treatment of phantom limb pain, smoking cessation, and personalized nutrition based on glycemic response. The average number of enrolled participants in the studies was 71 (range 8-214), and the average follow-up study duration was 69 days (range 3-180). Of the 8 interventions, 6 (75%) showed statistical significance (at the P=.05 level) in health outcomes. This review found that digital health interventions incorporating machine learning algorithms in real-life studies can be useful and effective. Given the low number of studies identified in this review and that they did not follow a rigorous machine learning evaluation methodology, we urge the research community to conduct further studies in intervention settings following evaluation principles and demonstrating the potential of machine learning in clinical practice.


Benefits of exercise with mini tennis in intellectual disabilities: effects on body image and psychopathology.
The present study is aimed at evaluating the efficacy of an introductory mini tennis programme as a therapeutic aid in the psychosocial rehabilitation of participants affected by mild/moderate intellectual disability in semi-residential care.Two groups (N=12) of participants diagnosed with intellectual disability, one of which followed the mini tennis rehabilitation programme, were compared at time t0, t1 (after 2 months) and t2 (after 6 months).Psychopathological status was assessed by means of the Italian version of the Assessment and Information Rating Profile (AIRP). Motor coordination, lateral dominance and body scheme were assessed by means of structured tools.Psychopathological total scores showed a statistically significant decrease in the experimental group in comparison with the control group. A statistical decrease in the group with the mini tennis rehabilitation programme was found also in the anxiety sub-scale while the sub-scales schizophrenia, depression, adjustment disorder, personality problems, somatoform disorders and psychosexual disorders did not reach any statistical difference between groups.A statistically significant increase in the visuo manual coordination was highlighted in the experimental versus the control group. No statistically significant differences were reported with regard to general movement skills, dynamic balance and coordination.In spite of the limitations of this study, the results obtained are encouraging and suggest the potential efficacy of mini tennis as an auxiliary aid in rehabilitation programmes, particularly to improve visuo manual coordination skills and to boost the patient/participants' self esteem. These findings warrant confirmation by further research studies.


The enterotoxin of Bacteroides fragilis is a metalloprotease.
During the past decade, strains of Bacteroides fragilis that produce an enterotoxin have been implicated in diarrheal disease in animals and humans. The extracellular enterotoxin has been purified and characterized as a single polypeptide (M(r), approximately 20,000). Single specific primer-PCR was used to clone a portion of the B. fragilis enterotoxin gene. The recombinant protein expressed by the cloned gene fragment reacted with monospecific antibodies to B. fragilis enterotoxin by enzyme-linked immunosorbent assay and immunoblot analysis. The deduced amino acid sequence revealed a signature zinc-binding consensus motif (HEXXHXXGXXH/Met-turn) characteristic of metalloproteases termed metzincins. Sequence comparisons showed close identity to matrix metalloproteases (e.g., human fibroblast collagenase) within the zinc-binding and Met-turn region. Purified enterotoxin contained 1 g-atom of Zn2+ per molecule and hydrolyzed gelatin, azocoll, actin, tropomyosin, and fibrinogen. The enterotoxin also underwent autodigestion. The N-terminal amino acid sequences of two autodigestion products were identical to the deduced amino acid sequence of the recombinant enterotoxin and revealed cleavage at Cys-Leu and Ser-Leu peptide bonds. Gelatinase (type IV collagenase) activity comigrated with the toxin when analyzed by gel fractionation and zymography, indicating that protease activity is due to the enterotoxin and not to a contaminating protease(s). Optimal proteolytic activity occurred at 37 degrees C and pH 6.5. Primary proteolytic cleavage sites in actin were identified, revealing cleavage at Gly-Met and Thr-Leu peptide bonds. Enzymatic activity was inhibited by metal chelators but not by inhibitors of other classes of proteases. Additionally, cytotoxic activity of the enterotoxin on human carcinoma HT-29 cells was inhibited by acetoxymethyl ester EDTA. The metalloprotease activity of the enterotoxin suggests a possible mechanism for enterotoxicity and may have additional implications in the study of disease caused by B. fragilis.


Inflammatory responses to pulmonary application of PEI-based siRNA nanocarriers in mice.
Polymeric non-viral vector systems for pulmonary application of siRNA are promising carriers, but have failed to enter clinical trials because of safety and efficiency problems. Therefore, improving their transfection efficiency, as well as their toxicological profile, is the subject of intensive research efforts. Six different poly(ethylene imine) (PEI)-based nanocarriers, with hydrophilic and hydrophobic PEG modifications, were toxicologically evaluated for pulmonary application in mice. Nanocarriers were intratracheally instilled to determine their toxicological profile, with particular focus on the inflammatory response in the lungs. Nanocarriers from both groups caused an acute inflammatory response in the lungs, albeit with different resolution kinetics and cytotoxicity. Hydrophobic modifications caused a severe inflammatory response with increased epithelial barrier permeability, accompanied by an acute antioxidant response. Hydrophilic modifications, with high PEG-grafting degrees, induced less proinflammatory effects without depleting macrophages and disrupting the epithelial/endothelial barrier in the lungs, while showing only a minor oxidative stress response. For pulmonary applications, local proinflammatory effects should be optimized by further development of nanocarriers with highly grafted PEG-PEI-based carriers or Jeffamine-modified hydrophobic PEI modifications.


Inferring false beliefs from the actions of oneself and others: an fMRI study.
The ability to make judgments about mental states is critical to social interactions. Simulation theory suggests that the observer covertly mimics the activity of the observed person, leading to shared states of mind between the observer and the person observed. We tested this hypothesis by investigating the neural networks activated while subjects watched videos of themselves and of others lifting a box, and judged the beliefs of the actors about the weight of the box. A parietal premotor circuit was recruited during action perception, and the activity started earlier when making judgments about one's own actions as opposed to those of others. This earlier activity in action-related structures can be explained by simulation theory on the basis that when one observes one's own actions, there is a closer match between the simulated and perceived action than there is when one observes the actions of others. When the observers judged the actions to reflect a false belief, there was activation in the superior temporal sulcus, orbitofrontal, paracingulate cortex and cerebellum. We suggest that this reflects a mismatch between the perceived action and the predicted action's outcomes derived from simulation.


Evidence for Increased 5α-Reductase Activity During Early Childhood in Daughters of Women With Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a heritable, complex genetic disease. Animal models suggest that androgen exposure at critical developmental stages contributes to disease pathogenesis. We hypothesized that genetic variation resulting in increased androgen production produces the phenotypic features of PCOS by programming during critical developmental periods. Although we have not found evidence for increased in utero androgen levels in cord blood in the daughters of women with PCOS (PCOS-d), target tissue androgen production may be amplified by increased 5α-reductase activity analogous to findings in adult affected women. It is possible to noninvasively test this hypothesis by examining urinary steroid metabolites. We performed this study to investigate whether PCOS-d have altered androgen metabolism during early childhood. Twenty-one PCOS-d, 1-3 years old, and 36 control girls of comparable age were studied at an academic medical center. Urinary steroid metabolites were measured by gas chromatography/mass spectrometry. Twenty-four hour steroid excretion rates and precursor to product ratios suggestive of 5α-reductase and 11β-hydroxysteroid dehydrogenase activities were calculated. Age did not differ but weight for length Z-scores were higher in PCOS-d compared to control girls (P = .02). PCOS-d had increased 5α-tetrahydrocortisol:tetrahydrocortisol ratios (P = .04), suggesting increased global 5α-reductase activity. There was no evidence for differences in 11β-hydroxysteroid dehydrogenase activity. Steroid metabolite excretion was not correlated with weight. Our findings suggest that differences in androgen metabolism are present in early childhood in PCOS-d. Increased 5α-reductase activity could contribute to the development of PCOS by amplifying target tissue androgen action.


Reducing unwanted trauma memories by imaginal exposure or autobiographical memory elaboration: an analogue study of memory processes.
Unwanted memories of traumatic events are a core symptom of post-traumatic stress disorder. A range of interventions including imaginal exposure and elaboration of the trauma memory in its autobiographical context are effective in reducing such unwanted memories. This study explored whether priming for stimuli that occur in the context of trauma and evaluative conditioning may play a role in the therapeutic effects of these procedures. Healthy volunteers (N = 122) watched analogue traumatic and neutral picture stories. They were then randomly allocated to 20 min of either imaginal exposure, autobiographical memory elaboration, or a control condition designed to prevent further processing of the picture stories. A blurred picture identification task showed that neutral objects that preceded traumatic pictures in the stories were subsequently more readily identified than those that had preceded neutral stories, indicating enhanced priming. There was also an evaluative conditioning effect in that participants disliked neutral objects that had preceded traumatic pictures more. Autobiographical memory elaboration reduced the enhanced priming effect. Both interventions reduced the evaluative conditioning effect. Imaginal exposure and autobiographical memory elaboration both reduced the frequency of subsequent unwanted memories of the picture stories.


Prophage S2 mutants in Haemophilus influenzae: a technique for their production and isolation.
A procedure utilizing nitrosoguanidine has been developed to produce defective and temperature-sensitive mutants of prophage (S2) in lysogenic Haemophilus influenzae. The system should be generally applicable to all temperate phage systems. At saturating concentrations of phage DNA, more than 25 percent of recipient mutant lysogenic bacteria can be transformed to the wild type.


A short bout of HFD promotes long-lasting hepatic lipid accumulation.
A short bout of high fat diet (HFD) impairs glucose tolerance and induces hepatic steatosis in mice. Here, we aimed to elaborate on long-lasting effects of short-term high fat feeding. As expected, one week of HFD significantly impaired glucose tolerance. Intriguingly, recovery feeding with a standard rodent diet for 8 weeks did not fully normalize glucose tolerance. In addition, mice exposed to a short bout of HFD revealed significantly increased liver fat accumulation paralleled by elevated portal free fatty acid levels after 8 weeks of recovery feeding compared to exclusively chow-fed littermates. In conclusion, a short bout of HFD has long-lasting effects on hepatic lipid accumulation and glucose tolerance.


A measurement error model for physical activity level as measured by a questionnaire with application to the 1999-2006 NHANES questionnaire.
Systematic investigations into the structure of measurement error of physical activity questionnaires are lacking. We propose a measurement error model for a physical activity questionnaire that uses physical activity level (the ratio of total energy expenditure to basal energy expenditure) to relate questionnaire-based reports of physical activity level to true physical activity levels. The 1999-2006 National Health and Nutrition Examination Survey physical activity questionnaire was administered to 433 participants aged 40-69 years in the Observing Protein and Energy Nutrition (OPEN) Study (Maryland, 1999-2000). Valid estimates of participants' total energy expenditure were also available from doubly labeled water, and basal energy expenditure was estimated from an equation; the ratio of those measures estimated true physical activity level ("truth"). We present a measurement error model that accommodates the mixture of errors that arise from assuming a classical measurement error model for doubly labeled water and a Berkson error model for the equation used to estimate basal energy expenditure. The method was then applied to the OPEN Study. Correlations between the questionnaire-based physical activity level and truth were modest (r = 0.32-0.41); attenuation factors (0.43-0.73) indicate that the use of questionnaire-based physical activity level would lead to attenuated estimates of effect size. Results suggest that sample sizes for estimating relationships between physical activity level and disease should be inflated, and that regression calibration can be used to provide measurement error-adjusted estimates of relationships between physical activity and disease.


Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.
Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.


Psychotic experiences in the context of depression: The cumulative role of victimization.
Previous studies have reported an association between depression and psychotic experiences, but little is known about what drives this co-occurrence. This study tests the hypothesis that exposure to trauma and bullying may strengthen the relation between depression and psychotic experiences. A total of 799 college students completed self-report questionnaires on psychotic experiences, depression, bullying, and sexual trauma. Hierarchical linear regression analyses were conducted to test the direct relationship between depression and psychotic experiences, as well as interactions. Approximately 20% of respondents reported a history of being bullied, and 7% reported exposure to childhood sexual trauma. There was a significant direct relationship between depression and psychotic experiences. The association between depression and psychotic experiences was significantly stronger among respondents who were victims of both bullying and sexual violence compared to those who experienced either exposure alone, or who were not exposed to either form of victimization. These findings suggest that cumulative exposure to trauma and victimization may contribute to the co-occurrence of depression and psychotic experiences. History of victimization should be assessed among individuals with depressive symptoms to improve treatment plans and outcomes.


Rehabilitation after resurfacing hip arthroplasty: cost-utility analysis alongside a randomized controlled trial.
To assess the costs, effects, and cost-utility of an accelerated physiotherapy programme versus a standard physiotherapy programme following resurfacing hip arthroplasty. A cost-utility analysis alongside a randomized controlled trial. A UK National Health Service hospital and patients' homes. A total of 80 male resurfacing hip arthroplasty patients randomized post procedure to one of the two programmes. The accelerated physiotherapy programme commenced in hospital with patients being fully weight bearing, without hip precautions, and following a range of exercises facilitating gait re-education, balance, and lower limb strength. Standard physiotherapy commenced in hospital, but hip precautions were used and exercises were only partially weight bearing. In both groups, patients continued with their exercises at home for an eight-week period. Data on healthcare contacts were collected from patients to 12 months and costed using unit costs from national sources. Information was also collected on patients' costs. Health-related quality of life was measured using the EuroQol EQ-5D questionnaire and used to estimate quality-adjusted life years (QALYs) to 12 months. Mean costs and QALYs for each trial arm were compared. On average, the accelerated physiotherapy programme was less expensive (mean cost difference -£200; 95% confidence interval: -£656 to £255) and more effective (mean QALY difference 0.13; 95% confidence interval: 0.05 to 0.21) than standard physiotherapy and had a high probability of being cost-effective. From the National Health Service perspective, an accelerated physiotherapy programme for male patients undergoing revision of total hip arthroplasty (RHA) is very likely to be cost-effective when compared to a standard physiotherapy programme.


The use of subtelomeric probes to study mental retardation.
In this chapter, we focus on the genetic basis of mental retardation (MR), specifically the use of subtelomeric probes to provide new diagnoses in idiopathic MR. We discuss both the background to the clinical demand for diagnoses and the technological advances that culminated in the development of subtelomeric testing strategies. We explain the theory behind these strategies and briefly outline the protocols involved, giving the advantages, limitations, and pitfalls of the analyses. Finally, we give an overview of the MR subtelomeric studies to date and how subtelomeric testing has become a widely used tool in clinical diagnostic laboratories, particularly in the diagnosis of unexplained MR, but also in other fields of clinical medicine. The conclusion addresses the overall impact that subtelomeric testing has had on the diagnosis of MR, the implications for patients and their families, and future research avenues for exploring the genetic causes of MR and improving our overall understanding of neurocognitive development.


Advances in diagnostic tests for bacterial STDs.
Because of their asymptomatic nature and nonspecific symptoms, laboratory tests are often required to diagnose a sexually transmitted infection. Over the past few years, there have been advances in technology, such as the development of nucleic acid amplification assays, which have improved our ability to diagnose infections caused by Chlamydia trachomatis. The finding that nucleic acid amplification tests can detect more infected individuals and are useful in screening low prevalence populations, has led to the development of strategies designed to reduce the cost of these assays without significantly impacting their sensitivity. The development of new tests for the diagnosis of syphilis has gained momentum from the report of a synthetic VDRL antigen, which will result in better nontreponemal antibody tests for syphilis. In spite of the completion of the genome sequence of Treponema pallidum and its annotation, we are still unable to cultivate this microorganism in vitro. However, the molecular revolution has resulted in the development of PCR assays for detecting Treponema pallidum in various types of clinical specimens, and to the production of recombinant antigens for use in tests that detect treponemal-specific antibodies. Further research will improve the availability of low cost, sensitive tests for the diagnosis of sexually transmitted infections. The English version of this paper is available too at:http://www.insp.mx/salud/index.html.


Children's hostile intent attributions and emotional distress: What do parents perceive?
Traditionally, assessments of social information processing and associated emotional distress have used children's self-reports. We posit that additional informants, such as parents, may help illuminate the association between these variables and aggression. Our sample was composed of 222 dual-parent families of fourth-grade children (103 boys; 119 girls). Children responded to instrumental and relational provocations and their parents read the same scenarios and responded the way they believed their child would. Peer nominations provided aggression scores. We explored how means differed by provocation type (relational vs. instrumental), informant (mother, father, and child), and gender of child. The results also suggest that parent perceptions may effectively predict children's participation in relational and physical aggression, above and beyond the child's self-reports.


[Cancer cluster analysis. The case of the Campdorà District in Girona, Spain].
A conglomerate of cases may be defined as the onset of a number of cases of a disease larger than would be expected for a certain population group, geographical area or a certain timeframe. In the case of cancer, the study of conglomerates entails a number of specific characteristics as compared to other groups of diseases. This work is aimed at proposing a protocol affording the possibility of conducting the study of cancer conglomerates in time and/or space. This article is illustrated with a practical application in the case of the Campdorà District in Girona. Following a proposed protocol for the study of conglomerates, a description is provided of several statistical tools making it possible to draw a comparison among the existence of time-related groupings, as well as the related risk. During the period studied (1994-2002), no excessive statistically significant number of cancer cases seemed to have occurred in the Campdorà District in Girona.


Sexual and reproductive health in Accra, Ghana.
To describe sexual and reproductive health among women in Accra and explore the burden of sexual and reproductive ill health among this urban population. Cross-sectional study. We analysed data from the WHSA-II (n=2814), a cross-sectional household survey on women's health, and supplemental data from an in-depth survey (n=400), focus groups discussions (n=22) and in-depth interviews (n=20) conducted among a sub-sample of women which focused specifically on reproductive health issues. Modern contraceptive use was uncommon. More than one third of women reported ever using abstinence; condoms, injectables and the pill were the most commonly reported modern methods ever used. The total fertility rate among this sample of women was just 2.5 births. We found a considerable burden of sexual and reproductive ill health; one in ten women reported menstrual irregularities and almost one quarter of women reported symptoms of a Sexually Transmitted Infection (STI) or Reproductive Tract Infection (RTI) in the past 6 months. Focus group results and in-depth interviews reveal misperceptions about contraception side-effects and a lack of information. In urban Ghana, modern contraceptive use is low and a significant proportion of women experience reproductive ill health (defined here as menstrual irregularity or RTI, UTI, STI symptoms). Increased access to information, products and services about for preventive care and contraception could improve reproductive health. More research on healthy sexuality and the impact of reproductive ill health on sexual experience is needed.


Will physician unions improve health system performance?
In the public debate over the extension of collective bargaining rights to independent physicians, union proponents' primary argument has been that patients would benefit from allowing physicians to bargain collectively with health plans. This article examines the likely effects of physician unions on the U.S. health care system. Specifically considered are likely effects on economic efficiency, quality, access, and cost. Under none of these criteria are physician unions likely to improve health system performance, particularly when compared with available alternative strategies for dealing with problems identified by union proponents.


Consciousness Without Content: A Look at Evidence and Prospects.
Many traditions in the East have proposed that consciousness without content is possible and could be achieved with mental training. However, it is not clear whether such a state is possible given that intentionality is a critical property of mentality and consciousness in many theories of consciousness. A prominent recent attempt to account for such states of "minimal phenomenal experience" is the ascending reticular arousal system (ARAS) model, which proposes a specific type of non-conceptual representational content to address such a state. Consciousness without content can also be understood by studying related or similar states of minimal phenomenal experience and this paper discusses such findings from such states including dreamless sleep experience and their implications. One way to argue for the need for proposing consciousness without content is to locate a property of consciousness that would necessitate postulating it. A continuous state of consciousness without content may be needed to understand continuity of conscious experience. Finally, I discuss the implications of consciousness without content for current theories of consciousness.


Effects of different resuscitation fluid on severe acute pancreatitis.
To compare effects of different resuscitation fluid on microcirculation, inflammation, intestinal barrier and clinical results in severe acute pancreatitis (SAP). One hundred and twenty patients with SAP were enrolled at the Pancreatic Disease Institute between January 2007 and March 2010. The patients were randomly treated with normal saline (NS group), combination of normal saline and hydroxyethyl starch (HES) (SH group), combination of normal saline, hydroxyethyl starch and glutamine (SHG group) in resuscitation. The ratio of normal saline to HES in the SH and SHG groups was 3:1. The glutamine (20% glutamine dipeptide, 100 mL/d) was supplemented into the resuscitation liquid in the SHG group. Complications and outcomes including respiratory and abdominal infection, sepsis, abdominal hemorrhage, intra-abdominal hypertension, abdominal compartment syndrome (ACS), renal failure, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), operation intervention, length of intensive care unit stay, length of hospital stay, and mortality at 60 d were compared. Moreover, blood oxygen saturation (SpO2), gastric intramucosal pH value (pHi), intra-abdominal pressure (IAP), inflammation cytokines, urine lactulose/mannitol (L/M) ratio, and serum endotoxin were investigated to evaluate the inflammatory reaction and gut barrier. Compared to the NS group, patients in the SH and SHG groups accessed the endpoint more quickly (3.9 ± 0.23 d and 4.1 ± 0.21 d vs 5.8 ± 0.25 d, P < 0.05) with less fluid volume (67.26 ± 28.53 mL/kg/d, 61.79 ± 27.61 mL/kg per day vs 85.23 ± 21.27 mL/kg per day, P < 0.05). Compared to the NS group, incidence of renal dysfunction, ARDS, MODS and ACS in the SH and SHG groups was obviously lower. Furthermore, incidence of respiratory and abdominal infection was significantly decreased in the SH and SHG groups, while no significant difference in sepsis was seen. Moreover, less operation time was needed in the SH and SHG group than the NS group, but the difference was not significant. The mortality did not differ significantly among these groups. Blood SpO2 and gastric mucosal pHi in the SH and SHG groups increased more quickly than in the NS group, while IAP was significantly decreased in the SH and SHG group. Moreover, the serum tumor necrosis factor-α, interleukin-8 and C-reactive protein levels in the SH and SHG groups were obviously lower than in the NS group at each time point. Furthermore, urine L/M ratio and serum endotoxin were significantly lower in the SH group and further decreased in the SHG group. Results indicated that combination of normal saline, HES and glutamine are more efficient in resuscitation of SAP by relieving inflammation and sustaining the intestinal barrier.


Nitrification in a soil-aquifer treatment system: comparison of potential nitrification and concentration profiles in the vadose zone.
The oxidation of ammonium in the vadose zone of soil aquifer systems is discussed and examined by detailed analysis of the depth profiles of dissolved oxygen, nitrate and ammonium concentrations in the vadose zone of a soil-aquifer treatment (SAT) system of a municipal wastewater treatment system of the Tel Aviv metropolitan area. Nitrification kinetics and ammonium adsorption capacity studies show that neither the nitrification rate nor the ammonium adsorption capacity controls the capacity of the Shafdan SAT system for ammonium removal. Evaluation of the ammonium adsorption capacity of the soil reveals that under ideal conditions, a depth of less than 50 cm is sufficient to adsorb all the ammonium supplied in a flooding cycle. In-field studies show that all the ammonium is concentrated within the first 80 cm of the vadose zone. A depth profile of the Potential Nitrification (P.N), a measure of the local amount and activity of nitrifiers, is presented for the first time in the vadose zone of a SAT system showing that there are sufficient nitrifiers to oxidize all the ammonia that is supplied in a flooding cycle within less than 2 h, under optimal microbiological conditions based on the existing nitrifiers and their spatial distribution. The biodegradation rate in the field corresponds to first order ammonium conversion with a kinetic coefficient of 8.0 ± 0.2 d-1. Accordingly, the average measured rate was 8.6 ± 5.8 mg NH4+-N per kg per d for in-field tests, which can be compared to the average P.N, with a value of 34.5 ± 16.8 mg NH4+-N per kg per d. The results suggest that a SAT design, taking into account full ammonium removal capacity, is feasible and can rely on the evaluation of the ammonium adsorption capacity in the SAT soil, the ammonium input and the P.N of the equilibrated target soil under conditions simulating the operation of the infiltrating basins.


Mesothelioma with rhabdoid features: an ultrastructural and immunohistochemical study of 10 cases.
Mesotheliomas with rhabdoid morphology are rare and only two individual case reports have been documented in the literature. This author reports a series of 10 cases of mesotheliomas with rhabdoid features, nine of which originated in the pleura and one in the peritoneum. Eight of the patients were men and two were women. Six patients had a history of asbestos exposure. Histologically, seven of the mesotheliomas were epithelioid, two sarcomatoid, and one biphasic. The proportion of the rhabdoid cells seen in these cases constituted 15-75% of the individual tumors. Cytoplasmic staining in the rhabdoid cells was seen for pan-keratin and vimentin in all 10 cases, for keratin 7 in eight of eight, for calretinin in nine of 10, and for keratin 5/6 in seven of nine. Nuclear positivity for WT1 was observed in the rhabdoid cells of four of seven cases and membranous reactivity for mesothelin in four of six, and for podoplanin in two of six. Only one case showed desmin positivity in sparse cells in the nonrhabdoid component of the tumor. All of the cases were negative for CEA, MOC-31, TAG-72, CD15, CD34, bcl2, muscle-specific actin, and TTF-1. Ultrastructural studies revealed paranuclear collections of intermediate filaments, but no evidence of rhabdomyoblastic differentiation was seen. The mean survival of five of the six patients for whom this information was available was 3.8 months. The remaining patient had a survival time of 1 year. It is important for pathologists to be aware that mesotheliomas can present rhabdoid features, not only because they can be confused with other malignancies that can exhibit a similar morphology, but also because of their apparently unusually aggressive behavior. The value of immunohistochemistry and electron microscopy in the differential diagnosis of these tumors is discussed.


Quantifying the risk-reduction potential of new Modified Risk Tobacco Products.
Quantitative risk assessment of novel Modified Risk Tobacco Products (MRTP) must rest on indirect measurements that are indicative of disease development prior to epidemiological data becoming available. For this purpose, a Population Health Impact Model (PHIM) has been developed to estimate the reduction in the number of deaths from smoking-related diseases following the introduction of an MRTP. One key parameter of the model, the F-factor, describes the effective dose upon switching from cigarette smoking to using an MRTP. Biomarker data, collected in clinical studies, can be analyzed to estimate the effects of switching to an MRTP as compared to quitting smoking. Based on transparent assumptions, a link function is formulated that translates these effects into the F-factor. The concepts of 'lack of sufficiency' and 'necessity' are introduced, allowing for a parametrization of a family of link functions. These can be uniformly sampled, thus providing different 'scenarios' on how biomarker-based evidence can be translated into the F-factor to inform the PHIM.


Toward high-resolution prediction and design of transmembrane helical protein structures.
The prediction and design at the atomic level of membrane protein structures and interactions is a critical but unsolved challenge. To address this problem, we have developed an all-atom physical model that describes intraprotein and protein-solvent interactions in the membrane environment. We evaluated the ability of the model to recapitulate the energetics and structural specificities of polytopic membrane proteins by using a battery of in silico prediction and design tests. First, in side-chain packing and design tests, the model successfully predicts the side-chain conformations at 73% of nonexposed positions and the native amino acid identities at 34% of positions in naturally occurring membrane proteins. Second, the model predicts significant energy gaps between native and nonnative structures of transmembrane helical interfaces and polytopic membrane proteins. Third, distortions in transmembrane helices are successfully recapitulated in docking experiments by using fragments of ideal helices judiciously defined around helical kinks. Finally, de novo structure prediction reaches near-atomic accuracy (<2.5 A) for several small membrane protein domains (<150 residues). The success of the model highlights the critical role of van der Waals and hydrogen-bonding interactions in the stability and structural specificity of membrane protein structures and sets the stage for the high-resolution prediction and design of complex membrane protein architectures.