Identification of socioeconomic groups at increased risk for smoking in European countries: looking beyond educational level.
Educational level is most often used to identify social groups with increased prevalence of smoking. Other indicators of socioeconomic position (SEP) might, however, be equally or even more discriminatory. This study examined the extent to which smoking behavior is related to other socioeconomic indicators in addition to educational level. Data were derived from the European Household Panel. We selected data for 45,765 respondents aged 25-60 years from nine European countries. The association between six different SEP indicators and smoking prevalence was examined using prevalence rate ratios (RRs) estimated through log linear regression analyses. In univariate analyses, most selected SEP indicators were associated with smoking. In multivariate analyses, educational level, occupational class, accumulated wealth (measured by household assets), and housing tenure retained independent effects on smoking (RRs about 1.20). The effects observed for activity status and household income were small and insignificant in nearly all populations. In northern Europe, educational level had the greatest predictive value in the younger age groups; occupational class and housing tenure predicted most of smoking prevalence in the older age groups. The results showed a less pronounced and more varied pattern in southern Europe. Our results indicate that smoking prevalence is related not only to educational level but also to occupational class and measures of accumulated wealth (other than income). These measures should be used in addition to educational level to identify groups at increased risk for smoking.


Estimating the coverage of mental health programmes: a systematic review.
The large treatment gap for people suffering from mental disorders has led to initiatives to scale up mental health services. In order to track progress, estimates of programme coverage, and changes in coverage over time, are needed. Systematic review of mental health programme evaluations that assess coverage, measured either as the proportion of the target population in contact with services (contact coverage) or as the proportion of the target population who receive appropriate and effective care (effective coverage). We performed a search of electronic databases and grey literature up to March 2013 and contacted experts in the field. Methods to estimate the numerator (service utilization) and the denominator (target population) were reviewed to explore methods which could be used in programme evaluations. We identified 15 735 unique records of which only seven met the inclusion criteria. All studies reported contact coverage. No study explicitly measured effective coverage, but it was possible to estimate this for one study. In six studies the numerator of coverage, service utilization, was estimated using routine clinical information, whereas one study used a national community survey. The methods for estimating the denominator, the population in need of services, were more varied and included national prevalence surveys case registers, and estimates from the literature. Very few coverage estimates are available. Coverage could be estimated at low cost by combining routine programme data with population prevalence estimates from national surveys.


Surgical approaches to the pineal region.
The pineal region can harbor highly diverse histologic tumor subtypes. Because optimal therapeutic strategies vary with tumor type, an accurate diagnosis is the foundation of enlightened management decisions. Either stereotactic biopsy or open surgery is essential for securing tissue for pathologic examination. Biopsy has the advantage of ease and minimal invasiveness but is associated with more sampling errors than open surgery. The emergence of endoscopic techniques and stereotactic radiosurgery provide complementary options to improve pineal tumor management, and will assume greater importance in the neurosurgeon's armamentarium.


Spinal projection of spindle afferents of the longissimus lumborum muscles of the cat.
The connections and monosynaptic projections of muscle spindle afferents of individual heads of the longissimus lumborum have been studied in cats by natural stimulation, by electrical stimulation and by spike-triggered averaging from single identified afferents. The spindle afferents were classified by sensitivity to vibration and by the effect of succinylcholine on their response to ramp-and-hold muscle stretches. Axonal conduction and synaptic effects were recorded as field potentials and focal synaptic potentials during systematic exploration of the spinal cord in segments L1 to L4 with extracellular metal microelectrodes, singly and in linear arrays. Ascending branches of afferent axons within the cord had a significantly higher mean conduction velocity (CV: 56.5 m s(-1)) than descending branches (40.8 m s(-1)). The CV of ascending branches was significantly positively correlated with a measure of the strength of intrafusal bag(2) muscle fibre contacts, but not to a measure of bag(1) contacts. Two sites of monosynaptic excitatory projection in the cord were identified, namely to the intermediate region (laminae V, VI and VII) and to ventral horn region (laminae VIII and IX). In tests of 154 single afferents, signs of central projection were detected for 60, providing 122 regions of maximum negative focal synaptic potentials (FSPs) of mean amplitude 7.51 microV. Their longitudinal spacing indicated that axons gave off descending collaterals at intervals of 1.5-3.5 mm. Based on the amplitude of FSPs, the projection of secondary afferents is stronger than that of primaries in the intermediate region and possibly also in the ventral horn region. Evidence is also presented that spindle afferent input from different heads of the longissimus converges into any given spinal segment and that input in one spinal root projects to adjacent segments. It is concluded that the organization of the longissimus monosynaptic spindle input favours relatively tonic and diffuse stretch reflexes.


Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril.
Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.


Choreographing Death: A Social Phenomenology of Medical Aid-in-dying in the United States.
This article draws on ethnographic research on the implementation of Vermont's 2013 medical aid-in-dying (AID) law to explore a fundamental paradox: While public discourse characterizes AID as a mechanism for achieving an individually controlled autonomous death, the medico-legal framework that organizes it enlists social support and cultivates dependencies. Therefore, while patients pursuing AID may avoid certain types of dependency-such as those involved in bodily care-the process requires them to affirm and strengthen other bureaucratic, material, and affective forms. By tracing the social phenomenology of several AID deaths, I illustrate how AID results in distinctive forms of sociality and dependency that require terminally ill people and caregivers to embrace a collaborative stance toward choreographing death. I argue that assisted dying offers an opportunity to resist dominant U.S. cultural narratives that view dependency in purely negative terms and reimagine the relationships between disability, dependency, and care at the end of life.


A flood lamination strategy based on transportation network with time delay.
Over the last few years, the frequency and intensity of floods has become more marked due to the influence of climate change. The engendered problems are related to the safety of goods and persons. These considerations require predictive management that will limit water height downstream. In the literature, numerous works have described flow modeling and management. The work presented in this paper is interested in quantitative management by means of flood expansion areas placed along the river and for which we have size and location. The performance of the management system depends on the time and height of gate opening, which will influence wave mitigation. The proposed management method is based on use of a transportation network with time delay from which the volume of water to be stored is calculated.


Functional synaptic connections made by regenerated retinal ganglion cell axons in the superior colliculus of adult hamsters.
Regenerated synaptic connections in the damaged mammalian visual system were studied in adult hamsters in which retinal ganglion cells (RGCs) regrew their axons through autologous peripheral nerve grafts directed from the stump of the transected optic nerve to the superior colliculus (SC). Unitary responses to illumination of small areas of the visual field were recorded within the superficial laminae of the reinnervated SC 23 to 60 weeks after grafting. Each element of a typical bursting response to light consisted of a terminal potential (TP) (half width 164 +/- 25 microseconds, amplitude up to 171 microV) arising from a regenerated RGC axon terminal arborization, followed at a latency of 268 +/- 63 microseconds by a longer duration negative focal synaptic potential (FSP) (half width 938 +/- 396 msec, amplitude up to 188 microV) reflecting EPSPs in neurons within the terminal field of the regenerated RGC axon. The FSP but not the TP was attenuated in a dose-dependent manner by iontophoretic application of GABA. In some cases spikes arose from FSPs after the first two or three impulses of a train, presumably reflecting summation of EPSPs to threshold for excitation in SC neurons contacted by the regenerated RGC axon terminals. Up to one-third of the area of the SC can be infiltrated by arborizations of the regenerated RGC axons that enter the SC through a nerve graft inserted in the lateral aspect of the SC. These experiments indicate that terminal arborizations of individual regenerated RGC axons can synapse with multiple neurons in the SC and that convergence of inputs from regenerated RGC axons is not required for activation of SC neurons in response to light.


Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors.
The presence of somatic mitochondrial DNA (mtDNA) mutations in cancer cells has been interpreted in controversial ways, ranging from random neutral accumulation of mutations, to positive selection for high pathogenicity, or conversely to purifying selection against high pathogenicity variants as occurs at the population level. Here we evaluated the predicted pathogenicity of somatic mtDNA mutations described in cancer and compare these to the distribution of variations observed in the global human population and all possible protein variations that could occur in human mtDNA. We focus on oncocytic tumors, which are clearly associated with mitochondrial dysfunction. The protein variant pathogenicity was predicted using two computational methods, MutPred and SNPs&GO. The pathogenicity score of the somatic mtDNA variants were significantly higher in oncocytic tumors compared to non-oncocytic tumors. Variations in subunits of Complex I of the electron transfer chain were significantly more common in tumors with the oncocytic phenotype, while variations in Complex V subunits were significantly more common in non-oncocytic tumors. Our results show that the somatic mtDNA mutations reported over all tumors are indistinguishable from a random selection from the set of all possible amino acid variations, and have therefore escaped the effects of purifying selection that act strongly at the population level. We show that the pathogenicity of somatic mtDNA mutations is a determining factor for the oncocytic phenotype. The opposite associations of the Complex I and Complex V variants with the oncocytic and non-oncocytic tumors implies that low mitochondrial membrane potential may play an important role in determining the oncocytic phenotype.


Novel transcatheter therapies for treating tricuspid regurgitation.
Until recently, tricuspid valve (TV) disease has been relatively neglected for a long time, but recently tricuspid regurgitation (TR) has attracted attention. Although the prognosis of patients with these disorders is poor, the high mortality and morbidity associated with TV surgery have resulted in many patients not receiving surgical therapy. Current guidelines recommend that TV surgery should be considered in patients with severe TR who are symptomatic or have progressive right ventricle (RV) dilatation or dysfunction. In the absence of severe RV or left ventricle dysfunction, surgery should be considered in cases of severe pulmonary vascular disease or hypertension; however, it is difficult to assess RV dysfunction. Symptoms of right heart failure are more nonspecific and difficult to diagnose than those of left heart failure. Furthermore, the severity of TR is easily influenced by the use of diuretics. These factors lead to difficulties in patient selection and in determination of optimal timing for surgery. Transcatheter therapies for TR have begun to emerge as an alternative for patients with severe symptomatic TR who are at high-risk for standard surgery. Although initial results from a recent international multicenter registry have demonstrated that transcatheter TV therapy is feasible and safe, its clinical experience is still under development. In the present review, we describe the currently available techniques of transcatheter TV intervention and preliminary clinical results.


Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.
The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.


Emergence and global spread of Listeria monocytogenes main clinical clonal complex.
The bacterial foodborne pathogen Listeria monocytogenes clonal complex 1 (Lm-CC1) is the most prevalent clonal group associated with human listeriosis and is strongly associated with cattle and dairy products. Here, we analyze 2021 isolates collected from 40 countries, covering Lm-CC1 first isolation to present days, to define its evolutionary history and population dynamics. We show that Lm-CC1 spread worldwide from North America following the Industrial Revolution through two waves of expansion, coinciding with the transatlantic livestock trade in the second half of the 19th century and the rapid growth of cattle farming and food industrialization in the 20th century. In sharp contrast to its global spread over the past century, transmission chains are now mostly local, with limited inter- and intra-country spread. This study provides an unprecedented insight into L. monocytogenes phylogeography and population dynamics and highlights the importance of genome analyses for a better control of pathogen transmission.


FoxO, autophagy, and cardiac remodeling.
In response to changes in workload, the heart grows or shrinks. Indeed, the myocardium is capable of robust and rapid structural remodeling. In the setting of normal, physiological demand, the heart responds with hypertrophic growth of individual cardiac myocytes, a process that serves to maintain cardiac output and minimize wall stress. However, disease-related stresses, such as hypertension or myocardial infarction, provoke a series of changes that culminate in heart failure and/or sudden death. At the other end of the spectrum, cardiac unloading, such as occurs with prolonged bed rest or weightlessness, causes the heart to shrink. In recent years, considerable strides have been made in deciphering the molecular and cellular events governing pro- and anti-growth events in the heart. Prominent among these mechanisms are those mediated by FoxO (Forkhead box-containing protein, O subfamily) transcription factors. In many cell types, these proteins are critical regulators of cell size, viability, and metabolism, and their importance in the heart is just emerging. Also in recent years, evidence has emerged for a pivotal role for autophagy, an evolutionarily conserved pathway of lysosomal degradation of damaged proteins and organelles, in cardiac growth and remodeling. Indeed, evidence for activated autophagy has been detected in virtually every form of myocardial disease. Now, it is clear that FoxO is an upstream regulator of both autophagy and the ubiquitin-proteasome system. Here, we discuss recent advances in our understanding of cardiomyocyte autophagy, its governance by FoxO, and the roles each of these plays in cardiac remodeling.


Serodiagnosis of infectious mononucleosis with a bovine erythrocyte glycoprotein.
A glycoprotein from bovine erythrocyte membrane was evaluated in two immunoassays as a reagent for the serodiagnosis of infectious mononucleosis (IM). We previously reported that a partially purified preparation of this glycoprotein, when attached to latex beads, agglutinated in the presence of IM heterophile antibody. In the present study, we used a highly purified form of the glycoprotein both as an agglutinating reagent, covalently bound to latex, and in a solid-phase sandwich-type radioimmunoassay (RIA) for IM antibody detection in a larger population of patients. We tested serum samples from college students with symptoms suggestive of IM with the latex reagent (143 samples) and with the RIA (245 samples). Correlation of these two tests, both with each other and with the classical differentially absorbed, agglutination tests for Paul-Bunnell antibody in IM sera, using fresh sheep or horse cells, was excellent (greater than 97% agreement). The new tests also corresponded in most cases with a rapid, unabsorbed preserved horse erythrocyte slide test. However, in this study of 245 samples, both apparent false-positives (5 samples) and apparent false-negatives (3 samples) were observed with this slide test. In conclusion, we found that the bovine glycoprotein as a reagent can facilitate the diagnosis of IM, giving results comparable to those with erythrocyte agglutination tests on differentially absorbed sera. The advantages are ease and speed of performance (latex test), potential for automation (RIA test), stability and uniformity of the glycoprotein reagent (latex and RIA tests), and most importantly, the ability to use unabsorbed sera (latex and RIA tests).


Verification of cascade optical coherence tomography for freeform optics form metrology.
Freeform optical components enable dramatic advances for optical systems in both performance and packaging. Surface form metrology of manufactured freeform optics remains a challenge and an active area of research. Towards addressing this challenge, we previously reported on a novel architecture, cascade optical coherence tomography (C-OCT), which was validated for its ability of high-precision sag measurement at a given point. Here, we demonstrate freeform surface measurements, enabled by the development of a custom optical-relay-based scanning mechanism and a unique high-speed rotation mechanism. Experimental results on a flat mirror demonstrate an RMS flatness of 14 nm (∼λ/44 at the He-Ne wavelength). Measurement on a freeform mirror is achieved with an RMS residual of 69 nm (∼λ/9). The system-level investigations and validation provide the groundwork for advancing C-OCT as a viable freeform metrology technique.


Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and arterial oxygen saturation at high altitude.
There is a significant genetic influence on arterial oxygen saturation (Sa(O(2))) in high-altitude (HA) residents. It is not known whether this is true of lowlanders ascending to HA. The I allele of the angiotensin-converting enzyme (ACE) gene is associated with low ACE activity and elite endurance performance. An excess of the I allele has also been reported in South American natives living over 3,000 m and among elite HA mountaineers who demonstrate extreme endurance in a hypoxic environment, where maintenance of Sa(O(2)) is crucial to performance. We postulated that the I allele may confer an advantage at HA through genotype-dependent alterations in Sa(O(2)). Rapid ascent (n = 32) and slow ascent groups (n = 40), ascending to approximately 5,000 m over 12.0 and 18.5 days, respectively, had their Sa(O(2)) assessed throughout and compared with their ACE genotype. Resting Sa(O(2)) was independent of the ACE genotype and remained so for the slow ascent group, in whom the fall in Sa(O(2)) with ascent was genotype independent. However, Sa(O(2)) with ascent was significantly associated with the ACE genotype in the rapid ascent group (p = 0.01) with a relatively sustained Sa(O(2)) in the II subjects. These data are the first to report an association of the I allele with the maintenance of Sa(O(2)) at HA.


Determination of the single polyadenylation site of the human pro alpha 1(II) collagen gene.
Several cDNA clones for the human type II procollagen mRNA were isolated from a cartilage cDNA library. Six of the clones containing the longest inserts were subjected to restriction site mapping for alignment. All these six clones extended to the poly A tail. The longest clone, containing a 1470 bp insert, was named pHCAR3. Sequencing of pHCAR3 made it clear that neither of the two canonical AATAAA sequences of the human type II collagen gene is used as the polyadenylation signal. Two 60 bp stretches of high interspecies homology terminating in a hexanucleotide ATTAAA, located 23 nucleotides upstream of the poly A tail, apparently have an important role in determining the single polyadenylation signal for this gene. S1 protection experiments confirmed these observations.


Single-stranded DNA-binding protein hSSB1 is critical for genomic stability.
Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein-protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co-localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences diverse endpoints in the cellular DNA damage response.


Robotic radical prostatectomy in high-risk prostate cancer: current perspectives.
Around 20%-30% of patients diagnosed with prostate cancer (PCa) still have high-risk PCa disease (HRPC) that requires aggressive treatment. Treatment of HRPC is controversial, and multimodality therapy combining surgery, radiation therapy, and androgen deprivation therapy have been suggested. There has been a trend toward performing radical prostatectomy (RP) in HRPC and currently, robot-assisted laparoscopic RP (RARP) has become the most common approach. Number of publications related to robotic surgery in HRPC is limited in the literature. Tissue and Tumor characteristics might be different in HRPC patients compared to low-risk group and increased surgical experience for RARP is needed. Due to the current literature, RARP seems to have similar oncologic outcomes including surgical margin positivity, biochemical recurrence and recurrence-free survival rates, additional cancer therapy needs and lymph node (LN) yields with similar complication rates compared to open surgery in HRPC. In addition, decreased blood loss, lower rates of blood transfusion and shorter duration of hospital stay seem to be the advantages of robotic surgery in this particular patient group. RARP in HRPC patients seems to be safe and technically feasible with good intermediate-term oncologic results, acceptable morbidities, excellent short-term surgical and pathological outcomes and satisfactory functional results.


Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) phase II trial.
We treated 3262 patients with intravenous recombinant tissue plasminogen activator (rt-PA) within four hours of the onset of chest pain thought to be caused by myocardial infarction. Of these patients, 1636 were then randomly assigned to treatment according to an invasive strategy consisting of coronary arteriography 18 to 48 hours after the administration of rt-PA, followed by prophylactic percutaneous transluminal coronary angioplasty (PTCA) if arteriography demonstrated suitable anatomy; 1626 patients were randomly assigned to treatment according to a conservative strategy, as part of which arteriography and PTCA were to be performed only in patients with spontaneous or exercise-induced ischemia. In the group assigned to the invasive strategy, PTCA was attempted in 928 of the 1636 patients (56.7 percent); the procedure was anatomically successful in 93.3 percent. In the group assigned to the conservative strategy, 216 patients (13.3 percent) underwent clinically indicated PTCA within 14 days of the onset of symptoms. Reinfarction or death within 42 days, the primary end point, occurred in 10.9 percent of the group assigned to the invasive strategy and in 9.7 percent of those assigned to the conservative strategy (P not significant). There were no significant differences between the two groups in the ejection fraction at rest or during exercise, either at hospital discharge or six weeks after randomization. Eleven of 582 patients (1.9 percent) who received 150 mg of rt-PA and 15 of 2952 patients (0.5 percent) who received 100 mg of rt-PA had intracranial hemorrhage. A subgroup of 1390 patients who were eligible for short-term intravenous beta-blockade were randomly assigned to receive 15 mg of intravenous metoprolol immediately, followed by oral metoprolol, or oral metoprolol begun on day 6. The ejection fraction and the incidence of death in the two groups were similar during the hospital period. Total mortality within the first 6 days and at 42 days was also similar. However, in the group that received intravenous metoprolol, 16 patients had nonfatal reinfarctions and 107 patients had recurrent ischemic episodes by six days after entry into the study, as compared with 31 and 147 patients, respectively, among those randomly assigned to deferred oral beta-blockade (P = 0.02 and P = 0.005, respectively); the latter comparison was considered statistically significant according to the study criteria.(ABSTRACT TRUNCATED AT 400 WORDS)


The costs associated with sleep symptoms among patients with fibromyalgia.
To assess the costs associated with sleep symptoms among patients with fibromyalgia (FM). Patients reporting physician-diagnosed FM from the National Health and Wellness Survey were categorized into three groups based on the number of sleep symptoms reported: two or more sleep symptoms (n = 1353), one sleep symptom (n = 574) and no sleep symptoms (n = 269). Annual direct and indirect costs were compared among the groups controlling for relevant confounders. After adjusting for demographic and health characteristics, patients with FM with one, two or more sleep symptoms had higher annual physician costs (US$12,328 and US$12,261, respectively) and higher annual emergency room visit costs (US$846 and US$729, respectively) than patients with FM without any sleep symptoms (physician visit costs: US$9845; emergency room visit costs: US$527; all p < 0.05). Similarly, both patients with one (US$18,100) and two or more sleep symptoms (US$18,428) reported higher total indirect costs compared with those without any sleep symptoms (US$14,711; p < 0.05). Among the FM population, sleep symptoms were prevalent and associated with higher direct and indirect costs, suggesting improved management may have long-term cost savings.


Preschool healthcare utilisation related to home oxygen status.
To determine, in prematurely born children who had bronchopulmonary dysplasia (BPD), if respiratory morbidity, healthcare utilisation, and cost of care during the preschool years were influenced by use of supplementary oxygen at home after discharge from the neonatal intensive care unit. Observational study. Four tertiary neonatal intensive care units. 190 children, median gestational age 27 weeks (range 22-31), 70 of whom received supplementary oxygen when discharged home. Review of hospital and general practitioner records together with a parent completed respiratory questionnaire. Healthcare utilisation, cost of care, cough, wheeze, and use of an inhaler. Seventy children had supplementary oxygen at home (home oxygen group), but only one had a continuous requirement for home oxygen beyond 2 years of age. There were no significant differences in the gestational age or birth weight of the home oxygen group compared with the rest of the cohort. However, between 2 and 4 years of age inclusive, the home oxygen group had more outpatient attendances (p = 0.0021) and specialist attendances (p = 0.0023), and, for respiratory problems, required more prescriptions (p<0.0001). Their total cost of care was higher (p<0.0001). In addition, more of the home oxygen group wheezed more than once a week (p = 0.0486) and were more likely to use an inhaler (p<0.0001). Children with BPD who have supplementary oxygen at home after discharge have increased respiratory morbidity and healthcare utilisation in the preschool years.


An opportunity for improving osteoporosis treatment in home health care.
To examine osteoporosis prevention and treatment among home health care (HHC) patients at risk of fragility fracture in a large, Midwestern integrated HHC system. All patients who received HHC services in 2006 were identified. International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes and pharmaceutical data were examined between January 1, 2004 and December 31, 2005 to determine risk status (high vs average) for fragility fracture. Patients with a documented diagnosis of osteoporosis, osteopenia, previous fragility fracture, stroke, or those taking a glucocorticoid were categorized as high risk. Pharmaceutical data (eg, estrogen, bisphosphonates) were obtained during the same 2-year period to determine treatment status. Descriptive statistics documented the proportion at high risk and treatment status. Inferential statistics tested differences in characteristics (age, gender, race, number of comorbidities) among high-risk patients with and without treatment. 2798 patients were seen in HHC during 2006 and had utilization data available in 2004 and 2005. Of these, 754 were categorized as high risk and 2044 as average risk. Approximately one third (34%) of high-risk patients received osteoporosis medication compared to 4% of average risk (P < .0001). We found no treatment differences based on age. Those with higher comorbidity profiles were less likely to receive treatment (P < .0001). Only 34% of HHC patients at high risk for fracture received adequate treatment. Patients with more comorbidities were least likely to receive treatment. Since these individuals are receiving medical and nursing care, an opportunity exists to increase treatment rates for those at greatest risk.


Taste receptors of the gut: emerging roles in health and disease.
Recent progress in unravelling the nutrient-sensing mechanisms in the taste buds of the tongue has triggered studies on the existence and role of chemosensory cells in the gut. Indeed, the gastrointestinal tract is the key interface between food and the human body and can sense basic tastes in much the same way as the tongue, through the use of similar G-protein-coupled taste receptors. These receptors 'taste' the luminal content and transmit signals that regulate nutrient transporter expression and nutrient uptake, and also the release of gut hormones and neurotransmitters involved in the regulation of energy and glucose homeostasis. Hence, they play a prominent role in the communication between the lumen, epithelium, smooth muscle cells, afferent nerve fibres and the brain to trigger adaptive responses that affect gastrointestinal function, food intake and glucose metabolism. This review summarises how sensing of nutrients by taste receptors along the gut plays a key role in the process of digestion, and how disturbances or adaptations of these chemosensory signalling pathways may contribute to the induction or resolution of a number of pathological conditions related to diabetes, obesity, or diet-induced symptom generation in irritable bowel syndrome. Targeting these receptors may represent a promising novel route for the treatment of a number of these diseases.


Single particle maximum likelihood reconstruction from superresolution microscopy images.
Point localization superresolution microscopy enables fluorescently tagged molecules to be imaged beyond the optical diffraction limit, reaching single molecule localization precisions down to a few nanometers. For small objects whose sizes are few times this precision, localization uncertainty prevents the straightforward extraction of a structural model from the reconstructed images. We demonstrate in the present work that this limitation can be overcome at the single particle level, requiring no particle averaging, by using a maximum likelihood reconstruction (MLR) method perfectly suited to the stochastic nature of such superresolution imaging. We validate this method by extracting structural information from both simulated and experimental PALM data of immature virus-like particles of the Human Immunodeficiency Virus (HIV-1). MLR allows us to measure the radii of individual viruses with precision of a few nanometers and confirms the incomplete closure of the viral protein lattice. The quantitative results of our analysis are consistent with previous cryoelectron microscopy characterizations. Our study establishes the framework for a method that can be broadly applied to PALM data to determine the structural parameters for an existing structural model, and is particularly well suited to heterogeneous features due to its single particle implementation.


Global human tissue profiling and protein network analysis reveals distinct levels of transcriptional germline-specificity and identifies target genes for male infertility.
Mammalian spermatogenesis is a process that involves a complex expression program in both somatic and germ cells present in the male gonad. A number of studies have attempted to define the transcriptome of male meiosis and gametogenesis in rodents and primates. Few human transcripts, however, have been associated with testicular somatic cells and germ cells at different post-natal developmental stages and little is known about their level of germline-specificity compared with non-testicular tissues. We quantified human transcripts using GeneChips and a total of 47 biopsies from prepubertal children diagnosed with undescended testis, infertile adult patients whose spermatogenesis is arrested at consecutive stages and fertile control individuals. These results were integrated with data from enriched normal germ cells, non-testicular expression data, phenotype information, predicted regulatory DNA-binding motifs and interactome data. Among 3580 genes for which we found differential transcript concentrations in somatic and germ cells present in human testis, 933 were undetectable in 45 embryonic and adult non-testicular tissues, including many that were corroborated at protein level by published gene annotation data and histological high-throughput protein immunodetection assays. Using motif enrichment analyses, we identified regulatory promoter elements likely involved in germline development. Finally, we constructed a regulatory disease network for human fertility by integrating expression signals, interactome information, phenotypes and functional annotation data. Our results provide broad insight into the post-natal human testicular transcriptome at the level of cell populations and in a global somatic tissular context. Furthermore, they yield clues for genetic causes of male infertility and will facilitate the identification of novel cancer/testis genes as targets for cancer immunotherapies.


Plasticity of DNA methylation in mouse T cell activation and differentiation.
Circulating CD4+ T helper cells are activated through interactions with antigen presenting cells and undergo differentiation into specific T helper cell subsets depending on the type of antigen encountered. In addition, the relative composition of the circulating CD4+ T cell population changes as animals mature with an increased percentage of the population being memory/effector type cells. Here, we report on the highly plastic nature of DNA methylation at the genome-wide level as T cells undergo activation, differentiation and aging. Of particular note were the findings that DNA demethylation occurred rapidly following T cell activation and that all differentiated T cell populations displayed lower levels of global methylation than the non-differentiated population. In addition, T cells from older mice had a reduced level of DNA methylation, most likely explained by the increase in the memory/effector cell fraction. Although significant genome-wide changes were observed, changes in DNA methylation at individual genes were restricted to specific cell types. Changes in the expression of enzymes involved in DNA methylation and demethylation reflect in most cases the changes observed in the genome-wide DNA methylation status. We have demonstrated that DNA methylation is dynamic and flexible in CD4+ T cells and changes rapidly both in a genome-wide and in a targeted manner during T cell activation, differentiation. These changes are accompanied by parallel changes in the enzymatic complexes that have been implicated in DNA methylation and demethylation implying that the balance between these opposing activities may play a role in the maintaining the methylation profile of a given cell type but also allow flexibility in a cell population that needs to respond rapidly to environmental signals.


Sediment Contaminants and Infauna Associated with Recreational Boating Structures in a Multi-Use Marine Park.
Multi-use marine parks achieve conservation through spatial management of activities. Zoning of marine parks in New South Wales, Australia, includes high conservation areas and special purpose zones (SPZ) where maritime activities are concentrated. Although such measures geographically constrain anthropogenic impacts, we have limited understanding of potential ecological effects. We assessed sediment communities and contaminants adjacent to boating infrastructure (boat ramps, jetties and a marina) in a SPZ from the Clyde Estuary in Batemans Marine Park. Metal concentrations and fines content were elevated at boating structures compared to reference sites. Species richness was higher at sites with boating structures, where capitellid polychaetes and nematodes dominated the communities. Changes associated with boating structures were localised and did not extend beyond breakwalls or to reference sites outside the SPZ. The study highlights the benefits of appropriate zoning in a multi-use marine park and the potential to minimise stress on pristine areas through the application of spatial management.


Medical Crowdfunding for Unproven Medical Treatments: Should Gofundme Become a Gatekeeper?
Medical crowdfunding has raised many ethical concerns, among them that it may undermine privacy, widen health inequities, and commodify health care. One motivation for medical crowdfunding has received particular attention among ethicists. Recent studies have shown that many individuals are using crowdfunding to finance access to scientifically unsupported medical treatments. Recently, GoFundMe prohibited campaigns for antivaccination groups on the grounds that they "promote misinformation about vaccines" and for treatment at a German clinic offering unproven cancer treatments due to "the need to make sure people are equipped to make well-informed decisions." GoFundMe has not taken any additional actions to regulate the much larger presence of campaigns seeking to fund unproven medical interventions on the platform. In this article, we make the ethical case for intervention by GoFundMe and other crowdfunding platforms.


Impact of a web-based treatment decision aid for early-stage prostate cancer on shared decision-making and health outcomes: study protocol for a randomized controlled trial.
At an early stage, prostate cancer patients are often eligible for more than one treatment option, or may choose to defer curative treatment. Without a pre-existing superior option, a patient has to weigh his personal preferences against the risks and benefits of each alternative to select the most appropriate treatment. Given this context, in prostate cancer treatment decision-making, it is particularly suitable to follow the principles of shared decision-making (SDM), especially with the support of specific instruments like decision aids (DAs). Although several alternatives are available, present tools are not sufficiently compatible with routine clinical practice. To overcome existing barriers and to stimulate structural implementation of DAs and SDM in clinical practice, a web-based prostate cancer treatment DA was developed to fit clinical workflow. Following the structure of an existing DA, Dutch content was developed, and values clarification methods (VCMs) were added. The aim of this study is to investigate the effect of this DA on (shared) treatment choice and patient-reported outcomes. Nineteen Dutch hospitals are included in a pragmatic, cluster randomized controlled trial, with an intervention and a control arm. In the intervention group, the DA will be offered after diagnosis, and a summary of the patients' preferences, which were identified with the DA, can be discussed by the patient and his clinician during later consultation. Patients in the control group will receive information and decisional support as usual. Results from both groups on decisional conflict, treatment choice and the experience with involvement in the decision-making process are compared. Patients are requested to fill in questionnaires after treatment decision-making but before treatment is started, and 6 and 12 months later. This will allow the development of treatment satisfaction, decisional regret, and quality of life to be monitored. Clinicians from both groups will evaluate their practice of information provision and decisional support. This study will describe a web-based prostate cancer treatment DA with VCMs. The effect of this DA on the decision-making process and subsequent patient reported outcomes will be evaluated. The Netherlands National Trial Register: NTR4554, registration date 1 May 2014.


Perception of face and body expressions using electromyography, pupillometry and gaze measures.
Traditional emotion theories stress the importance of the face in the expression of emotions but bodily expressions are becoming increasingly important as well. In these experiments we tested the hypothesis that similar physiological responses can be evoked by observing emotional face and body signals and that the reaction to angry signals is amplified in anxious individuals. We designed three experiments in which participants categorized emotional expressions from isolated facial and bodily expressions and emotionally congruent and incongruent face-body compounds. Participants' fixations were measured and their pupil size recorded with eye-tracking equipment and their facial reactions measured with electromyography. The results support our prediction that the recognition of a facial expression is improved in the context of a matching posture and importantly, vice versa as well. From their facial expressions, it appeared that observers acted with signs of negative emotionality (increased corrugator activity) to angry and fearful facial expressions and with positive emotionality (increased zygomaticus) to happy facial expressions. What we predicted and found, was that angry and fearful cues from the face or the body, attracted more attention than happy cues. We further observed that responses evoked by angry cues were amplified in individuals with high anxiety scores. In sum, we show that people process bodily expressions of emotion in a similar fashion as facial expressions and that the congruency between the emotional signals from the face and body facilitates the recognition of the emotion.


An Investigation into the Etiological Agents of Swine Dysentery in Australian Pig Herds.
Swine dysentery (SD) is a mucohemorrhagic colitis, classically seen in grower/finisher pigs and caused by infection with the anaerobic intestinal spirochete Brachyspira hyodysenteriae. More recently, however, the newly described species Brachyspira hampsonii and Brachyspira suanatina have been identified as causing SD in North America and/or Europe. Furthermore, there have been occasions where strains of B. hyodysenteriae have been recovered from healthy pigs, including in multiplier herds with high health status. This study investigated whether cases of SD in Australia may be caused by the newly described species; how isolates of B. hyodysenteriae recovered from healthy herds compared to isolates from herds with disease; and how contemporary isolates compare to those recovered in previous decades, including in their plasmid gene content and antimicrobial resistance profiles. In total 1103 fecal and colon samples from pigs in 97 Australian herds were collected and tested. Of the agents of SD only B. hyodysenteriae was found, being present in 34 (35.1%) of the herds, including in 14 of 24 (58%) herds that had been considered to be free of SD. Multilocus sequence typing applied to 96 isolates from 30 herds and to 53 Australian isolates dating from the 1980s through the early 2000s showed that they were diverse, distinct from those reported in other countries, and that the 2014/16 isolates generally were different from those from earlier decades. These findings provided evidence for ongoing evolution of B. hyodysenteriae strains in Australia. In seven of the 20 herds where multiple isolates were available, two to four different sequence types (STs) were identified. Isolates with the same STs also were found in some herds with epidemiological links. Analysis of a block of six plasmid virulence-associated genes showed a lack of consistency between their presence or absence and their origin from herds currently with or without disease; however, significantly fewer isolates from the 2000s and from 2014/16 had this block of genes compared to isolates from the 1980s and 1990s. It is speculated that loss of these genes may have been responsible for the occurrence of milder disease occurring in recent years. In addition, fewer isolates from 2014/16 were susceptible to the antimicrobials lincomycin, and to a lesser extent tiamulin, than those from earlier Australian studies. Four distinct multi-drug resistant strains were identified in five herds, posing a threat to disease control.


Genome-wide RNAi screening identifies genes inhibiting the migration of glioblastoma cells.
Glioblastoma Multiforme (GBM) cells are highly invasive, infiltrating into the surrounding normal brain tissue, making it impossible to completely eradicate GBM tumors by surgery or radiation. Increasing evidence also shows that these migratory cells are highly resistant to cytotoxic reagents, but decreasing their migratory capability can re-sensitize them to chemotherapy. These evidences suggest that the migratory cell population may serve as a better therapeutic target for more effective treatment of GBM. In order to understand the regulatory mechanism underlying the motile phenotype, we carried out a genome-wide RNAi screen for genes inhibiting the migration of GBM cells. The screening identified a total of twenty-five primary hits; seven of them were confirmed by secondary screening. Further study showed that three of the genes, FLNA, KHSRP and HCFC1, also functioned in vivo, and knocking them down caused multifocal tumor in a mouse model. Interestingly, two genes, KHSRP and HCFC1, were also found to be correlated with the clinical outcome of GBM patients. These two genes have not been previously associated with cell migration.


Pharmacy students' opinions on civility and preferences regarding professors.
To determine the types of classroom behavior that pharmacy students consider uncivil, participation in such behaviors, what type of professor and classroom setting they prefer, and changes in these opinions over time. A survey instrument was used to collect data about students' feelings concerning incivility, participation in uncivil behaviors, and preferences concerning classroom experience. Demographic data were used to identify characteristics of student populations and ensure the same students were studied over different time periods. Younger students felt cheating was the most uncivil classroom behavior while older students most disliked cell phone/beeper use. Chewing gum was least offensive for all groups. Students desired that teachers cared about their learning experience, but few would phone a professor at home. Differences in views concerning civility were found among pharmacy students in their first, third, and fourth years, which may indicate that students' beliefs, actions, and preferences change as they progress through the curriculum.


Factors associated with intraocular pressure-induced acute visual field depression.
To determine the factors associated with visual field depression produced by artificial elevation of intraocular pressure (IOP). The visual threshold was determined at 26 locations in the central visual field at a spontaneous IOP, at 30 mm Hg, at 40 mm Hg, and at the IOP immediately following release of the suction cup used to elevate the IOP artificially in 33 subjects with and without glaucoma. The net decrease in threshold sensitivity at each IOP level relative to sensitivity obtained at the spontaneous IOP was calculated (acute visual field depression). Factors potentially influencing the acute visual field depression between subjects were determined with stepwise regression. The reciprocal of ocular perfusion pressure, a clinical measure, was strongly correlated with acute visual field depression (dependent variable), particularly at 40 mm Hg (at 30 mm Hg, r=0.412, P=.02, n=32; and at 40 mm Hg, r=0.813, P<.001, n=33). When a second variable, the diagnosis of glaucoma, was included in the regression at 40 mm Hg, it contributed significantly (partial r=0.650, P<.001, n=26). The degree of glaucomatous damage (vertical cup-disc ratio or baseline Humphrey 24-2 visual field mean deviation) failed to correlate with acute field depression, with or without correction for ocular perfusion pressure. The elevation of IOP produces acute, reversible visual field depression. This depression is largely dependent on the subject's ocular perfusion pressure. The degree of depression is greater in those with glaucoma but is not strictly related to the degree of glaucomatous damage.


Factors associated with school nurses' HPV vaccine attitudes for school-aged youth.
School nurses are at the intersection of the healthcare and school communities, thus, they can be considered opinion leaders in providing health advice - including information about the human papillomavirus (HPV) vaccine - to parents and students. This study examined school nurses' attitudes toward the HPV vaccine based on age, years as a school nurse, geographic location, urban vs. rural work setting, HPV and vaccine knowledge, perception of role as opinion leaders, and school district support in providing health education. Participants (n = 413) were systematically sampled from the National Association of School Nurses' membership and completed a web-based survey. Multiple regression was used to predict positive HPV vaccine attitudes. The model was statistically significant accounting for 50.8% of the variance (F [9, 400] = 45.96, p < .001). Positive attitudes regarding the HPV vaccine were predicted by higher HPV and vaccine knowledge (β = .096, p < .001) and stronger perceptions of role as opinion leaders for the vaccine (β = .665, p < .001). No other variables were found to be statistically significant. These results suggest knowledge is essential in predicting positive attitudes, but not the strongest predictor as perceptions of role as opinion leaders was more crucial in terms of predicting school nurses' positive attitudes towards HPV vaccine. Despite school nurses being seen as champions for adolescent vaccines, they need additional professional development to increase their HPV vaccine knowledge and attitudes to encourage parents and adolescents to consider the uptake of HPV vaccination. To engage school nurses' in promoting HPV vaccine uptake, interventions need to focus on increasing school nurses' perception of their role as opinion leaders for HPV vaccine and knowledge to increase positive attitudes towards HPV vaccination for youth.


A genome-wide association study of antidepressant response in Koreans.
We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.


AGMO Inhibitor Reduces 3T3-L1 Adipogenesis.
Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30-100 µM and 5-20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.


Assessment of Salivary Nitric Oxide Levels in Elite University Athletes in Japan: Findings From a Cross Sectional Study Design.
High-intensity exercise affects the level of salivary nitric oxide (NO) with an impact on oxidative stress such as a reactive nitrogen-oxide species. However, in athletes with high-intensity training, the relationship between salivary NO levels and oxidative stress is yet to be clear. Additionally, the association of salivary NO levels and the common health disorders of athletes is unknown. Thus, the aim of this cross-sectional study was to clarify the relationship between salivary NO levels and oxidative stress, and the health/medical disorders existing in elite class university athletes. In 250 athletes (males, 151 and females, 99) from undergraduate levels of Japanese University, we investigated the relationship between levels of salivary NO and oxidative stress markers: derived reactive oxygen species (d-ROMs) and biological antioxidant potential (BAP), and also examined that whether salivary NO levels are associated with diseases. There were no significant association between the levels of salivary NO and oxidative stress markers (such as d-ROM and BAP). From the questionnaire, asthma was the most prevalent as evident from medical history of the athletes. Additionally, the salivary NO levels were higher (520 ± 43 µmol/L vs. 375 ± 13 µmol/L, P < 0.05) in the asthma group (n = 9) than in the non-asthma group (n = 241). We determined the optimal cut-off value (P = 0.019) of the salivary NO levels for asthma was 425 µmol/L, with a sensitivity of 88.9% and specificity of 61.8% (area under the curve (AUC), 0.73). Our results suggest that the high levels of salivary NO in trained university athletes in Japan may potentially predict asthma. And this salivary NO level is not associated with markers of oxidative stress and existing diseases in athletes studied here.


Fast tracking intensive care units and operation rooms during the COVID-19 pandemic in resource limited settings.
The ongoing pandemic of COVID-19 has affected more than 43 million people all over the world with about 280000 deaths worldwide at the time of writing this article The outcome of this pandemic is impossible to predict at the present time as the numbers of both, infected patients and those dying of the disease are increasing on a daily basis. China, Italy, France, Spain, Germany, United Kingdom, and USA are the worst affected countries. All these countries have robust health care systems but despite this there has been a huge shortage of health care facilities especially intensive care beds in these countries. A country like India has different challenges as far as medical care during this pandemic is concerned. The need of the hour is to improve the health care system as a whole. In the present pandemic this involves setting up of patients screening facilities for the disease, enhancing the number of hospital beds, setting up of dedicated high dependency units, intensive care units and operation theatres for COVID positive patients. The present article describes in brief the way this can be done in a short time.


Changing hospital practices to increase the duration of breastfeeding.
To change the breastfeeding policy in a university teaching hospital in accord with the Ten Steps to Successful Breastfeeding of the United Nations Children's Fund and World Health Organization and to assess the impact of hospital practices on the duration of breastfeeding. One hundred ninety-two and 392 postpartum women in a maternity ward were interviewed in 1990 and 1993, respectively, regarding how they were feeding their infants and feeding practices in the hospital. Between these two periods, the hospital infant-feeding policy was reviewed and revised in accord with the Ten Steps. Two hundred seventy of the mothers interviewed in 1993 were interviewed again when their infants were 4 months old regarding the duration of full and partial breastfeeding. By 1993, more newborns were put to the breast in the first hour of life (63.2% vs 24.8%); fewer breastfed infants were fed foods other than breast milk (27.9% vs 46.7%); and more mothers received breastfeeding guidance from hospital staff (81.9% vs 61.3%). The duration of breastfeeding in 1993 was longer for women who did not receive formula in the hospital, who were not given discharge packs containing formula and/or coupons, and who roomed-in more than 60% of the time. These associations persisted after controlling for confounding. Infant-feeding policies and practices are amenable to change, and policies such as the Baby-Friendly Hospital Initiative may contribute to an increase in the duration of breastfeeding.


A nationwide analysis of re-operation after kidney transplant.
We aimed to report the rate and short-term outcomes of patients undergoing re-operation following kidney transplant in the U.S. The Nationwide Inpatient Sample (NIS) database was used to examine the clinical data of patients undergoing kidney transplant and re-operation during same the hospitalization from 2002-2012. Multivariate regression analysis was performed to compare outcomes of patients with and without re-operation. We sampled a total of 35 058 patients who underwent kidney transplant. Of these, 770 (2.2%) had re-operation during the same hospitalization. Re-operation was associated with a significant increase in mortality (30.4% vs. 3%; adjusted odds ratio [AOR] 4.62; p<0.01), mean total hospital charges ($249 425 vs. $145 403; p<0.01), and mean hospitalization length of patients (18 vs. 7 days; p<0.01). The most common day of re-operation was postoperative Day 1. Hemorrhagic complication (64.2%) was the most common reason for re-operation, followed by urinary tract complications (9.9%) and vascular complications (3.6%). Preoperative coagulopathy (AOR 3.35; p<0.01) was the strongest predictor of need for re-operation, hemorrhagic complications (AOR 3.08; p<0.01), and vascular complications (AOR 2.50; p<0.01). Also, hypertension (AOR 1.26; p<0.01) and peripheral vascular disorders (AOR 1.25; p=0.03) had associations with hemorrhagic complications. Re-operation after kidney transplant most commonly occurs on postoperative Day 1 and occurs in 2.2% of cases. It is associated with significantly increased mortality, hospitalization length, and total hospital charges. Hemorrhage is the most common complication. Preoperative coagulopathy is the strongest factor predicting the need for re-operation, vascular complications, and hemorrhagic complications.


Production of embryonic and fetal-like red blood cells from human induced pluripotent stem cells.
We have previously shown that human embryonic stem cells can be differentiated into embryonic and fetal type of red blood cells that sequentially express three types of hemoglobins recapitulating early human erythropoiesis. We report here that we have produced iPS from three somatic cell types: adult skin fibroblasts as well as embryonic and fetal mesenchymal stem cells. We show that regardless of the age of the donor cells, the iPS produced are fully reprogrammed into a pluripotent state that is undistinguishable from that of hESCs by low and high-throughput expression and detailed analysis of globin expression patterns by HPLC. This suggests that reprogramming with the four original Yamanaka pluripotency factors leads to complete erasure of all functionally important epigenetic marks associated with erythroid differentiation regardless of the age or the tissue type of the donor cells, at least as detected in these assays. The ability to produce large number of erythroid cells with embryonic and fetal-like characteristics is likely to have many translational applications.


THE HIGH COST OF LOW VALUE CARE.
The main focus of this study is bridging the "evidence gap" between frontline decision-making in health care and the actual evidence, with the hope of reducing unnecessary diagnostic testing and treatments. From our work in pulmonary embolism (PE) and over ordering of computed tomography pulmonary angiography, we integrated the highly validated Wells' criteria into the electronic health record at two of our major academic tertiary hospitals. The Wells' clinical decision support tool triggered for patients being evaluated for PE and therefore determined a patients' pretest probability for having a PE. There were 12,759 patient visits representing 11,836 patients, 51% had no D-dimer, 41% had a negative D-dimer, and 9% had a positive D-dimer. Our study gave us an opportunity to determine which patients were very low probabilities for PE, with no need for further testing.


Medical students' evaluations of curriculum innovations at ten North American medical schools.
The authors recount medical educators' calls in the 1980s to reform general professional medical education by supplementing the standard lecture-lab biomedical curriculum with new biopsychosocial pedagogy and emphases. They then report selected medical students' evaluations of corresponding curriculum reform efforts that were in place by 1990 at eight U.S. and two Canadian medical schools known for being innovators. From interviews conducted in 1992-93 with a group of three to nine medical students at each school, the authors report two findings. First, the students' positive evaluations converged: at all ten schools they invariably appreciated curriculum reform efforts of any sort that encouraged individuation, connection, and diversity. Second, the students' negative evaluations diverged: specifically, those enrolled at the smaller schools with more distinctly teaching-service missions, schools where innovation was more wholesale, even extending across the entire curriculum, objected to curricula that provide too much in the way of new pedagogy and emphases and too little standard instruction; conversely, those enrolled at the larger schools with more comprehensive teaching-research-service missions, schools where innovation must be more piecemeal, often course by course, objected to curricula that provided too little in the way of new pedagogy and emphases and too much standard instruction. Suggesting that the smaller schools studied may be over-supplementing--and the larger schools under-supplementing--standard biomedical with new biopsychosocial pedagogy and emphases, the authors make two recommendations: first, that medical educators at schools of every size and sort contemplating curriculum reform of any scope recognize that medical students invariably appreciate educational opportunities for individuation, connection, and diversity; second, that the same educators, but especially those at the smaller teaching-service medical schools considering more wholesale innovation, recognize that medical students must soon compete for residencies and posts in a rapidly changing health care environment and thus want effective instruction per se, whether it be delivered by a lecturer or a tutor, in class or in tutorial, on a ward or in a clinic. That would be the meaning, they conclude, of student-centered learning, however it were tailored.


A Systematic Review of Physical Activity Interventions in Individuals with Binge Eating Disorders.
Our systematic review aims to assess the overall evidence available in the literature regarding the role of physical activity (PA) in individuals with binge eating disorder (BED) and better understand the potential underlying mechanisms of action. Currently, the most effective and well-established psychological treatment for BED is cognitive behavioral therapy (CBT) with a remission rate around 80%. CBT is sometimes combined with pharmacotherapy targeting comorbidities associated with BED, such as obesity and depression. Another avenue of treatment that has been less studied is PA. It has been suggested that PA addresses the underlying mechanisms of BED and, thus, increases treatment efficiency. This systematic review provides additional knowledge concerning the benefits of PA in the treatment of individuals with BED including reduction of binge eating (BE) episodes and improvement in other associated comorbidities. Potential mechanisms of action of PA include neurochemical alterations affecting the reward system, reduction of negative affect, and its anorexigenic effects.


Nonconvex Sparse Regularization for Deep Neural Networks and Its Optimality.
Recent theoretical studies proved that deep neural network (DNN) estimators obtained by minimizing empirical risk with a certain sparsity constraint can attain optimal convergence rates for regression and classification problems. However, the sparsity constraint requires knowing certain properties of the true model, which are not available in practice. Moreover, computation is difficult due to the discrete nature of the sparsity constraint. In this letter, we propose a novel penalized estimation method for sparse DNNs that resolves the problems existing in the sparsity constraint. We establish an oracle inequality for the excess risk of the proposed sparse-penalized DNN estimator and derive convergence rates for several learning tasks. In particular, we prove that the sparse-penalized estimator can adaptively attain minimax convergence rates for various nonparametric regression problems. For computation, we develop an efficient gradient-based optimization algorithm that guarantees the monotonic reduction of the objective function.


Peak longitudinal strain most accurately reflects myocardial segmental viability following acute myocardial infarction - an experimental study in open-chest pigs.
The extension and the transmurality of the myocardial infarction are of high predictive value for clinical outcome. The aim of the study was to characterize the ability of longitudinal, circumferential and radial strain measured by 2-dimensional speckle tracking echocardiography (2D-STE) to predict the extent of necrosis in myocardial segments following acute myocardial infarction and to separate transmural necrotic segments from non-transmural necrotic segments in a full 18-segment porcine model. 2D-STE strain was assessed in long- and short-axis following myocardial infarction in ten open-chest anesthetized pigs. Strain was defined according to systolic peak values. In segments displaying both negative and positive peaks, only the peak with the highest absolute value was utilized. Necrosis was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and expressed as percent of each myocardial segment. Significant correlations were found between the extension of necrosis and all measured parameters of myocardial deformation (p < 0.001), but was stronger for longitudinal strain (r(2) = 0.52) than circumferential strain (r(2) = 0.38) and radial strain (r(2) = 0.23). The area under the receiver operator characteristic curve (AUC) for separating transmural necrotic segments (>50% necrosis) from predominantly viable segments (0-50% necrosis) was significantly larger for longitudinal strain (AUC = 0.98, CI = 0.97-1.00) when compared with circumferential strain (AUC = 0.91, CI = 0.84-0.97, p < 0.05) and radial strain (AUC = 0.90, CI = 0.83 - 0.96, p < 0.01), indicating a stronger ability of longitudinal strain to identify segments with transmural necrosis. Peak strain values derived from 2D-STE correlate well with the extent of necrosis in myocardial segments following acute myocardial infarction. Longitudinal strain most accurately reflects myocardial segmental viability in this setting.


Feed- and feed additives-related aspects of gut health and development in weanling pigs.
The development of new/different management and feeding strategies to stimulate gut development and health in newly-weaned pigs, in order to improve growth performance while minimizing the use of antimicrobial compounds such as antibiotic growth promotants (AGP) and heavy mineral compounds, is essential for the long-term sustainability of the pig industry. Factors including the sub-optimal intake of nutrients and energy, inappropriate microbiota biomass and (or) balance, immature and compromised immune function, and psychosomatic factors caused by weaning can compromise both the efficiency of digestion and absorption and intestinal barrier function through mucosal damage and alteration of tight junction integrity. As a consequence, pigs at weaning are highly susceptible to pathogenic enteric conditions such as post-weaning diarrhea that may be caused by serotypes of enterotoxigenic Escherichia coli. Many dietary components, e.g., protein, fiber, feed additives and minerals, are known to influence microbial growth in the gastrointestinal tract that in turn can impact upon pig growth and health, although the relationships between these are sometimes not necessarily apparent or obvious. In a world climate of increased scrutiny over the use of antibiotics per se in pig production, certain feed additives are seen as alternatives/replacements to antibiotics, and have evolved in some cases to have important roles in everyday commercial pig nutrition. Nevertheless and in general, there remains inconsistency and variability in the efficacy of some feed additives and in cases of severe disease outbreaks, for example, therapeutic antibiotics and/or heavy minerals such as zinc oxide (ZnO) are generally relied upon. If feed ingredients and (or) feed additives are to be used with greater regularity and reliability, then it is necessary to better understand the mechanisms whereby antibiotics and minerals such as ZnO influence animal physiology, in conjunction with the use of appropriate challenge models and in vitro and in vivo techniques.


Partial replacement of saturated fatty acids with almonds or walnuts lowers total plasma cholesterol and low-density-lipoprotein cholesterol.
Sixteen normolipidemic male volunteers aged 41 +/- 9 y (mean +/- SD) consumed a diet providing 36% of energy as fat (92 g fat/d) for 9 wk. A daily supplement of nuts (providing half of the total fat intake) was provided against a common background diet. In the first 3-wk period the background diet was supplemented with raw peanuts (50 g/d), coconut cubes (40 g/d), and a coconut confectionary bar (50 g/d), designed to provide 47 g fat with a ratio of polyunsaturated to monounsaturated to saturated fatty acids (P:M:S) to match the Australian diet (reference diet). During the following 3 wk the background diet was supplemented with monounsaturated fatty acid-rich raw almonds (84 g/d), equivalent to 46 g fat, and during the final 3-wk period the background diet was supplemented with polyunsaturated fatty acid-rich walnuts (68 g/d), equivalent to 46 g fat. Compared with the reference diet there were significant reductions in total and LDL cholesterol, 7% and 10%, respectively, after supplementation with almonds, and 5% and 9%, respectively, after supplementation with walnuts.


Current strategies and applications of tissue engineering in dentistry--a review Part 2.
The three main key elements used in tissue engineering are the stem cells, morphogens and the scaffolds that, under a conductive external influence (environment) combine in the engineering of tissues. Part 1 of this two-part review article described in detail the various stem cells, morphogens and scaffolds that can be used in tissue engineering. This second article describes the various ways in which these three key elements can be used to engineer biological tissues. A number of strategies and technologies (Figure 1) such as, stem cell therapy, gene therapy, guided tissue regeneration, self-assembling systems, etc have been proposed. The field of tissue engineering has recently shown promising results and good future prospects in dentistry for the development of restorations to replace lost tooth structure with a functional replacement.


Systematic review and meta-analysis of prognostic factors of acute exacerbation of idiopathic pulmonary fibrosis.
To clarify prognostic factors of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). A systematic review and meta-analysis. Medline, Embase and Science Citation Index Expanded were searched from 2002 through 1 March 2019. The review included primary studies addressing the association between the outcomes such as all-cause mortality of AE of IPF and its potential prognostic factors, which were designated as any clinical information related to the outcomes. Two reviewers extracted relevant data independently and assessed risk of bias. Univariate results were pooled using a random-effect model if at least three studies were available. Prognostic factors were determined based on significant and consistent results on both univariate and multivariate analyses in the majority of studies. Out of a total of 6763 articles retrieved, 37 were eligible and 31 potential prognostic factors for all-cause mortality were selected. Each study was subject to certain methodological shortcomings. The following five factors were statistically significant by a meta-analysis of univariate results, which was confirmed by multivariate analysis, that is, Acute Physiology and Chronic Health Evaluation (APACHE) II score (HR 1.10, 1.01 to 1.19), partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio (ORs 0.99 in two studies and HRs 0.31 and 0.99 in two studies, respectively), lactate dehydrogenase (LDH) (HRs 1.002, 1.003, 1.01 and 1.02), white blood cell (WBC) count (OR 1.38, 1.04 to 1.83) and oxygen therapy before AE (HRs 3.68, 1.05 to 12.9 and 2.34, 1.04 to 5.28) (multivariate analysis, 95% CI). APACHE II score, PaO2/FiO2 ratio, LDH, WBC count and oxygen therapy before AE were deemed as prognostic factors of AE of IPF. Although there are some methodological limitations in this study, these findings are reliable due to consistent results by both univariate and multivariate analyses. CRD42018106172.


Multiple lines of evidence for the origin of domesticated chili pepper, Capsicum annuum, in Mexico.
The study of crop origins has traditionally involved identifying geographic areas of high morphological diversity, sampling populations of wild progenitor species, and the archaeological retrieval of macroremains. Recent investigations have added identification of plant microremains (phytoliths, pollen, and starch grains), biochemical and molecular genetic approaches, and dating through (14)C accelerator mass spectrometry. We investigate the origin of domesticated chili pepper, Capsicum annuum, by combining two approaches, species distribution modeling and paleobiolinguistics, with microsatellite genetic data and archaeobotanical data. The combination of these four lines of evidence yields consensus models indicating that domestication of C. annuum could have occurred in one or both of two areas of Mexico: northeastern Mexico and central-east Mexico. Genetic evidence shows more support for the more northern location, but jointly all four lines of evidence support central-east Mexico, where preceramic macroremains of chili pepper have been recovered in the Valley of Tehuacán. Located just to the east of this valley is the center of phylogenetic diversity of Proto-Otomanguean, a language spoken in mid-Holocene times and the oldest protolanguage for which a word for chili pepper reconstructs based on historical linguistics. For many crops, especially those that do not have a strong archaeobotanical record or phylogeographic pattern, it is difficult to precisely identify the time and place of their origin. Our results for chili pepper show that expressing all data in similar distance terms allows for combining contrasting lines of evidence and locating the region(s) where cultivation and domestication of a crop began.


Investigation of secreted protein transcripts as early biomarkers for type 1 diabetes in the mouse model.
Type 1 diabetes (T1D) represents a serious health burden in the world, complicated by the fact that disease onset can be preceded by a long time period without evident clinical signs. It would be then of critical importance to detect the disease in its early stages. In this direction, we seek here to identify early preinflammatory markers for autoimmune diabetes, mining our previously reported transcriptome data relevant to distinct early sub-phenotypes in the NOD mouse, associated with early insulin autoantibodies (E-IAA). More specifically we focus on secreted or transmembrane protein transcripts, identifying in this category 71 differentially expressed transcripts which are regulated at the early preinflammatory stages of T1D in the pancreatic lymph nodes (PLN). Following the expression patterns of these 71 transcripts, correspondence analysis (a multivariate analysis method) reveals a clear-cut segregation of the individual samples according to the early subphenotype used. Thus the 71 transcripts coding for secreted proteins constitute a candidate-set of predictive biomarkers for the development of autoimmune damage of the β cells of the pancreas. The majority of these genes have human orthologs and accordingly they represent potential candidate biomarkers for the human disease. In addition, for predictive purposes, the analysis reveals the possibility to reduce significantly the size of the candidate-set in practice, with various genes displaying identical expression profiles.


Psychosocial factors at work and inflammatory markers: protocol for a systematic review and meta-analysis.
Chronic inflammation may be a mediator for the development of cardiovascular disease (CVD), metabolic diseases and psychotic and neurodegenerative disorders. Meta-analytic associations between work-related psychosocial factors and inflammatory markers have shown that work-related psychosocial factors could affect the flexibility and balance of the immune system. However, few systematic reviews or meta-analyses have investigated the association between work-related psychosocial factors and inflammatory markers. Based on prospective studies, the present investigation will conduct a comprehensive systematic review and meta-analysis of the association between work-related psychosocial factors and inflammatory markers. The systematic review and meta-analysis will include published studies identified from electronic databases (PubMed, EMBASE, PsycINFO, PsycARTICLES, Web of Science and Japan Medical Abstracts Society) according to recommendations of the Meta-analysis of Observational Studies in Epidemiology guideline. Inclusion criteria are studies that: examined associations between work-related psychosocial factors and increased inflammatory markers; used longitudinal or prospective cohort designs; were conducted among workers; provided sufficient data for calculating ORs or relative risk with 95% CIs; were published as original articles in English or Japanese; and were published up to the end of 2017. Study selection, data extraction, quality assessment and statistical syntheses will be conducted by 14 investigators. Any inconsistencies or disagreements will be resolved through discussion. The quality of studies will be evaluated using the Risk of Bias Assessment Tool for Non-randomized Studies. The investigation study will be based on published studies, so ethics approval is not required. The results of this study will be submitted for publication in a scientific peer-reviewed journal. The findings may be useful for assessing risk factors for increased inflammatory markers in the workplace and determining future approaches for preventing CVD, metabolic diseases and psychotic and neurodegenerative disorders. CRD42018081553.


High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease.
The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization. HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.


The classification of diabetes by clinical and C-peptide criteria. A prospective population-based study.
To evaluate both the concordance in the classification of diabetes by clinical and C-peptide criteria and, prospectively, the consistency of the classification by C-peptide. Individuals with diabetes who were enlisted in the prospective epidemiological study of diabetic neuropathy (Rochester Diabetic Neuropathy Study [RDNS]) were classified clinically by National Diabetes Data Group (NDDG) criteria to IDDM and NIDDM at entry to the study. In addition, C-peptide response to 1 mg glucagon was measured at entry for the classification to IDDM (basal C-peptide, < 0.17 pmol/ml; increment above basal, < 0.07 pmol/ml) and NIDDM (all other responses) and for concordance with the clinical classification made. The consistency of the C-peptide response was assessed every 2 years for up to 8 years. Among 346 individuals with diabetes, 84 were classified as IDDM and 262 as NIDDM by clinical algorithm. COncordance with the C-peptide response occurred in 89% of the patients and remained consistent during 8 years of follow-up. Among the 37 patients with discordant clinical and C-peptide classification, those considered clinically to have NIDDM had a consistent IDDM C-peptide response during follow-up, and most of those considered to have IDDM clinically eventually showed an IDDM C-peptide response during follow-up. Clinical criteria for the classification of diabetes are highly correlated with the assessment of insulin secretory reserve. A small number of individuals considered to have NIDDM clinically or by C-peptide have or develop an IDDM peptide response.


A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279.
It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma (gamma)-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10(5) gravitational radii.


Impact of joint contractures on functioning and social participation in older individuals--development of a standard set (JointConFunctionSet): study protocol.
Joint contractures are frequent in older individuals in geriatric care settings. Even though they are used as indicator of quality of care, there is neither a common standard to describe functioning and disability in patients nor an established standardized assessment to describe and quantify the impact of joint contractures on patients' functioning. Thus, the aim of our study is (1) to develop a standard set for the assessment of the impact of joint contractures on functioning and social participation in older individuals and (2) to develop and validate a standardized assessment instrument for describing and quantifying the impact of joint contractures on the individuals' functioning. The standard set for joint contractures integrate the perspectives of all potentially relevant user groups, from the affected individuals to clinicians and researchers. The development of this set follows the methodology to develop an International Classification of Functioning Disability and Health (ICF) Core Set and involves a formal decision-making and consensus process. Evidence from four preparatory studies will be integrated including qualitative interviews with patients, a systematic review of the literature, a survey with health professionals, and a cross sectional study with patients affected by joint contractures. The assessment instrument will be developed using item-response-theory models. The instrument will be validated. The standard set for joint contractures will provide a list of aspects of functioning and health most relevant for older individuals in geriatric care settings with joint contractures. This list will describe body functions, body structures, activities and participation and related environmental factors. This standard set will define what aspects of functioning should be assessed in individuals with joint contractures and will be the basis of the new assessment instrument to evaluate the impact of joint contractures on functioning and social participation.


Transcriptional enhancement of Smn levels in motoneurons is crucial for proper axon morphology in zebrafish.
An unresolved mystery in the field of spinal muscular atrophy (SMA) is why a reduction of the ubiquitously expressed Smn protein causes defects mostly in motoneurons. We addressed the possibility that this restricted vulnerability stems from elevated Smn expression in motoneurons. To explore this, we established an ex vivo zebrafish culture system of GFP-marked motoneurons to quantitatively measure Smn protein and smn mRNA levels as well as promoter activity in motoneurons versus other cell types. Importantly, we uncovered that Smn levels are elevated in motoneurons by means of transcriptional activation. In addition, we identified the ETS family transcription factor Etv5b to be responsible for increased smn transcription in motoneurons. Moreover, we established that the additional supply of Smn protein in motoneurons is necessary for proper axonogenesis in a cell-autonomous manner. These findings demonstrate the reliance of motoneurons on more Smn, thereby adding a novel piece of evidence for their increased vulnerability under SMA conditions.


Anthocyanins Delay Ageing-Related Degenerative Changes in the Liver.
Liver ageing is a significant risk factor for chronic liver diseases. Anthocyanin is a food additive that has previously shown efficacy in increasing longevity. Here, we tested whether anthocyanins could protect young mice from accelerated ageing of the liver. Kunming mice were injected with D-galactose to accelerate ageing and were given 20 or 40 mg/kg anthocyanins as an intervention. After eight weeks, whole liver function and structure were evaluated, and the expression levels of genes involved in the DNA damage signalling pathway were assessed by Western blot analysis. Anthocyanins delayed the reduction of the liver index (p < 0.05), hepatic tissue injury and fibrosis. Anthocyanins also maintained the stability of the redox system (GSH-PX, T-SOD and MDA) in plasma and liver structures (p < 0.001) and reduced the levels of inflammatory factors (IL-1, IL-6 and TNF-α) in the liver (p < 0.05). Moreover, the expression levels of sensors (ATM and ATR), mediators (H2AX and γ-H2AX) and effectors (Chk1, Chk2, p53 and p-p53) in the DNA damage signalling pathway were all reduced. Anthocyanins could be widely used in the field of health products to slow ageing-related deterioration of liver function and structure by inhibiting DNA damage.