Does repeated palpation-digitization of pelvic landmarks for measurement of innominate motion introduce a systematic error?--A psychometric investigation.
Palpation-digitization technique for measurement of innominate motion involves repeated manual palpation-digitization of pelvic landmarks, which could introduce a systematic variation between subsequent trials and thereby influence final innominate angular measurement. The aim of this study is to quantify the effect of repeated palpation-digitization errors on overall variability of innominate vector length measurements; and to determine if there is a systematic variation between subsequent repeated trials. A single group repeated measures study, using four testers and fourteen healthy participants, was conducted. Four pelvic landmarks, left and right posterior superior iliac spine and anterior superior iliac spine, were palpated and digitized using 3D digitizing stylus of Polhemus electromagnetic tracking device, for ten consecutive trials by each tester in their random order. The ten individual trials of innominate vector lengths measured by each tester for each participant were used for the analysis. Repeated measures ANOVA demonstrated a very small effect of repeated trial factor (≤0.66%) as well as error component (≤0.32%) on innominate vector length variability. Further, residual versus order plots demonstrated a random pattern of errors across zero; thus indicating no systematic variation between subsequent trials of innominate vector length measurements.


Recent progress in the understanding of B-cell functions in autoimmunity.
Our early concepts of the normal role of B cells in immunity focused on their ability to produce antibodies (Ab) and in the case of autoimmune diseases autoAbs, some of which were pathogenic. Over the past 10 years, it has became apparent that B cells display a variety of characteristics, other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating T-cell subsets and dendritic cell (DC) function through cytokine production, and in activation of T cells. Receptors editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Transgenic animal models have now shown that B cells are necessary for many autoimmune diseases although their Ab products are not required in some cases. Negative signalling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domain-containing protein tyrosine phosphatase-1 has also been documented. In fact, we have now reached a new era whereby the B cell has returned as an important contributor to autoimmune disorders, so that the race is on to characterize signalling regulation via the B-cell receptor and coreceptors. Identification of such molecules and their potential defects should lead to effective ways of controlling the immune response and in particular preventing the development of autoimmune states. The classical view of B cells in the biology of immune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing Ab turns out to be rather naïve. Indeed, studies over the last few years indicate that this view is far from complete, and suggest that B lymphocytes have extraordinarily diverse functions within the immune system. Furthermore, it is becoming increasingly clear that the pathogenesis of autoimmune diseases cannot solely be accounted for by T cells, and intrinsic abnormalities of B cells have been described in such conditions. In this brief review we highlight some recent observations in the context of B lymphocyte in pathophysiology, and focus on their revival as pivotal players the pathophysiology in autoimmune diseases. Yet, it remains difficult to provide a model of how important B cells are in immunity and autoimmunity.


Plasmid-mediated rifampicin resistance in Pseudomonas fluorescens.
Rifampicin is an antibiotic mostly used to treat tuberculosis and leprosy, and, occasionally, other diseases. Resistance is due to alterations in membrane permeability or to mutation in the rpoB gene coding for mRNA polymerase. Both these mechanisms originate via chromosomal mutation. However, a rifampicin-resistant Pseudomonas fluorescens strain harboured a multiresistance plasmid which transferred rifampicin resistance when transformed into P. putida or Escherichia coli. Rifampicin readily diffused into the sensitive cells of the E. coli and P. putida recipients, but the transformants with the plasmid, pSCL were resistant to the drug and did not accumulate it. Potassium cyanide restored the diffusion of rifampicin into the resistant cells, indicating that an efflux pump was involved in the resistance mechanism. The resistance of the transformants and the wild strain was also abolished in sphaeroplasts generated by EDTA lysozyme treatment. Analysis of membrane proteins by SDS-PAGE revealed the presence of two new proteins in the plasmid-containing cells of E. coli, P. putida and P. fluorescens and not in the plasmid-free cells. These may be involved in the efflux of rifampicin.


Comparing different models of the development of verb inflection in early child Spanish.
How children acquire knowledge of verb inflection is a long-standing question in language acquisition research. In the present study, we test the predictions of some current constructivist and generativist accounts of the development of verb inflection by focusing on data from two Spanish-speaking children between the ages of 2;0 and 2;6. The constructivist claim that children's early knowledge of verb inflection is only partially productive is tested by comparing the average number of different inflections per verb in matched samples of child and adult speech. The generativist claim that children's early use of verb inflection is essentially error-free is tested by investigating the rate at which the children made subject-verb agreement errors in different parts of the present tense paradigm. Our results show: 1) that, although even adults' use of verb inflection in Spanish tends to look somewhat lexically restricted, both children's use of verb inflection was significantly less flexible than that of their caregivers, and 2) that, although the rate at which the two children produced subject-verb agreement errors in their speech was very low, this overall error rate hid a consistent pattern of error in which error rates were substantially higher in low frequency than in high frequency contexts, and substantially higher for low frequency than for high frequency verbs. These results undermine the claim that children's use of verb inflection is fully productive from the earliest observable stages, and are consistent with the constructivist claim that knowledge of verb inflection develops only gradually.


Evidence for an altered adenovirus DNA polymerase in cells infected with the mutant H5ts149.
The N complementation group of adenovirus (Ad) serotype 5 mutants, which are temperature sensitive for viral DNA synthesis in vivo, has been used to study a 140,000-dalton DNA polymerase (Pol) that copurified with the 80,000-dalton terminal protein precursor (pTP). Extracts prepared from HeLa cells infected with the N group mutant H5ts149 at nonpermissive temperature were unable to synthesize viral DNA. The defect in these extracts was specifically reversed by addition of the Pol purified from wild-type Ad-infected cytosol. Addition of the pTP, free of the Pol, did not restore replicative activity to H5ts149 extracts. The reactions studied depend on the presence of the DNA template and include the initiation reaction (the covalent attachment of dCMP to the pTP) and the selective replication of Ad DNA restriction endonuclease fragments containing the origin sequences. Glycerol gradient sedimentation showed that a replicative activity representing the pTP-Pol complex was greatly reduced in H5ts149 extracts as compared with wild-type extracts, suggesting some alteration in the mutant. A pool of pTP free of Pol was detected on these gradients in extracts from both wild-type and H5ts149-infected cells. In addition, the initiation and elongation of Ad DNA catalyzed by H5ts149 extracts prepared from cells grown at permissive temperatures was more labile to urea inactivation than extracts prepared from cells infected with wild-type virus. These results, considered together with the mapping of the H5ts149 mutation within an open reading frame approximately large enough to code for the 140,000-dalton DNA polymerase [Gingeras, T. R., Sciaky, D., Gelinas, R. E., Bing-Dong, J., Yen, C. E., Kelly, M. M., Bullock, P. A., Parsons, B. L., O'Neill, K. E. & Roberts, R. J. (1982) J. Biol. Chem. 257, 13475-13491; Alestrom, P., Akusjarui, G., Pettersson, M. & Pettersson, U. (1982) J. Biol. Chem. 257, 13492-13498], suggest that the Pol is a virally encoded protein, as is the pTP.


Methane emissions from natural gas compressor stations in the transmission and storage sector: measurements and comparisons with the EPA greenhouse gas reporting program protocol.
Equipment- and site-level methane emissions from 45 compressor stations in the transmission and storage (T&S) sector of the US natural gas system were measured, including 25 sites required to report under the EPA greenhouse gas reporting program (GHGRP). Direct measurements of fugitive and vented sources were combined with AP-42-based exhaust emission factors (for operating reciprocating engines and turbines) to produce a study onsite estimate. Site-level methane emissions were also concurrently measured with downwind-tracer-flux techniques. At most sites, these two independent estimates agreed within experimental uncertainty. Site-level methane emissions varied from 2-880 SCFM. Compressor vents, leaky isolation valves, reciprocating engine exhaust, and equipment leaks were major sources, and substantial emissions were observed at both operating and standby compressor stations. The site-level methane emission rates were highly skewed; the highest emitting 10% of sites (including two superemitters) contributed 50% of the aggregate methane emissions, while the lowest emitting 50% of sites contributed less than 10% of the aggregate emissions. Excluding the two superemitters, study-average methane emissions from compressor housings and noncompressor sources are comparable to or lower than the corresponding effective emission factors used in the EPA greenhouse gas inventory. If the two superemitters are included in the analysis, then the average emission factors based on this study could exceed the EPA greenhouse gas inventory emission factors, which highlights the potentially important contribution of superemitters to national emissions. However, quantification of their influence requires knowledge of the magnitude and frequency of superemitters across the entire T&S sector. Only 38% of the methane emissions measured by the comprehensive onsite measurements were reportable under the new EPA GHGRP because of a combination of inaccurate emission factors for leakers and exhaust methane, and various exclusions. The bias is even larger if one accounts for the superemitters, which were not captured by the onsite measurements. The magnitude of the bias varied from site to site by site type and operating state. Therefore, while the GHGRP is a valuable new source of emissions information, care must be taken when incorporating these data into emission inventories. The value of the GHGRP can be increased by requiring more direct measurements of emissions (as opposed to using counts and emission factors), eliminating exclusions such as rod-packing vents on pressurized reciprocating compressors in standby mode under Subpart-W, and using more appropriate emission factors for exhaust methane from reciprocating engines under Subpart-C.


Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator.
Time-dependent inactivation (TDI) of human cytochromes P450 3A4 (CYP3A4) is a major cause of clinical drug-drug interactions (DDIs). Human liver microsomes (HLM) are commonly used as an enzyme source for evaluating the inhibition of CYP3A4 by new chemical entities. The inhibition data can then be extrapolated to assess the risk of human DDIs. Using this approach, under- and overpredictions of in vivo DDIs have been observed. In the present study, human hepatocytes were used as an alternative to HLM. Hepatocytes incorporate the effects of other mechanisms of drug metabolism and disposition (i.e., phase II enzymes and transporters) that may modulate the effects of TDI on clinical DDIs. The in vitro potency (K(I) and k(inact)) of five known CYP3A4 TDI drugs (clarithromycin, diltiazem, erythromycin, verapamil, and troleandomycin) was determined in HLM (pooled, n = 20) and hepatocytes from two donors (D1 and D2), and the results were extrapolated to predict in vivo DDIs using a Simcyp population trial-based simulator. Compared with observed DDIs, the predictions derived from HLM appeared to be overestimated. The predictions based on TDI measured in hepatocytes were better correlated with the DDIs (n = 37) observed in vivo (R(2) = 0.601 for D1 and 0.740 for D2) than those from HLM (R(2) = 0.451). In addition, with the use of hepatocytes a greater proportion of the predictions were within a 2-fold range of the clinical DDIs compared with using HLM. These results suggest that DDI predictions from CYP3A4 TDI kinetics in hepatocytes could provide an alternative approach to balance HLM-based predictions that can sometimes substantially overestimate DDIs and possibly lead to erroneous conclusions about clinical risks.


Smartphones : evidence-based user-interface design.
Smartphones have become increasingly popular among every segment of the population. Caregivers do not want to miss out on this evolution and express interest in using mobile devices to perform their everyday care. This tendency has been well understood by many software providers who have produced many medical applications for smartphones. Before going a step further and developing tools to manage Clinical Information System data on handheld devices, it is wise to ask ourselves whether these new tools are well adapted to the healthcare environment. Indeed, some studies have raised concerns regarding the efficiency of these handheld devices to input medical data, especially with the induced errors. In this paper, we look to adopt a rigorous approach to acquire evidence about these concerns through a prospective study. In order to get this evidence, the study compares several input interfaces in the context of recording vital signs on mobile devices. We would like to discover not only which interface is the most efficient, but also which one is the least prone to errors.


Developmental origins of colon smooth muscle dysfunction in IBS-like rats.
Epidemiological studies show that subsets of adult and pediatric patients with irritable bowel syndrome (IBS) have prior exposures to psychological or inflammatory stress. We investigated the cellular mechanisms of colonic smooth muscle dysfunction in adult rats subjected to neonatal inflammation. Ten-day-old male rat pups received 2,4,6-trinitrobenzene sulfonic acid to induce colonic inflammation. Colonic circular smooth muscle strips were obtained 6 to 8 wk later. We found that about half of the neonate pups subjected to inflammatory insult showed a significant increase in expression of the pore-forming α1C-subunit of Cav1.2b channels in adult life. These were the same rats in whom Vip mRNA increased in the colon muscularis externae. Additional experiments showed reduced interaction of histone deacetylase (HDAC) 3 with α1C1b promoter that increased the acetylation of histone H3 lysine 9 (H3K9) in the core promoter region. Vasoactive intestinal peptide (VIP) treatment of naïve muscularis externae swiftly recruited CREB-binding protein (CBP) to the α1C1b promoter and dissociated HDAC3 from this region to initiate transcription. The CBP interaction with the α1C1b promoter was transient, but the dissociation of HDAC3 persisted to sustain H3K9 hyperacetylation and increase in transcription. Intraperitoneal treatment of adult naïve rats with butyrate mimicked the effects of neonatal colon inflammation. We concluded that neonatal inflammation upregulates VIP in the colon muscularis externae, which modulates epigenetic events at the α1C1b promoter to activate α1C1b gene transcription. Inflammatory insult in early life may be one of the etiologies of smooth muscle dysfunction in adult life, which contributes to the altered motility function in patients with diarrhea-predominant IBS.


Interpretation of chest radiographs in infants with cough and fever.
An understanding of the appearance of the infant chest radiograph requires an understanding of the anatomy and the physiologic, immunologic, and pathologic processes in the infant's chest. The authors describe the features of the infant chest that most influence the appearance of the chest radiograph in infants with cough and fever. They discuss why confusion sometimes occurs when radiology residents and general radiologists familiar with adult chest radiographs first evaluate the infant chest radiograph. The radiographic appearance of acute inflammation does not look the same in infants as it does in older children and adults. The hallmark of inflammatory lung disease in the infant chest is air trapping on the chest radiograph.


Does Virtual Reality Improve Procedural Completion and Accuracy in an Intramedullary Tibial Nail Procedure? A Randomized Control Trial.
Artificial reality technologies are currently being explored as potential options to improve surgical education. Previous studies have primarily examined the efficacy of artificial reality in laparoscopic procedures, but to our knowledge, none have been performed in orthopaedically relevant procedures such as intramedullary tibial nailing, which calls for more versatile large-scale movements. Does a virtual reality simulator with or without a standard technique guide result in (1) a higher proportion of participants who completed the insertion of an intramedullary tibial nail in a synthetic bones model and (2) greater procedural accuracy than does training with a technique guide alone? Twenty-five first- and second-year medical students without prior exposure to intramedullary tibial nail insertion were recruited. Participants were randomly assigned to the technique guide control group (n = 8), the virtual reality group (n = 8), or the virtual reality and technique guide group (n = 9). The technique guide was adapted from a commercially available technique guide, which participants in the assigned groups could use to prepare as much as desired. The virtual reality simulation was based on the same procedure, and we used a commercially available virtual reality simulator that we purchased for this task. Participants in the virtual reality experimental groups completed the simulation on three separate sessions, at a set interval of 3 to 4 days apart. After 10 to 14 days of preparation, all participants attempted to insert an intramedullary nail into an intact, compact bone-model tibia that lacked surrounding soft tissue. Participants were given written hints if requested, but no other assistance was given. A procedure was considered complete if the nail and screw were properly placed. Procedural accuracy was defined as the number of incorrect steps normalized out of the 16 possible performed. After the procedure, one orthopaedic surgeon assessed a blinded video of the participant performing it so the assessor could not recognize the individual or that individual's gender. Additionally, the assessor was unaware of which group each participant had been randomized to during the evaluation. A higher proportion of participants in the virtual reality group (6 of 8) and the virtual reality and technique guide group (7 of 9) completed the intramedullary nail than did participants in the technique guide group (2 of 8; p = 0.01). There was no difference in completion between the virtual reality groups (p = 0.89). Participants in the virtual reality and virtual reality and technique guide had fewer normalized incorrect steps than did participants in the technique guide group (3.2 ± 0.1 of 16 and 3.1 ± 0.1 of 16 versus 5.7 ± 0.2 of 16, respectively; p = 0.02 for comparisons of virtual reality groups to technique guide, p = 0.63 between the virtual reality group). Virtual reality increased both procedural accuracy and the completion proportion compared with a technique guide in medical students. Based on our findings, virtual reality may help residents learn the procedural workflow and movements required to perform surgical procedures. Future studies should examine how and when exactly the technology can be applied to residencies and its impact on residents. Level I, therapeutic study.


IL-4 and IL-10 modulation of CD40-mediated signaling of monocyte IL-1beta synthesis and rescue from apoptosis.
Previous studies have demonstrated that the interaction of CD40 on monocytes with CD40 ligand, present on activated CD4+ T cells, induces monocyte inflammatory cytokine synthesis and rescues monocytes from apoptosis. These findings suggest a role for CD40 signaling of monocyte activation in the maintenance and/or exacerbation of nonseptic (e.g., autoimmune) inflammatory responses. In the present study the effects of the modulatory cytokines IL-4 and IL-10 on CD40-mediated signaling of monocyte IL-1beta synthesis and rescue from apoptosis were examined. Both IL-4 and IL-10 decreased CD40-dependent IL-1beta synthesis in a dose-dependent manner individually and synergized in this effect when used concurrently, with minimal effect on CD40 surface expression. CD40 signaling of IL-1beta synthesis was shown to be dependent on the induction of protein tyrosine kinase (PTK) activity, and both IL-4 and IL-10 diminished CD40-mediated tyrosine phosphorylation of monocyte cellular proteins. However, IL-4, but not IL-10, blocked CD40-mediated rescue from apoptosis, an event that we have demonstrated previously to be dependent on PTK activity as well. Together these results suggest that in monocytes 1) both IL-4 and IL-10 target CD40-induced PTK activity in the down-regulation of IL-1beta synthesis; and 2) IL-4 and IL-10 have divergent effects on the CD40 signaling pathway, in that these cytokines are synergistic with respect to their abilities to inhibit CD40-mediated IL-1beta synthesis and differ in their abilities to block CD40-mediated rescue from apoptosis.


Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation.
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1β (IL-1β) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1β production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.


Treatment of severe keratoconjunctivitis sicca by parotid duct transposition after tympanic neurectomy in rabbits.
To investigate the feasibility of parotid duct transposition after tympanic neurectomy to treat severe keratoconjunctivitis sicca (KCS) in rabbits. Thirty rabbits were divided into three groups in experiment 1. One eye was operated on, and the contralateral eye served as the control. In the KCS group, the lacrimal gland, harderian gland, and nictitating membrane were removed. In the group with parotid duct transposition (DT), the parotid duct was transposed into the lower conjunctival fornix. In the group with parotid duct transposition after tympanic neurectomy (DTTN), the tympanic nerve was resected in addition to parotid duct transposition. Schirmer test was performed and density of corneal staining was determined monthly after surgery, and goblet cell density was measured at postoperative month 3. In experiment 2, the tympanic nerve was resected on one side in 12 rabbits. Both sides of the parotid gland were resected for histopathology at intervals of 2 months to 1 year after surgery. Tear secretion from operated eyes at rest increased significantly after surgery in the treatment groups compared with the KCS group. Tear secretion from operated eyes after chewing was significantly lower in the DTTN than in the DT group. The corneal staining scores were higher in the operated than in the control eyes of the three groups, without significant difference among the operated eyes. Parotid gland atrophy on the operated side occurred at postoperative month 4 and recovered to normal 1 year after surgery. Parotid duct transposition after tympanic neurectomy could effectively reduce gustatory epiphora but may be insufficient to promote ocular surface health.


Electrophysiologic, inotropic and antiarrhythmic effects of propafenone, 5-hydroxypropafenone and N-depropylpropafenone.
We compared the electrophysiologic, inotropic and antiarrhythmic properties of propafenone and two metabolites, 5-hydroxy (5-OH) propafenone and N-depropyl (N-DP) propafenone. In 18 canine Purkinje fibers with normal maximum diastolic potentials, all drugs (1 x 10(-8) to 1 x 10(-5) M) reduced action potential amplitude and duration. However, propafenone and 5-OH propafenone reduced Vmax in a use-dependent fashion at a lower concentration than N-DP propafenone. In 16 Purkinje fibers, slow response action potentials were induced by 22 mM K+ and isoproterenol, 1 x 10(-6) M. Vmax was comparably reduced by all compounds at 1 x 10(-5) M, but action potential amplitude was not affected by 5-OH propafenone. In 16 other Purkinje fibers in which automaticity at low levels of membrane potential was induced by BaCl2 (0.25 mM), only 5-OH propafenone was effective in slowing the automatic rate at therapeutic concentrations (3 micrograms/ml). In 15 guinea pig papillary muscles, all three drugs had negative inotropic effects at concentrations greater than or equal to 1 x 10(-6) M. In conscious dogs with sustained ventricular tachycardia 24 hr after infarction, we injected propafenone or a metabolite through an atrial cannula. At similar plasma levels, neither propafenone (n = 6) nor N-DP propafenone (n = 6) suppressed the arrhythmia, whereas 5-OH propafenone eliminated ventricular tachycardia in four of six dogs, and was more effective against monomorphic than polymorphic ventricular tachycardia. Hence, the two major metabolites of propafenone have important electrophysiologic effects, and 5-OH propafenone is more potent than the parent compound as a antiarrhythmic drug in the 24-hr Harris dog.


The centromeric retrotransposons of rice are transcribed and differentially processed by RNA interference.
Retrotransposons consist of significant portions of many complex eukaryotic genomes and are often enriched in heterochromatin. The centromeric retrotransposon (CR) family in grass species is colonized in the centromeres and highly conserved among species that have been diverged for >50 MY. These unique characteristics have inspired scientists to speculate about the roles of CR elements in organization and function of centromeric chromatin. Here we report that the CRR (CR of rice) elements in rice are highly enriched in chromatin associated with H3K9me2, a hallmark for heterochromatin. CRR elements were transcribed in root, leaf, and panicle tissues, suggesting a constitutive transcription of this retrotransposon family. However, the overall transcription level was low and the CRR transcripts appeared to be derived from relatively few loci. The majority of the CRR transcripts had chimerical structures and contained only partial CRR sequences. We detected small RNAs (smRNAs) cognate to nonautonomous CRR1 (noaCRR1) and CRR1, but not CRR2 elements. This result was also confirmed by in silico analysis of rice smRNA sequences. These results suggest that different CRR subfamilies may play different roles in the RNAi-mediated pathway for formation and maintenance of centromeric heterochromatin.


Cerebrovascular risk factors impact frontoparietal network integrity and executive function in healthy ageing.
Healthy cognitive ageing is a societal and public health priority. Cerebrovascular risk factors increase the likelihood of dementia in older people but their impact on cognitive ageing in younger, healthy brains is less clear. The UK Biobank provides cognition and brain imaging measures in the largest population cohort studied to date. Here we show that cognitive abilities of healthy individuals (N = 22,059) in this sample are detrimentally affected by cerebrovascular risk factors. Structural equation modelling revealed that cerebrovascular risk is associated with reduced cerebral grey matter and white matter integrity within a fronto-parietal brain network underlying executive function. Notably, higher systolic blood pressure was associated with worse executive cognitive function in mid-life (44-69 years), but not in late-life (>70 years). During mid-life this association did not occur in the systolic range of 110-140 mmHg. These findings suggest cerebrovascular risk factors impact on brain structure and cognitive function in healthy people.


Tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys.
Despite the high global burden of diseases caused by tobacco, valid and comparable prevalence data for patterns of adult tobacco use and factors influencing use are absent for many low-income and middle-income countries. We assess these patterns through analysis of data from the Global Adult Tobacco Survey (GATS). Between Oct 1, 2008, and March 15, 2010, GATS used nationally representative household surveys with comparable methods to obtain relevant information from individuals aged 15 years or older in 14 low-income and middle-income countries (Bangladesh, Brazil, China, Egypt, India, Mexico, Philippines, Poland, Russia, Thailand, Turkey, Ukraine, Uruguay, and Vietnam). We compared weighted point estimates and 95% CIs of tobacco use between these 14 countries and with data from the 2008 UK General Lifestyle Survey and the 2006-07 US Tobacco Use Supplement to the Current Population Survey. All these surveys had cross-sectional study designs. In countries participating in GATS, 48·6% (95% CI 47·6-49·6) of men and 11·3% (10·7-12·0) of women were tobacco users. 40·7% of men (ranging from 21·6% in Brazil to 60·2% in Russia) and 5·0% of women (0·5% in Egypt to 24·4% in Poland) in GATS countries smoked a tobacco product. Manufactured cigarettes were favoured by most smokers (82%) overall, but smokeless tobacco and bidis were commonly used in India and Bangladesh. For individuals who had ever smoked daily, women aged 55-64 years at the time of the survey began smoking at an older age than did equivalently aged men in most GATS countries. However, those individuals who had ever smoked daily and were aged 25-34-years when surveyed started to do so at much the same age in both sexes. Quit ratios were very low (<20% overall) in China, India, Russia, Egypt, and Bangladesh. The first wave of GATS showed high rates of smoking in men, early initiation of smoking in women, and low quit ratios, reinforcing the view that efforts to prevent initiation and promote cessation of tobacco use are needed to reduce associated morbidity and mortality. Bloomberg Philanthropies' Initiative to Reduce Tobacco Use, Bill and Melinda Gates Foundation, Brazilian and Indian Governments.


Deubiquitination of FANCD2 is required for DNA crosslink repair.
Monoubiquitination of FANCD2 and PCNA promotes DNA repair. It causes chromatin accumulation of FANCD2 and facilitates PCNA's recruitment of translesion polymerases to stalled replication. USP1, a protease that removes monoubiquitin from FANCD2 and PCNA, was thought to reverse the DNA damage response of these substrates. We disrupted USP1 in chicken cells to dissect its role in a stable genetic system. USP1 ablation increases FANCD2 and PCNA monoubiquitination but unexpectedly results in DNA crosslinker sensitivity. This defective DNA repair is associated with constitutively chromatin-bound, monoubiquitinated FANCD2. In contrast, persistent PCNA monoubiquitination has negligible impact on DNA repair or mutagenesis. USP1 was previously shown to autocleave after DNA damage. In DT40, USP1 autocleavage is not stimulated by DNA damage, and expressing a noncleavable mutant in the USP1 knockout strain partially rescues crosslinker sensitivity. We conclude that efficient DNA crosslink repair requires FANCD2 deubiquitination, whereas FANCD2 monoubiquitination is not dependent on USP1 autocleavage.


Preparing the Next Generation of Diverse Biomedical Researchers: The University of North Texas Health Science Center's Initiative for Maximizing Student Development (IMSD) Predoctoral Program.
The National Science Foundation (NSF) reports that underrepresented minority students are just as interested as their White counterparts in majoring in science upon entering college.1 However, the numbers of those receiving bachelors' degrees, attending graduate school, and earning doctorates remain lower than their White peers. To close this gap, the National Institutes of General Medical Science's (NIGMS) Initiative for Maximizing Student Development (IMSD) at University of Texas Health Science Center (UNTHSC) supports the timely completion of PhD degrees by underrepresented students and their transition into successful biomedical research careers. Throughout UNTHSC's IMSD training program, we have designed interventions anchored by the central hypothesis that PhD attainment requires attentiveness to multiple factors (knowledge, psychosocial, financial and self-efficacy). An assessment of program outcomes demonstrates a progressive increase in trainee retention. Importantly, not-withstanding quantitative measurable outcomes, trainee and mentor evaluations express the value in addressing multiple factors relevant to their success. Since 1996, our cumulative success of underrepresented minority students completing the doctorate increased from 64% (1996) to 84% completion (2018). Herein, we describe the UNTHSC IMSD training approach spanning its performance over two five-year cycles (2004-2008; 2009-2013) and new interventions created from lessons learned that influenced UNTHSC's newly awarded IMSD program (2017-2022).


Ageing in general practice (AGP) trial: a cluster randomised trial to examine the effectiveness of peer education on GP diagnostic assessment and management of dementia.
Dementia is increasing in prevalence as the population ages. An earlier rather than later diagnosis allows persons with dementia and their families to plan ahead and access appropriate management. However, most diagnoses are made by general practitioners (GPs) later in the course of the disease and are associated with management that is poorly adherent to recommended guidelines. This trial examines the effectiveness of a peer led dementia educational intervention for GPs. The study is a cluster randomised trial, conducted across three states and five sites. All GPs will complete an audit of their consenting patients aged 75 years or more at three time points - baseline, 12 and 24 months. GPs allocated to the intervention group will receive two educational sessions from a peer GP or nurse, and will administer the GPCOG to consenting patients at baseline and 12 months. The first education session will provide information about dementia and the second will provide individualised feedback on audit results. GPs in the waitlist group will receive the RACGP Guidelines by post following the 12 month audit Primary outcomes are carer and consumer quality of life and depression. Secondary outcomes include: rates of GP identification of dementia compared to a more detailed gold standard assessment conducted in the patient's home; GP identification of differential diagnoses including reversible causes of cognitive impairment; and GP referral to specialists, Alzheimers' Australia and support services. A "case finding" and a "screening" group will be compared and the psychometrics of the GPCOG will be examined. Approximately 2,000 subjects aged 75 years and over will be recruited through approximately 160 GPs, to yield approximately 200 subjects with dementia (reducing to 168 by 24 months). The trial outlined in this paper has been peer reviewed and supported by the Australian National Health and Medical Research Council. At the time of submission of this paper 2,034 subjects have been recruited and the intervention delivered to 114 GPs. Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000117415.


Dynamic multi-segmental postural control in patients with chronic non-specific low back pain compared to pain-free controls: A cross-sectional study.
Reduced postural control is thought to contribute to the development and persistence of chronic non-specific low back pain (CNLBP). It is therefore frequently assessed in affected patients and commonly reported as the average amount of postural sway while standing upright under a variety of sensory conditions. These averaged linear outcomes, such as mean centre of pressure (CP) displacement or mean CP surface areas, may not reflect the true postural status. Adding nonlinear outcomes and multi-segmental kinematic analysis has been reported to better reflect the complexity of postural control and may detect subtler postural differences. In this cross-sectional study, a combination of linear and nonlinear postural parameters were assessed in patients with CNLBP (n = 24, 24-75 years, 9 females) and compared to symptom-free controls (CG, n = 34, 22-67 years, 11 females). Primary outcome was postural control measured by variance of joint configurations (uncontrolled manifold index, UI), confidence ellipse surface areas (CEA) and approximate entropy (ApEn) of CP dispersion during the response phase of a perturbed postural control task on a swaying platform. Secondary outcomes were segment excursions and clinical outcome correlates for pain and function. Non-parametric tests for group comparison with P-adjustment for multiple comparisons were conducted. Principal component analysis was applied to identify patterns of segmental contribution in both groups. CNLBP and CG performed similarly with respect to the primary outcomes. Comparison of joint kinematics revealed significant differences of hip (P < .001) and neck (P < .025) angular excursion, representing medium to large group effects (r's = .36 - .51). Significant (P's < .05), but moderate correlations of ApEn (r = -.42) and UI (r = -.46) with the health-related outcomes were observed. These findings lend further support to the notion that averaged linear outcomes do not suffice to describe subtle postural differences in CNLBP patients with low to moderate pain status.


Addressing the social determinants of health at the local level: Opportunities and challenges.
The gradient in health inequalities reflects a relationship between health and social circumstance, demonstrating that health worsens as you move down the socio-economic scale. For more than a decade, the Norwegian National government has developed policies to reduce social inequalities in health by levelling the social gradient. The adoption of the Public Health Act in 2012 was a further movement towards a comprehensive policy. The main aim of the act is to reduce social health inequalities by adopting a Health in All Policies approach. The municipalities are regarded key in the implementation of the act. The SODEMIFA project aimed to study the development of the new public health policy, with a particular emphasis on its implementation in municipalities. In the SODEMIFA project, a mixed-methods approach was applied, and the data consisted of surveys as well as qualitative interviews. The informants were policymakers at the national and local level. Our findings indicate that the municipalities had a rather vague understanding of the concept of health inequalities, and even more so, the concept of the social gradient in health. The most common understanding was that policy to reduce social inequalities concerned disadvantaged groups. Accordingly, policies and measures would be directed at these groups, rather than addressing the social gradient. A movement towards an increased understanding and adoption of the new, comprehensive public health policy was observed. However, to continue this process, both local and national levels must stay committed to the principles of the act.


[Effect of transcutaneous auricular vagus nerve stimulation on hyperglycemia and insulin receptors expression in impaired glucose tolerance rats].
To explore the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on blood glucose regulation and the expression of insulin receptors (INR) of hypothalamus, liver and skeletal muscle tissues in impaired glucose tolerance (IGT) rats, so as to reveal its mechanisms underlying improvement of IGT. Thirty-six male Wistar rats were randomly divided into control, model, transcutaneous auricular none-vagus nerve stimulation (tnVNS), and taVNS groups (n=9 in each group). The IGT model was established by feeding the rats with high-fat and high-sugar diet for 5 weeks, and subsequent intraperitoneal injection of a dose of streptozotocin (20 mg/kg). Transcutaneous electrostimulation (2 mA, 2 Hz/15 Hz) was applied to auricular concha (taVNS) or auricular margin (tnVNS), respectively. The treatment was conducted for 30 min once daily for 4 weeks. The body weight, fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG) were recorded every week. The contents of plasma insulin (INS), glucagon (GC), glycosylated hemoglobin (GHbA1c) were detected by using enzyme linked immunosorbent assay (ELISA). The expression levels of INR in hypothalamus, liver and skeletal muscle tissues were detected by Western blot. After modeling, the rats' body weight, the contents of FPG, 2 h PG, GC and GHbA1c were significantly up-regulated (P<0.001, P<0.05, P<0.01), and the content of INS and expression of INR in hypothalamus, liver and skeletal muscle tissues were significantly down-regulated in the model group compared with the control group (P<0.001, P<0.01, P<0.05). Following the treatment, the increased FPG, 2 h PG, GC, and the decreased INS and INR expression of hypothalamus, liver and skeletal muscle tissues were apparently reversed in the taVNS group relevant to the model group (P<0.001, P<0.01, P<0.05). Compared with the tnVNS group, the FPG and 2 h PG contents were considerable decreased, and the content of INS and INR expression of hypothalamus and liver were obviously increased in the taVNS group (P<0.001, P<0.05, P<0.01). taVNS can improve the blood glucose and insulin sensitivity in IGT rats, which may contribute to its effectiveness in up-regulating the expression of INR in hypothalamus, liver and skeletal muscle tissues.


Role of ion-selective membranes in the carbon balance for CO2 electroreduction via gas diffusion electrode reactor designs.
In this work, the effect of ion-selective membranes on the detailed carbon balance was systematically analyzed for high-rate CO2 reduction in GDE-type flow electrolyzers. By using different ion-selective membranes, we show nearly identical catalytic selectivity for CO2 reduction, which is primarily due to a similar local reaction environment created at the cathode/electrolyte interface via the introduction of a catholyte layer. In addition, based on a systematic exploration of gases released from electrolytes and the dynamic change of electrolyte speciation, we demonstrate the explicit discrepancy in carbon balance paths for the captured CO2 at the cathode/catholyte interface via reaction with OH- when using different ion-selective membranes: (i) the captured CO2 could be transported through an anion exchange membrane in the form of CO3 2-, subsequently releasing CO2 along with O2 in the anolyte, and (ii) with a cation exchange membrane, the captured CO2 would be accumulated in the catholyte in the form of CO3 2-, while (iii) with the use of a bipolar membrane, the captured CO2 could be released at the catholyte/membrane interface in the form of gaseous CO2. The unique carbon balance path for each type of membrane is linked to ion species transported through the membranes.


Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons.
Mammalian reproduction is dependent upon intermittent delivery of luteinizing hormone-releasing hormone (LHRH) to the anterior pituitary. This mode of secretion is required to sensitize maximally the gonadotrophs to LHRH stimulation and to regulate gonadotropin gene expression. While LHRH secretion is pulsatile in nature, the origin of the pulse generator is unknown. In this report, we show that this oscillator could be located within the LHRH neuronal network. When immortalized LHRH neurons are placed into a perifusion system, LHRH is secreted into the medium in a pulsatile fashion under basal conditions. LHRH secretion and the number of LHRH pulses are reduced when calcium is removed from the medium. Perifusion also influences pro-LHRH processing, since the molar ratio of its processed products varies dramatically when the cells are transferred from a static system. Several different cellular mechanisms may underlie these changes in secretion and processing. Lucifer yellow experiments reveal that some cells are dye-coupled. Hence, these cells could be electrically coupled through gap junctions such that secretion from individual cells could be coordinated. Secretion could also be synchronized through the observed synapse-like contacts. These contacts could perform a negative-feedback role to regulate not only the amount of LHRH released but also the molecular forms secreted. The organization of LHRH neurons into interconnected clusters could serve to coordinate LHRH secretion from individual cells and, thereby, orchestrate functions in vivo as diverse as the onset of puberty, the timing of ovulation, and the duration of lactational infertility.


Returning to work while breastfeeding.
Mothers who work outside the home initiate breastfeeding at the same rate as mothers who stay at home. However, the breastfeeding continuance rate declines sharply in mothers who return to work. While the work environment may be less than ideal for the breastfeeding mother, obstacles can be overcome. Available breast pump types include manual pumps, battery-powered pumps, electric diaphragm pumps, electric piston pumps, and hospital-grade electric piston pumps. Electric piston pumps may be the most suitable type for mothers who work outside the home for more than 20 hours per week; however, when a mother is highly motivated, any pump type can be successful in any situation. Conservative estimates suggest that breast milk can be stored at room temperature for eight hours, refrigerated for up to eight days, and frozen for many months. A breastfeeding plan can help the working mother anticipate logistic problems and devise a practical pumping schedule. A mother's milk production usually is well established by the time her infant is four weeks old; it is best to delay a return to work until at least that time, and longer if possible.


Kappa opioid receptor endocytosis by dynorphin peptides.
Internalization and downregulation are important steps in the modulation of receptor function. Recent work with the beta2 adrenergic and opioid receptors have implicated these processes in receptor-mediated activation of mitogen-activated protein kinase (MAPK). We have used CHO cells expressing epitope-tagged rat kappa opioid receptors (rKORs) and prodynorphin-derived peptides to characterize the agonist-mediated endocytosis of rKORs and activation of MAPK. Kappa receptor-selective peptides induced receptor internalization and downregulation whereas nonpeptide agonists did not. An examination of the ability of dynorphin A-17-related peptides (lacking C-terminal amino acids) to promote KOR internalization, inhibition of adenylyl cyclase, and MAPK phosphorylation revealed that the N-terminal seven residues play an important role in eliciting these responses. Both dynorphin peptides and nonpeptide agonists induced rapid and robust phosphorylation of MAPKs. Taken together, these results point to a difference in the ability of dynorphin peptides and nonpeptide ligands to promote rKOR endocytosis and support the view that rKOR internalization is not required for MAPK activation.


Ossicular Chain Lesions in Tympanic Perforations and Chronic Otitis Media without Cholesteatoma.
The first aim was to determine the prevalence, kind, and functional effects on hearing of ossicular chain suffering (OCS) in chronic otitis without cholesteatoma (NCOM) and tympanic perforations (TP). The second aim was to correlate the findings with clinical parameters and hearing level. The study group comprised 250 consecutive patients affected by NCOM and who were subjected to tympanoplasty and never operated on before. Each patient underwent preoperative pure tone audiometry. Ossicles were evaluated during surgery. The incidence of OCS in NCOM was reported in 15-62% of the patients. Ossicular chain suffering was found in 26 out of the 250 patients included in the overall sample (10%). It was found in 7% of the patients affected by TP without otorrhea and in 19% of the patients affected by chronic ear discharge with drum perforation. OCS was found most frequently in posterior eardrum perforations and in patients with bilateral disease. The incus was the ossicle most frequently interested by resorption (92% of the patients). The air conduction threshold and air bone gap were more impaired in NCOM than in TP. Ossicular chain damages in patients with non-cholesteatomatous middle ear pathologies are not frequent and are present in no more than 10% of the patients, but lesions found were similar to those reported in patients with cholesteatoma. Otorrhea, posterior perforation, and bilateral disease can be considered as good predictors of OCS.


Zebrafish ift57, ift88, and ift172 intraflagellar transport mutants disrupt cilia but do not affect hedgehog signaling.
Cilia formation requires intraflagellar transport (IFT) proteins. Recent studies indicate that mammalian Hedgehog (Hh) signaling requires cilia. It is unclear, however, if the requirement for cilia and IFT proteins in Hh signaling represents a general rule for all vertebrates. Here we examine zebrafish ift57, ift88, and ift172 mutants and morphants for defects in Hh signaling. Although ift57 and ift88 mutants and morphants contained residual maternal protein, the cilia were disrupted. In contrast to previous genetic studies in mouse, mutations in zebrafish IFT genes did not affect the expression of Hh target genes in the neural tube and forebrain and had no quantitative effect on Hh target gene expression. Zebrafish IFT mutants also exhibited no dramatic changes in the craniofacial skeleton, somite formation, or motor neuron patterning. Thus, our data indicate the requirement for cilia in the Hh signal transduction pathway may not represent a universal mechanism in vertebrates.


Inverse problem approaches for stationary Fourier transform spectrometers.
A design of a miniaturized stationary Fourier transform IR spectrometer has been developed that produces a two-dimensional interferogram. The latter is disturbed by effects like parasitic interferences or disparities in the cutoff wavelength of the pixels. Thus, a simple Fourier transform cannot be used to estimate the spectrum of the scene. However, as these defects are deterministic, they can be measured and taken into account by inversion methods. A regularization term can also be added. The first experimental results prove the efficiency of this processing methodology.


Do small doses of atropine (<0.1 mg) cause bradycardia in young children?
To determine the heart rate response to atropine (<0.1 mg) in anaesthetised young infants. Prospective, observational and controlled. Elective surgery. Sixty unpremedicated healthy infants less than 15 kg were enrolled. Standard monitoring was applied. Anaesthesia was induced by mask with nitrous oxide (66%) and oxygen (33%) followed by sevoflurane (8%). Intravenous (IV) atropine (5 µg/kg) was flushed into a fast flowing IV. The ECG was recorded continuously from 30 s before the atropine until 5 min afterwards. The incidence of bradycardia and arrhythmias was determined from the ECGs by a blinded observer. The median (IQR) age was 6.5 (4-12) months and the mean (95% CI) weight was 8.6 (8.1 to 9.1) kg. The mean (95% CI) dose of atropine was 40.9 (37.3 to 44) µg. Bradycardia did not occur. Two infants developed premature atrial contractions and one developed a premature ventricular contraction. When compared with baseline values, heart rate increased by 7% 30 s after atropine, 14% 1 min after atropine and 25% 5 min after atropine. Twenty-nine infants (48%) experienced tachycardia (>20% above baseline rate) after atropine lasting 222.7 s (range 27.9-286). The change in heart rate 5 min after atropine was inversely related to the baseline heart rate. The upper 95% CI for the occurrence of bradycardia in the entire population of infants based on a zero incidence in this study is 5%. These results rebut the notion that atropine <0.1 mg IV causes bradycardia in young infants. ClinicalTrials.gov #NCT01819064.


Handling Difficult Cryo-ET Samples: A Study with Primary Neurons from Drosophila melanogaster.
Cellular neurobiology has benefited from recent advances in the field of cryo-electron tomography (cryo-ET). Numerous structural and ultrastructural insights have been obtained from plunge-frozen primary neurons cultured on electron microscopy grids. With most primary neurons having been derived from rodent sources, we sought to expand the breadth of sample availability by using primary neurons derived from 3rd instar Drosophila melanogaster larval brains. Ultrastructural abnormalities were encountered while establishing this model system for cryo-ET, which were exemplified by excessive membrane blebbing and cellular fragmentation. To optimize neuronal samples, we integrated substrate selection, micropatterning, montage data collection, and chemical fixation. Efforts to address difficulties in establishing Drosophila neurons for future cryo-ET studies in cellular neurobiology also provided insights that future practitioners can use when attempting to establish other cell-based model systems.


Endothelial cell tolerance to hypoxia. Potential role of purine nucleotide phosphates.
The ability of cells to tolerate hypoxia is critical to their survival, but varies greatly among different cell types. Despite alterations in many cellular responses during hypoxic exposure, pulmonary arterial endothelial cells (PAEC) retain their viability and cellular integrity. Under similar experimental conditions, other cell types, exemplified by renal tubular epithelial cells, are extremely hypoxia sensitive and are rapidly and irreversibly damaged. To investigate potential mechanisms by which PAEC maintain cellular and functional integrity under these conditions, we compared the turnover of adenine and guanine nucleotides in hypoxia tolerant PAEC and in hypoxia-sensitive renal tubular endothelial cells under various hypoxic conditions. Under several different hypoxic conditions, hypoxia-tolerant PAEC maintained or actually increased ATP levels and the percentage of these nucleotides found in the high energy phosphates, ATP and GTP. In contrast, in hypoxia-sensitive renal tubular endothelial cells, the same high energy phosphates were rapidly depleted. Yet, in both cell types, there were minor alterations in the uptake of the precusor nucleotide and its incorporation into the appropriate purine nucleotide phosphates and marked decreases in ATPase and GTPase activity. This maintenance of high energy phosphates in hypoxic PAEC suggests that there exists tight regulation of ATP and GTP turnover in these cells and that preservation of these nucleotides may contribute to the tolerance of PAEC to acute and chronic hypoxia.


Adiponectin mediated MHC class II mismatched cardiac graft rejection in mice is IL-4 dependent.
Adiponectin regulates glucose and fatty-acid metabolism but its role in chronic graft rejection mediated by Th2 cytokines remains ill-defined. Wild type and adiponectin-null mice were used as graft recipients in mouse MHC class II disparate cardiac transplantation (bm12 toB6) and the graft rejection was monitored. In adiponectin-null mice we observed that the cellular infiltrate of eosinophils, CD4(+) and CD8(+) T cells was reduced in grafts compared to the controls as was collagen deposition and vessel occlusion. A similar outcome was observed for skin transplants except that neutrophil infiltration was increased. Low levels of IL-4 were detected in the grafts and serum. The effect of adiponectin signaling on IL-4 expression was further investigated. Treatment with AMPK and p38 MAPK inhibitors blocked adiponectin enhanced T cell proliferation in mixed lymphocyte reactions. Inhibition of AMPK reduced eosinophil infiltration in skin grafts in wild type recipients and in contrast AMPK activation increased eosinophils in adiponectin-null recipients. The addition of adiponectin increased IL-4 production by the T cell line EL4 with augmented nuclear GATA-3 and phospho-STAT6 expression which were suppressed by knockdown of adiponectin receptor 1 and 2. Our results demonstrate a direct effect of adiponectin on IL-4 expression which contributes to Th2 cytokine mediated rejection in mouse MHC class II histoincompatible transplants. These results add to our understanding of the interrelationship of metabolism and immune regulation and raise the possibility that AMPK inhibitors may be beneficial in selected types of rejection.


Piezospectroscopic measurements capturing the evolution of plasma spray-coating stresses with substrate loads.
Plasma-spray coatings have a unique microstructure composed of various types of microcracks and weakly bonded interfaces which dictate their nonlinear mechanical properties. The intrinsic photo-luminescence (PL) characteristics of alpha-alumina (α-Al2O3) within these coatings offer a diagnostic functionality, enabling these properties to be probed experimentally at the microscale, under substrate loading. The piezospectroscopic (PS) measurements from the coatings are capable of revealing microstructural stress at high spatial resolution. Here, for the first time, the evolution of stresses within air plasma spray (APS) coatings under increasing substrate loads were captured using piezospectroscopy. With mechanical cycling of the substrate, the PS properties revealed anelastic and inelastic behavior and a relaxation of residual tensile stress within the APS coatings. With decreasing substrate thickness, the coating was observed to sustain more stress, as the substrate's influence on the mechanical behavior decreased. The findings provide an insight into the microstructural response that can serve as the basis for model validation and subsequently drive the design process for these coatings.


The perspectives of South African general surgeons regarding their postgraduate training.
Background. There is a perception among general surgeons that there are deficiencies in surgical training in South Africa (SA). Dependence on under-resourced state training institutions possibly plays a role. The opinions of qualified surgeons may make an invaluable contribution in this regard.Objectives. To canvass the perceptions of SA general surgeons regarding certain aspects of their training.Methods. An electronic postal survey was conducted. All general surgeons on the Association of Surgeons of South Africa database were requested to complete a structured questionnaire. Four Likert scale items were interrogated: knowledge acquisition, surgical skill, research, and practice management.Results. Eighty-eight surgeons responded. Knowledge acquisition and surgical skills development were regarded positively, except for a perceived deficiency in availability of newer technologies. Exposure to surgical research was viewed as beneficial and useful. However, the mandatory research project during training was not perceived as useful for current careers. Training in practice management was perceived as severely deficient.Conclusion. This survey highlights positive perceptions of general surgeons regarding the acquisition of knowledge and surgical skills during training in SA, but some negative views emerged regarding research, exposure to newer technology, and especially practice management training.


The effects of urbanization on net primary productivity in southeastern China.
Net primary productivity (NPP) is one of the major ecosystem products on which human societies rely heavily. However, rapid urban sprawl and its associated dense population and economic conditions have generated great pressure on natural resources, food security, and environments. It is valuable to understand how urban expansion and associated demographic and economic conditions affect ecosystem functions. This research conducted a case study in Southeastern China to examine the impacts of urban expansion and demographic and economic conditions on NPP. The data sources used in research include human settlement developed through a combination of MODIS, DMSP-OLS and Landsat ETM+ images, the annual NPP from MODIS, and the population and gross domestic product (GDP) from the 2000 census data. Multiple regression analysis and nonlinear regression analysis were used to examine the relationships of NPP with settlement, population and GDP. This research indicates that settlement, population and GDP have strongly negative correlation with NPP in Southeastern China, but the outcomes were nonlinear when population or GDP reached certain thresholds.


Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.
Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini-agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.


COBA-Cohort: a prospective cohort of HIV-negative men who have sex with men, attending community-based HIV testing services in five European countries (a study protocol).
Community-based voluntary counselling and testing (CBVCT) services for men who have sex with men (MSM) can reach those most-at-risk and provide an environment for gay men that is likely to be non-stigmatising. Longitudinal data on the behaviour of HIV-negative MSM are scarce in Europe. The aim of this protocol, developed during the Euro HIV Early Diagnosis And Treatment (EDAT) project, is to implement a multicentre community-based cohort of HIV-negative MSM attending 15 CBVCT services in 5 European countries. (1) To describe the patterns of CBVCT use, (2) to estimate HIV incidence, and to identify determinants of (3) HIV seroconversion and (4) HIV and/or sexually transmitted infection (STI) test-seeking behaviour. All MSM aged 18 years or over and who had a negative HIV test result are invited to participate in the COmmunity-BAsed Cohort (COBA-Cohort). Study enrolment started in February 2015, and is due to continue for at least 12 months at each study site. Follow-up frequency depends on the testing recommendations in each country (at least 1 test per year). Sociodemographic data are collected at baseline; baseline and follow-up questionnaires both gather data on attitudes and perceptions, discrimination, HIV/STI testing history, sexual behaviour, condom use, and pre- and post-exposure prophylaxis. Descriptive, exploratory and multivariate analyses will be performed to address the main research objectives of this study, using appropriate statistical tests and models. These analyses will be performed on the whole cohort data and stratified by study site or country. The study was approved by the Public Health authorities of each country where the study is being implemented. Findings from the COBA-Cohort study will be summarised in a report to the European Commission, and in leaflets to be distributed to study participants. Articles and conference abstracts will be submitted to peer-reviewed journals and conferences.


Leveraging genome-wide datasets to quantify the functional role of the anti-Shine-Dalgarno sequence in regulating translation efficiency.
Studies dating back to the 1970s established that sequence complementarity between the anti-Shine-Dalgarno (aSD) sequence on prokaryotic ribosomes and the 5' untranslated region of mRNAs helps to facilitate translation initiation. The optimal location of aSD sequence binding relative to the start codon, the full extents of the aSD sequence and the functional form of the relationship between aSD sequence complementarity and translation efficiency have not been fully resolved. Here, we investigate these relationships by leveraging the sequence diversity of endogenous genes and recently available genome-wide estimates of translation efficiency. We show that-after accounting for predicted mRNA structure-aSD sequence complementarity increases the translation of endogenous mRNAs by roughly 50%. Further, we observe that this relationship is nonlinear, with translation efficiency maximized for mRNAs with intermediate levels of aSD sequence complementarity. The mechanistic insights that we observe are highly robust: we find nearly identical results in multiple datasets spanning three distantly related bacteria. Further, we verify our main conclusions by re-analysing a controlled experimental dataset.


Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents.
Pharmacokinetic and pharmacodynamic data on adrenergic agents in children have revealed wide ranges of plasma clearance rates and hemodynamic responses in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, graded i.v. dobutamine infusions of 0.5, 2.5 and 5.0 micrograms/kg/min were sequentially administered to healthy children and adolescents. Plasma dobutamine concentrations and hemodynamic responses, including echocardiographic measures of systolic and diastolic function, were determined at each infusion rate. Pharmacodynamic data were evaluated by both threshold modeling and mean hemodynamic responses to each infusion rate. Mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. These data establish that the previously published wide variability in dobutamine clearance is not due simply to underlying disease states. Dobutamine clearance was linear over the dosage range evaluated. Dobutamine improved systolic function even at plasma concentrations attained with infusion rates as low as 1 to 2 micrograms/kg/min. The improved systolic function was at least partially due to inotropic effects. In addition, dobutamine improved diastolic function and reduced afterload. Chronotropic effects were observed in only two subjects and only at higher plasma concentrations than the other hemodynamic effects. Individualized threshold modeling effectively described the log-linear relationship between plasma dobutamine concentration and hemodynamic response beyond the threshold concentration.


Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature.
Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4-BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers' cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.


Clinical features of GH deficiency and effects of 3 years of GH replacement in adults with controlled Cushing's disease.
Patients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment. Data were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA; n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed. The cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (-6 CD group versus -5 NFPA group, P<0.01). In untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.


A Perioperative Smoking Cessation Intervention With Varenicline, Counseling, and Fax Referral to a Telephone Quitline Versus a Brief Intervention: A Randomized Controlled Trial.
The effectiveness of perioperative interventions to quit smoking with varenicline has not been compared with brief interventions. Our objective was to determine the efficacy of a comprehensive smoking cessation program versus a brief intervention for smoking cessation. In this prospective, multicenter study, 296 patients were randomized to participate in a smoking cessation program (one 10- to 15-minute counseling session, pharmacotherapy with varenicline, an educational pamphlet, and a fax referral to a telephone quitline); or brief advice and self-referral to a telephone quitline. The primary outcome was the 7-day point prevalence (PP) abstinence at 12 months after surgery. Secondary outcomes included abstinence at 1, 3, and 6 months. Multivariable generalized linear regression was used to identify independent variables related to abstinence. The 7-day PP abstinence for the smoking cessation program versus brief advice group was 42.4% vs 26.2% (relative risk [RR], 1.62; 95% confidence interval [CI], 1.16-2.25; P = .003) at 12 months. The 7-day PP abstinence at 1, 3, and 6 months was higher in the smoking cessation group versus the brief advice group: 45.7% vs 25.5% (RR, 1.79; 95% CI, 1.29-2.49; P < .001), 46.4% vs 26.9% (RR, 1.72; 95% CI, 1.25-2.37; P< .001), and 45.0% vs 26.2% (RR, 1.72; 95% CI, 1.24-2.38; P < .001), respectively. Participating in the smoking cessation group predicted abstinence at 12 months (RR, 1.58; 95% CI, 1.12-2.21; P = .0087). A perioperative smoking cessation program with counseling, pharmacotherapy with varenicline, an educational pamphlet, and a fax referral to a quitline increased abstinence from smoking 1, 3, 6, and 12 months after surgery versus a brief intervention.


Effects of Low-Intensity Microwave Radiation on Oxidant-Antioxidant Parameters and DNA Damage in the Liver of Rats.
The continuously increasing usage of cell phones has raised concerns about the adverse effects of microwave radiation (MWR) emitted by cell phones on health. Several in vitro and in vivo studies have claimed that MWR may cause various kinds of damage in tissues. The aim of this study is to examine the possible effects of exposure to low-intensity MWR on DNA and oxidative damage in the livers of rats. Eighteen Sprague-Dawley male rats were divided into three equal groups randomly (n = 6). Group 1 (Sham-control): rats were kept under conditions the same as those of other groups, except for MWR exposure. Group 2: rats exposed to 1800 MHz (SAR: 0.62 W/kg) at 0.127 ± 0.04 mW/cm2 power density, and Group 3: rats exposed to 2,100 MHz (SAR: 0.2 W/kg) at 0.038 ± 0.03 mW/cm2 power density. Microwave application groups were exposed to MWR 2 h/day for 7 months. At the end of the exposure period, the rats were sacrificed and DNA damage, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and total oxidant-antioxidant parameter analyses were conducted in their liver tissue samples. It was found that 1800 and 2100 MHz low-intensity MWR caused a significant increase in MDA, 8-OHdG, total oxidant status, oxidative stress index, and comet assay tail intensity (P < 0.05), while total antioxidant status levels (P < 0.05) decreased. The results of our study showed that whole-body exposure to 1800 and 2100 MHz low-intensity MWR emitted by cell phones can induce oxidative stress by altering oxidant-antioxidant parameters and lead to DNA strand breaks and oxidative DNA damage in the liver of rats. Bioelectromagnetics. 2021;42:76-85. © 2020 Bioelectromagnetics Society.


Gaussian core model phase diagram and pair correlations in high Euclidean dimensions.
The physical properties of a classical many-particle system with interactions given by a repulsive Gaussian pair potential are extended to arbitrarily high Euclidean dimensions. The goals of this paper are to characterize the behavior of the pair correlation function g(2) in various density regimes and to understand the phase properties of the Gaussian core model (GCM) as parametrized by dimension d. To this end, we explore the fluid (dilute and dense) and crystalline solid phases. For the dilute regime of the fluid phase, a cluster expansion of g(2) in reciprocal temperature beta is presented, the coefficients of which may be evaluated analytically due to the nature of the Gaussian potential. We present preliminary results concerning the convergence properties of this expansion. The analytical cluster expansion is related to numerical approximations for g(2) in the dense fluid regime by utilizing hypernetted chain, Percus-Yevick, and mean-field closures to the Ornstein-Zernike equation. Based on the results of these comparisons, we provide evidence in support of a decorrelation principle for the GCM in high Euclidean dimensions. In the solid phase, we consider the behavior of the freezing temperature T(f)(rho) in the limit rho-->+infinity and show T(f)(rho)-->0 in this limit for any d via a collective coordinate argument. Duality relations with respect to the energies of a lattice and its dual are then discussed, and these relations aid in the Maxwell double-tangent construction of phase coexistence regions between dual lattices based on lattice summation energies. The results from this analysis are used to draw conclusions about the ground-state structures of the GCM for a given dimension.


[A history of antipsychotic long-acting injections in the treatment of schizophrenia].
From a historical perspective, this article describes the use of antipsychotic long-acting injections (LAI) in the treatment of schizophrenia, a disorder that was defined in the final years of the 19th century. An efficient treatment for schizophrenia was discovered only in 1952 with the introduction of chlorpromazine, a phenothiazine derivative. Fairly soon, antipsychotics became available as LAI. The first compounds were fluphenazine enanthate (1966) and decanoate (1968) whose development is attributed to G.R. Daniel, a medical director at Squibb & Sons. Other first-generation antipsychotics long-acting injections (FGA-LAIs) were introduced in a rapid succession in the 1960s and 1970s. FGA-LAIs made a key contribution to the development of community psychiatry. As neuroleptics emptied psychiatric hospitals, it was important to ensure that patients could be taken care of in outpatient facilities. FGA-LAIs prevented covert non-compliance. Compliance was further reinforced by the social and psychological support of patients. The introduction of second-generation antipsychotics (SGA) led to a loss of interest in FGA-LAIs. This is evidenced by a drop in the number of papers published on this topic. The interest in LAI was revived with the introduction of the first SGA-LAI in 2003. Four different preparations have been approved in the decade between 2003 and 2013. SGA-LAIs differ from FGA-LAIs in the technology that is used to produce the depot effect, and also in the treatment objectives. The rationale for using SGA-LAIs is not only to prevent relapses due to treatment interruption, but also to achieve more constant plasma levels in order to reduce side effects due to excessive plasma levels and loss of efficacy due to insufficient plasma levels. Also, treatment objectives are no longer limited to controlling acute symptoms. Treatment objectives now include the alleviation of negative symptoms and cognitive deficits that are key prognostic factors.


Integrating multi-scale data on homologous recombination into a new recognition mechanism based on simulations of the RecA-ssDNA/dsDNA structure.
RecA protein is the prototypical recombinase. Members of the recombinase family can accurately repair double strand breaks in DNA. They also provide crucial links between pairs of sister chromatids in eukaryotic meiosis. A very broad outline of how these proteins align homologous sequences and promote DNA strand exchange has long been known, as are the crystal structures of the RecA-DNA pre- and postsynaptic complexes; however, little is known about the homology searching conformations and the details of how DNA in bacterial genomes is rapidly searched until homologous alignment is achieved. By integrating a physical model of recognition to new modeling work based on docking exploration and molecular dynamics simulation, we present a detailed structure/function model of homology recognition that reconciles extremely quick searching with the efficient and stringent formation of stable strand exchange products and which is consistent with a vast body of previously unexplained experimental results.


Anxiety in a cohort of Swiss women participating in a mammographic screening programme.
To follow up anxiety in a cohort of women screened for breast cancer. Within the framework of a pilot screening programme for breast cancer in the Canton of Vaud (Switzerland), a cohort of 924 participants aged 50-70 years were invited to answer questions on anxiety related to mammography screening. Anxiety was measured using a specific tool, the psychological consequences questionnaire (PCQ), and a new single item, direct question, breast cancer anxiety indicator (BCA). Participants were asked to fill in the questionnaire at four different phases: at screening, before the result, and 2 and 8 weeks after the result. The final response rate was 93.7%. Predictors of anxiety at each phase were assessed using multiple regression. Among those screening negative (94.7%), anxiety at screening was very low and remained so during the screening process. Among those screening false positive, anxiety was significantly higher 8 weeks after having received a negative diagnosis. Predictors of anxiety before screening were lower education and higher age, with a strong exogenous anxiety component. For subsequent phases, the initial anxiety score and education were the main determinants. Furthermore, a false positive result at screening was the most important predictor of anxiety 2 months after negative diagnosis. Anxiety measured with the BCA was strongly correlated with the PCQ. Anxiety was very low at screening and remained so during the process for negative women. Initial anxiety level was a strong predictor of anxiety during the entire process, up to 8 weeks after a negative result, and could be easily assessed using the BCA. The sustained higher anxiety level among those screening false positive is an undesirable side effect of the programme.


Development and Initial Validation of the Caregiver Perceptions About Communication With Clinical Team Members (CAPACITY) Measure.
Despite the important role that family caregivers play managing the care of persons with complex health needs, little is known about how caregivers perceive themselves to be recognized and valued by health care professionals. Our objective was to develop and validate a novel measure, the CAregiver Perceptions About CommunIcation with Clinical Team members (CAPACITY) instrument. Questions focus on perceived quality of communication with the health care team and the extent to which caregivers believe that the health care team considers their capacity and preferences in decision making. A confirmatory factor analysis supported a two-factor solution addressing communication and capacity. Internal consistency reliability was .90 for the communication domain and .93 for the capacity domain. Correlations between these two subscales and individual difference measures provided evidence of convergent and discriminant validity. The CAPACITY instrument may be a useful performance measure that quantifies the extent to which caregivers' experience person- and family-centered health care.


Induction of Neural Crest Stem Cells From Bardet-Biedl Syndrome Patient Derived hiPSCs.
Neural crest cells arise in the embryo from the neural plate border and migrate throughout the body, giving rise to many different tissue types such as bones and cartilage of the face, smooth muscles, neurons, and melanocytes. While studied extensively in animal models, neural crest development and disease have been poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells (hiPSCs) have become easier to generate, and several streamlined protocols have enabled robust differentiation of hiPSCs to the neural crest lineage. Thus, a unique opportunity is offered for modeling neurocristopathies using patient specific stem cell lines. In this work, we make use of hiPSCs derived from patients affected by the Bardet-Biedl Syndrome (BBS) ciliopathy. BBS patients often exhibit subclinical craniofacial dysmorphisms that are likely to be associated with the neural crest-derived facial skeleton. We focus on hiPSCs carrying variants in the BBS10 gene, which encodes a protein forming part of a chaperonin-like complex associated with the cilium. Here, we establish a pipeline for profiling hiPSCs during differentiation toward the neural crest stem cell fate. This can be used to characterize the differentiation properties of the neural crest-like cells. Two different BBS10 mutant lines showed a reduction in expression of the characteristic neural crest gene expression profile. Further analysis of both BBS10 mutant lines highlighted the inability of these mutant lines to differentiate toward a neural crest fate, which was also characterized by a decreased WNT and BMP response. Altogether, our study suggests a requirement for wild-type BBS10 in human neural crest development. In the long term, approaches such as the one we describe will allow direct comparison of disease-specific cell lines. This will provide valuable insights into the relationships between genetic background and heterogeneity in cellular models. The possibility of integrating laboratory data with clinical phenotypes will move us toward precision medicine approaches.


Is ribavirin prophylaxis effective for nosocomial transmission of Crimean-Congo hemorrhagic fever?
Crimean-Congo hemorrhagic fever (CCHF) is a viral zoonotic disease that is transmitted primarily through contact with ticks. Nosocomial cases and outbreaks of CCHF have been reported from many countries. Health care workers (HCWs) are at risk of exposure to CCHF. In our study, we evaluated seven HCWs' exposure to confirmed CCHF patients' infected blood and body fluids and prophylactic efficacy of the ribavirin on nosocomial transmission of CCHF retrospectively. Between 2007 and 2013, 150 CCHF cases were admitted to our clinic. During the follow-up of these patients, four doctors and three nurses had contact with infected blood and body fluids through needle stick injury, contact of skin and mucosal surfaces, and probable aerosolization. All of the index cases' diagnoses of CCHF were confirmed during the contact. Ribavirin prophylaxis was administered within 0.5-1 h in six out of seven cases. All of these cases' CCHF virus PCR results were negative. One physician had no contact with infected blood or body fluid, so ribavirin prophylaxis was not administered. The physician developed CCHF and diagnosis was confirmed. Although efficacy of ribavirin for prophylaxis is not clear and very few data exist on prophylactic usage of ribavirin, lack of clinical manifestations in our cases that were given ribavirin compared with the developed clinical manifestations in the physician may be explained by the prophylactic efficacy of the ribavirin.


Adaptive integration in the visual cortex by depressing recurrent cortical circuits.
Neurons in the visual cortex receive a large amount of input from recurrent connections, yet the functional role of these connections remains unclear. Here we explore networks with strong recurrence in a computational model and show that short-term depression of the synapses in the recurrent loops implements an adaptive filter. This allows the visual system to respond reliably to deteriorated stimuli yet quickly to high-quality stimuli. For low-contrast stimuli, the model predicts long response latencies, whereas latencies are short for high-contrast stimuli. This is consistent with physiological data showing that in higher visual areas, latencies can increase more than 100 ms at low contrast compared to high contrast. Moreover, when presented with briefly flashed stimuli, the model predicts stereotypical responses that outlast the stimulus, again consistent with physiological findings. The adaptive properties of the model suggest that the abundant recurrent connections found in visual cortex serve to adapt the network's time constant in accordance with the stimulus and normalizes neuronal signals such that processing is as fast as possible while maintaining reliability.


Improving the Generalizability of Convolutional Neural Network-Based Segmentation on CMR Images.
Background: Convolutional neural network (CNN) based segmentation methods provide an efficient and automated way for clinicians to assess the structure and function of the heart in cardiac MR images. While CNNs can generally perform the segmentation tasks with high accuracy when training and test images come from the same domain (e.g., same scanner or site), their performance often degrades dramatically on images from different scanners or clinical sites. Methods: We propose a simple yet effective way for improving the network generalization ability by carefully designing data normalization and augmentation strategies to accommodate common scenarios in multi-site, multi-scanner clinical imaging data sets. We demonstrate that a neural network trained on a single-site single-scanner dataset from the UK Biobank can be successfully applied to segmenting cardiac MR images across different sites and different scanners without substantial loss of accuracy. Specifically, the method was trained on a large set of 3,975 subjects from the UK Biobank. It was then directly tested on 600 different subjects from the UK Biobank for intra-domain testing and two other sets for cross-domain testing: the ACDC dataset (100 subjects, 1 site, 2 scanners) and the BSCMR-AS dataset (599 subjects, 6 sites, 9 scanners). Results: The proposed method produces promising segmentation results on the UK Biobank test set which are comparable to previously reported values in the literature, while also performing well on cross-domain test sets, achieving a mean Dice metric of 0.90 for the left ventricle, 0.81 for the myocardium, and 0.82 for the right ventricle on the ACDC dataset; and 0.89 for the left ventricle, 0.83 for the myocardium on the BSCMR-AS dataset. Conclusions: The proposed method offers a potential solution to improve CNN-based model generalizability for the cross-scanner and cross-site cardiac MR image segmentation task.


Risk factors for restless legs syndrome in dialysis patients.
Restless legs syndrome (RLS) is a movement disorder that affects 6.6-62% of dialysis patients. The aims of this multicentre cross-sectional study were to document the frequency, prevalence and severity of RLS in patients attending 5 dialysis centres for chronic hospital haemodialysis (HHD) and to identify associated risk factors. The diagnosis of RLS was made using the criteria of The International Restless Legs Study Group. The following data were collected: age; gender; duration of renal replacement therapy (RRT); current smoking status; urea reduction ratio; weekly erythropoietin dose; weekly intravenous iron dose; prescribed beta blocker; prescribed renin/angiotensin system inhibitors and pre-dialysis blood concentrations of haemoglobin, ferritin, total calcium (corrected for albumin), albumin, phosphate, parathyroid hormone. Associations with RLS were analysed by univariate and multivariate logistic regression. Data relating to 277 of 295 patients who had been attending for regular HHD for > 3 months were collected. RLS was present in 127 (45.8%). 82 (29.6%), 27 (9.7%) and 18 (6.5%) patients had mild, moderate and severe RLS, respectively. 39 patients (14.1%) were prescribed medicines aimed at reducing RLS. 30 (76.9%) of these 39 patients still had RLS. Female gender (RR 2.17; p = 0.01), increasing duration since first dialysis (RR 1.06 per year; p = 0.03) and increasing body weight (RR 1.02 per kg; p = 0.02) were independent risk factors for RLS by multivariate analysis. In contrast to previous studies, we found no association with iron status, haemoglobin, serum phosphate or smoking. There is a high prevalence of RLS in our population and therapeutic intervention appears to have limited efficacy. The associations with female gender, duration of RRT and body weight deserve further study.


Enhancement of fluorescent properties of near-infrared dyes using clickable oligoglycerol dendrons.
Near-infrared (NIR) fluorescent dyes are gaining increased attention due to their potential to serve as molecular probes for in vivo imaging. Here, we demonstrate that oligoglycerol dendrons effectively enhance the fluorescence properties of an NIR dye by increasing the solubility in water and the prevention of aggregate formation. First- and second-generation oligoglycerol dendrons were conjugated to an NIR dye via a dipolar-cycloaddition (click) reaction. The two new dye conjugates exhibited enhanced NIR fluorescent emission and considerably higher fluorescent quantum yields than the dye alone. The high photostability measured for one of the oligoglycerol-linked dyes, in comparison to commonly used fluorogenic dyes such as Cy5 and Cy7, was validated using fluorescence microscopy of macrophages.


International Quotidian Dialysis Registry: Annual report 2010.
The International Quotidian Dialysis Registry (IQDR) is a global initiative designed to study practices and outcomes associated with the use of hemodialysis (HD) regimens of increased frequency and/or duration. The IQDR grew out of the initiative that lead to the randomized prospective studies of nocturnal HD and short hours daily dialysis vs. conventional thrice weekly HD that are conducted by the Frequent Hemodialysis Network sponsored by the National Institutes of Health. These 2 separate studies are drawing to a close and the first results are expected to be reported later this year. These studies use surrogate outcomes for their primary endpoints as they are not powered to look at outcomes of mortality and hospitalization. The IQDR attempts to aggregate long-term follow-up data from centers utilizing alternative HD regimens worldwide and will have adequate statistical power to examine those important outcomes. To date, the IQDR has enrolled patients from Canada, the United States, Australia, New Zealand, and France and has linked with commercial databases and national registries. This sixth annual report of the IQDR describes: (1) An update on the governance structure; (2) The recommendations made at the first general meetings of the IQDR Scientific Committee and Advisory Board; (3) The status of those recommendations; (4) A summary of current data sources and participating registries; (5) The status of recruitment to date; (6) The creation of a specific Canadian IQDR data set and; (7) The current research agenda.


Growth hormone acts on the synthesis and secretion of alpha-casein in bovine mammary epithelial cells.
To study the effect of growth hormone (GH) on the functions of mammary epithelia, we examined the effect of GH on the synthesis and secretion of alpha-casein in a bovine mammary epithelial cell (BMEC) clonal line, which was established from a 26-d-pregnant Holstein heifer. GH receptors (GHR) were observed in the BMEC on the membrane as well as in the cytoplasm. After BMEC were plated onto cell culture inserts, GH stimulated alpha-casein release in both the presence and absence of the lactogenic hormone complex, which included dexamethasone, insulin and prolactin (DIP). DIP enhanced the effect of GH on alpha-casein release. Although alpha(s1-) casein mRNA expression was not detected in untreated control cells, its expression was observed in BMEC in response to the GH, DIP and GH + DIP treatments. Expression was greater for GH and GH + DIP than for just DIP. Expression of GHR mRNA was increased by DIP treatment, while the mRNA expression was little changed by GH treatment. We conclude that GH acts on BMEC and induces the expression of both the alpha-casein gene and protein. GHR gene expression was shown to be regulated by DIP and GHR. GHR may be involved in a synergic effect between GH and DIP on casein secretion. These results suggest that GH, in addition to its widely accepted homeorhetic role in vivo, also can act on the mammary parenchyma, and that the effects of GH on mammary epithelial cells could partly account for the clear galactopoietic effect of recombinant bovine GH seen in lactating dairy cows.