Functional Impairment in Patients with Panic Disorder.
Anxiety and depression and sociodemographic factors such as age, gender, education level, income, and marital status among people with panic disorder (PD) are associated with functional impairment in the areas of work, social, and family. Although both PD-specific scales such as the Panic Disorder Severity Scale (PDSS) and Anxiety Sensitivity Inventory-Revised (ASI-R) and early trauma have been investigated, their relationship with functional impairment in PD patients has not been clarified. This study included 267 PD patients. The PDSS, Beck Depression Inventory (BDI), ASI-R, and Early Trauma Inventory were used. Pearson's correlation and multiple linear regression analyses were performed. The Sheehan Disability Scale (SDS) was administered to assess the functional impairment level in PD patients. Our findings showed that high levels of PDSS, BDI, and ASI-R were significantly correlated with the functional impairment among PD patients. Multiple regression analyses showed that PDSS, BDI, and ASI-R can predict the functional impairment levels, and PDSS and ASI-R were significantly associated with lost and underproductive days in PD patients. Panic-specific symptoms, depression, and AS are associated with functional impairment level in PD patients. Elevated symptom severity can play a role by affecting productivity and daily responsibilities in PD patients.


Fast statistical measurement of aspect ratio distribution of gold nanorod ensembles by optical extinction spectroscopy.
Fast and accurate geometric characterization and metrology of noble metal nanoparticles such as gold nanorod (NR) ensembles is highly demanded in practical production, trade, and application of nanoparticles. Traditional imaging methods such as transmission electron microscopy (TEM) need to measure a sufficiently large number of nanoparticles individually in order to characterize a nanoparticle ensemble statistically, which are time-consuming and costly, though accurate enough. In this work, we present the use of optical extinction spectroscopy (OES) to fast measure the aspect ratio distribution (which is a critical geometric parameter) of gold NR ensembles statistically. By comparing with the TEM results experimentally, it is shown that the mean aspect ratio obtained by the OES method coincides with that of the TEM method well if the other NR structural parameters are reasonably pre-determined, while the OES method is much faster and of more statistical significance. Furthermore, the influences of these NR structural parameters on the measurement results are thoroughly analyzed and the possible measures to improve the accuracy of solving the ill-posed inverse scattering problem are discussed. By using the OES method, it is also possible to determine the mass-volume concentration of NRs, which is helpful for improving the solution of the inverse scattering problem while is unable to be obtained by the TEM method.


Dietary patterns, Mediterranean diet, and endometrial cancer risk.
This study examines the association between dietary patterns and endometrial cancer risk. A case-control study of endometrial cancer was conducted from 1996 to 1999 in the San Francisco Bay Area in white, African-American, and Latina women age 35-79. Dietary patterns were defined using a principal components analysis; scoring dietary intake based on correspondence to a Mediterranean-style diet; and by jointly categorizing intake of fruits/vegetables and dietary fat. Four dietary patterns were identified and labeled "plant-based," "western," "ethnic," and "phytoestrogen-rich." None of these dietary patterns nor adherence to a Mediterranean diet (to the extent consumed by this population) was associated with endometrial cancer risk. However, among non-users of supplements, greater consumption of the "western" dietary pattern was associated with a 60% increase in risk (95% CI: 0.95-2.7 per unit change; P-interaction = 0.10). A diet characterized by high fat consumption increased risk, regardless of fruit and vegetable consumption (OR = 1.4, 95% CI: 0.97-2.1 for high fat, low fruit/vegetable intake and OR = 1.4, 95% CI: 0.95-2.1 for high fat, high fruit/vegetable intake compared to low fat, high fruit/vegetable intake). Thus, while like others we found that dietary fat increases endometrial cancer risk, the evaluation of dietary patterns did not provide any additional information regarding risk.


The roles of the N-linked glycans and extension regions of soybean beta-conglycinin in folding, assembly and structural features.
Beta-conglycinin, one of the dominant storage proteins of soybean, is a trimer composed of three subunits, alpha, alpha' and beta. All subunits are N-glycosylated and alpha and alpha' contain extension regions in addition to the core regions common to all subunits. Non-glycosylated individual subunits and deletion mutants (alpha(c) and alpha'(c)) lacking the extension regions of alpha and alpha' were expressed in Escherichia coli. All recombinant proteins were purified to near homogeneity and appeared to have the correct conformation, as judged by CD, density-gradient centrifugation and gel-filtration profiles, indicating that the N-linked glycans and extension regions are not essential for the folding and the assembly into trimers of beta-conglycinin. Density-gradient centrifugation, gel-filtration and differential scanning calorimetry profiles of the recombinant proteins and the native beta-conglycinin indicated that the N-linked glycans and extension regions contribute to the dimension of beta-conglycinin but not to the density and the thermal stability. Comparing the solubilities of the individual subunits with those of deletion mutants, only the alpha and alpha' subunits were soluble at lower ionic strength (mu < 0.25) at around the pH value of the endoplasmic reticulum. This suggests that the extension regions play an important role in the prevention of aggregation in the endoplasmic reticulum in analogy with the N-linked glycans.


TCF/LEF regulation of the topologically associated domain ADI promotes mESCs to exit the pluripotent ground state.
Mouse embryonic stem cells (mESCs) can be maintained in vitro in defined N2B27 medium supplemented with two chemical inhibitors for GSK3 and MEK (2i) and the cytokine leukemia inhibitory factor (LIF), which act synergistically to promote self-renewal and pluripotency. Here, we find that genetic deletion of the four genes encoding the TCF/LEF transcription factors confers mESCs with the ability to self-renew in N2B27 medium alone. TCF/LEF quadruple knockout (qKO) mESCs display dysregulation of several genes, including Aire, Dnmt3l, and IcosL, located adjacent to each other within a topologically associated domain (TAD). Aire, Dnmt3l, and IcosL appear to be regulated by TCF/LEF in a β-catenin independent manner. Moreover, downregulation of Aire and Dnmt3l in wild-type mESCs mimics the loss of TCF/LEF and increases mESC survival in the absence of 2iL. Hence, this study identifies TCF/LEF effectors that mediate exit from the pluripotent state.


Active perception: sensorimotor circuits as a cortical basis for language.
Action and perception are functionally linked in the brain, but a hotly debated question is whether perception and comprehension of stimuli depend on motor circuits. Brain language mechanisms are ideal for addressing this question. Neuroimaging investigations have found specific motor activations when subjects understand speech sounds, word meanings and sentence structures. Moreover, studies involving transcranial magnetic stimulation and patients with lesions affecting inferior frontal regions of the brain have shown contributions of motor circuits to the comprehension of phonemes, semantic categories and grammar. These data show that language comprehension benefits from frontocentral action systems, indicating that action and perception circuits are interdependent.


[Risk factors associated with cognitive impairment in aged: Cross-sectional study].
With the increase in life expectancy, conditions related to older age have increased in incidence, one of these pathologies is Cognitive Impairment (CI), which has a prevalence of up to 28%, conditions that increase the presence of CI are known. However, there is controversy about the factors that increase the risk of CI. To determine the factors associated with cognitive impairment in older adults. We conducted a cross-sectional, analytical, observational, retroprolective study that included adults ≥65 years of age, with no history of cerebral vascular event, cranioencephalic trauma. Demographic factors were analyzed, CI was assessed with the Mini Mental State Examination test. For statistical analysis we used Odds Ratio (OR) and 95% confidence interval (95% CI) for each factor and multiple logistic regression as multivariate analysis. 420 older adults were included, 61% were women, 32.6% with age >75 years, 84.5% with schooling <9 years, in the multiple logistic regression the following were independent factors for the presence of mild CI: dependence on basic activities of daily living (ADLs) with OR 5.88, absence of cognitive stimulation RM 4.50, age >75 years OR 2.92, polypharmacy OR 2.16, uncontrolled blood pressure OR 1.92. ADLs dependence, absence of cognitive stimulation, age >75 years, polypharmacy and uncontrolled blood pressure are risk factors associated with CI in older adults.


Effects of blood sample age at time of separation on measured cytokine concentrations in human plasma.
Measurement of peripheral blood cytokines and other immunomodulatory proteins is a useful and popular tool for assessing human immune responses to a wide range of assaults. A common challenge in this work is obtaining fresh, high-quality samples and limiting the time between blood collection and the separation of plasma or serum from cells. In this study we sought to determine the effect of sample age at the time of processing on the measured levels of 41 soluble immune mediators. Two cohorts were examined: healthy lab donors and trauma patients, who have significant immune perturbation. Whole-blood samples were aliquoted, and plasma was isolated, at days 0, 1, 2, and 3 after collection. Multiplexing techniques were used to measure protein concentrations, and general estimating equations were used to determine if there was a significant change over time. Over the 3-day period examined, only 15 of the 41 proteins showed no significant change in either cohort. Among the remaining proteins both increases and decreases were observed, with changes ranging from 2.4% per day to 325% per day. Proteins with significant changes in one cohort did not always show significant changes in the other group. These results support the need to separate plasma or serum from whole blood as quickly as possible and/or to standardize the length of time to processing within a given study of peripheral blood protein concentrations. When this is not possible, care should be taken to account for differences due to sample age.


Drivers with untreated sleep apnea. A cause of death and serious injury.
Three patients with untreated sleep apnea fell asleep while driving and caused serious automobile accidents. One person died, another became permanently paraplegic, and the three patients with sleep apnea were seriously injured in these crashes. This sequela of sleep apnea is not surprising, since subjects with sleep apnea may be poor drivers with a high accident rate and a high incidence of "near-miss" vehicular incidents. Because drivers with untreated sleep apnea may cause a large number of preventable automobile accidents, physicians have specific duties involving these drivers. First, physicians must try to identify impaired drivers with sleep apnea before they have an accident; routinely asking patients about loud snoring and hypersomnolence may help identify these impaired drivers. Second, physicians must consider the diagnosis of sleep apnea when examining patients who fall asleep while driving. Next, physicians must warn their patients with sleep apnea about the risks of driving with untreated sleep apnea. Finally, physicians must treat any seriously impaired driver with sleep apnea and keep these patients from driving until they can receive successful treatment.


Improved wound stability with a modified minimally invasive surgical technique in the regenerative treatment of isolated interdental intrabony defects.
This paper describes a modified surgical approach of the minimally invasive surgical technique (modified minimally invasive surgical technique, M-MIST) and preliminarily evaluates its applicability and clinical performances in the treatment of isolated deep intrabony defects in combination with amelogenins. Twenty deep isolated intrabony defects in 20 patients were studied. Fifteen were surgically accessed with the M-MIST, while in five sites, which presented a lingual intrabony component, the conventional MIST had to be applied. The M-MIST consisted of a buccal incision of the defect-associated papilla, according to the principles of the papilla preservation techniques. Only a buccal flap was raised while the interdental papilla was left in situ. The granulation tissue filling the defect was dissected and removed, leaving the interdental and palatal tissues untouched. Root instrumentation and application of the regenerative material were performed before suturing. Primary closure of the flaps was attained with a single internal modified mattress suture. Surgery was performed with the aid of an operating microscope and microsurgical instruments. The surgical chair-time of the M-MIST-treated sites (N=15) was 56+/-8.64 min. Early wound healing was uneventful: primary wound closure was attained and maintained in all sites. No oedema or haematoma was noted. Patients did not report pain or discomfort. The 1-year clinical attachment level (CAL) gain was 4.5+/-1.4 mm in defects 6+/-1.5 mm deep. Residual probing depths (PDs) were 3.1+/-0.6 mm. A minimal increase of 0.1+/-0.3 mm in gingival recession between baseline and 1 year was observed. M-MIST was applicable on 15 isolated interproximal defects out of 20 selected ones. It resulted in very limited patient morbidity and excellent clinical improvements. These outcomes should be confirmed in a larger study.


Low concentrations of trifluoperazine arrest the cell division cycle of Saccharomyces cerevisiae at two specific stages.
Low concentrations of trifluoperazine (TFP) reversibly inhibited vegetative growth of Saccharomyces cerevisiae. The cell cycle was analysed by flow cytometry using haploid a cells synchronized by alpha-factor arrest and several temperature-sensitive cell division cycle mutants (cdc). Cells were pulse-labelled with fluorescein-labelled concanavalin A (ConA-FITC) to determine cell division or stained with propidium iodide to determine the stage of cell cycle arrest by TFP. Cell growth was estimated from the changes in the relative intensity of scattered light, and budding was determined microscopically. When TFP was added before Start on release from alpha-factor arrest, after release of cdc28-arrested cells, and at transition from stationary phase to vegetative growth, cell growth, budding and DNA synthesis were inhibited. When TFP was added after execution of spindle pole body duplication, cell growth, bud emergence and DNA synthesis were not inhibited but cell division was inhibited and the cells arrested with buds at G2M Using cdc mutants, the second stage of arrest by TFP was determined to be just before medial-nuclear division.


High detection frequency and genetic diversity of porcine circovirus 3 (PCV-3) in Namibian backyard farms and warthogs.
Since its first identification in 2015, porcine circovirus 3 (PCV-3) has been reported worldwide with a high frequency and in the presence of several clinical conditions, although its impact on pig health and productivity is still debated. Data on the presence of PCV-3 in Africa are, however, limited. A previous study performed on commercial pigs in Namibia failed to identify the pathogen. In the present study, the viral circulation in backyard farms, characterised by lower biosecurity measures and frequent animal exchange between farms, was assessed. The susceptibility of warthogs to PCV-3 infection and their potential epidemiological role were also evaluated. Tonsils from 77 pigs from backyard piggeries and 55 warthogs were collected in different regions of Namibia and tested by PCR. Positive samples were sequenced and compared to PCV-3 strains circulating globally. Forty-two out of 77 pigs (54.54 %) and 12 out of 55 warthogs (21.82 %) tested positive, demonstrating the presence of PCV-3 in the country and suggesting that the high biosecurity measures implemented in the commercial farms that previously tested negative for PCV-3 probably prevented viral introduction. The partial ORF2 gene was successfully sequenced in samples from 27 pigs and 6 warthogs. Genetically, the identified strains were part of 3 distinct groups which included both backyard pigs and warthogs from different regions of Namibia. There is also evidence for the occurrence of multiple introduction events most likely from Asian countries, either directly into Namibia or through other African countries. Considering the strict Namibian regulations on live animal importation, understanding the source of viral introduction is challenging, although semen importation or the habit of feeding backyard pigs with human food waste might have played a role. Pig exchanges between farms for breeding purposes or wildlife movements could also have been involved in PCV-3 dispersal within Namibia. Despite the significant advances in the field, further studies should be undertaken to properly understand PCV-3 epidemiology in Namibia and its impact on pig productivity and wildlife health.


Quality assurance in repeat films.
The Quality Assurance Program of Walter Reed Army Medical Center is described. This program has been in effect since January 1, 1978 and is ongoing. The logical derivation of the use of the repeat film analysis as the focus of the Quality Assurance Program is described in detail. This repeat analysis procedure includes (1) the collection of all repeat and discarded film; (2) the separation of all repeat and discarded film into types according to the etiology leading to their being discarded; and (3) evaluation of radiographic artifacts to analyzed the types of artifacts, the mistakes which lead to these artifacts, and the means of eliminating the causes of these artifacts. Artifacts are categorized according to patient error, physician error, radiographer error, machine error, film screen processor error, etc. Statistics of this analysis are presented from January 1, 1978 through July 1, 1979. Pertinent examples of different types of errors are illustrated and the logical step-by-step process leading to the elimination of causes is explained in detail.


Application of the ISTH bleeding score in hemophilia.
Hemophilia is an inherited bleeding disorder. With proper treatment and self-care, persons with hemophilia can maintain an active, productive lifestyle. Hemophilia can be mild, moderate, or severe, depending on the degree of plasma clotting factor deficiency. The aim of the study was to assess the utility of ISTH-BAT in diagnosis, determining severity of the bleeding condition in newly diagnosed and known hemophilia patients, compare the bleeding score (BS) in adult and pediatric groups and investigate its association with plasma factor levels. ISTH-BAT was used to assess BS in a total of 115 patients, 78 with hemophilia A, and 37 with hemophilia B and in 100 controls. BS was significantly higher in HA and HB patients as compared to controls, with no significant difference between HA and HB. The BS was very similar in newly diagnosed compared to known hemophilia patients, lower in pediatric compared to adult and higher in severe compared to mild HA patients. The ISTH BAT can help identify hemophilia patients. Therefore it is a useful tool to distinguish between affected and unaffected individuals with bleeding. Moreover, an important finding of our study is that there is no major difference between the scores in known and newly diagnosed patients.


A new small device made of glass for separating microplastics from marine and freshwater sediments.
Separating microplastics from marine and freshwater sediments is challenging, but necessary to determine their distribution, mass, and ecological impacts in benthic environments. Density separation is commonly used to extract microplastics from sediments by using heavy salt solutions, such as zinc chloride and sodium iodide. However, current devices/apparatus used for density separation, including glass beakers, funnels, upside-down funnel-shaped separators with a shut-off valve, etc., possess various shortcomings in terms of recovery rate, time consumption, and/or usability. In evaluating existing microplastic extraction methods using density separation, we identified the need for a device that allows rapid, simple, and efficient extraction of microplastics from a range of sediment types. We have developed a small glass separator, without a valve, taking a hint from an Utermöhl chamber. This new device is easy to clean and portable, yet enables rapid separation of microplastics from sediments. With this simple device, we recovered 94-98% of <1,000 µm microplastics (polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, and polystyrene). Overall, the device is efficient for various sizes, polymer types, and sediment types. Also, microplastics collected with this glass-made device remain chemically uncontaminated, and can, therefore, be used for further analysis of adsorbing contaminants and additives on/to microplastics.


Psychometric properties of the standardized assessment of concussion in youth football: Validity, reliability, and demographic factors.
The objective of this study was to determine the psychometrics (reliability, validity) of the original Standardized Assessment of Concussion (SAC) in a youth sample (ages 11 to 13). Demographic factors of race, level of vocabulary knowledge, mother's level of education were also considered. Over 150 youth football athletes completed the SAC and a brief battery of NIH Toolbox cognitive tests as part of a larger study on biomechanical factors in youth sport concussion. This was a within-subjects design (pre-season, post-season assessments), and correlational analysis of convergent and discriminant validity. Between groups analysis based on demographic differences was also employed. The pre-season SAC scores were not different by age; however, SAC scores were statistically different by race: t(155) = 3.162, p = .002, d = .519. Maternal level of education and participant vocabulary scores were related to racial group membership. Convergent and discriminant validity were established compared to NIH Toolbox tests of memory and speed. Pre-post-season tests for 108 participants established marginally acceptable test-retest reliability (ICC = .692). These data support the use of the original SAC in youth football although clinicians must be aware of racial differences in scores.


Reproductive life milestones in women with Parkinson's disease.
Reproductive life milestones were studied in 150 unselected women with idiopathic Parkinson's disease (PD) and in 300 postmenopausal healthy women (PM). Duration of reproductive life was found to be similar in the two groups. The women with PD reported significantly more premenstrual symptoms, fewer deliveries and abortions, and less use of contraception. Time and mode of menopause onset were similar in PD and PM, but the PD women reported significantly more hot flushes, less insomnia, depression, urinary incontinence and dyspareunia, and less recourse to hormone replacement therapy than the PM women. Women diagnosed with PD before the menopause reported more premenstrual symptoms and contraceptive use compared with those with postmenopausal PD onset, as well as a premenstrual worsening of PD symptoms in more than 50% of cases. Our data indicate poor adaptation of neuronal pathways to the hormonal fluctuations of reproductive life in women with PD, supporting the existence of a qualitative relationship between PD and reproductive events.


The Impact of Parental Injury on Children's Mental Health Diagnoses and Classes of Psychotropic Medication by Child Age.
Civilian and military research has linked parental illness and injury with increased overall mental health care and psychiatric medication use in children. Care for specific mental health conditions and medications by child age have not been reported. We sought to quantify the effect of parental illness and injury on child mental health care and psychiatric medication use in children overall and stratified by age. A self-controlled case series analyzed the impact of parental illness/injury on mental health and psychiatric medication use of military dependent children. Children were aged 2-16 years (51% male) when their parents were injured and received care in the Military Health System for 2 years before and 2 years after their parent's illness/injury. We used International Classification of Diseases 9th edition codes to identify outpatient mental healthcare visits. Outpatient care for 14 specific mental health diagnoses was classified using the Agency for Healthcare Research and Quality clinical classification system. Outpatient pharmacy records identified psychiatric medication prescriptions by therapeutic class. Parental illness/injury was identified by inclusion in the Military Health System Ill, Injured, and Wounded Warrior database. Adjusted negative binomial regression analysis compared rates of outpatient visits and medication days in the 2 years following parental illness/injury to the 2 years before the parent's illness/injury overall. Secondary analyses were stratified by age groups of 2-5 years (n = 158,620), 6-12 years (n = 239,614), and 13-16 years n = 86,768) and adjusted for parental pre-injury/illness deployment and child sex. Additional secondary analysis compared post-parental injury/illness care of children whose parents had post-traumatic stress disorder or traumatic brain injury to children of parents with physical/mental health injury/illness. There were 485,002 children of 272,211 parents injured during the study period. After adjustment for child sex, years of pre-injury/illness parental deployment, and child age, parental illness/injury was associated with increased mental visits across all categories of care except developmental diagnoses. Post-parental injury visits for suicidal ideation, alcohol abuse, mood, and anxiety disorders were all doubled. For children aged 2-5 years at parental illness/injury, the largest increases in care were in psychotic, anxiety, attention deficit, and mood disorders. In children aged 6-12 years, the largest increases were in psychotic conditions, suicidal ideation, and personality disorders. In adolescents aged 13-16 years, the largest increases were for alcohol and substance abuse disorders, with visits increasing by 4-5 times. For children of all ages, parental injury was associated with increased use of all therapeutic classes of psychiatric medications; use of stimulant medications was increased in younger children and decreased in older children following parental injury (P < .001). Parental illness/injury is associated with increased mental health care and days of psychiatric medication use in dependent children. Practitioners who care for families impacted by parental illness/injury should be cognizant of children's mental health risk. Early identification and treatment of child-related mental health issues can improve family functioning and increase military family readiness.


Variation of human amygdala response during threatening stimuli as a function of 5'HTTLPR genotype and personality style.
In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is associated with genetic factors as well as with emotional salience. The objective of this study was to explore the relevance of personality style for variability of amygdala response. We studied two groups (n=14 in each group) of healthy subjects categorized by contrasting cognitive styles with which they attribute salience to fearful stimuli: so-called phobic prone subjects who exaggerate potential environmental threat versus so-called eating disorders prone subjects who tend to be much less centered around fear. The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the 5' variable number tandem repeat (VNTR) polymorphism in the serotonin transporter. The fMRI results indicated that phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects. Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter. Moreover, brain activity during a working memory task did not differentiate the two groups. The results of the present study suggest that aspects of personality style are rooted in biological responses of the fear circuitry associated with processing of environmental information.


Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.
Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance breast cancer 1/2, early onset genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h2) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms (SNPs), nuclear mitotic apparatus protein 1, cyclin D1, cytochrome C oxidase copper chaperone, fibroblast growth factor receptor 2, TOX high mobility group box family member 3 and solute carrier family 4 member 7. These 6 SNPs, previously identified by genome-wide association studies, were considered to evaluate the additive and common environmental components that contribute to the development of breast cancer in nuclear (pedigrees including only first degree relationships) and in extended families (with at most third degree relationships). A total of 22 extended pedigrees, subsequently split into 52 nuclear pedigrees were analyzed. An example of splitting process from extended to nuclear pedigree is shown in Fig. 1. Firstly, an underline latent continuous trait (Y*) using breast cancer status and information of 6 breast cancer-associated SNPs was calculated. This novel trait summarized the susceptibility of breast cancer in each individual. Secondly, the h2 of Y* was estimated using an additive polygenic-common environment-unique error model. h2 was evaluated in extended and immediate pedigrees, obtaining comparable results. h2 accounts for ~40% of the total phenotypic variance, indicating a fairly strong additive genetic effect of breast cancer susceptibility. The present study indicated the importance of the evaluation and consideration of these six SNPs, which can be used as instrumental variables in order to obtain improved genetic models that are useful for h2 analysis.


Screening for tardive dyskinesia.
A program of routine Abnormal Involuntary Movement Scale (AIMS) examinations is contrasted with a referral system for detection of tardive dyskinesia in an outpatient schizophrenia clinic. Routine clinical use of the AIMS examination may have improved the early detection of tardive dyskinesia, which could result in a decrease in the morbidity associated with this disorder. Routine AIMS examinations also facilitated repeat discussions with patients about tardive dyskinesia, which provide an opportunity to obtain ongoing informed consent for treatment with neuroleptics.


Pharmacological modulation of nitric oxide release: new pharmacological perspectives, potential benefits and risks.
Nitric oxide is becoming an increasingly important signalling molecule implicated in a growing number of physiological and pathophysiological processes. Moreover, with the recent advances in nitric oxide biochemistry, many well known drugs have been shown to act totally or partially by modulating NO metabolism with varying therapeutic results. The classic organic nitrates have been shown to exhibit beneficial therapeutic but suffer from some well known pitfalls (tolerability induction, abrupt cephalea and hypotension). Similarly, sydnonimines, another well known class of NO donor drugs, have a characteristically low therapeutic index (i.e., cyanide toxicity). At present, pharmacological researchers are designing and synthesising various chemical compounds capable of modulating NO metabolism for therapeutic purposes that also possess an optimal therapeutic index. Specifically, various new classes of NO donors are under intense pharmacological investigation (such as S-nitrosothiols, diazeniumdiolates, furoxans, zeolites and so on), each characterised by a particular pharmacokinetic and pharmacodynamic profile. To known the pharmacological development of these new NO donor drugs could help to ameliorate the use of these molecules in various therapeutic protocols. In fact, the pharmacologically modulated nitric oxide release showed to have an important therapeutic impact in the treatment of diseases such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. At present, the most important obstacle in the field of new NO donor drugs seems to be carefully targeting NO release to a particular tissue at an optimal concentration, so as to achieve a beneficial action and to limit possible toxic effects.


Aerobic 2-ketogluconate metabolism of Klebsiella pneumoniae NCTC 418 grown in chemostat culture.
Klebsiella pneumoniae NCTC 418 is able to convert 2-ketogluconate intracellularly to 6-phosphogluconate by the combined action of an NADPH-dependent 2-ketogluconate reductase and gluconate kinase. Synthesis of the former enzyme was maximal under 2-ketogluconate-limited growth conditions. An instantaneous transition to a 2-ketogluconate-excess condition resulted in an acceleration of catabolism of this carbon source, accompanied by complete inhibition of biosynthesis. It is suggested that the cause of this inhibition resides in depletion of the NADPH pool due to the high rate at which NADPH is oxidized by 2-ketogluconate reductase.


Macrophages in bovine milk.
The high vacuolated mononuclear cells in milk from normal bovine mammary glands, usually designated epithelial cells, were examined for properties characteristic of macrophages. In vitro, these cells concentrated neutral red into cytoplasmic vacuoles, adhered rapidly to and spread on glass, and phagocytosed viable Streptococcus agalactiae and Staphylococcus aureus. Neutral red uptake was demonstrated in vivo, and the vacuolated mononuclear cells phagocytosed formalinkilled S aureus in vivo. These results suggest that these cells are macrophages.


Unpredicted transmission strategy of Gyrodactylus salaris (Monogenea: Gyrodactylidae): survival and infectivity of parasites on dead hosts.
The viviparous monogenean Gyrodactylus salaris continues to devastate Norwegian Atlantic salmon populations despite the extreme measures taken to control this pathogen. Increased understanding of parasite biology is needed to develop alternative control and management strategies of wild Atlantic salmon. We have examined temperature-dependent survival of G. salaris, both on and off the host. At 18 degrees C, survival off the host was 1 day, but at 3 degrees C parasites survived for 4 days. However, in contrast to assumptions made by earlier authors, many parasites remained with their host following its death. Ultrastructural evidence indicated that G. salaris individuals can feed on a dead host, and laboratory tests demonstrated that worms on their hosts more than double their life-span compared with individuals maintained off the host. Experimental infections also demonstrated that establishment and subsequent population growth of parasites previously maintained on dead hosts for 3 days, was similar to that of parasites transferred directly between living hosts. Hence, for G. salaris, dead infected hosts may increase the chances of successful transmission and be a potential important infection source in rivers and hatcheries.


Retrospective Time Perception in Korsakoff's Syndrome.
The authors investigated retrospective timing in participants with Korsakoff's syndrome. Patients were assessed on four retrospective tasks on which they were instructed to read three-digit numbers aloud (15 seconds), fill connected squares (30 seconds), decide whether words were abstract or concrete (45 seconds), or read aloud a text about mushroom picking (60 seconds). Participants were not aware of the task's timing until the end of the tasks, when they were asked to estimate the elapsed time. Results revealed an underestimation of the elapsed time in Korsakoff participants, suggesting that time is perceived to pass quickly for these participants.


Prostaglandin dehydrogenase is a target for successful induction of cervical ripening.
The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E2 or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE2 uses cell-specific EP2 receptor-mediated increases in Ca2+ to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE2 or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE2 or metabolism-resistant dimethyl-PGE2 resulted in preterm cervical ripening and delivery in mice. The ability of PGE2 to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of 15-PGDH elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for (i) the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE2-mediated cervical ripening or (ii) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.


Duration of asymptomatic status and outcomes following carotid endarterectomy and carotid artery stenting in the Carotid Revascularization Endarterectomy vs Stenting Trial.
Most carotid revascularization studies define asymptomatic as symptom-free for more than 180 days; however, it is unknown if intervention carries similar risk among those currently asymptomatic but with previous symptoms (PS) vs those who were always asymptomatic (AA). We compared the periprocedural and 4-year risks of PS vs AA patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) randomized to carotid endarterectomy (CEA) or carotid artery stenting (CAS)/angioplasty. Proportional hazards models adjusting for age, sex, and treatment were used to assess the risk of periprocedural stroke and/or death (S+D; any S+D during periprocedural period), stroke and death at 4 years (any S+D within the periprocedural period and ipsilateral stroke out to 4 years) and the primary end point at 4 years (any stroke, death, and myocardial infarction within the periprocedural period and ipsilateral stroke out to 4 years). Analysis was performed pooling the CEA-treated and CAS-treated patients, and separately for each treatment. Of 1181 asymptomatic patients randomized in CREST, 1104 (93%) were AA and 77 (7%) were PS. There was no difference in risk when comparing the AA and PS cohorts in the pooled CAS+CEA population for periprocedural S+D (2.0% vs 1.3%), S+D at 4 years (3.6% vs 3.2%), or the primary end point (5.2% vs 5.8%). There were also no differences among those assigned to CEA (periprocedural S+D, 1.5% vs 0%; S+D at 4 years, 2.7% vs 0%; or primary end point, 5.1% vs 2.4%) or CAS (periprocedural S+D, 2.5% vs 2.8%; S+D at 4 years, 4.4% vs 6.9%; or primary end point, 5.3% vs 9.8%) when analyzed separately. In CREST, only a small minority of asymptomatic patients had previous ipsilateral symptoms. The outcomes of periprocedural S+D, periprocedural S+D, and ipsilateral stroke up to 4 years, and the primary end point did not differ for AA patients compared with PS patients.


Antisense suppression of the small chloroplast protein CP12 in tobacco alters carbon partitioning and severely restricts growth.
The thioredoxin-regulated chloroplast protein CP12 forms a multienzyme complex with the Calvin-Benson cycle enzymes phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). PRK and GAPDH are inactivated when present in this complex, a process shown in vitro to be dependent upon oxidized CP12. The importance of CP12 in vivo in higher plants, however, has not been investigated. Here, antisense suppression of CP12 in tobacco (Nicotiana tabacum) was observed to impact on NAD-induced PRK and GAPDH complex formation but had little effect on enzyme activity. Additionally, only minor changes in photosynthetic carbon fixation were observed. Despite this, antisense plants displayed changes in growth rates and morphology, including dwarfism and reduced apical dominance. The hypothesis that CP12 is essential to separate oxidative pentose phosphate pathway activity from Calvin-Benson cycle activity, as proposed in cyanobacteria, was tested. No evidence was found to support this role in tobacco. Evidence was seen, however, for a restriction to malate valve capacity, with decreases in NADP-malate dehydrogenase activity (but not protein levels) and pyridine nucleotide content. Antisense repression of CP12 also led to significant changes in carbon partitioning, with increased carbon allocation to the cell wall and the organic acids malate and fumarate and decreased allocation to starch and soluble carbohydrates. Severe decreases were also seen in 2-oxoglutarate content, a key indicator of cellular carbon sufficiency. The data presented here indicate that in tobacco, CP12 has a role in redox-mediated regulation of carbon partitioning from the chloroplast and provides strong in vivo evidence that CP12 is required for normal growth and development in plants.


A computational exploration of bacterial metabolic diversity identifying metabolic interactions and growth-efficient strain communities.
Metabolic interactions involve the exchange of metabolic products among microbial species. Most microbes live in communities and usually rely on metabolic interactions to increase their supply for nutrients and better exploit a given environment. Constraint-based models have successfully analyzed cellular metabolism and described genotype-phenotype relations. However, there are only a few studies of genome-scale multi-species interactions. Based on genome-scale approaches, we present a graph-theoretic approach together with a metabolic model in order to explore the metabolic variability among bacterial strains and identify and describe metabolically interacting strain communities in a batch culture consisting of two or more strains. We demonstrate the applicability of our approach to the bacterium E. coli across different single-carbon-source conditions. A different diversity graph is constructed for each growth condition. The graph-theoretic properties of the constructed graphs reflect the inherent high metabolic redundancy of the cell to single-gene knockouts, reveal mutant-hubs of unique metabolic capabilities regarding by-production, demonstrate consistent metabolic behaviors across conditions and show an evolutionary difficulty towards the establishment of polymorphism, while suggesting that communities consisting of strains specifically adapted to a given condition are more likely to evolve. We reveal several strain communities of improved growth relative to corresponding monocultures, even though strain communities are not modeled to operate towards a collective goal, such as the community growth and we identify the range of metabolites that are exchanged in these batch co-cultures. This study provides a genome-scale description of the metabolic variability regarding by-production among E. coli strains under different conditions and shows how metabolic differences can be used to identify metabolically interacting strain communities. This work also extends the existing stoichiometric models in order to describe batch co-cultures and provides the extent of metabolic interactions in a strain community revealing their importance for growth.


A survival prediction model of rats in hemorrhagic shock using the random forest classifier.
Hemorrhagic shock is the cause of one third of deaths resulting from injury in the world. Although many studies have tried to diagnose hemorrhagic shock early and accurately, such attempts were inconclusive due to compensatory mechanisms of humans. The objective of this study was to construct a survival prediction model of rats in hemorrhagic shock using a random forest (RF) model, which is a newly emerged classifier acknowledged for its performance. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), lactate concentration (LC), and perfusion (PF) measured in rats were used as input variables for the RF model and its performance was compared with that of a logistic regression (LR) model. Before constructing the models, we performed a 5-fold cross validation for RF variable selection and forward stepwise variable selection for the LR model to see which variables are important for the models. For the LR model, sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (ROC-AUC) were 1, 0.89, 0.94, and 0.98, respectively. For the RF models, sensitivity, specificity, accuracy, and AUC were 0.96, 1, 0.98, and 0.99, respectively. In conclusion, the RF model was superior to the LR model for survival prediction in the rat model.


[Cardiovascular prevention and attitude of people towards behavior changes: state of the art].
In recent years the main focus of cardiovascular prevention has been to identify people without clinical evidence of coronary disease, but with a high risk of developing a clinical event. Long term follow up studies show that a young person with a high "Relative Risk" of presenting a cardiovascular event becomes an adult with a high "Absolute Risk" of suffering it. The aim of primary prevention is to avoid the appearance of cardiovascular diseases, delaying the development of atherosclerosis and its consequences. In this scenario, the first step is to increase awareness among healthy people of their own cardiovascular risk, enhancing their knowledge of their risk parameter values and generating a correct perception of the risk burden that those values mean. Literature review reveals that significant percentages of healthy individuals are unaware of their own values of blood pressure, total cholesterol and blood glucose. Furthermore, people aware of having abnormal parameters have low treatment compliance rates or evidence inconsistency between knowledge and behavior. This paper reviews educational strategies and other factors that influence this knowledge-behavior gap, such as the stages of behavior changes of the Prochaska and Diclemente Model. Evidence has shown that knowledge about cardiovascular risk factors is not enough to influence behavior and that the degree of preparation of people towards behavior changes is a strong predictor of the success of educational and counseling interventions. Local Chilean data from the RICAR project also shows that the profile of behavior change is different for each modifiable cardiovascular risk factor.


Spectral Talbot phenomena of frequency combs induced by cross-phase modulation in optical fibers.
Cross-phase modulation (XPM) of a frequency comb (finite-duration optical pulse sequence) by an intense, long Gaussian pump pulse is theoretically investigated, and new effects, namely, frequency-domain self-imaging phenomena (integer and fractional Talbot effects), are reported. The conditions favorable for observing spectral self-imaging phenomena by XPM are derived and numerically confirmed. The effects of nonidealities in a practical experiment (e.g., group-delay walk-off and dispersion) are also evaluated. One can use spectral self-imaging to tune the free spectral range of a frequency comb (without affecting the shape and bandwidth of the individual passbands) simply by adjusting the pump power in a fiber XPM scheme.


Genetic organization of the region around UNC-15 (I), a gene affecting paramyosin in Caenorhabditis elegans.
In the nematode Caenorhabditis elegans mutants in the gene unc-15 (I) affect the muscle protein paramyosin (Waterston, Fishpool and Brenner 1977). We have characterized 20 ethyl methanesulfonate-induced mutations in essential genes closely linked to unc-15. These lethals defined 16 new complementation groups. In the 0.65 map-unit interval around unc-15 defined by dpy-14 and unc-56, seven newly identified genes have been mapped relative to five existing genes. At present, the average distance between genes in this region is approximately 0.05 map units. Two genes, unc-15 and unc-13, are only 0.025 map units apart. Partial fine-structures maps of alleles of these two genes have been constructed. This analysis of unc-15 and genes adjacent to it is the first in a series of genetic and biochemical studies directed towards understanding the control of unc-15 expression.


National South African HIV prevalence estimates robust despite substantial test non-participation.
South African (SA) national HIV seroprevalence estimates are of crucial policy relevance in the country, and for the worldwide HIV response. However, the most recent nationally representative HIV test survey in 2012 had 22% test non-participation, leaving the potential for substantial bias in current seroprevalence estimates, even after controlling for selection on observed factors. To re-estimate national HIV prevalence in SA, controlling for bias due to selection on both observed and unobserved factors in the 2012 SA National HIV Prevalence, Incidence and Behaviour Survey. We jointly estimated regression models for consent to test and HIV status in a Heckman-type bivariate probit framework. As selection variable, we used assigned interviewer identity, a variable known to predict consent but highly unlikely to be associated with interviewees' HIV status. From these models, we estimated the HIV status of interviewed participants who did not test. Of 26 710 interviewed participants who were invited to test for HIV, 21.3% of females and 24.3% of males declined. Interviewer identity was strongly correlated with consent to test for HIV; declining a test was weakly associated with HIV serostatus. Our HIV prevalence estimates were not significantly different from those using standard methods to control for bias due to selection on observed factors: 15.1% (95% confidence interval (CI) 12.1 - 18.6) v. 14.5% (95% CI 12.8 - 16.3) for 15 - 49-year-old males; 23.3% (95% CI 21.7 - 25.8) v. 23.2% (95% CI 21.3 - 25.1) for 15 - 49-year-old females. The most recent SA HIV prevalence estimates are robust under the strongest available test for selection bias due to missing data. Our findings support the reliability of inferences drawn from such data.


Female moorhens compete for small fat males.
Female moorhens in flocks competed with each other to obtain mates. The heaviest females won most of the agonistic encounters, and these females paired with males that had large fat reserves. Fat males tended to be small, possibly because of energetic constraints on birds of large body size. Females paired with fat males initiated more nesting attempts in a season.


Health and environmental implications of using composted household and yard waste bedding in a cattle feedlot.
A study was conducted to determine the safety and feasibility of using municipal solid waste compost (MSWC) as a bedding material for cattle feedlots. Two pens in an open-front pole barn were bedded with either corn stalks or MSWC in each of two feeding periods (blocks) with two pens (23 x 34 m) per block. Block 1 used 336 heifers (initial BW, 398 kg) during a 104-d period (summer), and Block 2 used 276 steers (initial BW, 412 kg) during a 92-d period (winter). Blood concentrations of regulated elements (Cd, Cu, Mo, Pb, Ni, and Zn), electrolytes, glucose, or liver and kidney enzymes were unaffected (P > .05) by use of either bedding material. Polychlorinated biphenyls in perirenal fat were not detectable (< .5 ppm) in cattle bedded with either material. At slaughter, kidney Cu and kidney and liver Pb concentrations were greater (P < .05) for cattle bedded with MSWC. Despite this, tissue concentrations of these elements were well within those considered normal for healthy cattle. Regulated element concentrations of feed did not differ (P > .05) between diets within period, and neither did DMI or DM digestibility; therefore, cattle bedded with MSWC were likely inhaling additional amounts of these elements and excreting them through feces. More MSWC than corn stalks was required to supply a dry bed per animal daily (P < .05). Soiled bedding (manure as-is) output was similar (P > .05) for both bedding materials. On a DM basis, more manure (P < .05) was removed from the pen bedded with MSWC in Block 2. Total manure N and P removed was similar for both bedding materials. Nitrogen and P concentrations in manure were lower (P < .05) during Block 2, but total manure N removed was greater (P < .05) during Block 2. Total manure P removed from the pens was not affected by season. Under the conditions of this study, MSWC seemed to be a safe and effective bedding material for cattle feedlots.


K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association.
K201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial. It is believed to stabilize the closed state of the RyR2 (cardiac ryanodine receptor) by increasing its affinity for the FKBP12.6 (12.6 kDa FK506 binding protein) [Wehrens, Lehnart, Reiken, Deng, Vest, Cervantes, Coromilas, Landry and Marks (2004) Science 304, 292-296]. In the present study, we investigated the effect of K201 on spontaneous Ca2+ release induced by Ca2+ overload in rat ventricular myocytes and in HEK-293 cells (human embryonic kidney cells) expressing RyR2 and the role of FKBP12.6 in the action of K201. We found that K201 abolished spontaneous Ca2+ release in cardiac myocytes in a concentration-dependent manner. Treating ventricular myocytes with FK506 to dissociate FKBP12.6 from RyR2 did not affect the suppression of spontaneous Ca2+ release by K201. Similarly, K201 was able to suppress spontaneous Ca2+ release in FK506-treated HEK-293 cells co-expressing RyR2 and FKBP12.6. Furthermore, K201 suppressed spontaneous Ca2+ release in HEK-293 cells expressing RyR2 alone and in cells co-expressing RyR2 and FKBP12.6 with the same potency. In addition, K201 inhibited [3H]ryanodine binding to RyR2-wt (wild-type) and an RyR2 mutant linked to ventricular tachycardia and sudden death, N4104K, in the absence of FKBP12.6. These observations demonstrate that FKBP12.6 is not involved in the inhibitory action of K201 on spontaneous Ca2+ release. Our results also suggest that suppression of spontaneous Ca2+ release and the activity of RyR2 contributes, at least in part, to the anti-arrhythmic properties of K201.


Obtaining the optimal treatment outcome with tazarotene.
Tazarotene topical gel (Tazorac) is a vitamin A derivative and the first topical retinoid to demonstrate therapeutic success in treating plaque-type psoriasis. It has been available in the United States since 1997. Tazarotene offers long-term remission in many patients and may be used in combination with corticosteroids and UVB therapy for even better results. Due to its potency as a vitamin derivative, tazarotene is also associated with irritation in some patients. Patients must be educated about proper application of the drug and realistic expectations for treatment outcome.


Cytotoxicity of autologous Epstein-Barr virus-transformed cells mediated by interleukin-2 dependent, long-term T cell cultures is augmented by beta, but not alpha, recombinant interferon.
The immunomodulatory effect of two highly purified recombinant human interferons (IFN) on T cell-mediated cytotoxicity of autologous Epstein-Barr virus-transformed B cells (EBV-LCL) was assessed. Interferon beta ser, but not alpha 76, potentiated the destruction mediated by interleukin-2 (IL-2) dependent, long-term T cell cultures. The degree of potentiation of specific cytotoxicity was dependent on the concentration of the exogenously added IFN beta ser. In contrast to the potentiation of T cell-mediated cytotoxicity, IFN beta ser and alpha 76 did not modulate the cytotoxic activity of cytotoxic T cell clones that are specifically reactive to autologous EBV-LCL. These results indicate that the selective potentiation of EBV-LCL-reactive T cell-mediated cytotoxicity by IFN beta ser may not be due to a direct IFN effect on the cytotoxic T cells (CTLs) themselves. Rather, our results are consistent with IFN beta ser augmenting cytotoxic T cell reactivity indirectly, possibly via its influence on other immunoregulatory cells. Although the precise mechanism whereby IFN beta ser may potentiate cytotoxicity is not yet defined, the synergistic action of IFN beta ser and IL-2 on long-term CTL cultures offers an alternate means to selectively enhance a desirable cytotoxic response.


Hammerhead redux: does the new structure fit the old biochemical data?
The cleavage rates of 78 hammerhead ribozymes containing structurally conservative chemical modifications were collected from the literature and compared to the recently determined crystal structure of the Schistosoma mansoni hammerhead. With only a few exceptions, the biochemical data were consistent with the structure, indicating that the new structure closely resembles the transition state of the reaction. Since all the biochemical data were collected on minimal hammerheads that have a very different structure, the minimal hammerhead must be dynamic and occasionally adopt the quite different extended structure in order to cleave.


The analysis of fertility quality of life and the influencing factors of patients with repeated implantation failure.
The objective of this study was to investigate the current status of fertility quality of life (QoL) and explore the influencing factors for infertile women with repeated implantation failure (RIF). The sample consisted of 137 infertile women with RIF who were under treatment from January 2019 to December 2019 in the Reproductive Medical Center of Ruijin Hospital, affiliated with Shanghai Jiaotong University School of Medicine in China. A general information questionnaire, FertiQoL scale, perceived social support scale (PSSS), self-rating anxiety scale (SAS), and self-rating depression scale (SDS) were used to analyse the fertility QoL and related factors of RIF patients. The total fertility QoL score of RIF patients was 60.44 ± 11.60. The results of multivariate regression analysis showed that residence, financial difficulties, male infertility, BMI index, depression, and family social support were the main factors that influenced the fertility QoL of RIF patients (adjusted R2 = 0.762). Based on the results of this study, RIF patients' psychological status must be addressed. Corresponding interventions such as building a sound family and social support system, creating a good medical environment and offering diverse health education should be provided to improve the fertility QoL of RIF patients.


Cognitive coping with the threat of rape: vigilance and cognitive avoidance.
Individual differences in women's avoidant and vigilant style in coping with the threat of rape were explored in four studies. In the first study, 97 women read a rape scenario and completed measures of cognitive vigilance and avoidance. They also provided ratings of fear of rape and anticipated coping problems in case of sexual assault. Vigilance was associated with significantly higher levels of fear of rape and anticipation of more severe coping problems. No effects were found for cognitive avoidance. Study 2 replicated these findings with a sample of 275 women. In addition, it showed that high vigilance was associated with significantly more rape-preventive behaviors. Study 3, including 172 women, was an online study on the effect of cognitive coping style on fear of rape, anticipated coping problems, and two behavioral measures of rape avoidance. High vigilance was related to higher levels of fear of rape, anticipation of more severe coping problems, and more rape-preventive behaviors. Finally, Study 4 (N=210) showed that individual differences in cognitive coping style affected rape-related affect and behavior in the absence of a rape scenario, underlining the chronic salience of the threat of rape for women. Vigilance was positively related to fear of rape, rape-avoidance behavior, and anticipated coping problems. In contrast, a negative relationship was found between cognitive avoidance and fear of rape, rape-avoidance strategies, and anticipated coping problems. Across the four studies, no evidence was found for an interactive effect of cognitive avoidance and vigilance, as suggested by the construct of repression versus sensitization. The findings are discussed in the light of previous research on repression-sensitization in coping with threatening information.


Comparative analysis of cleaning ability of two rotary instrument systems: Mtwo and ProTaper® universal. An in vitro scanning electron microscopic study.
This study is to compare the cleaning effectiveness of two Ni-Ti files systems. Thirty single-rooted human teeth were selected and two NiTi rotary systems were used. Group A: canal shaping with ProTaper® Universal (Dentsply Tulsa Dental Specialties, Tulsa, OK) (PTU); Group B: (n=15) canal shaping with Mtwo Ni-Ti instruments (Sweden and Martina, Padova, Italy) and apical finishing with Mtwo Apical Ni-Ti instruments (Sweden and Martina, Padova, Italy). The amount of debris and smear layer were quantified on a basis of a numerical evaluation scale. The data established for scoring the debris and the smear layer was recorded separately and statistically analysed using the Kruskal-Wallis test. No significant differences were found for debris. Mtwo instruments resulted in significantly less smear layer (P less than 0.05) compared with ProTaper® Universal. Under the conditions of this study, Mtwo resulted in significantly less smear layer compared with canal preparation with ProTaper® Universal.


Dependence of the dielectric constant of electrolyte solutions on ionic concentration: A microfield approach.
We present a microfield approach for studying the dependence of the orientational polarization of the water in aqueous electrolyte solutions upon the salt concentration and temperature. The model takes into account the orientation of the solvent dipoles due to the electric field created by ions, and the effect of thermal fluctuations. The model predicts a dielectric functional dependence of the form ɛ(c)=ɛ_{w}-βL(3αc/β),β=ɛ_{w}-ɛ_{ms}, where L is the Langevin function, c is the salt concentration, ɛ_{w} is the dielectric of pure water, ɛ_{ms} is the dielectric of the electrolyte solution at the molten salt limit, and α is the total excess polarization of the ions. The functional form gives a remarkably accurate description of the dielectric constant for a variety of salts and a wide range of concentrations.


Native human autoantibodies targeting GIPC1 identify differential expression in malignant tumors of the breast and ovary.
We have been studying the native humoral immune response to cancer and have isolated a library of fully human autoantibodies to a variety of malignancies. We previously described the isolation and characterization of two fully human monoclonal antibodies, 27.F7 and 27.B1, from breast cancer patients that target the protein known as GIPC1, an accessory PDZ-domain binding protein involved in regulation of G-protein signaling. Human monoclonal antibodies, 27.F7 and 27.B1, to GIPC1 demonstrate specific binding to malignant breast cancer tissue with no reactivity with normal breast tissue. The current study employs cELISA, flow cytometry, Western blot analysis as well as immunocytochemistry, and immunohistochemistry. Data is analyzed statistically with the Fisher one-tail and two-tail tests for two independent samples. By screening several other cancer cell lines with 27.F7 and 27.B1 we found consistently strong staining of other human cancer cell lines including SKOV-3 (an ovarian cancer cell line). To further clarify the association of GIPC1 with breast and ovarian cancer we carefully studied 27.F7 and 27.B1 using immunocytochemical and immunohistochemical techniques. An immunohistochemical study of normal ovarian tissue, benign, borderline and malignant ovarian serous tumors, and different types of breast cancer revealed high expression of GIPC1 protein in neoplastic cells. Interestingly, antibodies 27.F7 and 27.B1 demonstrate differential staining of borderline ovarian tumors. Examination of different types of breast cancer demonstrates that the level of GIPC1 expression depends on tumor invasiveness and displays a higher expression than in benign tumors. The present pilot study demonstrates that the GIPC1 protein is overexpressed in ovarian and breast cancer, which may provide an important diagnostic and prognostic marker and will constitute the basis for further study of the role that this protein plays in malignant diseases. In addition, this study suggests that human monoclonal antibodies 27.F7 and 27.B1 should be further evaluated as potential diagnostic tools.


Addressing Hidden Hunger in School-Aged Children and Adolescents within the Context of the Food System.
Over the past decade, public health advocates and policymakers have grappled with the increasing issue of the double burden of malnutrition. Building on the Sustainable Development Goals and the United Nations Decade of Action on Nutrition, strengthening food systems is paramount to addressing hidden hunger, otherwise known as micronutrient deficiencies, and the provision of healthy, sufficient quality and quantity, affordable, safe, and culturally acceptable food. Using the UNICEF Innocenti Framework on Food Systems for Children and Adolescents as guidance, this review identifies four evidence-based food system strategies to drive improvements in micronutrient deficiencies in low- and middle-income countries in the context of school-aged children and adolescents: agriculture, food supply chains, food environments, and social behavioral change communication. With multiple players and drivers in the picture, strong and reliable oversight from national and local governments is required, through accountability, regulation, and sustained commitment to creating policies and proper infrastructure to support healthy food consumption and limit access to unhealthy food items. Moreover, given the complexity of hidden hunger, a holistic systems approach with a "right to food" lens is required to begin addressing and improving the diets and nutrition of children and adolescents. This involves synergistic and collaborative actions from all actors within the food system, as well as interactions with systems that have the ability to deliver nutrition interventions at scale. These systems include health, water and sanitation, education, and social protection. Only through partnerships and collaboration between all drivers, determinants, and key components of the food system, including its interactions with other global systems, will we be able to appropriately address hidden hunger in school-aged children and adolescents.


An image is worth a thousand words: why nouns tend to dominate verbs in early word learning.
Nouns are generally easier to learn than verbs (e.g., Bornstein, 2005; Bornstein et al., 2004; Gentner, 1982; Maguire, Hirsh-Pasek, & Golinkoff, 2006). Yet, verbs appear in children's earliest vocabularies, creating a seeming paradox. This paper examines one hypothesis about the difference between noun and verb acquisition. Perhaps the advantage nouns have is not a function of grammatical form class but rather related to a word's imageability. Here, word imageability ratings and form class (nouns and verbs) were correlated with age of acquisition according to the MacArthur-Bates Communicative Development Inventory (CDI) (Fenson et al., 1994). CDI age of acquisition was negatively correlated with words' imageability ratings. Further, a word's imageability contributes to the variance of the word's age of acquisition above and beyond form class, suggesting that at the beginning of word learning, imageability might be a driving factor.


Cardiac dilatation index as an indicator of terminal central congestion evaluated using postmortem CT and forensic autopsy data.
Previous studies demonstrated possible application of postmortem quantitative CT data analysis of the heart and lung in situ to investigate terminal cardiopulmonary pathophysiology. The present study analyzed virtual CT morphometric and autopsy data of the heart to investigate terminal central congestion in forensic autopsy cases (n=113, within 3 days postmortem); the virtual total heart weight in situ was estimated using CT morphometry, and the difference from and ratio to the measured weight at autopsy were calculated as indicators of heart blood pooling and the cardiac dilatation index (CDI) before dissection, respectively. There were substantial differences between the estimated heart blood pooling in situ and volume recovered at autopsy, including a characteristic decrease in drowning, alcohol/sedative-hypnotic intoxication and sudden cardiac death (SCD), possibly due to blood redistribution after thoracic dissection. The estimated in situ heart blood pool and CDI values were higher in SCD but lower in fatal hemorrhage and hemopericardium, as well as in acute mechanical asphyxiation and hyperthermia (heatstroke). In addition, there was a significant difference in heart blood pooling between mechanical asphyxiation or drowning and SCD. The CDI was significantly lower in fatal hyperthermia (heatstroke) than in drowning, fatal methamphetamine abuse, alcohol/sedative-hypnotic intoxication and SCD. These findings suggest the usefulness of applying the CDI and postmortem heart blood volume in situ as supplementary indicators of terminal central congestion, especially for investigating deaths from hemorrhage, hemopericardium, hyperthermia (heatstroke) and SCD.


An evaluation of the analgesia induced by morphine gamma-hydroxybutyrate.
Experiments were performed to determine 1) whether synergism existed between morphine and gamma-hydroxybutyrate in the production of analgesia and 2) the effect of each of these agents on pain-induced changes in brain amino acid content in mice. The analgetic ED50 for both agents was determined using hot plate and tail-flick procedures. The combination of one-half the ED50 of each agent produced an effect equivalent to the ED50 of either agent administered alone in the hot plate but not in the tail-flick test. Although both agents produced an unresponsiveness to noxious stimulation, only morphine prevented pain-induced alterations in brain GABA and glutamate levels.


Developing new competencies in healthcare practitioners in the field.
The Life-long Learning concept is one which is appropriate for those who have (or create) the opportunities to develop their competencies once they are in an operational role. All models of healthcare delivery and management are VOLATILE and therefore the way of addressing new competencies cannot be prescriptive or stand still for too long, but the concepts do endure. Learning, in order to 'keep up to date' is very necessary--technology, new clinical practices and interventions, new drug interactions, increased patient demands ... all add to the need to move with the times. This paper addresses some of the issues surrounding this challenge in the domain of informatics in support of healthcare delivery and management.


Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells.
An expression construct containing the cDNA encoding a modified aequorea green fluorescent protein (GFP) ligated to the 5'-end of the rat androgen receptor (AR) cDNA (GFP-AR) was used to study the intracellular dynamics of the receptor movement in living cells. In three different cell lines, ie. PC3, HeLa, and COS1, unliganded GFP-AR was seen mostly in the cytoplasm and rapidly (within 15-60 min) moved to the nuclear compartment after androgen treatment. Upon androgen withdrawal, the labeled AR migrated back to the cytoplasmic compartment and maintained its ability to reenter the nucleus on subsequent exposure to androgen. Under the condition of inhibited protein synthesis by cycloheximide (50 microg/ml), at least four rounds of receptor recycling after androgen treatment and withdrawal were recorded. Two nonandrogenic hormones, 17beta-estradiol and progesterone at higher concentrations (10(-7)/10(-6) M), were able to both transactivate the AR-responsive promoter and translocate the GFP-AR into the nucleus. Similarly, antiandrogenic ligands, cyproterone acetate and casodex, were also capable of translocating the cytoplasmic AR into the nucleus albeit at a slower rate than the androgen 5alpha-dihydrotestosterone (DHT). All AR ligands with transactivation potential, including the mixed agonist/antagonist cyproterone acetate, caused translocation of the GFP-AR into a subnuclear compartment indicated by its punctate intranuclear distribution. However, translocation caused by casodex, a pure antagonist, resulted in a homogeneous nuclear distribution. Subsequent exposure of the casodex-treated cell to DHT rapidly (15-30 min) altered the homogeneous to punctate distribution of the already translocated nuclear AR. When transported into the nucleus either by casodex or by DHT, GFP-AR was resistant to 2 M NaCl extraction, indicating that the homogeneously distributed AR is also associated with the nuclear matrix. Taken together, these results demonstrate that AR requires ligand activation for its nuclear translocation where occupancy by only agonists and partial agonists can direct it to a potentially functional subnuclear location and that one receptor molecule can undertake multiple rounds of hormonal signaling; this indicates that ligand dissociation/inactivation rather than receptor degradation may play a critical role in terminating hormone action.


Urinary excretion of isomers of biliverdin after destruction in vivo of haemoproteins and haemin.
The amount and isomeric composition of urinary biliverdin in rabbits were analysed by h.p.l.c. Physiological values were maintained after the injection of haemin. On the other hand, when haemoglobins from several mammalian species were injected into rabbits, the excretion of biliverdin-IX alpha and biliverdin-IX beta were increased 6-18-fold and 32-66-fold respectively over physiological excretion. Injection of myoglobin resulted in a 44-fold increase in excretion of the IX alpha-isomer. Coupled oxidation with ascorbate of haemoglobin and myoglobin by oxygen produced mainly the IX alpha- and IX beta-isomers from haemoglobin and the IX alpha-isomer from myoglobin. The destruction of part of the haem from injected haemoproteins by non-enzymic chemical degradation would account for the observed respective increases in the excretion of biliverdin isomers. The excretion of biliverdin isomers after the injection of phenylhydrazine into rabbits was similar to that after the injection of haemoglobin.


Predictors of adherence to a structured exercise program and physical activity participation in community dwellers after stroke.
Aim. To investigate predictors of adherence to group-based exercise and physical activity participation among stroke survivors. Methods. 76 stroke survivors participated (mean age 66.7 years). Adherence was the percentage of classes attended over one year. Physical activity was the average pedometer steps/day measured over seven days at the end of the trial. Possible predictors included baseline measures of demographics, health, quality of life, falls, fear of falling, cognition, and physical functioning. Results. Mean class attendance was 60% (SD 29%). Only one variable (slow choice stepping reaction time) was an independent predictor of higher class attendance, explaining 5% of the variance. Participants completed an average of 4,365 steps/day (SD 3350). Those with better physical functioning (choice stepping reaction time, postural sway, maximal balance range, 10-m walk, or 6-min walk) or better quality of life (SF-12 score) took more steps. A model including SF-12, maximal balance range, and 6-min walk accounted for 33% of the variance in average steps/day. Conclusions. The results suggest that better physical functioning and health status are predictors of average steps taken per day in stroke survivors and that predicting adherence to group exercise in this group is difficult.


Arthroscopic optical coherence tomography provides detailed information on articular cartilage lesions in horses.
Arthroscopy enables direct inspection of the articular surface, but provides no information on deeper cartilage layers. Optical coherence tomography (OCT), based on measurement of reflection and backscattering of light, is a diagnostic technique used in cardiovascular surgery and ophthalmology. It provides cross-sectional images at resolutions comparable to that of low-power microscopy. The aim of this study was to determine if OCT is feasible for advanced clinical assessment of lesions in equine articular cartilage during diagnostic arthroscopy. Diagnostic arthroscopy of 36 metacarpophalangeal joints was carried out ex vivo. Of these, 18 joints with varying degrees of cartilage damage were selected, wherein OCT arthroscopy was conducted using an OCT catheter (diameter 0.9 mm) inserted through standard instrument portals. Five sites of interest, occasionally supplemented with other locations where defects were encountered, were arthroscopically graded according to the International Cartilage Repair Society (ICRS) classification system. The same sites were evaluated qualitatively (ICRS classification and morphological description of the lesions) and quantitatively (measurement of cartilage thickness) on OCT images. OCT provided high resolution images of cartilage enabling determination of cartilage thickness. Comparing ICRS grades determined by both arthroscopy and OCT revealed poor agreement. Furthermore, OCT visualised a spectrum of lesions, including cavitation, fibrillation, superficial and deep clefts, erosion, ulceration and fragmentation. In addition, with OCT the arthroscopically inaccessible area between the dorsal MC3 and P1 was reachable in some cases. Arthroscopically-guided OCT provided more detailed and quantitative information on the morphology of articular cartilage lesions than conventional arthroscopy. OCT could therefore improve the diagnostic value of arthroscopy in equine orthopaedic surgery.


The Significance of BRAFV600E Mutation in Thyroid Cancer in Terms of Novel Targeted Therapies - Overview of Current Knowledge and Studies.
About 50% of papillary thyroid cancers, the most common type of all thyroid malignancies, harbor the BRAFV600E mutation. The prognostic value of this mutation is still under debate, but according to many studies, the BRAF mutation significantly downregulates genes involved in the iodine metabolism of tumor follicular cells. This mutation can be also found in some dedifferentiated and anaplastic thyroid cancers, which raises the issue of the selective advantage of novel targeted therapies. The aim of this review is to discuss the significance of the BRAF mutation mostly in radioiodine-refractory thyroid cancers (RR-TC) with respect to recent preclinical and clinical studies reporting the results of different RAF and MEK inhibitors. BRAF mutation detection in progressive RR-TC could play a role in decision-making of targeted therapies in the near future. So far, only multi-kinase inhibitors (sorafenib and lenvatinib) are legally accepted. On the other hand, for patients with disseminated BRAF mutant malignant melanoma or lung cancer, selective treatments with RAF and MEK inhibitors (vemurafenib, dabrafenib, and trametinib) are available. A crucial advantage of these inhibitors in the treatment of thyroid cancer is their ability to restore expression of the genes involved in iodine metabolism in cancer cells that have lost this ability, thus opening the door for radioiodine treatment again. Key words thyroid cancer - BRAF mutation - biological therapy - tyrosine kinase inhibitor - MEK inhibitor The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2018 Accepted: 1. 8. 2018.


Biosignature Preservation Potential in Playa Evaporites: Impacts of Diagenesis and Implications for Mars Exploration.
Assessing biosignature preservation potential (BPP) in ancient habitable environments on Mars is a top NASA priority. We address this goal through the study of Miocene-Pliocene evaporites of the Verde Formation (central Arizona). We assessed the effects of diagenesis on BPP, integrating outcrop-scale observations with six lab analyses: thin-section petrography, X-ray diffraction, Raman spectroscopy, total organic carbon (TOC), electron probe microanalysis (EPMA), and visible to near-infrared (VNIR) reflectance spectroscopy. We recognized five facies and their diagenetic pathways. Two facies included mudstones which contain clusters of displacive growth gypsum (DGG). Early DGG was altered during diagenesis by dissolution forming crystal cavities and later underwent recrystallization, cation substitution, and sulfate dehydration. Another facies was identified by lenticular beds dominated by halite and late diagenetic thenardite (Na2SO4). These pods are overlain by a sequence of interbedded gray and red mudstones which record cyclic oxidation and Fe-oxide cementation. During the Pleistocene, a lacustrine environment developed, accompanied by magnesite cementation of playa mudstones. TOC analyses were used as a proxy for inferring the BPP in each facies. The highest BPP was associated with both red and gray mudstone facies. This study provides a taphonomic framework for playa environments on Earth that record the impacts of diagenesis on BPP, with potential applications to Mars sample return (MSR) missions.


Combining Three Cohorts of World Trade Center Rescue/Recovery Workers for Assessing Cancer Incidence and Mortality.
Three cohorts including the Fire Department of the City of New York (FDNY), the World Trade Center Health Registry (WTCHR), and the General Responder Cohort (GRC), each funded by the World Trade Center Health Program have reported associations between WTC-exposures and cancer. Results have generally been consistent with effect estimates for excess incidence for all cancers ranging from 6 to 14% above background rates. Pooling would increase sample size and de-duplicate cases between the cohorts. However, pooling required time consuming steps: obtaining Institutional Review Board (IRB) approvals and legal agreements from entities involved; establishing an honest broker for managing the data; de-duplicating the pooled cohort files; applying to State Cancer Registries (SCRs) for matched cancer cases; and finalizing analysis data files. Obtaining SCR data use agreements ranged from 6.5 to 114.5 weeks with six states requiring >20 weeks. Records from FDNY (n = 16,221), WTCHR (n = 29,372), and GRC (n = 33,427) were combined de-duplicated resulting in 69,102 unique individuals. Overall, 7894 cancer tumors were matched to the pooled cohort, increasing the number cancers by as much as 58% compared to previous analyses. Pooling resulted in a coherent resource for future research for studies on rare cancers and mortality, with more representative of occupations and WTC- exposure.


Inhibition by pertussis toxin of the activation of Na(+)-dependent uridine transport in dimethyl-sulphoxide-induced HL-60 leukaemia cells.
The effects of pertussis toxin on the Na(+)-dependent transport of uridine were studied in HL-60 leukaemia cells induced to differentiate along the granulocytic or monocytic pathways by dimethyl sulphoxide (DMSO) or phorbol 12-myristate 13-acetate (PMA) respectively. Pertussis toxin at 50 ng/ml completely inhibited the activation of Na(+)-dependent uridine transport and consequently prevented the formation of intracellular pools of free uridine which occurs in HL-60 cells induced to differentiate by DMSO. The inhibition of Na(+)-dependent uridine transport by pertussis toxin in cells exposed to DMSO was associated with a 14-fold decrease in affinity, with no change in Vmax. Pertussis toxin, however, had no effect on Na(+)-dependent uridine transport in PMA-induced HL-60 cells. Furthermore, 500 ng of cholera toxin/ml had no effect on the Na(+)-dependent uptake of uridine in DMSO-treated HL-60 cells. These results suggest that the activation of the Na(+)-dependent transport of uridine in HL-60 cells induced to differentiate along the granulocytic pathway by DMSO is coupled to a pertussis-toxin-sensitive guanine-nucleotide binding protein (G-protein).


Pathway and stability of protein folding.
We describe an experimental approach to the problem of protein folding and stability which measures interaction energies and maps structures of intermediates and transition states during the folding pathway. The strategy is based on two steps. First, protein engineering is used to remove interactions that stabilize defined positions in barnase, the RNAse from Bacillus amyloliquefaciens. The consequent changes in stability are measured from the changes in free energy of unfolding of the protein. Second, each mutation is used as a probe of the structure around the wild-type side chain during the folding process. Kinetic measurements are made on the folding and unfolding of wild-type and mutant proteins. The kinetic and thermodynamic data are combined and analysed to show the role of individual side chains in the stabilization of the folded, transition and intermediate states of the protein. The protein engineering experiments are corroborated by nuclear magnetic resonance studies of hydrogen exchange during the folding process. Folding is a multiphasic process in which alpha-helices and beta-sheet are formed relatively early. Formation of the hydrophobic core by docking helix and sheet is (partly) rate determining. The final steps involve the forming of loops and the capping of the N-termini of helices.


Tracking Bilateral Lower Limb Kinematics of Distance Runners on Treadmill Using a Single Inertial Measurement Unit.
Distance running related injuries are common, and many ailments have been associated with faulty posture. Conventional measurement of running kinematics requires sophisticated motion capture system in laboratory. In this study, we developed a wearable solution to accurately predict lower limb running kinematics using a single inertial measurement unit placed on the left lower leg. The running data collected from participants was used to train a model using long short-term memory (LSTM) neural networks with an inter-subject approach that predicted lower limb kinematics with an average accuracy of 80.2%, 85.8%, and 69.4% for sagittal hip, knee and ankle joint angles respectively for the ipsilateral limb. A comparable accuracy range was observed for the contralateral limb. The average RMSE (root mean squared error) of sagittal hip, knee and ankle were 8.76°, 13.13°, and 9.67° respectively for the ipsilateral limb. Analysis of contralateral limb kinematics was performed. The model established in this study can be used as a monitoring device to track essential running kinematics in natural running environments. Besides, the wearable solution can be an integral part of a real-time gait retraining biofeedback system for injury prevention and rehabilitation.


[Iron deficiency anemia. Modern diagnostic and treatment strategy. Criteria for therapeutic efficacy].
Modern views of epidemiology, etiology and pathogenesis of iron deficiency anemia are considered. Mechanisms of iron metabolism regulation are described based on the most important literature data and the results of the authors' research. The authors present their own and literature clinical experience of using iron-containing drugs with reference to the existing recommendations on the treatment of iron deficiency anemia. Causes of low treatment efficiency are discussed and the ways to address this problem are proposed based on the published results of clinical research.


Food Insecurity and Health Outcomes of Children With Intellectual and Developmental Disabilities in the United States.
We aimed to (a) provide nationally representative estimates of food insecurity (FI) among children with intellectual and developmental disabilities (IDD), and (b) determine the association between FI and four health outcomes (overall health, problem behavior, activities of daily living, functional limitations) in 5,657 children with IDD compared to 1:1 propensity score matched children without IDD. Mixed-effects ordered logistic regression models were used. Children with IDD were more likely to experience FI than children without IDD (43.3% vs. 30.0%, p < 0.001). FI and IDD were independently associated with worse scores on all four health outcomes. Having both FI and IDD further exacerbated the adverse impacts on these health outcomes. The association was stronger among children with moderate-to-severe FI than those with mild FI.


Explainable machine learning identifies multi-omics signatures of muscle response to spaceflight in mice.
The adverse effects of microgravity exposure on mammalian physiology during spaceflight necessitate a deep understanding of the underlying mechanisms to develop effective countermeasures. One such concern is muscle atrophy, which is partly attributed to the dysregulation of calcium levels due to abnormalities in SERCA pump functioning. To identify potential biomarkers for this condition, multi-omics data and physiological data available on the NASA Open Science Data Repository (osdr.nasa.gov) were used, and machine learning methods were employed. Specifically, we used multi-omics (transcriptomic, proteomic, and DNA methylation) data and calcium reuptake data collected from C57BL/6 J mouse soleus and tibialis anterior tissues during several 30+ day-long missions on the international space station. The QLattice symbolic regression algorithm was introduced to generate highly explainable models that predict either experimental conditions or calcium reuptake levels based on multi-omics features. The list of candidate models established by QLattice was used to identify key features contributing to the predictive capability of these models, with Acyp1 and Rps7 proteins found to be the most predictive biomarkers related to the resilience of the tibialis anterior muscle in space. These findings could serve as targets for future interventions aiming to reduce the extent of muscle atrophy during space travel.


Evaluation of a pharmacist-managed amiodarone monitoring program.
Because of the potential for serious adverse effects, patients treated with amiodarone must be carefully screened and routinely monitored for potential liver, thyroid, and pulmonary toxicity. However, laboratory and pulmonary monitoring rates have been found to be substantially lower than recommended in guidelines, including those of the North American Society of Pacing and Electrophysiology (NASPE, 2007). To (a) assess rates of laboratory monitoring of liver, thyroid, and pulmonary function and adverse events in a pharmacist-managed amiodarone monitoring program compared with usual care in an integrated health care system and (b) estimate return on investment (ROI) from this intervention. This retrospective cohort study used clinic and enrollment data to identify those patients in the pharmacist-managed program and usual care who received at least 100 days of amiodarone therapy with the first prescription for amiodarone (index) from June 1, 2007, through May 31, 2009 (index date). Laboratory test monitoring was recorded at baseline (up to 6 months before the index date), from 1-6 months after the index date, 7-12 months after the index date, and at any time during the year (months 1-12). Alanine aminotransferase (ALT) was evaluated for liver function. Thyroid-stimulating hormone (TSH) and, for patients with abnormal TSH ( less than 0.4 micro international units [uIU] per mL or greater than 4.0 uIU per mL), free thyroxine (T4) were evaluated for thyroid function. Rates of pulmonary function testing (PFT) were measured by the diffusion capacity of carbon monoxide tests (DLCO) and annual chest x-rays (CXR); electrocardiograms were not counted. Monitoring rates were compared using Pearson chi-square tests, and logistic regression was used to compare the odds of testing (ALT, TSH, T4, CXR, PFT) between the 2 groups at any time during the year after the index date. Concomitant uses of amiodarone with high-dose statins and of amiodarone with digoxin were compared using Pearson chi-square tests. Hospitalizations and emergency room (ER) visits during the 12-month follow-up period were counted for (a) interstitial lung disease; (b) rhabdomyolysis for patients who received amiodarone with high-dose statins (either lovastatin greater than 40 mg per day or greater than 20 mg per day of simvastatin or atorvastatin); and (c) for patients with abnormal digoxin, ALT, TSH, or T4 levels, if the hospitalization occurred within 2 days of the abnormal laboratory value. There were 2,292 patients who received at least 100 days of amiodarone therapy and met the other inclusion criteria, of whom 181 patients (7.9%) were in the pharmacist-managed group and 2,111 received usual care. There were 90 (49.7%) new amiodarone users in the pharmacist-managed group and 990 (46.9%) in usual care. The 2 groups had similar demographic characteristics except race, with more whites and fewer African Americans, Asians, and Hispanics in usual care. Laboratory monitoring rates for ALT, TSH, and T4 were significantly higher in the pharmacist-managed group than usual care at the first and second 6 months and at baseline for ALT and TSH but not T4. Baseline CXR rates were significantly higher for the pharmacist-managed group than usual care (59.1% vs. 49.3%; P=0.011). Few patients in either group received PFT tests at baseline, 6.6% versus 3.6% (P=0.042). After controlling for covariates (age, gender, race, new vs. continuing use, and comorbidities), pharmacist-managed patients were significantly more likely to have at least 1 ALT test within the year after the index prescription (odds ratio [OR]=3.13, 95% CI=1.12-8.71), as well as a TSH test (OR=8.13, 95% CI=3.27-20.21) and T4 (OR=2.51, 95% CI=1.67-3.75). PFTs were also more likely to be given to these patients (OR=5.89, 95% CI=3.86-8.99). A higher percentage of patients in the pharmacist-managed group than in usual care were taking a high-dose statin during the 12-month follow-up period (47.5% vs. 36.2%, P=0.003), but of those patients, a greater proportion were switched to another statin (14.0% [n=12] vs. 7.5% [n=57], P=0.037) or a lower dose (9.3% [n=8] vs. 3.9% [n=30], P=0.022). Six patients in the usual care group (0.79% of patients on high-dose statins) developed rhabdomyolysis, and 5 (0.24% of all patients in usual care) had an admission for interstitial lung disease. The proportions of patients using amiodarone and digoxin concomitantly were similar in the 2 groups (35.9% vs. 31.3%, P=0.197). Among patients with abnormal laboratory results for ALT, TSH, and T4, or digoxin, there were 2 all-cause hospitalizations and 1 ER visit in the pharmacist-managed group and 34 all-cause hospitalizations and 18 ER visits in the usual care group during the follow-up year. Assuming that all hospitalizations and ER visits incurred in the usual care group were avoid- able, approximately $2.14 could be saved for every dollar spent on the pharmacist-managed amiodarone monitoring program. Pharmacist management of patients treated with amiodarone was associated with improved monitoring of recommended laboratory tests and PFTs.