Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10000 women in Guanacaste, Costa Rica,.
The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as > or = CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia. A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993-1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing > or = CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop >or = CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions >or = CIN 2 served as both the censoring outcome and our surrogate for cancer risk. Participation during follow-up was high (near 90%). Suspected > or = CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected > or = CIN 2 came from the large group perceived at entry as being at low risk of developing > or = CIN 2, but the greatest rates of progression to > or = CIN 2 were observed among women perceived at entry to be at highest risk of > or = CIN 2, based on their cytology, virology, or sexual behavior. The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed to building knowledge for the search for vaccines against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide.


Chemical constituents of Phragmanthera austroarabica A. G. Mill and J. A. Nyberg with potent antioxidant activity.
Phragmanthera austroarabica A.G. Mill. and J. A. Nyberg is a semi parasitic plant belonging to family Loranthaceae. It was collected from Saudi Arabia. It is widely used in folk medicine among the kingdom in treatment of various diseases including diabetes mellitus. The total alcoholic extract of P. austroarabica collected from Saudi Arabia was investigated for the chemical structure and prominent biological activity of the main constituents. Isolation of the active constituents was performed using different chromatographic techniques including column chromatography packed with silica or sephadex and preparative thin layer chromatography. The structures of the isolated compounds were established based on different spectroscopic data as mass spectrum, one-dimensional and two-dimensional nuclear magnetic resonance (correlation spectroscopy, heteronuclear single quantum coherence, and heteronuclear multiple-bond correlation). Phytochemical investigation of the plant resulted in isolation of 12 compounds. The isolated compounds were identified as chrysophanic acid, emodin, chrysophanic acid-8-O-glucoside, emodin-8-O-glucoside, pectolinarigenin, quercetin, dillenetin-3-O-glucoside, catechin, catechin-4'-O-gallate, methyl gallate, lupeol and ursolic acid. All the isolated phenolic compounds revealed significant free radical scavenging activities when tested using 2,2-diphenyl-1-picrylhydrazyl reagent. The antioxidant activities of the isolated compounds can justify the use of P. austroarabica in traditional medicine for treatment of diabetes and verify its possible application as an antihyperglycemic drug.


CRISPR/Cas9 Mutagenesis Reveals Versatile Roles of Hox Genes in Crustacean Limb Specification and Evolution.
Crustaceans possess a diverse array of specialized limbs. Although shifts in Hox gene expression domains have been postulated to play a role in generating this limb diversity, little functional data have been provided to understand the precise roles of Hox genes during crustacean development. We used a combination of CRISPR/Cas9-targeted mutagenesis and RNAi knockdown to decipher the function of the six Hox genes expressed in the developing mouth and trunk of the amphipod Parhyale hawaiensis. These experimentally manipulated animals display specific and striking homeotic transformations. We found that abdominal-A (abd-A) and Abdominal-B (Abd-B) are required for proper posterior patterning, with knockout of Abd-B resulting in an animal with thoracic type legs along what would have been an abdomen, and abd-A disruption generating a simplified body plan characterized by a loss of specialization in both abdominal and thoracic appendages. In the thorax, Ubx is necessary for gill development and for repression of gnathal fate, and Antp dictates claw morphology. In the mouth, Scr and Antp confer the part-gnathal, part-thoracic hybrid identity of the maxilliped, and Scr and Dfd prevent antennal identity in posterior head segments. Our results allow us to define the role Hox genes play in specifying each appendage type in Parhyale, including the modular nature by which some appendages are patterned by Hox gene inputs. In addition, we define how changes in Hox gene expression have generated morphological differences between crustacean species. Finally, we also highlight the utility of CRISPR/Cas9-based somatic mutagenesis in emerging model organisms.


A touch of glue to complete bacteriophage assembly: the tail-to-head joining protein (THJP) family.
Bacteriophage SPP1 is a nanomachine built to infect the bacterium Bacillus subtilis. The phage particle is composed of an icosahedric capsid, which contains the viral DNA, and a long non-contractile tail. Capsids and tails are produced in infected cells by two distinct morphogenetic pathways. Characterization of the suppressor-sensitive mutant SPP1sus82 showed that it produces DNA-filled capsids and tails but is unable to assemble complete virions. Its purified tails have a normal length but lack a narrow ring that tapers the tail end found at the tail-to-head interface. The mutant is defective in production of gp17. The gp17 ring is exposed in free tails competent for viral assembly but becomes shielded in the final virion structure. Recombinant gp17 is active in an in vitro assay to stick together capsids and tails present in extracts of SPP1sus82-infected cells, leading to formation of infectious particles. Gp17 thus plays a fundamental role in the tail-to-head joining reaction, the ultimate step of virus particle assembly. This is the conserved function of gp17 and its structurally related proteins like lambda gpU. This family of proteins can also provide fidelity to termination of the tail tube elongation reaction in a subset of phages including coliphage lambda.


Malaria is an important cause of anaemia in primigravidae: evidence from a district hospital in coastal Kenya.
A study was undertaken in order to determine the prevalence and aetiology of anaemia in pregnancy in coastal Kenya, so as to establish locally important causes and enable the development of appropriate intervention strategies. 275 women attending the antenatal clinic at Kilifi district hospital, Kenya, were recruited in November 1993. The prevalence of anaemia (haemoglobin [Hb] < 11 g/dL) was 75.6%, and the prevalence of severe anaemia (Hb < 7g/dL) was 9.8% among all parities; 15.3% of 73 primigravidae were severely anaemic, compared with 7.9% of 202 multigravidae (P = 0.07). In primigravidae, malaria infection (Plasmodium falciparum) was strongly associated with moderate and severe anaemia (chi 2 test for trend, P = 0.003). Severe anaemia was more than twice as common in women with peripheral parasitaemia as in those who were aparasitaemic, and parasitaemia was associated with a 2.2g/dL decrease in mean haemoglobin level (P < 0.001). In multigravidae, iron deficiency and hookworm infection were the dominant risk factors for anaemia. Folate deficiency and human immunodeficiency virus infection were not strongly associated with anaemia. It is suggested that an intervention that can effectively reduce malaria infection in primigravidae could have a major impact on the health of these women and their infants.


Association of Perioperative Red Blood Cell Transfusions With Venous Thromboembolism in a North American Registry.
Increasing evidence supports the role of red blood cells (RBCs) in physiological hemostasis and pathologic thrombosis. Red blood cells are commonly transfused in the perioperative period; however, their association with postoperative thrombotic events remains unclear. To examine the association between perioperative RBC transfusions and postoperative venous thromboembolism (VTE) within 30 days of surgery. This analysis used prospectively collected registry data from the American College of Surgery National Surgical Quality Improvement Program (ACS-NSQIP) database, a validated registry of 525 teaching and nonteaching hospitals in North America. Participants included patients in the ACS-NSQIP registry who underwent a surgical procedure from January 1 through December 31, 2014. Data were analyzed from July 1, 2016, through March 15, 2018. Risk-adjusted odds ratios (aORs) were estimated using multivariable logistic regression. The primary outcome was the development of postoperative VTE (deep venous thrombosis [DVT] and pulmonary embolism [PE]) within 30 days of surgery that warranted therapeutic intervention; DVT and PE were also examined separately as secondary outcomes. Subgroup analyses were performed by surgical subtypes. Propensity score matching was performed for sensitivity analyses. Of 750 937 patients (56.8% women; median age, 58 years; interquartile range, 44-69 years), 47 410 (6.3%) received at least 1 perioperative RBC transfusion. Postoperative VTE occurred in 6309 patients (0.8%) (DVT in 4336 [0.6%]; PE in 2514 [0.3%]; both DVT and PE in 541 [0.1%]). Perioperative RBC transfusion was associated with higher odds of VTE (aOR, 2.1; 95% CI, 2.0-2.3), DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1), independent of various putative risk factors. A significant dose-response effect was observed with increased odds of VTE as the number of intraoperative and/or postoperative RBC transfusion events increased (aOR, 2.1 [95% CI, 2.0-2.3] for 1 event; 3.1 [95% CI, 1.7-5.7] for 2 events; and 4.5 [95% CI, 1.0-19.4] for ≥3 events vs no intraoperative or postoperative RBC transfusion; P < .001 for trend). In subgroup analyses, the association between any perioperative RBC transfusion and postoperative VTE remained statistically significant across all surgical subspecialties analyzed. The association between any perioperative RBC transfusion and the development of postoperative VTE also remained robust after 1:1 propensity score matching (47 142 matched pairs; matched OR, 1.9; 95% CI, 1.8-2.1). The results of this study suggest that perioperative RBC transfusions may be significantly associated with the development of new or progressive postoperative VTE, independent of several putative confounders. These findings, if validated, should reinforce the importance of rigorous perioperative management of blood transfusion practices.


The floral organ number4 gene encoding a putative ortholog of Arabidopsis CLAVATA3 regulates apical meristem size in rice.
To understand the molecular mechanism regulating meristem development in the monocot rice (Oryza sativa), we describe here the isolation and characterization of three floral organ number4 (fon4) alleles and the cloning of the FON4 gene. The fon4 mutants showed abnormal enlargement of the embryonic and vegetative shoot apical meristems (SAMs) and the inflorescence and floral meristems. Likely due to enlarged SAMs, fon4 mutants produced thick culms (stems) and increased numbers of both primary rachis branches and floral organs. We identified FON4 using a map-based cloning approach and found it encodes a small putatively secreted protein, which is the putative ortholog of the Arabidopsis (Arabidopsis thaliana) CLAVATA3 (CLV3) gene. FON4 transcripts mainly accumulated in the small group of cells at the apex of the SAMs, whereas the rice ortholog of CLV1 (FON1) is expressed throughout the SAMs, suggesting that the putative FON4 ligand might be sequestered as a possible mechanism for rice meristem regulation. Exogenous application of the peptides FON4p and CLV3p corresponding to the CLV3/ESR-related (CLE) motifs of FON4 and CLV3, respectively, resulted in termination of SAMs in rice, and treatment with CLV3p caused consumption of both rice and Arabidopsis root meristems, suggesting that the CLV pathway in limiting meristem size is conserved in both rice and Arabidopsis. However, exogenous FON4p did not have an obvious effect on limiting both rice and Arabidopsis root meristems, suggesting that the CLE motifs of Arabidopsis CLV3 and FON4 are potentially functionally divergent.


A method to assess obstetric outcomes using the 10-Group Classification System: a quantitative descriptive study.
Internationally, the 10-Group Classification System (TGCS) has been used to report caesarean section rates, but analysis of other outcomes is also recommended. We now aim to present the TGCS as a method to assess outcomes of labour and delivery using routine collection of perinatal information. This research is a methodological study to describe the use of the TGCS. Stavanger University Hospital (SUH), Norway, National Maternity Hospital Dublin, Ireland and Slovenian National Perinatal Database (SLO), Slovenia. 9848 women from SUH, Norway, 9250 women from National Maternity Hospital Dublin, Ireland and 106 167 women, from SLO, Slovenia. All women were classified according to the TGCS within which caesarean section, oxytocin augmentation, epidural analgesia, operative vaginal deliveries, episiotomy, sphincter rupture, postpartum haemorrhage, blood transfusion, maternal age >35 years, body mass index >30, Apgar score, umbilical cord pH, hypoxic-ischaemic encephalopathy, antepartum and perinatal deaths were incorporated. There were significant differences in the sizes of the groups of women and the incidences of events and outcomes within the TGCS between the three perinatal databases. The TGCS is a standardised objective classification system where events and outcomes of labour and delivery can be incorporated. Obstetric core events and outcomes should be agreed and defined to set standards of care. This method provides continuous and available observations from delivery wards, possibly used for further interpretation, questions and international comparisons. The definition of quality may vary in different units and can only be ascertained when all the necessary information is available and considered together.


Dominance in Domestic Dogs: A Quantitative Analysis of Its Behavioural Measures.
A dominance hierarchy is an important feature of the social organisation of group living animals. Although formal and/or agonistic dominance has been found in captive wolves and free-ranging dogs, applicability of the dominance concept in domestic dogs is highly debated, and quantitative data are scarce. Therefore, we investigated 7 body postures and 24 behaviours in a group of domestic dogs for their suitability as formal status indicators. The results showed that high posture, displayed in most dyadic relationships, and muzzle bite, displayed exclusively by the highest ranking dogs, qualified best as formal dominance indicators. The best formal submission indicator was body tail wag, covering most relationships, and two low postures, covering two-thirds of the relationships. In addition, both mouth lick, as included in Schenkel's active submission, and pass under head qualified as formal submission indicators but were shown almost exclusively towards the highest ranking dogs. Furthermore, a status assessment based on changes in posture displays, i.e., lowering of posture (LoP) into half-low, low, low-on-back or on-back, was the best status indicator for most relationships as it showed good coverage (91% of the dyads), a nearly linear hierarchy (h' = 0.94, p<0.003) and strong unidirectionality (DCI = 0.97). The associated steepness of 0.79 (p<0.0001) indicated a tolerant dominance style for this dog group. No significant correlations of rank with age or weight were found. Strong co-variation between LoP, high posture, and body tail wag justified the use of dominance as an intervening variable. Our results are in line with previous findings for captive wolves and free-ranging dogs, for formal dominance with strong linearity based on submission but not aggression. They indicate that the ethogram for dogs is best redefined by distinguishing body postures from behavioural activities. A good insight into dominance hierarchies and its indicators will be helpful in properly interpreting dog-dog relationships and diagnosing problem behaviour in dogs.


Aggressive surgical management of gallbladder cancer: at what cost?
An aggressive operative approach to gallbladder cancer has been advocated because of improved long-term survival, but data on short-term outcomes are lacking. Therefore, the purpose of this study was to analyze the postoperative outcomes of patients undergoing operative management of gallbladder cancer. Data from the American College of Surgeons-National Surgical Quality Improvement Program (2005-2009) were queried for patients with a diagnosis of gallbladder cancer. Outcomes included serious morbidity, overall morbidity, and mortality. For the 613 patients identified, the median age was 67 years, and 64% were female. A potentially curative operation was performed in 424 (69%) patients, including cholecystectomy alone (n =150, 35%), partial hepatectomy (n = 249, 59%), and extensive hepatectomy (n = 25, 6%). Overall morbidity rates for these procedures were 21%, 19%, and 28%, respectively. Mortality was greater (P < .001) in patients undergoing extensive hepatectomy (16%) compared with those undergoing cholecystectomy (7%) or partial hepatectomy (2%). Partial hepatectomy is the most common procedure performed for gallbladder cancer and is a safe operation. A small minority of younger, healthier patients undergoes an extensive hepatectomy, but the mortality of this operation is greater. This analysis suggests that patients with gallbladder cancer should be managed at high-volume centers.


Role of gene duplications in the adaptation of Salmonella typhimurium to growth on limiting carbon sources.
Duplication-containing cells are selected when growth of Salmonella typhimurium is limited by the availability of any one of several carbon and energy sources. Under conditions of extreme starvation, growth occurs almost exclusively in the duplication-containing fraction of the population. Cells with duplications of one large segment of the chromosome are repeatedly selected regardless of which of these carbon sources limits growth. The duplicated chromosomal segment encodes the transport systems for all of these carbon sources. This duplication is not selected during growth on a carbon source for which the permease is not included within the duplication segment. This suggests that the growth advantage conferred by the duplication may be due to increased transport of the limiting carbon source. Inclusion of the permease alone is not sufficient to explain the growth advantage of the duplications, since other common duplications that include the permease are not selected.


Ligand pose and orientational sampling in molecular docking.
Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys-Enhanced (DUD-E) benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20,000 molecular orientations in the binding site (and so from about 1×10(10) to 4×10(10) to 1×10(11) to 2×10(11) to 5×10(11) mean atoms scored per target, since multiple conformations are sampled per orientation), the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field.


Fractal gait patterns are retained after entrainment to a fractal stimulus.
Previous work has shown that fractal patterns in gait can be altered by entraining to a fractal stimulus. However, little is understood about how long those patterns are retained or which factors may influence stronger entrainment or retention. In experiment one, participants walked on a treadmill for 45 continuous minutes, which was separated into three phases. The first 15 minutes (pre-synchronization phase) consisted of walking without a fractal stimulus, the second 15 minutes consisted of walking while entraining to a fractal visual stimulus (synchronization phase), and the last 15 minutes (post-synchronization phase) consisted of walking without the stimulus to determine if the patterns adopted from the stimulus were retained. Fractal gait patterns were strengthened during the synchronization phase and were retained in the post-synchronization phase. In experiment two, similar methods were used to compare a continuous fractal stimulus to a discrete fractal stimulus to determine which stimulus type led to more persistent fractal gait patterns in the synchronization and post-synchronization (i.e., retention) phases. Both stimulus types led to equally persistent patterns in the synchronization phase, but only the discrete fractal stimulus led to retention of the patterns. The results add to the growing body of literature showing that fractal gait patterns can be manipulated in a predictable manner. Further, our results add to the literature by showing that the newly adopted gait patterns are retained for up to 15 minutes after entrainment and showed that a discrete visual stimulus is a better method to influence retention.


Incidence of gallstone disease in Italy: results from a multicenter, population-based Italian study (the MICOL project).
To evaluate gallstone incidence and risk factors in a large population-based study. Gallstone incidence and risk factors, were evaluated by structured questionnaire and physical examination, respectively, in 9611 of 11 109 (86.5%) subjects who were gallstone-free at the cross-sectional study. Six centers throughout Italy enrolled 9611 subjects (5477 males, 4134 females, aged 30-79 years), 9517 of whom were included into analysis: 424 subjects (4.4%) had gallstones and 61 (0.6%) had been cholecystectomized yielding a cumulative incidence of 0.67% per year (0.66% in males, 0.81% in females). Increasing age, a high body mass index (BMI), a history of diabetes, peptic ulcer and angina, and low cholesterol and high triglyceride levels were identified as risk factors in men while, in females, the only risk factors were increasing age and a high BMI. Increasing age and pain in the right hypocondrium in men and increasing age in females were identified as predictors of gallstones. Pain in the epigastrium/right hypocondrium was the only symptom related to gallstones; furthermore, some characteristics of pain (forcing to rest, not relieved by bowel movements) were significantly associated with gallstones. No correlation was found between gallstone characteristics and clinical manifestations, while increasing age in men and increasing age and BMI in females were predictors of pain. Increasing age and BMI represent true risk factors for gallstone disease (GD); pain in the right hypocondrium and/or epigastrium is confirmed as the only symptom related to gallstones.


Brain Structural Effects of Psychopharmacological Treatment in Bipolar Disorder.
Bipolar disorder is associated with subtle neuroanatomical deficits including lateral ventricular enlargement, grey matter deficits incorporating limbic system structures, and distributed white matter pathophysiology. Substantial heterogeneity has been identified by structural neuroimaging studies to date and differential psychotropic medication use is potentially a substantial contributor to this. This selective review of structural neuroimaging and diffusion tensor imaging studies considers evidence that lithium, mood stabilisers, antipsychotic medication and antidepressant medications are associated with neuroanatomical variation. Most studies are negative and suffer from methodological weaknesses in terms of directly assessing medication effects on neuroanatomy, since they commonly comprise posthoc assessments of medication associations with neuroimaging metrics in small heterogenous patient groups. However the studies which report positive findings tend to form a relatively consistent picture whereby lithium and antiepileptic mood stabiliser use is associated with increased regional grey matter volume, especially in limbic structures. These findings are further supported by the more methodologically robust studies which include large numbers of patients or repeated intra-individual scanning in longitudinal designs. Some similar findings of an apparently ameliorative effect of lithium on white matter microstructure are also emerging. There is less support for an effect of antipsychotic or antidepressant medication on brain structure in bipolar disorder, but these studies are further limited by methodological difficulties. In general the literature to date supports a normalising effect of lithium and mood stabilisers on brain structure in bipolar disorder, which is consistent with the neuroprotective characteristics of these medications identified by preclinical studies.


COXPRESdb: a database of comparative gene coexpression networks of eleven species for mammals.
Coexpressed gene databases are valuable resources for identifying new gene functions or functional modules in metabolic pathways and signaling pathways. Although coexpressed gene databases are a fundamental platform in the field of plant biology, their use in animal studies is relatively limited. The COXPRESdb (http://coxpresdb.jp) provides coexpression relationships for multiple animal species, as comparisons of coexpressed gene lists can enhance the reliability of gene coexpression determinations. Here, we report the updates of the database, mainly focusing on the following two points. First, we updated our coexpression data by including recent microarray data for the previous seven species (human, mouse, rat, chicken, fly, zebrafish and nematode) and adding four new species (monkey, dog, budding yeast and fission yeast), along with a new human microarray platform. A reliability scoring function was also implemented, based on coexpression conservation to filter out coexpression with low reliability. Second, the network drawing function was updated, to implement automatic cluster analyses with enrichment analyses in Gene Ontology and in cis elements, along with interactive network analyses with Cytoscape Web. With these updates, COXPRESdb will become a more powerful tool for analyses of functional and regulatory networks of genes in a variety of animal species.


Percutaneous nephrolithotomy for pediatric urolithiasis.
Pediatric urolithiasis is a management dilemma as a number of treatment options are available such as shock wave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), and retrograde intrarenal surgery (RIRS). PCNL offers good clearance rates in a single hospital stay. The concerns with PCNL include the use of large instrument in pediatric kidneys, parenchymal damage and the associated effects on renal function, radiation exposure with fluoroscopy, and the risk of major complications including sepsis and bleeding. Evolution of pediatric PCNL technique such as miniaturization of instruments, limitation of tract size and advanced intracorporeal lithotripters have resulted in this technique being widely utilized for achieving stone-free status in appropriate patients. Many of the patients in our country come from remote areas thereby requiring special considerations during treatment. This also necessitates complete clearance in a single shorter hospital stay. PCNL appears to be the optimal option available in this scenario. The literature suggests that even complex and staghorn calculi can be tackled with this approach. The choice of the method to gain access is a matter of experience and personal preference. Ultrasound offers the advantage of visualization of spleen, liver and avoids injury. Miniaturization of instruments, particularly smaller nephroscopes and the potential to use lasers will decrease the morbidity and improve the clearance rates further. In this article, we analyze the management of pediatric urolithiasis with PCNL. We discuss our technique and analyze the results, complications and technique mentioned in the contemporary literature.


Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein.
Multiple sclerosis (MS) may be an autoimmune disease mediated by T cells specific for a myelin protein. Investigations have demonstrated myelin basic protein (MBP)-reactive T cells that were activated in vivo in MS patients, suggesting that MBP may be a target antigen in MS. The variable (V) region of the T cell receptor (TCR) beta chain was examined among 83 T cell lines from both MS patients and healthy subjects that were reactive with the immunodominant region of human MBP (residues 84 to 102) or with a second immunodominant region of MBP (143 to 168). V beta 17 and to a lesser extent V beta 12 were frequently used in recognition of MBP(84-102) among different individuals. In contrast, V beta 17 was very infrequent among lines reactive with MBP (143-168). These data demonstrate shared TCR V beta gene usage for the recognition of immunodominant regions of the human autoantigen MBP. Such TCR structures may be used as targets for specific immunotherapy in MS.


Differential daily expression of Per1 and Per2 mRNA in the suprachiasmatic nucleus of fetal and early postnatal mice.
It is well known that there are circadian rhythms of 2-deoxyglucose uptake and neuronal firing in the rat suprachiasmatic nucleus (SCN) during fetal and early postnatal periods. A core clock mechanism in the mouse SCN appears to involve a transcriptional feedback loop in which CLOCK and BMAL1 function as positive regulators and three mPeriod (mPer) genes play a role in negative feedback. Per genes expression occurs not only in the adult SCN but also in the fetal SCN. However, the developmental change in these genes remains unclear. In this experiment, we examined the day--night pattern of expression of Per1 and Per2 mRNA in the mouse SCN and cerebral cortex on embryonic day 17, postnatal day 3, and in young adult mice under a light-dark cycle. Daily rhythms of mRNA content were observed in mPer1 but not mPer2 in the fetal SCN. Interestingly, the expression of mPer2 in the SCN was high throughout the entire day, and a significant daily rhythm of this gene was observed on postnatal day 6. The expression pattern of SCN mPer1 in constant darkness was similar to that seen in the light-dark cycle. The present results suggest that the daily oscillation of mPer1 but not of mPer2 in the SCN in fetal and early postnatal mice may be associated with the daily rhythms of 2-deoxyglucose uptake and neuronal firing.


MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.
Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.


A novel gene, CBP1, encoding a putative extracellular chitin-binding protein, may play an important role in the hydrophobic surface sensing of Magnaporthe grisea during appressorium differentiation.
The conidial germ tube of the rice blast fungus, Magnaporthe grisea, differentiates a specialized cell, an appressorium, required for penetration into the host plant. Formation of the appressorium is also observed on artificial solid substrata such as polycarbonate. A novel emerging germ tube-specific gene, CBP1 (chitin-binding protein), was found in a cDNA subtractive differential library. CBP1 coded for a putative extracellular protein (signal peptide) with two similar chitin-binding domains at both ends of a central domain with homology to fungal chitin deacetylases and with a C-terminus domain rich in Ser/Thr related extracellular matrix protein such as agglutinin. The consensus sequence of the chitin-binding domain found in CBP1 has never been reported in fungi and is similar to the chitin-binding motif in plant lectins and plant chitinases classes I and IV. CBPI was disrupted in order to identify its function. Null mutants of CBP1 failed to differentiate appressoria normally on artificial surface but succeeded in normally differentiating appressoria on the plant leaf surface. Since the null mutant Cbp1- showed abnormal appressorium differentiation only on artificial surfaces and was sensitive to the chemical inducers, CBP1 seemed to play an important role in the recognition of physical factors on solid surfaces.


Intracellular electrical activity in human urinary bladder smooth muscle: the effect of high sucrose medium.
The primary key to pharmacotherapy of bladder instability is in the excitation-contraction coupling of detrusor smooth muscle cells. To study this process, simultaneous recordings of mechanical and electrical activity are required. However, recording of mechanical activity induces movement, which may affect the quality of intracellular recordings. We therefore compared the electrical activity of human detrusor smooth muscle cells in normal Krebs' solution and in a hypertonic solution, which immobilizes the tissue, enabling us to study the effect of movement on the membrane potential. Carbachol and KCl were applied to induce contractions. Sucrose in the medium made the tissue rigid and abolished its movement, while the electrical response was not affected. When compared with recordings in normal Krebs' solution, the average resting membrane potential was not altered. However, the membrane potential was more stable, with far less spike-shaped potentials. The spike-shaped potential amplitude was larger, while the duration was decreased. Impairing the ability of tissue movement resulted in changes in the electrophysiological properties of detrusor smooth muscle cells. The results suggest that stretch has an effect on L-type Ca2+ channels.


A multi-professional short-term group intervention for informal caregivers of patients using a home palliative care service.
Informal carers of home palliative care patients have high unmet needs. However, interventions for carers are few. This research-based short-term group intervention addresses the information and support needs of carers. Multiprofessional informal teaching is combined with peer support. The intervention was designed by integrating the findings from a qualitative study and the evidence on needs and interventions, in order to address the key issues of feasibility, acceptability, and accessibility. Qualitative data from attendees showed that identifying with other carers and validating feelings, asking questions of professionals, and providing each other with support and encouragement were valuable outcomes from the group.


Anatomical and histological characteristics of the lungs in the ground squirrel (Spermophilus citellus).
The aim of this work was to study the topography, morphology, vascularisation, histology and innervation of the lungs in the ground squirrel (Spermophilus citellus) and compare these data with those concerning the rat, mole rat, rabbit and mouse. The research was carried out on 15 animals. It was revealed that the right lung has four lobes (cranial, middle, caudal and accessory lobes), while the left lung is not divided into segments. The functional vessels are a. pulmonalis dextra et sinistra and vv. pulmonales (5-6), while the nutritive vessels of the lungs are a. bronchoesophagea dextra and v. bronchoesophagea dextra. Histological tissue sections of the lungs revealed that the wall of terminal bronchioles contains no cartilage and the mucosal epithelium is pseudostratified, cubic and ciliated. Clara cells (club cells, bronchiolar exocrine cells) are present but have no cilia. The lung alveolar diameter is 37 μm on average, and the thickness of the alveolar wall and the interalveolar septa is 1.38 μm. Destruction of the alveolar walls, accumulation of erythrocytes in the capillaries of alveolar septa and destruction of the cytolemma of the capillary endothelium were detected. In addition, connective tissue fibres and peripheral nerves were detected by silver impregnation.


Scytalidium dimidiatum causing recalcitrant subcutaneous lesions produces melanin.
Scytalidium dimidiatum is a pigmented dematiaceous coelomycete that typically causes chronic superficial skin diseases and onychomycosis, as well as deeper infections, such as subcutaneous abscesses, mycetoma, and even fungemia in immunocompromised patients. A second species, Scytalidium hyalinum, has hyaline hyphae and arthroconidia and is considered by some authors to be an albino mutant of S. dimidiatum. This study aimed to confirm the presence of melanin or melanin-like compounds (which have been previously implicated in the virulence of other fungal pathogens) in S. dimidiatum from a patient with multiple subcutaneous nodules. Treatment of the hyphae and arthroconidia with proteolytic enzymes, denaturant, and concentrated hot acid yielded dark particles, which were stable free radicals, consistent with their identification as melanins. Extracted melanin particles from S. dimidiatum cultures were labeled by melanin-binding monoclonal antibodies (MAbs) from Sporothrix schenckii, Aspergillus fumigatus, and Cryptococcus neoformans. Lesional skin from the patient infected with S. dimidiatum contained fungal cells that were labeled by melanin-binding MAbs, and digestion of the tissue yielded dark particles that were also reactive. S. hyalinum was also subjected to the melanin extraction protocol, but no dark particles were yielded.


Attentional focus and performance anxiety: effects on simulated race-driving performance and heart rate variability.
Previous studies have demonstrated that an external focus can enhance motor learning compared to an internal focus. The benefits of adopting an external focus are attributed to the use of less effortful automatic control processes, while an internal focus relies upon more effort-intensive consciously controlled processes. The aim of this study was to compare the effectiveness of a distal external focus with an internal focus in the acquisition of a simulated driving task and subsequent performance in a competitive condition designed to increase state anxiety. To provide further evidence for the automatic nature of externally controlled movements, the study included heart rate variability (HRV) as an index of mental effort. Sixteen participants completed eight blocks of four laps in either a distal external or internal focus condition, followed by two blocks of four laps in the competitive condition. During acquisition, the performance of both groups improved; however, the distal external focus group outperformed the internal focus group. The poorer performance of the internal focus group was accompanied by a larger reduction in HRV, indicating a greater investment of mental effort. In the competition condition, state anxiety increased, and for both groups, performance improved as a function of the increased anxiety. Increased heart rate and self-reported mental effort accompanied the performance improvement. The distal external focus group also outperformed the internal focus group across both neutral and competitive conditions and this more effective performance was again associated with lower levels of HRV. Overall, the results offer support for the suggestion that an external focus promotes a more automatic mode of functioning. In the competitive condition, both foci enhanced performance and while the improved performance may have been achieved at the expense of greater compensatory mental effort, this was not reflected in HRV scores.


A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection.
SARS-CoV-2 causes ongoing pandemic coronavirus disease of 2019 (COVID-19), infects the cells of the lower respiratory tract that leads to a cytokine storm in a significant number of patients resulting in severe pneumonia, shortness of breathing, respiratory and organ failure. Extensive studies suggested the role of Vitamin D in suppressing cytokine storm in COVID-19 and reducing viral infection; however, the precise molecular mechanism is not clearly known. In this work, bioinformatics and systems biology approaches were used to understand SARS-CoV-2 induced cytokine pathways and the potential mechanism of Vitamin D in suppressing cytokine storm and enhancing antiviral response. This study used transcriptome data and identified 108 differentially expressed host genes (DEHGs) in SARS-CoV-2 infected normal human bronchial epithelial (NHBE) cells compared to control. Then, the DEHGs was integrated with the human protein-protein interaction data to generate a SARS-CoV-2 induced host gene regulatory network (SiHgrn). Analysis of SiHgrn identified a sub-network "Cluster 1" with the highest MCODE score, 31 up-regulated genes, and predominantly associated immune and inflammatory response. Interestingly, the iRegulone tool identified that "Cluster 1" is under the regulation of transcription factors STAT1, STAT2, STAT3, POU2F2, and NFkB1, collectively referred to as "host response signature network". Functional enrichment analysis with NDEx revealed that the "host response signature network" is predominantly associated with critical pathways, including "cytokines and inflammatory response", "non-genomic action of Vitamin D", "the human immune response to tuberculosis", and "lung fibrosis". Finally, in-depth analysis and literature mining revealed that Vitamin D binds with its receptor and could work through two different pathways: (i) it inhibits the expression of pro-inflammatory cytokines through blocking the TNF induced NFkB1 signaling pathway; and (ii) it initiates the expression of interferon-stimulating genes (ISGs) for antiviral defense program through activating the IFN-α induced Jak-STAT signaling pathway. This comprehensive study identified the pathways associated with cytokine storm in SARS-CoV-2 infection. The proposed underlying mechanism of Vitamin D could be promising in suppressing the cytokine storm and inducing a robust antiviral response in severe COVID-19 patients. The finding in this study urgently needs further experimental validations for the suitability of Vitamin D in combination with IFN-α to control severe COVID-19.


Deflection and trapping of spatial solitons in linear photonic potentials.
We investigate the dynamics of spatial optical solitons launched in a medium with a finite perturbation of the refractive index. For longitudinally short perturbations of super-Gaussian transverse profile, as the input power varies we observe a transition from a wave-like behavior where solitons break up into multiple fringes to a particle-like behavior where solitons acquire a transverse velocity retaining their shape. For longitudinally long perturbations with an attractive potential solitons get trapped inside the well and propagate with transverse periodic oscillations, resulting in an efficient power-dependent angular steering or deflection. Using the Ehrenfest theorem we derive analytical expressions for soliton trajectory, and achieve excellent agreement between theory and numerical simulations for large powers, that is, narrow solitons.


Behavioural response of the malaria vector Anopheles gambiae to host plant volatiles and synthetic blends.
Sugar feeding is critical for survival of malaria vectors and, although discriminative plant feeding previously has been shown to occur in Anopheles gambiae s.s., little is known about the cues mediating attraction to these plants. In this study, we investigated the role of olfaction in An. gambiae discriminative feeding behaviour. Dual choice olfactometer assays were used to study odour discrimination by An. gambiae to three suspected host plants: Parthenium hysterophorus (Asteraceae), Bidens pilosa (Asteraceae) and Ricinus communis (Euphorbiaceae). Sugar content of the three plant species was determined by analysis of their trimethylsilyl derivatives by coupled gas chromatography-mass spectrometry (GC-MS) and confirmed with authentic standards. Volatiles from intact plants of the three species were collected on Super Q and analyzed by coupled GC-electroantennographic detection (GC-EAD) and GC-MS to identify electrophysiologically-active components whose identities were also confirmed with authentic standards. Active compounds and blends were formulated using dose-response olfactory bioassays. Responses of females were converted into preference indices and analyzed by chi-square tests. The amounts of common behaviourally-active components released by the three host plants were compared with one-way ANOVA. Overall, the sugar contents were similar in the two Asteraceae plants, P. hysterophorus and B. pilosa, but richer in R. communis. Odours released by P. hysterophorus were the most attractive, with those from B. pilosa being the least attractive to females in the olfactometer assays. Six EAD-active components identified were consistently detected by the antennae of adult females. The amounts of common antennally-active components released varied with the host plant, with the highest amounts released by P. hysterophorus. In dose-response assays, single compounds and blends of these components were attractive to females but to varying levels, with one of the blends recording a significantly attractive response from females when compared to volatiles released by either the most preferred plant, P. hysterophorus (χ2 = 5.23, df = 1, P < 0.05) or as a synthetic blend mimicking that released by P. hysterophorus. Our results demonstrate that (a) a specific group of plant odours attract female An. gambiae (b) females use both qualitative and quantitative differences in volatile composition to associate and discriminate between different host plants, and (c) altering concentrations of individual EAD-active components in a blend provides a practical direction for developing effective plant-based lures for malaria vector management.


Dynamic shift effect on bistability in nonlinear optical microcavities.
The shift of optical cavity modes oscillates due to the time-varying refractive index under Kerr nonlinearity. To reveal its impact on bistability, we present a time-average approach that includes this dynamic shift characteristic in the expression of nonlinear transmission. It predicts the monotonous decrease of the maximum transmission with the increase of the frequency detuning. Also, the frequency detuning to start bistability should be corrected as about 2. Our analyses are supported by the simulations based on the finite-difference time-domain technique.


Ten recent insights for our understanding of cooperation.
Since Hamilton published his seminal papers in 1964, our understanding of the importance of cooperation for life on Earth has evolved beyond recognition. Early research was focused on altruism in the social insects, where the problem of cooperation was easy to see. In more recent years, research into cooperation has expanded across the entire tree of life, and has been revolutionized by advances in genetic, microbiological and analytical techniques. We highlight ten insights that have arisen from these advances, which have illuminated generalizations across different taxa, making the world simpler to explain. Furthermore, progress in these areas has opened up numerous new problems to solve, suggesting exciting directions for future research.


Crystal structure of rice Rubisco and implications for activation induced by positive effectors NADPH and 6-phosphogluconate.
The key enzyme of plant photosynthesis, D-ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), must be activated to become catalytically competent via the carbamylation of Lys201 of the large subunit and subsequent stabilization by Mg(2+) coordination. Many biochemical studies have reported that reduced nicotinamide adenine dinucleotide phosphate (NADPH) and 6-phosphogluconate (6PG) function as positive effectors to promote activation. However, the structural mechanism remains unknown. Here, we have determined the crystal structures of activated rice Rubisco in complex with NADPH, 6PG, or 2-carboxy-D-arabinitol 1,5-bisphosphate (2CABP). The structures of the NADPH and 6PG complexes adopt open-state conformations, in which loop 6 at the catalytic site and some other loops are disordered. The structure of the 2CABP complex is in a closed state, similar to the previous 2CABP-bound activated structures from other sources. The catalytic sites of the NADPH and 6PG complexes are fully activated, despite the fact that bicarbonate (NaHCO(3)) was not added into the crystallization solution. In the catalytic site, NADPH does not interact with Mg(2+) directly but interacts with Mg(2+)-coordinated water molecules, while 6PG interacts with Mg(2+) directly. These observations suggest that the two effectors promote Rubisco activation by stabilizing the complex of Mg(2+) and the carbamylated Lys201 with unique interactions and preventing its dissociation. The structure also reveals that the relaxed complex of the effectors (NADPH or 6PG), distinct from the tight-binding mode of 2CABP, would allow rapid exchange of the effectors in the catalytic sites by substrate D-ribulose 1,5-bisphosphate for catalysis in physiological conditions.


Contamination assessment of orthodontic bands after different pre-cleaning methods at a tertiary care hospital.
Infection control in dentistry is a major concern due to risk of transmission of communicable diseases. The aim of this study is to evaluate and compare the efficacy of various pre-cleaning methods for the tried-in orthodontic bands. An in-vitro experimental study was conducted at the Central Sterilization Services Department (Dental Clinic) and the Microbiology lab at our university hospital. A total of 130 bands were included in our study which comprised 10 controls and the rest were equally divided into three groups according to the pre-cleaning methods, i.e. manual scrubbing, enzymatic solution and a combination of both. The orthodontic bands were incubated in the brain heart infusion broth at 37 °C for five days after pre-cleaning and sterilisation in a steam autoclave and were assessed for any bacterial growth. The chi-square test was applied to determine any significant association between the various pre-cleaning methods and the frequency of bands that showed growth. Effect size was calculated using the phi coefficient. The enzyme method revealed 5% of the sample to exhibit bacterial growth, whereas manual scrubbing and the combination of both showed no growth. There was no statistically significant difference among the three methods (P = 0.131). Further investigations showed the presence of Staphylococcus non-aureus bacterial species in contaminated bands from group II. All pre-cleaning methods were found to be equally effective in the decontamination of bands. Hence, the tried-in bands can be safely reused after pre-cleaning and sterilisation.


The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT.
FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non-small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1-driven drug resistance in the clinic. IMPLICATIONS: The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial-mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.


Non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease.
Non-invasive ventilation (NIV) with bi-level positive airway pressure (BiPAP) is commonly used to treat patients admitted to hospital with acute hypercapnic respiratory failure (AHRF) secondary to an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). To compare the efficacy of NIV applied in conjunction with usual care versus usual care involving no mechanical ventilation alone in adults with AHRF due to AECOPD. The aim of this review is to update the evidence base with the goals of supporting clinical practice and providing recommendations for future evaluation and research. We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and PsycINFO, and through handsearching of respiratory journals and meeting abstracts. This update to the original review incorporates the results of database searches up to January 2017. All randomised controlled trials that compared usual care plus NIV (BiPAP) versus usual care alone in an acute hospital setting for patients with AECOPD due to AHRF were eligible for inclusion. AHRF was defined by a mean admission pH < 7.35 and mean partial pressure of carbon dioxide (PaCO2) > 45 mmHg (6 kPa). Primary review outcomes were mortality during hospital admission and need for endotracheal intubation. Secondary outcomes included hospital length of stay, treatment intolerance, complications, changes in symptoms, and changes in arterial blood gases. Two review authors independently applied the selection criteria to determine study eligibility, performed data extraction, and determined risk of bias in accordance with Cochrane guidelines. Review authors undertook meta-analysis for data that were both clinically and statistically homogenous, and analysed data as both one overall pooled sample and according to two predefined subgroups related to exacerbation severity (admission pH between 7.35 and 7.30 vs below 7.30) and NIV treatment setting (intensive care unit-based vs ward-based). We reported results for mortality, need for endotracheal intubation, and hospital length of stay in a 'Summary of findings' table and rated their quality in accordance with GRADE criteria. We included in the review 17 randomised controlled trials involving 1264 participants. Available data indicate that mean age at recruitment was 66.8 years (range 57.7 to 70.5 years) and that most participants (65%) were male. Most studies (12/17) were at risk of performance bias, and for most (14/17), the risk of detection bias was uncertain. These risks may have affected subjective patient-reported outcome measures (e.g. dyspnoea) and secondary review outcomes, respectively.Use of NIV decreased the risk of mortality by 46% (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.38 to 0.76; N = 12 studies; number needed to treat for an additional beneficial outcome (NNTB) 12, 95% CI 9 to 23) and decreased the risk of needing endotracheal intubation by 65% (RR 0.36, 95% CI 0.28 to 0.46; N = 17 studies; NNTB 5, 95% CI 5 to 6). We graded both outcomes as 'moderate' quality owing to uncertainty regarding risk of bias for several studies. Inspection of the funnel plot related to need for endotracheal intubation raised the possibility of some publication bias pertaining to this outcome. NIV use was also associated with reduced length of hospital stay (mean difference (MD) -3.39 days, 95% CI -5.93 to -0.85; N = 10 studies), reduced incidence of complications (unrelated to NIV) (RR 0.26, 95% CI 0.13 to 0.53; N = 2 studies), and improvement in pH (MD 0.05, 95% CI 0.02 to 0.07; N = 8 studies) and in partial pressure of oxygen (PaO2) (MD 7.47 mmHg, 95% CI 0.78 to 14.16 mmHg; N = 8 studies) at one hour. A trend towards improvement in PaCO2 was observed, but this finding was not statistically significant (MD -4.62 mmHg, 95% CI -11.05 to 1.80 mmHg; N = 8 studies). Post hoc analysis revealed that this lack of benefit was due to the fact that data from two studies at high risk of bias showed baseline imbalance for this outcome (worse in the NIV group than in the usual care group). Sensitivity analysis revealed that exclusion of these two studies resulted in a statistically significant positive effect of NIV on PaCO2. Treatment intolerance was significantly greater in the NIV group than in the usual care group (risk difference (RD) 0.11, 95% CI 0.04 to 0.17; N = 6 studies). Results of analysis showed a non-significant trend towards reduction in dyspnoea with NIV compared with usual care (standardised mean difference (SMD) -0.16, 95% CI -0.34 to 0.02; N = 4 studies). Subgroup analyses revealed no significant between-group differences. Data from good quality randomised controlled trials show that NIV is beneficial as a first-line intervention in conjunction with usual care for reducing the likelihood of mortality and endotracheal intubation in patients admitted with acute hypercapnic respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease (COPD). The magnitude of benefit for these outcomes appears similar for patients with acidosis of a mild (pH 7.30 to 7.35) versus a more severe nature (pH < 7.30), and when NIV is applied within the intensive care unit (ICU) or ward setting.


Self-Adjustment of Upper Electrical Stimulation Levels in CI Programming and the Effect on Auditory Functioning.
With current cochlear implants (CIs), CI recipients achieve good speech perception in quiet surroundings. However, in acoustically complex, real-life environments, speech comprehension remains difficult and sound quality often remains poor. It is, therefore, a challenge to program CIs for such environments in a clinic. The CI manufacturer Cochlear Ltd. recently introduced a remote control that enables CI recipients to alter the upper stimulation levels of their user programs themselves. In this concept, called remote assistant fitting (RAF), bass and treble controls can be adjusted by applying a tilt to emphasize either the low- or high-frequency C-levels, respectively. This concept of self-programming may be able to overcome limitations associated with fine-tuning the CI sound processor in a clinic. The aim of this study was to investigate to what extent CI recipients already accustomed to their clinically fitted program would adjust the settings in daily life if able to do so. Additionally, we studied the effects of these changes on auditory functioning in terms of speech intelligibility (in quiet and in noise), noise tolerance, and subjectively perceived speech perception and sound quality. Twenty-two experienced adult CI recipients (implant use >12 months) participated in this prospective clinical study, which used a within-subject repeated measures design. All participants had phoneme scores of ≥70% at 65 dB SPL in quiet conditions, and all used a Cochlear Nucleus CP810 sound processor. Auditory performance was tested by a speech-in-quiet test, a speech-in-noise test, an acceptable noise level test, and a questionnaire about perceived auditory functioning, that is, a speech and sound quality (SSQ-C) questionnaire. The first session consisted of a baseline test in which the participants used their own CI program and were instructed on how to use RAF. After the first session, participants used RAF for 3 weeks at home. After these 3 weeks, the participants returned to the clinic for auditory functioning tests with their self-adjusted programs and completed the SSQ-C. Fifteen participants (68%) adjusted their C-level frequency profile by more than 5 clinical levels for at least one electrode. Seven participants preferred a higher contribution of the high frequencies relative to the low frequencies, while five participants preferred more low-frequency stimulation. One-third of the participants adjusted the high and low frequencies equally, while some participants mainly used the overall volume to change their settings. Several parts of the SSQ-C questionnaire scores showed an improvement in perceived auditory functioning after the subjects used RAF. No significant change was found on the auditory functioning tests for speech-in-quiet, speech-in-noise, or acceptable noise level. In conclusion, the majority of experienced CI users made modest changes in the settings of their programs in various ways and were able to do so with the RAF. After altering the programs, the participants experienced an improvement in speech perception in quiet environments and improved perceived sound quality without compromising auditory performance. Therefore, it can be concluded that self-adjustment of CI settings is a useful and clinically applicable tool that may help CI recipients to improve perceived sound quality in their daily lives.


Disorganised stroma determined on pre-treatment breast cancer biopsies is associated with poor response to neoadjuvant chemotherapy: Results from the NEOZOTAC trial.
The tumor-associated stroma is of importance for tumor progression and is generally accepted to have a significant influence on patient prognosis. However, little is known regarding specific features of tumor-associated stromal tissues and response to (neoadjuvant) chemotherapy. This study investigated the predictive value of extracellular matrix organization on response to chemotherapy in patients treated in the NEOZOTAC trial. Stromal organisation was analyzed via a simple method using image analysis software on hematoxylin and eosin (H&E)-stained slides from primary tumor biopsies collected as part of the NEOZOTAC trial. Heidenhain's AZAN trichrome-stained slides were also analyzed for comparison of collagen evaluation. Sections were stained for phospho-Smad2 (pS2) in order to determine the relationship of TGF-β signaling with stromal organization. A statistically significant relationship was observed between stroma consisting of organised collagen and pathological response to neoadjuvant chemotherapy (Odds Ratio 0.276, 95%CI 0.124-0.614, P = 0.002). This parameter was also related to ER-status (P = 0.003), clinical tumor -status (P = 0.041), nodal status (P = 0.029) and pS2 status (P = 0.025). Correlation between stromal organisation determined on H&E-stained and AZAN-stained tissue sections was high (Pearson's correlation coefficient = 0.806). Intratumoral stromal organisation determined using pre-treatment breast cancer biopsies was related to pathological response to chemotherapy. This parameter might play a role in the management of breast cancer for identifying those patients that are likely to benefit from neoadjuvant chemotherapy.


Experiences, Perspectives, and Barriers to Physical Activity Parenting Practices for Chinese Early Adolescents.
Parents play an important role in shaping youth's lifestyle behaviors. This study aimed to investigate physical activity parenting practices (PAPP) for Chinese early adolescents and compare reporting discrepancies between parents and adolescent boys and girls. Fifty-five adolescent-parent dyads participated in 16 paired focus group interviews, and an additional 122 dyads completed questionnaire surveys with open-ended questions. Participants were recruited from 3 public middle schools in Suzhou, China. Qualitative data were analyzed inductively using an open-coding scheme. Frequencies of codes were compared by parent-child role and adolescent gender using chi-square tests. Eighteen types of PAPP were identified and grouped into 6 categories: goals/control, structure, parental physical activity participation, communication, support, and discipline. These PAPP were viewed as promotive, preventive, or ineffective. Participants had mixed opinions on the effects of 11 PAPP and identified parental, adolescent, and environmental barriers for parents to promote youth physical activity. Compared with parents, adolescents were more likely to value the effects of setting expectation, scheduling, and coparticipation as well as dislike pressuring, restriction, and punishment. Girls were more likely to favor coparticipation and were more sensitive about negative communication than boys. Parents paid more attention to environmental barriers, whereas adolescents, especially girls, focused more on personal issues. Future studies need to address both positive and negative PAPP as well as perception discrepancies by child-parent role and adolescent gender to generate more evidence to promote parents as favorable socialization agents of youth physical activity.


Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
In patients with early-stage breast cancer treated with breast-conserving surgery, randomized trials have found little difference in local control and survival outcomes between patients treated with conventionally fractionated (CF-) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. However, it remains controversial whether these results apply to all subgroups of patients. We therefore developed an evidence-based guideline to provide direction for clinical practice. A task force authorized by the American Society for Radiation Oncology weighed evidence from a systematic literature review and produced the recommendations contained herein. The majority of patients in randomized trials were aged 50 years or older, had disease Stage pT1-2 pN0, did not receive chemotherapy, and were treated with a radiation dose homogeneity within ±7% in the central axis plane. Such patients experienced equivalent outcomes with either HF-WBI or CF-WBI. Patients not meeting these criteria were relatively underrepresented, and few of the trials reported subgroup analyses. For patients not receiving a radiation boost, the task force favored a dose schedule of 42.5 Gy in 16 fractions when HF-WBI is planned. The task force also recommended that the heart should be excluded from the primary treatment fields (when HF-WBI is used) due to lingering uncertainty regarding late effects of HF-WBI on cardiac function. The task force could not agree on the appropriateness of a tumor bed boost in patients treated with HF-WBI. Data were sufficient to support the use of HF-WBI for patients with early-stage breast cancer who met all the aforementioned criteria. For other patients, the task force could not reach agreement either for or against the use of HF-WBI, which nevertheless should not be interpreted as a contraindication to its use.


Metabolic syndrome and breast cancer in the me-can (metabolic syndrome and cancer) project.
Few studies have assessed the metabolic syndrome (MetS) as an entity in relation to breast cancer risk, and results have been inconsistent. We aimed to examine the association between MetS factors (individually and combined) and risk of breast cancer incidence and mortality. Two hundred ninety thousand women from Austria, Norway, and Sweden were enrolled during 1974-2005, with measurements of height, weight, blood pressure, and levels of glucose, cholesterol, and triglycerides. Relative risks (RR) of breast cancer were estimated using Cox proportional hazards regression for each MetS factor in quintiles and for standardized levels (z-scores) and for a composite z-score for the MetS. There were 4,862 incident cases of breast cancer and 633 deaths from breast cancer identified. In women below age 50, there was a decreased risk of incident cancer for the MetS (per 1-unit increment of z-score; RR, 0.83; 95% confidence interval, 0.76-0.90) as well as for the individual factors (except for glucose). The lowest risks were seen among the heaviest women. In women above age 60, there was an increased risk of breast cancer mortality for the MetS (RR, 1.23; 95% confidence interval, 1.04-1.45) and for blood pressure and glucose. The strongest association with mortality was seen for increased glucose concentrations. The MetS was associated with a decreased risk of incident breast cancer in women below age 50 with high body mass index, and with an increased risk of breast cancer mortality in women above 60. Lifestyle interventions as recommended for cardiovascular disease prevention may be of value to prevent breast cancer mortality in postmenopausal women.


The effect of unsaturated fatty acid and triglyceride oil addition on the mechanical and antibacterial properties of acrylic bone cements.
Acrylic bone cements have an elastic modulus several times higher than the surrounding trabecular bone. This has been hypothesized to contribute to certain clinical complications. There are indications that the addition of specific fatty acids and triglyceride oils may reduce the elastic modulus of these types of cements. Some of these additives also appear to have inherent antibiotic properties, although this has never been evaluated in bone cements. In this study, several types of fatty acids and triglyceride oils were evaluated for use in acrylic bone cements. Their mechanical properties were evaluated under uniaxial compression testing and selected cements were then further characterized in terms of microstructure, handling and antibacterial properties using scanning electron microscopy, polymerization temperature measurements, agar diffusion tests and bactericidal activity assays of cement extracts. It was found that any of the evaluated fatty acids or triglyceride oils could be used to tailor the stiffness of acrylic bone cements, although at varying concentrations, which also depended on the type of commercial base cement used. In particular, the addition of very small amounts of linoleic acid (<2.0 wt%) resulted in Young's moduli and compressive strengths in the range of human trabecular bone, while maintaining a similar setting time. Further, the addition of 12.6 wt% ricinoleic acid to Osteopal V cement was found to have a significant antibacterial effect, inhibiting growth of Staphylococcus aureus in an agar diffusion test as well as demonstrating 100% bactericidal activity against the same strain.


Design of biomimetic cellular scaffolds for co-culture system and their application.
The extracellular matrix of most natural tissues comprises various types of cells, including fibroblasts, stem cells, and endothelial cells, which communicate with each other directly or indirectly to regulate matrix production and cell functionality. To engineer multicellular interactions in vitro, co-culture systems have achieved tremendous success achieving a more realistic microenvironment of in vivo metabolism than monoculture system in the past several decades. Recently, the fields of tissue engineering and regenerative medicine have primarily focused on three-dimensional co-culture systems using cellular scaffolds, because of their physical and biological relevance to the extracellular matrix of actual tissues. This review discusses several materials and methods to create co-culture systems, including hydrogels, electrospun fibers, microfluidic devices, and patterning for biomimetic co-culture system and their applications for specific tissue regeneration. Consequently, we believe that culture systems with appropriate physical and biochemical properties should be developed, and direct or indirect cell-cell interactions in the remodeled tissue must be considered to obtain an optimal tissue-specific microenvironment.


Changes in Australian attitudes to alcohol policy: 1995-2010.
In 2009 Wilkinson and colleagues reported a downward trend in support for alcohol policy restrictions in Australia between 1995 and 2004. The aim of the current study is to examine more recent data on policy support in Australia, specifically for policies covering alcohol availability up to 2010, and to examine specific demographic shifts in support. Data was taken from the National Drug Strategy Household Surveys from 1995, 1998, 2001, 2004, 2007 and 2010 (n = 80,846), primarily responses to attitude items on policy restriction and demographic questions. The effects of age, sex, drinking patterns and income over time on three items addressing restriction of alcohol availability were assessed using a factorial analysis of variance. Although availability items are among the less popular policy restrictions put forward in the National Drug Strategy Household Surveys, 2004 actually represented a turning point in the decrease in popularity, with an increase in support since then. Though some groups show consistently higher rates of support than others for policy restrictions, the rate of change in support was fairly uniform across demographic and drinking groups. Despite the lack of an obvious catalyst, there has been an increase in support for alcohol policy restriction as it relates to general availability and accessibility since 2004. Furthermore, this increase does not appear to be a reflection of a change in a specific group of people, but appears to be occurring across the Australian population.


Electron transfer in an acidophilic bacterium: interaction between a diheme cytochrome and a cupredoxin.
Acidithiobacillus ferrooxidans, a chemolithoautotrophic Gram-negative bacterium, has a remarkable ability to obtain energy from ferrous iron oxidation at pH 2. Several metalloproteins have been described as being involved in this respiratory chain coupling iron oxidation with oxygen reduction. However, their properties and physiological functions remain largely unknown, preventing a clear understanding of the global mechanism. In this work, we focus on two metalloproteins of this respiratory pathway, a diheme cytochrome c4 (Cyt c4) and a green copper protein (AcoP) of unknown function. We first demonstrate the formation of a complex between these two purified proteins, which allows homogeneous intermolecular electron-transfer in solution. We then mimic the physiological interaction between the two partners by replacing one at a time with electrodes displaying different chemical functionalities. From the electrochemical behavior of individual proteins, we show that, while electron transfer on AcoP requires weak electrostatic interaction, electron transfer on Cyt c4 tolerates different charge and hydrophobicity conditions, suggesting a pivotal role of this protein in the metabolic chain. The electrochemical study of the proteins incubated together demonstrates an intermolecular electron transfer involving the protein complex, in which AcoP is reduced through the high potential heme of Cyt c4. Modelling of the electrochemical signals at different scan rates allows us to estimate the rate constant of this intermolecular electron transfer in the range of a few s-1. Possible routes for electron transfer in the acidophilic bacterium are deduced.


Future of Health: Findings from a survey of stakeholders on the future of health and healthcare in England.
This article presents findings from a survey conducted by RAND Europe at the request of the National Institute for Health Research (NIHR) to gather and synthesise stakeholder views on the future of health and healthcare in England in 20 to 30 years' time. The aim of the research was to generate an evidenced-based picture of the future health and healthcare needs, and how it might differ from today, in order to inform strategic discussions about the future priorities of the NIHR and the health and social care research communities more broadly. The survey provided a rich and varied dataset based on responses from 300 stakeholders in total. A wide range of fields were represented, including public health, social care, primary care, cancer, genomics, mental health, geriatrics, child health, patient advocacy and health policy. The respondent group also included a number of professional and private stakeholder categories, such as clinicians, policy experts, academics and patient and public representatives. The study findings validate a number of prominent health research priorities currently visible in England, such as antimicrobial resistance, the burden of dementia and age-related multi-morbidity, digital health and genomics. Interest in these areas and other themes, such as mental health, health inequalities and transforming health service models, cut across multiple disciplinary boundaries. However, it is clear that there are a variety of views among stakeholders on the relative importance of these areas of focus, and the best approach to manage their emergence in the coming decades. The full dataset of survey responses, for which permission to share was given, is a useful resource for those seeking to engage with a particular issue in more depth. The dataset can be found on NIHR's website at: http://nihr.ac.uk/news-and-events/documents/quotes.xls.


New therapeutic option for irritable bowel syndrome: serum-derived bovine immunoglobulin.
Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice. Oral serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown in clinical studies to reduce loose stools and improve stool consistency as well as other symptoms (i.e., abdominal pain, bloating, and urgency) in patients with irritable bowel syndrome with diarrhea (IBS-D) and human immunodeficiency virus-associated enteropathy. This case series reports the outcomes of 14 IBS patients who received SBI as an addition to standard of care at an individual physician's clinical practice. The patients: 2 IBS with constipation (IBS-C), 7 IBS-D, 2 mixed diarrhea and constipation IBS (IBS-M) and 3 undefined IBS (IBS-U; also described by some physicians as IBS-Bloating), ranged in age from 22-87 years. SBI (5 g or 10 g daily dose) was added to the patient's current standard care and followed for several weeks to determine if symptoms were improved with the addition of SBI. Overall, 12 of the 14 patients indicated some level of improvement through direct questioning of the patients regarding changes from the prior visit. One IBS-Bloating patient had a resolution of symptoms and two patients (1 IBS-Bloating and 1 IBS-C) discontinued therapy because of insufficient relief. The 12 patients who continued on therapy reported an overall improvement in symptoms with better stool consistency, decreased frequency as well as reductions in abdominal pain, bloating, distention, and incontinence. In most cases, therapeutic effects of SBI were seen within the first four weeks of therapy with continued improvements at subsequent visits. SBI has a multifaceted mechanism of action and may help to manage IBS by providing a distinct protein source required to normalize bowel function, gastrointestinal microbiota, and nutritionally enhance tight junction protein expression between intestinal epithelial cells. SBI as a medical food provides a safe option for patients with IBS-D but may have application in other forms of IBS.


Characterizing belief bias in syllogistic reasoning: A hierarchical Bayesian meta-analysis of ROC data.
The belief-bias effect is one of the most-studied biases in reasoning. A recent study of the phenomenon using the signal detection theory (SDT) model called into question all theoretical accounts of belief bias by demonstrating that belief-based differences in the ability to discriminate between valid and invalid syllogisms may be an artifact stemming from the use of inappropriate linear measurement models such as analysis of variance (Dube et al., Psychological Review, 117(3), 831-863, 2010). The discrepancy between Dube et al.'s, Psychological Review, 117(3), 831-863 (2010) results and the previous three decades of work, together with former's methodological criticisms suggests the need to revisit earlier results, this time collecting confidence-rating responses. Using a hierarchical Bayesian meta-analysis, we reanalyzed a corpus of 22 confidence-rating studies (N = 993). The results indicated that extensive replications using confidence-rating data are unnecessary as the observed receiver operating characteristic functions are not systematically asymmetric. These results were subsequently corroborated by a novel experimental design based on SDT's generalized area theorem. Although the meta-analysis confirms that believability does not influence discriminability unconditionally, it also confirmed previous results that factors such as individual differences mediate the effect. The main point is that data from previous and future studies can be safely analyzed using appropriate hierarchical methods that do not require confidence ratings. More generally, our results set a new standard for analyzing data and evaluating theories in reasoning. Important methodological and theoretical considerations for future work on belief bias and related domains are discussed.


Modelling the population-level impact of tai-chi on falls and fall-related injury among community-dwelling older people.
To model the population level impact of tai-chi on future rates of falls and fall-related injury in older people as a tool for policy development. An epidemiological and economic model for estimating population-level effectiveness of tai-chi. Australia, 2009. Patients or subjects Australian community-dwelling population aged 70+ years, ambulatory and without debilitating conditions or profound visual defects. Intervention Group-based tai-chi, for 1 h twice weekly for 26 weeks, assuming no sustained effect beyond the intervention period. Main outcome measure Total falls and fall-related hospitalisation prevented in 2009. Population-wide tai-chi delivery would prevent an estimated 5440 falls and 109 fall-related hospitalisations, resulting in a 0.18% reduction in the fall-related hospital admission rate for community-dwelling older people. The gross costs per fall and per fall-related hospital admission prevented were $A4414 (€3013) and $A220,712 (€150,684), respectively. A total investment of $A24.01 million (€16.39 million), equivalent to 4.2% of the cost of fall-related episodes of hospital care in 2003/4, would be required to provide tai-chi for 31,998 people and achieve this effect. Substantial investment in, and high population uptake of, tai-chi would be required to have a large effect on falls and fall-related hospitalisation rates. Although not accounted for in this study, investment in tai-chi is likely to be associated with additional significant health benefits beyond falls prevention. This approach could be applied to other interventions to assist selection of the most cost-effective falls-prevention portfolio for Australia and other countries.


Surgical options in 424 patients with primary breast cancer without systemic metastases.
Mastectomy was dictated by medical considerations in about 40% of 424 consecutive patients who had invasive breast cancer with no evidence of systemic metastases. Half of the women considered suitable for local excision of the breast cancer followed by radiotherapy (conservation) elected to have mastectomy, and intraoperative findings dictated mastectomy in about 20% of those electing conservation. Consequently, conservation was accomplished in about one quarter of those treated for breast cancer. Younger rather than older women more frequently expressed the desire for breast conservation.


Evidence-based treatment for opioid disorders: a 23-year national study of methadone dose levels.
Effective treatment for patients with opioid use problems is as critical as ever given the upsurge in heroin and prescription opioid abuse. Yet, results from prior studies show that the majority of methadone maintenance treatment (MMT) programs in the US have not provided dose levels that meet evidence-based standards. Thus, this paper examines the extent to which US MMT programs have made changes in the past 23 years to provide adequate methadone doses; we also identify factors associated with variation in program performance. Program directors and clinical supervisors of nationally-representative methadone treatment programs were surveyed in 1988 (n=172), 1990 (n=140), 1995 (n=116), 2000 (n=150), 2005 (n=146), and 2011 (n=140). Results show that the proportion of patients who received doses below 60 mg/day-the minimum recommended-declined from 79.5 to 22.8% in a 23-year span. Results from random effects models show that programs that serve a higher proportion of African-American or Hispanic patients were more likely to report low-dose care. Programs with Joint Commission accreditation were more likely to provide higher doses, as were a program that serves a higher proportion of unemployed and older patients. Efforts to improve methadone treatment practices have made substantial progress, but 23% of patients across the nation are still receiving doses that are too low to be effective.


Computerized two-lead resting ECG analysis for the detection of coronary artery stenosis after coronary revascularization.
Resting electrocardiogram (ECG) shows limited sensitivity and specificity for the detection of coronary artery disease (CAD), where patients with a history of coronary revascularization may pose special challenges. Several methods exist to enhance sensitivity and specificity of resting ECG for diagnosis of CAD, but such methods are not better than a specialist's judgement. We compared a new computer-enhanced, resting ECG analysis device, 3DMP, to coronary angiography to evaluate the device's accuracy in detecting hemodynamically relevant CAD. A convenience sample of 172 patients with a history of coronary revascularization scheduled for coronary angiography was evaluated with 3DMP before coronary angiography. 3DMP's sensitivity and specificity in detecting hemodynamically relevant coronary stenosis as diagnosed with coronary angiography were calculated as well as odds ratios for the 3DMP severity score and coronary artery disease risk factors. The 3DMP system accurately identified 50 of 55 patients as having hemodynamically relevant stenosis (sensitivity 90.9%, specificity 88.0%). Positive and negative predictive values for the identification of coronary stenosis as diagnosed in coronary angiograms were 62.7% and 97.8% respectively. Risk and demographic factors in a logistic regression model had a markedly lower predictive power for the presence of coronary stenosis in these patients than did 3DMP severity score (odds ratio 2.04 [0.74-5.62] vs. 73.57 [25.10-215.68]). A logistic regression combining severity score with risk and demographic factors did not add significantly to the prediction quality (odds ratio 80.00 [27.03-236.79]). 3DMP's computer-based, mathematically derived analysis of resting two-lead ECG data provides detection of hemodynamically relevant CAD in patients with a history of coronary revascularization with high sensitivity and specificity that appears to be at least as good as those reported for other resting and/or stress ECG methods currently used in clinical practice.


Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis.
A common characteristic of aging is loss of skeletal muscle (sarcopenia), which can lead to falls and fractures. MicroRNAs (miRNAs) are novel posttranscriptional modulators of gene expression with potential roles as regulators of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle with a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men [young: 31 ± 2 (n = 19); older: 73 ± 3 (n = 17)] were 1) analyzed for expression of miRNAs with a miRNA array, 2) validated with TaqMan quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets with the bioinformatics knowledge base software Ingenuity Pathways Analysis. Eighteen miRNAs were differentially expressed in older humans (P < 0.05 and >500 expression level). Let-7 family members Let-7b and Let-7e were significantly elevated and further validated in older subjects (P < 0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7s were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that mRNA expression of cell cycle regulators CDK6, CDC25A, and CDC34 were downregulated in older compared with young subjects (P < 0.05). In addition, PAX7 mRNA expression was lower in older subjects (P < 0.05). These data suggest that aging is characterized by a higher expression of Let-7 family members that may downregulate genes related to cellular proliferation. We propose that higher Let-7 expression may be an indicator of impaired cell cycle function possibly contributing to reduced muscle cell renewal and regeneration in older human muscle.


A Hidden Markov Model for 3D Catheter Tip Tracking With 2D X-ray Catheterization Sequence and 3D Rotational Angiography.
In minimal invasive image guided catheterization procedures, physicians require information of the catheter position with respect to the patient's vasculature. However, in fluoroscopic images, visualization of the vasculature requires toxic contrast agent. Static vasculature roadmapping, which can reduce the usage of iodine contrast, is hampered by the breathing motion in abdominal catheterization. In this paper, we propose a method to track the catheter tip inside the patient's 3D vessel tree using intra-operative single-plane 2D X-ray image sequences and a peri-operative 3D rotational angiography (3DRA). The method is based on a hidden Markov model (HMM) where states of the model are the possible positions of the catheter tip inside the 3D vessel tree. The transitions from state to state model the probabilities for the catheter tip to move from one position to another. The HMM is updated following the observation scores, based on the registration between the 2D catheter centerline extracted from the 2D X-ray image, and the 2D projection of 3D vessel tree centerline extracted from the 3DRA. The method is extensively evaluated on simulated and clinical datasets acquired during liver abdominal catheterization. The evaluations show a median 3D tip tracking error of 2.3 mm with optimal settings in simulated data. The registered vessels close to the tip have a median distance error of 4.7 mm with angiographic data and optimal settings. Such accuracy is sufficient to help the physicians with an up-to-date roadmapping. The method tracks in real-time the catheter tip and enables roadmapping during catheterization procedures.


Service use following attendance at an emergency department with an head injury: a 6-month survey.
To survey the attendance of patients presenting with a head injury (HI) at a UK emergency department (ED), identifying numbers, types of service and referral routes; to survey subsequent service use and to highlight the challenges in service planning and identifying which patients may potentially benefit from follow-up/rehabilitation input. A retrospective population-based case series study using multiple prospective and retrospective data sources. Adults from the National Health Service (NHS) Cambridgeshire catchment area attending an ED over a 6-month period with a HI were identified from detailed ED reports, and any service use within the hospital after injury was tracked using a number of data sources. 1036 patients presented on 1081 occasions with a HI during the 6 months. Of the 1081 HIs, 979 (91%) were mild (Glasgow Coma Scale (GCS) score 13-15), 70 (6%) were moderate (GCS score 9-12), and 32 (3%) were severe (GCS score <9). A number of types of referral routes and systems were identified and analysed: 873 (81%) patients were discharged directly from ED, with four offered HI-specific follow-up. Of 208 admissions, 27 (2%) were to neurosurgical care, and 35 (3%) patients were offered HI-specific follow-up, 24 of these being in a specialist neurotrauma clinic. Follow-up started between 1 and 18 months after injury. At 24 months after injury, follow-up for 10 of these was still ongoing. These study findings highlight the difficulties in identifying patients who would benefit from follow-up, in particular after mild HI. Our study findings will form the basis of a long-term follow-up study.