Strong microsite control of seedling recruitment in tundra.
The inclusion of environmental variation in studies of recruitment is a prerequisite for realistic predictions of the responses of vegetation to a changing environment. We investigated how seedling recruitment is affected by seed availability and microsite quality along a steep environmental gradient in dry tundra. A survey of natural seed rain and seedling density in vegetation was combined with observations of the establishment of 14 species after sowing into intact or disturbed vegetation. Although seed rain density was closely correlated with natural seedling establishment, the experimental seed addition showed that the microsite environment was even more important. For all species, seedling emergence peaked at the productive end of the gradient, irrespective of the adult niches realized. Disturbance promoted recruitment at all positions along the environmental gradient, not just at high productivity. Early seedling emergence constituted the main temporal bottleneck in recruitment for all species. Surprisingly, winter mortality was highest at what appeared to be the most benign end of the gradient. The results highlight that seedling recruitment patterns are largely determined by the earliest stages in seedling emergence, which again are closely linked to microsite quality. A fuller understanding of microsite effects on recruitment with implications for plant community assembly and vegetation change is provided.


Control of memory formation through regulated expression of a CaMKII transgene.
One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of calcium-calmodulin-dependent kinase II (CaMKII) resulted in a loss of hippocampal long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit memory task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit memory storage, in a manner that is independent of its potential role in development.


The effects of whirlpools baths in labor: a randomized, controlled trial.
Showers and tubs in labor were not generally used in our center. When three whirlpool baths (Jacuzzis) were ordered as part of our renovations, a randomized, controlled trial was initiated to explore their effects on narcotic and epidural requirements. This study employed an intent-to-treat design, and the sample size was estimated to account for the fact that some women would be unable to use the tub. The experimental group of 393 women was offered the tub during labor and the control group of 392 women received conventional care. No births occurred in the tub. The tub group required fewer pharmacologic agents than controls (66% vs 59%, p = 0.06), experienced fewer deliveries by forceps and vacuum (p = 0.019), and were more likely to have an intact perineum than the standard-care group (p = 0.019). Labor was longer for the tub group (p = 0.003), who coincidentally were more primiparous and in earlier labor on admission. No differences were noted in the low rates of maternal and newborn signs of infection in women with ruptured membranes. A subset of mothers expressed satisfaction with the tub experience and labor support. The cesarean rate among both groups was lower (8.9%) than our overall rate (16.6%) during the study period. Whirlpool baths in labor have positive effects on analgesia requirements, instrumentation rates, condition of the perineum, and personal satisfaction. Further study is being planned.


Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies.
Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women. Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14). Medical Research Council, Cancer Research UK.


Detection of Subsolid Nodules in Lung Cancer Screening: Complementary Sensitivity of Visual Reading and Computer-Aided Diagnosis.
The aim of this study was to compare computer-aided diagnosis (CAD) and visual reading for the detection of subsolid nodules (SSNs) in volumetrl measuremic low-dose computed tomography (LDCT) for lung cancer screening. Prospective visual detection (VD) and manuaent of SSN were performed in the 2303 baseline volumetric LDCTs of the Multicenter Italian Lung Detection trial. Baseline and 2- and 4-year LDCTs underwent retrospective CAD analysis, subsequently reviewed by 2 experienced thoracic radiologists. The reference standard was defined by the cumulative number of SSNs detected by any reading method between VD and CAD. The number of false-positive CAD marks per scan (FP/scan) was calculated. The positive predictive value of CAD was quantified per nodule (PPV) and per screenee (PPV). The sensitivity and negative predictive value were compared between CAD and VD. The longitudinal 3-time-point sensitivity of CAD was calculated in the subgroup of persistent SSNs seen by VD (ratio between the prevalent SSNs detected by CAD through 3 time points and the total number of persistent prevalent SSNs detected by VD) to test the sensitivity of iterated CAD analysis during a screening program. Semiautomatic characteristics (diameter, volume, and mass; both for whole nodule and solid component) were compared between SSN detected CAD-only or VD-only to investigate whether either reading method could suffer from specific sensitivity weakness related to SSN features. Semiautomatic and manual diameters were compared using Spearman ρ correlation and Bland-Altman plot. Computer-aided diagnosis and VD detected a total of 194 SSNs in 6.7% (155/2,303) of screenees at baseline LDCT. The CAD showed mean FP/scan of 0.26 (604/2,303); PPV 22.5% (175/779) for any SSN, with 54.4% (37/68) for PSN and 19.4% for NSN (138/711; P < 0.001); PPV 25.6% (137/536). The sensitivity of CAD was superior to that of VD (88.4% and 34.2%, P < 0.001), as well as negative predictive value (99.2% and 95.5%, P < 0.001). The longitudinal 3-time-point sensitivity of CAD was 87.5% (42/48). There was no influence of semiautomatic characteristics on the performance of either reading method. The diameter of the solid component in PSN was larger by CAD compared with manual measurement. At baseline, CAD detected 3 of 4 SSNs, which were first overlooked by VD and subsequently evolved to lung cancer. Computer-aided diagnosis and VD as concurrent reading methods showed complementary performance, with CAD having a higher sensitivity, especially for PSN, but requiring visual confirmation to reduce false-positive calls. Computer-aided diagnosis and VD should be jointly used for LDCT reading to reduce false-negatives of either lone method. The semiautomatic measurement of solid core showed systematic shift toward a larger diameter, potentially resulting in an up-shift within Lung CT Screening Reporting and Data System classification.


Effect of Roux-en-Y gastric bypass surgery on bile acid metabolism in normal and obese diabetic rats.
In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.


Wider recommendations for institutions made in the Brown Report following the BUAV investigation into the use of animals at Imperial College London.
In December 2013, a group of experts produced a report on the management of an animal unit at Imperial College London, following a BUAV investigation that found evidence of systematic failures in the care and monitoring of animals used in procedures there. The Brown Report looked at four areas: the animal welfare and ethical review body (AWERB); the operation of the unit; training; and overall culture. The report made 33 recommendations to improve practices at Imperial College, many of which were relevant to other institutions. In this report, we identify the recommendations that are applicable to all animal facilities, and redraft them as a checklist with supporting information to assist those reviewing their animal care policies. We support the Brown Report's recommendation that institutions should have a vision statement and an action plan, as well as a 'champion' for the Three Rs. We encourage all institutions that use animals to, as a first step, review the performance of their animal units against this checklist.


Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.
Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.


Isolation of atomically precise mixed ligand shell PdAu24 clusters.
Exposure of PdAu24(2-PET)18 (2-PET: 2-phenylethylthiolate) to BINAS (1,1-binaphthyl-2,2-dithiol) leads to species of composition PdAu24(2-PET)18-2x(BINAS)x due to ligand exchange reactions. The BINAS adsorbs in a specific mode that bridges the apex and one core site of two adjacent S(R)-Au-S(R)-Au-S(R) units. Species with different compositions of the ligand shell can be separated by HPLC. Furthermore, site isomers can be separated. For the cluster with exactly one BINAS in its ligand shell only one isomer is expected due to the symmetry of the cluster, which is confirmed by High-Performance Liquid Chromatography (HPLC). Addition of a second BINAS to the ligand shell leads to several isomers. In total six distinguishable isomers are possible for PdAu24(2-PET)14(BINAS)2 including two pairs of enantiomers concerning the adsorption pattern. At least four distinctive isomers are separated by HPLC. Calculations indicate that one of the six possibilities is energetically disfavoured. Interestingly, diastereomers, which have an enantiomeric relationship concerning the adsorption pattern of chiral BINAS, have significantly different stabilities. The relative intensity of the observed peaks in the HPLC does not reflect the statistical weight of the different isomers. This shows, as supported by the calculations, that the first adsorbed BINAS molecule influences the adsorption of the second incoming BINAS ligand. In addition, experiments with the corresponding Pt doped gold cluster reveal qualitatively the same behaviour, however with slightly different relative abundances of the corresponding isomers. This finding points towards the influence of electronic effects on the isomer distribution. Even for clusters containing more than two BINAS ligands a limited number of isomers were found, which is in contrast to the corresponding situation for monothiols, where the number of possible isomers is much larger.


MALDI MS in-source decay of glycans using a glutathione-capped iron oxide nanoparticle matrix.
A new matrix-assisted laser desorption ionization (MALDI) mass spectrometry matrix is proposed for molecular mass and structural determination of glycans. This matrix contains an iron oxide nanoparticle (NP) core with gluthathione (GSH) molecules covalently bound to the surface. As demonstrated for the monosaccharide glucose and several larger glycans, the mass spectra exhibit good analyte ion intensities and signal-to-noise ratios, as well as an exceptionally clean background in the low mass-to-charge (m/z) region. In addition, abundant in-source decay (ISD) occurs when the laser power is increased above the ionization threshold; this indicates that the matrix provides strong energy transfer to the sample. For five model glycans, ISD produced extensive glycosidic and cross-ring cleavages in the positive ion mode from singly charged precursor ions with bound sodium ions. Linear, branched, and cyclic glycans were employed, and all were found to undergo abundant fragmentation by ISD. (18)O labeling was used to clarify m/z assignment ambiguities and showed that the majority of the fragmentation originates from the nonreducing ends of the glycans. Studies with a peracetylated glycan indicated that abundant ISD fragmentation occurs even in the absence of hydroxyl groups. The ISD product ions generated using this new matrix should prove useful in the sequencing of glycans.


Lipid mediators in immune dysfunction after severe inflammation.
Sepsis, trauma, burns, and major surgical procedures activate common systemic inflammatory pathways. Nosocomial infection, organ failure, and mortality in this patient population are associated with a quantitatively different reprioritization of the circulating leukocyte transcriptome to the initial inflammatory insult, greater in both magnitude and duration, and secondary to multiple observed defects in innate and adaptive immune function. Dysregulation of inflammatory resolution processes and associated bioactive lipid mediators (LMs) mechanistically contribute to this phenotype. Recent data indicate the potential efficacy of therapeutic interventions that either reduce immunosuppressive prostaglandins (PGs) or increase specialized proresolving LMs. Here, we reassess the potential for pharmacological manipulation of these LMs as therapeutic approaches for the treatment of critical illness (CI).


Signal sequence processing is required for the assembly of LamB trimers in the outer membrane of Escherichia coli.
Proteins destined for either the periplasm or the outer membrane of Escherichia coli are translocated from the cytoplasm by a common mechanism. It is generally assumed that outer membrane proteins, such as LamB (maltoporin or lambda receptor), which are rich in beta-structure, contain additional targeting information that directs proper membrane insertion. During transit to the outer membrane, these proteins may pass, in soluble form, through the periplasm or remain membrane associated and reach their final destination via sites of inner membrane-outer membrane contact (zones of adhesion). We report lamB mutations that slow signal sequence cleavage, delay release of the protein from the inner membrane, and interfere with maltoporin biogenesis. This result is most easily explained by proposing a soluble, periplasmic LamB assembly intermediate. Additionally, we found that such lamB mutations confer several novel phenotypes consistent with an abortive attempt by the cell to target these tethered LamB molecules. These phenotypes may allow isolation of mutants in which the process of outer membrane protein targeting is altered.


Understanding acceptance of and adherence to a new formulation of paediatric antiretroviral treatment in the form of pellets (LPV/r)-A realist evaluation.
Improving access to paediatric HIV treatment requires large-scale antiretroviral treatment programmes and medication adapted to infants and children's needs. The World Health Organisation recommends lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors as first-line treatment for all HIV-infected children younger than three years, usually given as a syrup. A pellet formulation (i.e. tiny cylinders of compressed medication put in capsules) was developed to overcome the syrup formulation's disadvantages such as bitterness, toxicity and cold storage. This study assessed multi-level factors influencing caregivers' acceptance of and adherence to lopinavir/ritonavir pellets as well as their underlying mechanisms. A realist evaluation (a theory-driven evaluation method considering the social context and mechanisms of change), embedded in a clinical trial was carried out in three hospital settings in Kenya. Data were collected through document review, observations (n = 34) in home and clinic settings and semi-structured interviews (n = 44) with caregivers and providers. Data analysis was based on realist principles. High levels of treatment initiation and adherence were observed. Taste masking, neutral packaging and easy storage made the new formulation highly acceptable. Caregivers developed individual strategies to deliver the treatment, particularly to overcome specific problems e.g. in case of just-weaned babies or food shortage. A refined program theory emerged from the triangulated findings showing that ease of administration combined with increased self-efficacy and competences of the caregivers, and effective provider support contributed to high levels of adherence. Formulating combined antiretroviral treatment in the form of pellets is clearly a more acceptable solution for infants and children and their caregivers compared to the syrup. Further research in non-trial settings may shed light on factors related to providers, services and the health system that contribute to better adherence of such formulations.


Silicone oil pupil block glaucoma in a pseudophakic eye.
Intravitreal silicone oil achieves an effective endotamponade in patients with complex retinal detachments. Silicone oil displacement into the anterior chamber risks glaucoma and endothelial failure. We describe a 52-year-old patient with pseudophakia with silicone oil endotamponade presenting with visual loss and intraocular pressure of 60 mm Hg. Inferior YAG iridotomy was undertaken to repatriate silicone oil to the posterior segment. Despite normal intraocular pressure, acute corneal oedema occurred postiridotomy, resolving spontaneously over 2 weeks. Pupil block glaucoma secondary to silicone oil requires a management approach based on an understanding of silicone oil fluidics. Careful selection of inferior laser iridotomy site is critical to effectively reverse pupil block. Anterior migration of silicone oil in patients with pseudophakia is rare. We offer an hypothesis to explain unanticipated transient corneal oedema following silicone oil displacement from the anterior chamber. Clinicians must discuss the possibility of transient or permanent endothelial failure preoperatively in this patient group.


Weed management practices affect the diversity and relative abundance of physic nut mites.
Crop management practices determine weed community, which in turn may influence patterns of diversity and abundance of associated arthropods. This study aimed to evaluate whether local weed management practices influence the diversity and relative abundance of phytophagous and predatory mites, as well as mites with undefined feeding habits--of the families Oribatidae and Acaridae--in a physic nut (Jatropha curcas L.) plantation subjected to (1) within-row herbicide spraying and between-row mowing; (2) within-row herbicide spraying and no between-row mowing; (3) within-row weeding and between-row mowing; (4) within-row weeding and no between-row mowing; and (5) unmanaged (control). The herbicide used was glyphosate. Herbicide treatments resulted in higher diversity and relative abundance of predatory mites and mites with undefined feeding habit on physic nut shrubs. This was probably due to the toxic effects of the herbicide on mites or to removal of weeds. Within-row herbicide spraying combined with between-row mowing was the treatment that most contributed to this effect. Our results show that within-row weeds harbor important species of predatory mites and mites with undefined feeding habit. However, the dynamics of such mites in the system can be changed according to the weed management practice applied. Among the predatory mites of the family Phytoseiidae Amblydromalus sp. was the most abundant, whereas Brevipalpus phoenicis was the most frequent phytophagous mite and an unidentified oribatid species was the most frequent mite with undefined feeding habit.


Structural insights into the cubic-hexagonal phase transition kinetics of monoolein modulated by sucrose solutions.
Using DSC (differential scanning calorimetry), we measure the kinetics of the cubic-HII phase transition of monoolein in bulk sucrose solutions. We find that the transition temperature is dramatically lowered, with each 1 mol kg(-1) of sucrose concentration dropping the transition by 20 °C. The kinetics of this transition also slow greatly with increasing sucrose concentration. For low sucrose concentrations, the kinetics are asymmetric, with the cooling (HII-cubic) transition taking twice as long as the heating (cubic-HII) transition. This asymmetry in transition times is reduced for higher sucrose concentrations. The cooling transition exhibits Avrami exponents in the range of 2 to 2.5 and the heating transition shows Avrami exponents ranging from 1 to 3. A classical Avrami interpretation would be that these processes occur via a one or two dimensional pathway with variable nucleation rates. A non-classical perspective would suggest that these exponents reflect the time dependence of pore formation (cooling) and destruction (heating). New density measurements of monoolein show that the currently accepted value is about 5% too low; this has substantial implications for electron density modeling. Structural calculations indicate that the head group area and lipid length in the cubic-HII transition shrink by about 12% and 4% respectively; this reduction is practically the same as that seen in a lipid with a very different molecular structure (rac-di-12:0 β-GlcDAG) that makes the same transition. Thermodynamic considerations suggest there is a hydration shell about one water molecule thick in front of the lipid head groups in both the cubic and HII phases.


The influence of binocular visual deprivation on the development of visual-spatial attention.
This article examines the effects of visual input on the development of attention by comparing normal children to children, all more than 8 years old, who had been treated for bilateral congenital cataracts during infancy. In Experiment 1, patients pushed a button as soon as they detected a target that appeared 100, 400, or 800 msec after a central cue. The cue either validly cued the upcoming location or invalidly cued the wrong location. Patients (n = 16) performed normally at the 100 msec and 400 msec stimulus onset asynchrony (SOA). However, when the cue preceded the target by the 800 msec SOA, patients' reaction times were not affected by the validity of the cue, especially when deprivation had extended past 4 months of age. In Experiment 2, patients indicated which of two shapes appeared in the periphery 400 msec after a central cue, with those shapes surrounded by compatible or incompatible distractors. Patients (n = 15) differed from age-matched controls in (a) being slowed more by incompatible distractors on invalid trials, and (b) tending to show a larger than normal effect of the validity of the cue preceding targets in the upper visual field. Together, these findings suggest that the normal development of attention is influenced by early visual experience.


Comparison of Two Intraocular Lens Implantation Techniques in Pediatric Cataract Surgery in Terms of Postoperative Complications.
Pediatric cataract surgery differs substantially from adult cataract surgery. Numerous studies have focused on reducing the development of postoperative complications. To compare two intraocular lens implantation techniques used in pediatric cataract surgery in terms of postoperative complications. Case-control study. Patients who underwent pediatric cataract surgery and intraocular lens implantation between 2008 and 2016 were evaluated in this retrospective study. Patients aged 3-15 years with unilateral or bilateral cataract and without corneal pathology were included in the study. The patients were categorized into the following two groups: those who underwent posterior capsulorhexis and anterior vitrectomy using in-the-bag intraocular lens implantation (group 1) and those who underwent posterior capsulorhexis and intraocular lens implantation with the optic fixed behind the posterior capsulorhexis (group 2). Rates of postoperative visual axis opacification and complications (glaucoma, posterior synechiae, uveitic reaction, and intraocular lens decentration) were evaluated in these groups. The implanted intraocular lenses were either monoblock (AcrySof SN60AT intraocular lens), triple-piece (AcrySof MA60BM intraocular lens) foldable hydrophobic acrylic lenses, or multifocal lenses (AcrySof IQ ReSTOR). This retrospective study included 52 eyes of 37 patients. Group 1 comprised 26 eyes of 20 patients and group 2 comprised 26 eyes of 17 patients. During the follow-up, visual axis opacification was observed in two patients in group 1 but no patients in group 2. Regarding postoperative complications, there was no uveitic reaction, posterior synechiae, or intraocular lens decentration in either group. There was no significant difference between the groups in terms of the postoperative complications (p>0.05). There was no significant difference between in-the-bag intraocular lens implantation after posterior capsulorhexis and intraocular lens optic capture through posterior capsulorhexis in terms of the complications.


Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice.
The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage. To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide. mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h. These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.


Normal and abnormal development of the intrapericardial arterial trunks in humans and mice.
The definitive cardiac outflow channels have three components: the intrapericardial arterial trunks; the arterial roots with valves; and the ventricular outflow tracts (OFTs). We studied the normal and abnormal development of the most distal of these, the arterial trunks, comparing findings in mice and humans. Using lineage tracing and three-dimensional visualization by episcopic reconstruction and scanning electron microscopy, we studied embryonic day 9.5-12.5 mouse hearts, clarifying the development of the OFTs distal to the primordia of the arterial valves. We characterize a transient aortopulmonary (AP) foramen, located between the leading edge of a protrusion from the dorsal wall of the aortic sac and the distal margins of the two outflow cushions. The foramen is closed by fusion of the protrusion, with its cap of neural crest cells (NCCs), with the NCC-filled cushions; the resulting structure then functioning transiently as an AP septum. Only subsequent to this closure is it possible to recognize, more proximally, the previously described AP septal complex. The adjacent walls of the intrapericardial trunks are derived from the protrusion and distal parts of the outflow cushions, whereas the lateral walls are formed from intrapericardial extensions of the pharyngeal mesenchyme derived from the second heart field. We provide, for the first time, objective evidence of the mechanisms of closure of an AP foramen that exists distally between the lumens of the developing intrapericardial arterial trunks. Our findings provide insights into the formation of AP windows and the variants of common arterial trunk.


Key aspects of melatonin physiology: thirty years of research.
Numerous studies of melatonin, by now widely acknowledged as a circadian rhythm-affecting neurohormone, also describe its anti-oxidant, anti-cytotoxic or immune-modulating activity. While emphasizing the multifunctional aspect of melatonin action, this review presents the results of our thirty years of research, which point to the following conclusions: melatonin is capable of promoting platelet production by megakaryocytes, of acting on the latter's ion channels by way of the outward currents, and of performing a physiological anti-aggregation function thus lengthening platelet life span. Melatonin can be transported everywhere by platelets and, thanks to its lipophilicity, can cross cellular membranes easily, thus regulating blood-tissue exchanges and ensuring an improved haematic crisis. It interacts with endothelial cells by regulating their release of both relaxing-factor and contracting-factor, and with platelets by affecting their discharge of dense-body components. Finally, platelets could behave as mobile and itinerant serotonergic and/or melatonergic elements, a function comparable to the release of neurotransmitters by neurons of the central nervous system. This dynamism in melatonin physiology could prove to be a key in approaching tumour aetiopathogenesis.


Endothelin-1/endothelin-B receptor-mediated increases in NHE3 activity in chronic metabolic acidosis.
Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ET(B)) receptor increases NHE3 activity. To examine the role of the ET(B) receptor in the response to acidosis in vivo, the present studies examined ET(B) receptor-deficient mice, rescued from neonatal lethality by expression of a dopamine beta-hydroxylase promoter/ET(B) receptor transgene (Tg/Tg:ET(B)(-/-) mice). In proximal tubule suspensions from Tg/Tg:ET(B)(+/-) mice, 10(-8) M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ET(B)(-/-) mice. Acid ingestion for 7 days caused a greater decrease in blood HCO(3)(-) concentration in Tg/Tg:ET(B)(-/-) mice compared with Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice. Whereas acid ingestion increased apical membrane NHE3 by 42-46% in Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice, it had no effect on NHE3 in Tg/Tg:ET(B)(-/-) mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ET(B)(-/-) mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ET(B)(-/-) and Tg/Tg:ET(B)(+/+) mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ET(B) receptor.


Metastasis: recent discoveries and novel perioperative treatment strategies with particular interest in the hemostatic compound desmopressin.
Metastatic disease is responsible for most of cancer lethality. A main obstacle for therapy of advanced cancers is that the outcome of metastasis depends on a complex interplay between malignant and host cells. The perioperative period represents an underutilized window of opportunity for cancer treatment where tumor-host interactions can be modulated, reducing the risk of local recurrences and distant metastases. Blood-saving agents are attractive compounds to be administered during tumor surgery. Desmopressin (DDAVP) is a safe and convenient hemostatic peptide with proved antimetastastic properties in experimental models and veterinary clinical trials. The compound seems to induce a dual angiostatic and antimetastatic effect, breaking the cooperative function of cancer cells and endothelial cells during residual tumor progression. DDAVP is therefore an interesting lead compound to develop novel synthetic peptide analogs with enhanced antitumor properties.


Evidence for a catabolic role of glucagon during an amino acid load.
Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.


Derivation of a T cell line that is highly responsive to IL-4 and IL-2 (CT.4R) and of an IL-2 hyporesponsive mutant of that line (CT.4S).
The derivation of subline of CTLL cells that grow in IL-4/B cell stimulatory factor-1 is described. These cells, designated CT.4R cells, were obtained by extended culture of the CTLL line CT.EV in IL-4. CT.4R cells are highly responsive to both IL-4 and IL-2. Mutagenesis of CT.4R cells with ethylmethane sulfonate and selection for lack of expression of the p55 chain of the IL-2R was carried out and a clone was selected that was hyporesponsive to IL-2 but retained full sensitivity to IL-4. These cells, designated CT.4S cells, develop a very meager response to IL-2 at concentrations of 100 U/ml or less although that display vigorous responses to higher IL-2 concentrations. CT.4S cells give measurable responses to 3-10 U/ml (approximately 15-50 pg/ml) of IL-4. CT.4R and CT.4S cells fail to respond to IL-1, IL-3, IL-6, granulocyte-macrophage-CSF, granulocyte-CSF, CSF-1 or IFN-gamma. Thus, CT.4S cells can be used as a sensitive and specific bioassay for IL-4. ID CT.4R cells can be grown in either IL-4 or IL-2. When grown in IL-4, CT.4R cells express small amounts of the p55 chain of the IL-2R but rapidly upregulate their level of expression of p55 when IL-2 is added and rapidly diminish p55 expression when IL-2 is removed. Thus, although IL-2 and IL-4 both stimulate vigorous growth responses by CT.4R cells, they differ in their capacity to induce the expression of the p55 chain implying that their mechanisms of T cell stimulation are not identical.


Effect of Endotracheal Tube Cuff Shape on Postoperative Sore Throat After Endotracheal Intubation.
Although minor, a sore throat after endotracheal intubation can adversely affect patient satisfaction and postoperative function. We compared the effects of 2 endotracheal tube cuff shapes on postoperative sore throat. One hundred ninety-one adult patients were included in the study. After induction of anesthesia, patients were randomized to endotracheal intubation with a conventional cylindrical-shaped cuff (Group C, n = 95) or a tapered-shaped cuff (Group T, n = 96). The number of intubation attempts, time to achieve endotracheal intubation, and duration of intubation were recorded. Postoperative sore throat and hoarseness were assessed at 1, 6, and 24 hours after surgery. A 0- to 100-mm visual analog scale was used to evaluate sore throat severity. The primary outcome of this study was the overall cumulative incidence of postoperative sore throat in the 24-hour evaluation period in the 2 groups. The overall incidence of postoperative sore throat was lower in Group T than in Group C (32% vs 54%; relative risk = 0.60, 95% confidence interval: 0.43-0.85; P= .003). At 6 hours after surgery, the incidence and severity of postoperative sore throat were lower in Group T compared with Group C (Bonferroni-corrected P< .05). Postoperative hoarseness also occurred less frequently in Group T compared with Group C (19% vs 37%; P= .006). Group T had lower incidence of hoarseness at 1 and 6 hours after surgery than Group C (Bonferroni-corrected P< .05), but the incidence of hoarseness at 24 hours after surgery did not differ between groups. Intubation using an endotracheal tube with a tapered cuff reduced the incidence and severity of postoperative sore throat and the incidence of hoarseness after surgery when compared with an endotracheal tube with a cylindrical cuff.


Lifecycle of the invasive omnivore, Forficula auricularia, in Australian grain growing environments.
The European earwig, Forficula auricularia (L.) (Dermaptera: Forficulidae), is regarded as an important beneficial in many orchard environments but has the potential to be a plant pest in other systems, including to grain crops. Due to its agricultural importance, the lifecycle of F. auricularia has been widely studied in North America and Europe. However, much less is known in the southern hemisphere, including Australia where F. auricularia has been present for over 170 years. To elucidate the lifecycle of F. auricularia, we monitored five sites in grain-growing areas of southern Australia using two different trap types. Adults were found year-round, but most prevalent from late-spring to mid-winter. First instars were typically found from mid to late winter. Second, third and fourth instars occurred from winter through to late spring. The seasonal development of F. auricularia in Australia may be much earlier than observed in comparable North American studies. Degree day modelling highlights variation in development times across the active season for F. auricularia across our sites. Forficula auricularia is well adapted to the Australian grain growing environments. The timing of egg hatching aligns closely with crop emergence, juveniles then develop alongside the crop, and adult development occurs by harvest time in late spring. These findings are important given that many of these crops (canola, lucerne, pulses) are vulnerable to attack by F. auricularia during emergence and development. They also suggest a phenotypic capacity of this species to adapt different phenology after introduction into a novel environment. © 2020 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


MicroRNAs in the development of resistance to antiseizure drugs and their potential as biomarkers in pharmacoresistant epilepsy.
Although many new antiseizure drugs have been developed in the past decade, approximately 30%-40% of patients remain pharmacoresistant. There are no clinical tools or guidelines for predicting therapeutic response in individual patients, leaving them no choice other than to try all antiseizure drugs available as they suffer debilitating seizures with no relief. The discovery of predictive biomarkers and early identification of pharmacoresistant patients is of the highest priority in this group. MicroRNAs (miRNAs), a class of short noncoding RNAs negatively regulating gene expression, have emerged in recent years in epilepsy, following a broader trend of their exploitation as biomarkers of various complex human diseases. We performed a systematic search of the PubMed database for original research articles focused on miRNA expression level profiling in patients with drug-resistant epilepsy or drug-resistant precilinical models and cell cultures. In this review, we summarize 17 publications concerning miRNAs as potential new biomarkers of resistance to antiseizure drugs and their potential role in the development of drug resistance or epilepsy. Although numerous knowledge gaps need to be filled and reviewed, and articles share some study design pitfalls, several miRNAs dysregulated in brain tissue and blood serum were identified independently by more than one paper. These results suggest a unique opportunity for disease monitoring and personalized therapeutic management in the future.


Impact of estradiol patterns in clomiphene citrate/human menopausal gonadotropin/cetrorelix protocol.
The importance of serum estradiol changes associated with gonadotropin-releasing hormone antagonists is not clear. The purpose of the present study was to analyze the impact of estradiol changes after cetrorelix injection on the outcome of intracytoplasmic sperm injection (ICSI) cycles. This was a prospective observational study. One hundred and thirteen women with male-factor infertility who were undergoing first ICSI cycles were reviewed for this study. Excluding seven cycles with incomplete data, 106 cycles were included in the analysis. The women were stimulated with clomiphene citrate and human menopausal gonadotropin (hMG). Cetrorelix acetate (2.5 mg) was given when the leading follicles reached 14 mm. After cetrorelix administration, serum estradiol rose in 48 cycles (45.3%), plateaued in 26 cycles (24.5%) and dropped in 32 cycles (30.2%). Mean age and day-3 follicle-stimulating hormone, luteinizing hormone and estradiol levels were similar among the three groups. The mean ampoules of hMG used, estradiol levels on the day of human chorionic gonadotropin injection and the clinical outcomes, including numbers of oocytes retrieved and fertilization, implantation and pregnancy rates, were similar in all three groups regardless of the trend of estradiol. In conclusion, estradiol patterns after cetrorelix injection show no correlation with clinical outcome and ovarian reserve, and falling estradiol is not associated with adverse outcome.


Quantitative analysis of retinal ganglion cell survival with Rbpms immunolabeling in animal models of optic neuropathies.
To investigate whether a recently described retinal ganglion cell (RGC) marker Rbpms (RNA binding protein with multiple splicing) could be used for RGC quantification in various models of RGC degeneration. Optic nerve crush, excitotoxicity, and elevated intraocular pressure (IOP) rat models were used. Topographic analysis of Rbpms immunolabeling was performed on retinal wholemounts. Retrograde labelings with Fluorogold (FG) and III β-tubulin immunohistochemistry were compared. In the optic nerve crush model, 37%, 87%, and 93% of Rbpms-positive cells were lost 1, 2, and 4 weeks, respectively. Significant loss of Rbpms-positive cells was noted 1 week after intravitreal injection of 12, 30, and 120 nmol N-methyl-d-aspartate (NMDA), whereas coinjection of 120 nmol of NMDA along with MK-801 increased the cell number from 10% to 59%. Over 95% of Rbpms-positive cells were FG- and III β-tubulin-positive after injury caused by optic nerve crush and NMDA injection. In rats with elevated IOP, induced by trabecular laser photocoagulation, there was a significant loss of Rbpms-positive cells compared with that of contralateral controls (P = 0.0004), and cumulative IOP elevation showed a strong linear relationship with the quantification of RGCs by Rbpms immunolabeling and retrograde labeling with FG. More than 99% of the remaining Rbpms-positive cells were double-labeled with FG. Rbpms can reliably be used as an RGC marker for quantitative evaluation in rat models of RGC degeneration, regardless of the nature and the location of the primary site of the injury and the extent of neurodegeneration.


Bioengineering strategies for the treatment of peripheral arterial disease.
Peripheral arterial disease (PAD) is a progressive atherosclerotic disorder characterized by narrowing and occlusion of arteries supplying the lower extremities. Approximately 200 million people worldwide are affected by PAD. The current standard of operative care is open or endovascular revascularization in which blood flow restoration is the goal. However, many patients are not appropriate candidates for these treatments and are subject to continuous ischemia of their lower limbs. Current research in the therapy of PAD involves developing modalities that induce angiogenesis, but the results of simple cell transplantation or growth factor delivery have been found to be relatively poor mainly due to difficulties in stem cell retention and survival and rapid diffusion and enzymolysis of growth factors following injection of these agents in the affected tissues. Biomaterials, including hydrogels, have the capability to protect stem cells during injection and to support cell survival. Hydrogels can also provide a sustained release of growth factors at the injection site. This review will focus on biomaterial systems currently being investigated as carriers for cell and growth factor delivery, and will also discuss biomaterials as a potential stand-alone method for the treatment of PAD. Finally, the challenges of development and use of biomaterials systems for PAD treatment will be reviewed.


Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients.
To determine whether long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months. -Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20-300 mg/24 h, serum creatinine < 106.1 microM (1.2 mg/dl), supine systolic blood pressure (BP) < 150 mmHg, supine diastolic BP < 90 mmHg, and HbA1c < 10% were divided into four groups. Twenty-six patients with normotension were divided at random into two groups; one group received enalapril (5 mg/day) (NE group), the other did not receive enalapril (NC group). In the same way, 26 other patients who were already well-controlled with nifedipine (30 mg/day) over a long-term period (4-6 years) were divided at random into two groups; one received enalapril (5 mg/day) (HE group), the other did not receive enalapril (HC group). After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 x/divided by 1.3 to 55.5 x/divided by 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study. Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.


Fluorogenic NIR-probes based on 1,2,4,5-tetrazine substituted BF2-azadipyrromethenes.
A series of 1,2,4,5-tetrazine integrated near infrared (NIR) fluorophores based on the BF2 azadipyrromethene (NIR-AZA) class has been synthesised and their ability to modulate emission from low to high in response to Diels-Alder cycloaditions has been assessed. Substituents on the tetrazine component of the probe (Cl, OMe, p-NO2C6H4O) were seen to strongly influence quantum yields, fluorescence enhancement factors, and rates of cycloadditions. Cycloadditions between tetrazine-NIR-AZA constructs and a strained alkyne substrate were seen to be highly efficient in organic or aqueous solutions and in gels with high fluorescence enhancements of up to 48-fold observed. Real-time demonstration of the cycloaddition mediated fluorogenic property was achieved by imaging the "turn-on" reaction within a continous flow micro-reactor. Preliminary evidence indicates that excited state quenching involves a photoinduced electron transfer.


Risk Factor Associated with Negative Spouse HIV Seroconversion among Sero-Different Couples: A Nested Case-Control Retrospective Survey Study in 30 Counties in Rural China.
Antiretroviral therapy (ART) and condom use have been proven to reduce the risk of sexual transmission of human immunodeficiency virus (HIV) among HIV sero-different couples, but its full implementation remains a challenge. This study aims to assess HIV seroconversion rate of HIV-negative spouse and its associated risk factors among HIV sero-different couples in rural China. An open cohort of HIV sero-different couples enrolled in 30 counties in China between October 1, 2010, and September 30, 2012, and followed-up to December 31, 2012, was constructed retrospectively. A nested case-control study of risk factors of HIV seroconversion among sero-different couples was conducted in April and May of 2013, based on the open cohort. Sero-different couples with the HIV-negative spouse seroconverting at least 3 months after the previous negative diagnosis during cohort observation period were labeled as "case couples". The "control couples" were selected randomly from the same cohort that did not have the HIV-negative spouse seroconversion during the same period. The "case couples" and "control couples" were matched on gender, age, and region of residence. Sexual behaviors among HIV sero-different couples before and after the index spouses notifying their HIV infection status to their HIV-negative spouses were collected via face-to-face interview. Univariate and multivariate logistic regression models were used to assess factors associated with HIV seroconversion among HIV sero-different couples. Of 4481 HIV sero-different couples, a total of 53 seroconversions were observed within 5218 person-years of follow-up. The incidence rate was 1.02 (95%CI: 0.76-1.33) per 100 person-years. Forty "case couples" confirmed HIV-negative spouse seroconversions infected via marital sexual transmission, were matched to 80 "control couples". Of the 120 couples, 81(67.5%) were receiving ART, and 70 (58.3%) reported consistently used condoms during intercourse after the index spouse was diagnosed HIV infection. Multivariate conditional logistic regression analysis showed that the desire to conceive a child (OR = 5.18, 95% CI: 1.19-22.58) significantly increased the odds of HIV seroconversion. Protective factors of spousal HIV seroconversion were currently receiving ART (OR = 0.09, 95% CI: 0.01-0.67) and consistent condom use (OR = 0.05, 95% CI: 0.01-0.28). Intention to conceive a child is the most important risk factor for HIV seroconversion among sero-different couples. Specific efforts on scientific use of ART to assist sero-different couples to achieve their wish to conceive a healthy child are needed to minimize the risk of HIV transmission.


Comparing the microbial characteristics of rainwater in two operating rainwater tanks with different surface-to-volume ratios.
In this study, the microbial characteristics of rainwater in two tanks with different surface-to-volume ratios were investigated and compared to determine how the internal design features of storage tanks affect water quality. The particle and nutrient parameters of the rainwater, including turbidity, suspended solids, total organic carbon, and total phosphate, were lower in Tank 2, which had a surface-to-volume ratio 7.5 times greater than that of Tank 1. In addition, although the rainwater was collected from the same catchment area, the water in Tank 1 had greater numbers of bacteria, and the bacterial communities in the water differed between the two storage tanks. It appears that the differences in the inside surface structures of the rainwater tanks affected the microbial ecosystems. Increasing the surface-to-volume ratio in rainwater tanks may affect rainwater quality, because this extends the area for biofilm development. Further study of the role of biofilm in rainwater tank is required precisely, and its function needs to be considered in the design and management of rainwater tanks.


Multicomponent supplement containing Chlorella decreases arterial stiffness in healthy young men.
Chlorella, a unicellular green alga, contains various antioxidants and other nutrients such as amino acids and fiber. Previous studies have reported that supplementation with multiple antioxidants reduces arterial stiffness, a well-established cardiovascular risk factor. We investigated the effects of Chlorella intake on arterial stiffness using a single-blinded, placebo-controlled crossover study design. Fourteen young men took placebo or Chlorella tablets for four weeks, with a 12-week washout period between trials, in a randomized order. Before and after each trial, blood pressure, heart rate, and brachial-ankle pulse wave velocity, an index of arterial stiffness, were measured. Treatment compliance was comparable between the two groups. There were no differences in blood pressure and heart rate before and after supplementation in both the placebo and Chlorella groups. Brachial-ankle pulse wave velocity decreased after Chlorella intake (before vs after intake; 11.6 ± 0.2 vs 11.1 ± 0.1 m/s, p = 0.01), but not after placebo intake (11.4 ± 0.2 vs 11.4 ± 0.2 m/s, p = 0.98). Multicomponent analysis of the Chlorella-containing tablet detected nutrients that can reduce arterial stiffness, such as antioxidant vitamins, arginine, potassium, calcium, and n-3 unsaturated fatty acids. These results suggest that intake of a Chlorella-containing multicomponent supplement can decrease arterial stiffness.


Nucleotide sequence of pilA, the gene encoding the structural component of type 1 pili in Escherichia coli.
The pilA gene of Escherichia coli J96 encoding pilin, the structural component of type 1 pili, was sequenced and found to specify a polypeptide 159 amino acids long preceded by a 23-amino-acid signal peptide. As determined from the DNA sequence, the mature peptide lacked tryptophane and methionine, two amino acids previously shown to be lacking in type 1 pili from E. coli. Also, the amino-terminal sequence of amino acids inferred from the DNA sequence corresponded to earlier 20-amino-acid amino-terminal sequences determined by protein sequencing. In addition, piliation was abolished after a mutation was introduced into the pilA coding region in vitro. A possible site for initiation of transcription and a possible site encoding translation initiation were suggested 85 and 7 base pairs, respectively, from the pilA start codon. There appeared to be scant DNA sequence homology and scant amino acid sequence homology between type 1 pilin and other pilin species isolated from uropathogenic and enteropathogenic E. coli.


Chewing xylitol gum improves self-rated and objective indicators of oral health status under conditions interrupting regular oral hygiene.
Chewing xylitol gum provides oral health benefits including inhibiting Streptococcus mutans plaque. It is thought to be especially effective in conditions where it is difficult to perform daily oral cleaning. Our study aim was to determine the effects of chewing xylitol gum on self-rated and objective oral health status under a condition interfering with oral hygiene maintenance. A randomized controlled intervention trial was conducted on 55 healthy ≥ 20-year-old men recruited from the Japan Ground Self Defense Force who were undergoing field training. Participants were randomly assigned to a test group (chewing gum; n = 27) or a control group (no gum; n = 28) and the researchers were blinded to the group assignments. The Visual Analog Scale (VAS) scores of oral conditions subjectively evaluated oral health, and the stimulated salivary bacteria quantity objectively evaluated oral health 1 day before field training (baseline) and 4 days after the beginning of field training (follow-up). VAS scores of all three oral conditions significantly increased in the control group (malodor: p < 0.001; discomfort: p < 0.001; dryness: p < 0.001), but only two VAS scores increased in the test group (malodor: p = 0.021; discomfort: p = 0.002). The number of salivary total bacteria significantly increased in the control group (p < 0.01), while no significant change was observed in the test group (p = 0.668). Chewing xylitol gum positively affects self-rated and objective oral health status by controlling oral hygiene under conditions that interfere with oral hygiene maintenance.


Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs.
Cisplatin (90 mg/m2) was administered in a 5-minute bolus IV infusion to dogs at 8 AM (n = 6) or 4 PM (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 PM (PM group), compared with those treated at 8 AM (AM group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in BUN, serum creatinine concentration, urine gamma-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and BUN were significantly increased in the AM group, compared with the PM group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.


Significance of histological crescent formation in patients with diffuse proliferative lupus nephritis.
Although crescentic nephritis is not rare in diffuse proliferative lupus nephritis (DPLN), little is known about the clinicopathological features in DPLN with crescents worldwide. This study was undertaken to investigate the clinicopathological features and outcome of Chinese DPLN patients with different degrees of crescents. 520 DPLN patients with more than 10% histological crescents (cDPLN) were enrolled in this retrospective study. They were divided into three groups: group 1 (10%≤ crescents <25%, n = 240), group 2 (25%≤ crescents <50%, n = 160), and group 3 (crescents ≥50%, n = 120). Another 100 patients without histological crescents were enrolled as a control group. Clinicopathological features, treatment responses, and outcomes were compared among the four groups. There were 450 (86.6%) females and 70 (13.4%) males with an average age of 31.7 ± 11.4 years. Compared with the control group, cDPLN patients had shorter lupus nephritis duration (20.7 ± 34.1 vs. 30.4 ± 48.9 months), higher prevalence of rapidly progressive glomerulonephritis syndrome (21.8%), and gross hematuria (26.7%). Laboratory findings indicated more severe hypoproteinemia, hyperlipidemia, and renal insufficiency; heavier proteinuria and microscopic hematuria; higher tubular injury parameters, and lower serological activity in crescentic groups. Histologically, cDPLN patients have severe glomerular and tubulointerstitial lesions as well as extensive leukocyte infiltration together with a lesser degree of immune complex deposition. The proportion of death, end-stage renal disease, and treatment failure correlates positively with the degree of histological crescents. cDPLN patients with acute onset and short disease duration mostly show severe renal manifestations, less extrarenal organ involvement, lower serological activity, serious capillary necrosis, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration, less glomerular immune complex deposition, poor treatment response, and worse renal outcome.


A roadmap to implementing metal-organic frameworks in electronic devices: challenges and critical directions.
Metal-organic frameworks (MOFs) and related material classes are attracting considerable attention for applications such as gas storage, separations, and catalysis. In contrast, research focused on potential uses in electronic devices is in its infancy. Several sensing concepts in which the tailorable chemistry of MOFs is used to enhance sensitivity or provide chemical specificity have been demonstrated, but in only a few cases are MOFs an integral part of an actual device. The synthesis of a few electrically conducting MOFs and their known structural flexibility suggest that MOF-based electronic devices exploiting these properties could be constructed. It is clear, however, that new fabrication methods are required to take advantage of the unique properties of MOFs and extend their use to the realms of electronic circuitry. In this Concepts article, we describe the basic functional elements needed to fabricate electronic devices and summarize the current state of relevant MOF research, and then review recent work in which MOFs serve as active components in electronic devices. Finally, we propose a high-level roadmap for device-related MOF research, the objective of which is to stimulate thinking within the MOF community concerning the development these materials for applications including sensing, photonics, and microelectronics.


Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2.
Akt1 is frequently up-regulated in human tumors and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibition of the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depend on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.


Regulatory element copy number differences shape primate expression profiles.
Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences. Additionally, we identified 127 CNDs that were processed pseudogenes and some of which were expressed. Furthermore, there were copy number-different regulatory regions such as ultraconserved elements and long intergenic noncoding RNAs with the potential to affect expression. We postulate that CNDs of these conserved sequences fine-tune developmental pathways by altering the levels of RNA.


Suspended sediment in a high-Arctic river: An appraisal of flux estimation methods.
Quantifying fluxes of water, sediment and dissolved compounds through Arctic rivers is important for linking the glacial, terrestrial and marine ecosystems and to quantify the impact of a warming climate. The quantification of fluxes is not trivial. This study uses a 8-years data set (2005-2012) of daily measurements from the high-Artic Zackenberg River in Northeast Greenland to estimate annual suspended sediment fluxes based on four commonly used methods: M1) is the discharge weighted mean and uses direct measurements, while M2-M4) are one uncorrected and two bias corrected rating curves extrapolating a continuous concentration trace from measured values. All methods are tested on complete and reduced datasets. The average annual runoff in the period 2005-2012 was 190±25mio·m3y-1. The different estimation methods gave a range of average annual suspended sediment fluxes between 43,000±10,000ty-1 and 61,000±16,000ty-1. Extreme events with high discharges had a mean duration of 1day. The average suspended sediment flux during extreme events was 17,000±5000ty-1, which constitutes a year-to-year variation of 20-37% of the total annual flux. The most accurate sampling strategy was bi-daily sampling together with a sampling frequency of 2h during extreme events. The most consistent estimation method was an uncorrected rating curve of bi-daily measurements (M2), combined with a linear interpolation of extreme event fluxes. Sampling can be reduced to every fourth day, with both method-agreements and accuracies <±10%, using 7year averages. The specific annual method-agreements were <±10% for all years and the specific annual accuracies <±20% for 6years out of 7. The rating curves were less sensitive to day-to-day variations in the measured suspended sediment concentrations. The discharge weighted mean was not recommended in the high-Arctic Zackenberg River, unless sampling was done bi-daily, every day and events sampled high-frequently.


Non-pericyclic cycloaddition of gem-difluorosubstituted azomethine ylides to the C[double bond, length as m-dash]O bond: computational study and synthesis of fluorinated oxazole derivatives.
The cycloaddition of arenecarbaldehydes and α,α,α-trifluoroacetophenones with gem-difluoro-substituted azomethine ylides, generated from N-benzhydrylideneamines and difluorocarbene, occurs regioselectively to give, after hydrolysis, oxazolidin-4-ones. The primary cycloadducts of trifluoroacetophenones, 4,4-difluoro-5-trifluoromethyloxazolidine derivatives, are sufficiently stable to be isolated in reasonable to excellent yields. The results of correlation analysis and DFT calculations reveal a non-pericyclic step-wise mechanism of the reaction. The replacement of the two geminal hydrogen atoms in the azomethine ylide intermediate for fluorine atoms results in a dramatic change in the reaction mechanism from pericyclic to step-wise, proceeding via a zwitterion-like transition state in which no C-O bonding is observed.


CYP2C9 and VKORC1 polymorphisms are differently distributed in the Brazilian population according to self-declared ethnicity or genetic ancestry.
Warfarin-dosing pharmacogenetic algorithms have presented different performances across ethnicities, and the impact in admixed populations is not fully known. To evaluate the CYP2C9 and VKORC1 polymorphisms and warfarin-predicted metabolic phenotypes according to both self-declared ethnicity and genetic ancestry in a Brazilian general population plus Amerindian groups. Two hundred twenty-two Amerindians (Tupinikin and Guarani) were enrolled and 1038 individuals from the Brazilian general population who were self-declared as White, Intermediate (Brown, Pardo in Portuguese), or Black. Samples of 274 Brazilian subjects from Sao Paulo were analyzed for genetic ancestry using an Affymetrix 6.0(®) genotyping platform. The CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 g.-1639G>A (rs9923231) polymorphisms were genotyped in all studied individuals. The allelic frequency for the VKORC1 polymorphism was differently distributed according to self-declared ethnicity: White (50.5%), Intermediate (46.0%), Black (39.3%), Tupinikin (40.1%), and Guarani (37.3%) (p<0.001), respectively. The frequency of intermediate plus poor metabolizers (IM+PM) was higher in White (28.3%) than in Intermediate (22.7%), Black (20.5%), Tupinikin (12.9%), and Guarani (5.3%), (p<0.001). For the samples with determined ancestry, subjects carrying the GG genotype for the VKORC1 had higher African ancestry and lower European ancestry (0.14±0.02 and 0.62±0.02) than in subjects carrying AA (0.05±0.01 and 0.73±0.03) (p=0.009 and 0.03, respectively). Subjects classified as IM+PM had lower African ancestry (0.08±0.01) than extensive metabolizers (0.12±0.01) (p=0.02). The CYP2C9 and VKORC1 polymorphisms are differently distributed according to self-declared ethnicity or genetic ancestry in the Brazilian general population plus Amerindians. This information is an initial step toward clinical pharmacogenetic implementation, and it could be very useful in strategic planning aiming at an individual therapeutic approach and an adverse drug effect profile prediction in an admixed population.


Detecting COVID-19 infection hotspots in England using large-scale self-reported data from a mobile application: a prospective, observational study.
As many countries seek to slow the spread of COVID-19 without reimposing national restrictions, it has become important to track the disease at a local level to identify areas in need of targeted intervention. In this prospective, observational study, we did modelling using longitudinal, self-reported data from users of the COVID Symptom Study app in England between March 24, and Sept 29, 2020. Beginning on April 28, in England, the Department of Health and Social Care allocated RT-PCR tests for COVID-19 to app users who logged themselves as healthy at least once in 9 days and then reported any symptom. We calculated incidence of COVID-19 using the invited swab (RT-PCR) tests reported in the app, and we estimated prevalence using a symptom-based method (using logistic regression) and a method based on both symptoms and swab test results. We used incidence rates to estimate the effective reproduction number, R(t), modelling the system as a Poisson process and using Markov Chain Monte-Carlo. We used three datasets to validate our models: the Office for National Statistics (ONS) Community Infection Survey, the Real-time Assessment of Community Transmission (REACT-1) study, and UK Government testing data. We used geographically granular estimates to highlight regions with rapidly increasing case numbers, or hotspots. From March 24 to Sept 29, 2020, a total of 2 873 726 users living in England signed up to use the app, of whom 2 842 732 (98·9%) provided valid age information and daily assessments. These users provided a total of 120 192 306 daily reports of their symptoms, and recorded the results of 169 682 invited swab tests. On a national level, our estimates of incidence and prevalence showed a similar sensitivity to changes to those reported in the ONS and REACT-1 studies. On Sept 28, 2020, we estimated an incidence of 15 841 (95% CI 14 023-17 885) daily cases, a prevalence of 0·53% (0·45-0·60), and R(t) of 1·17 (1·15-1·19) in England. On a geographically granular level, on Sept 28, 2020, we detected 15 (75%) of the 20 regions with highest incidence according to government test data. Our method could help to detect rapid case increases in regions where government testing provision is lower. Self-reported data from mobile applications can provide an agile resource to inform policy makers during a quickly moving pandemic, serving as a complementary resource to more traditional instruments for disease surveillance. Zoe Global, UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK National Institute for Health Research, UK Medical Research Council and British Heart Foundation, Alzheimer's Society, Chronic Disease Research Foundation.


Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection.
Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE.


3D cryo-electron reconstruction of BmrA, a bacterial multidrug ABC transporter in an inward-facing conformation and in a lipidic environment.
ABC (ATP-binding cassette) membrane exporters are efflux transporters of a wide diversity of molecule across the membrane at the expense of ATP. A key issue regarding their catalytic cycle is whether or not their nucleotide-binding domains (NBDs) are physically disengaged in the resting state. To settle this controversy, we obtained structural data on BmrA, a bacterial multidrug homodimeric ABC transporter, in a membrane-embedded state. BmrA in the apostate was reconstituted in lipid bilayers forming a mixture of ring-shaped structures of 24 or 39 homodimers. Three-dimensional models of the ring-shaped structures of 24 or 39 homodimers were calculated at 2.3 nm and 2.5 nm resolution from cryo-electron microscopy, respectively. In these structures, BmrA adopts an inward-facing open conformation similar to that found in mouse P-glycoprotein structure with the NBDs separated by 3 nm. Both lipidic leaflets delimiting the transmembrane domains of BmrA were clearly resolved. In planar membrane sheets, the NBDs were even more separated. BmrA in an ATP-bound conformation was determined from two-dimensional crystals grown in the presence of ATP and vanadate. A projection map calculated at 1.6 nm resolution shows an open outward-facing conformation. Overall, the data are consistent with a mechanism of drug transport involving large conformational changes of BmrA and show that a bacterial ABC exporter can adopt at least two open inward conformations in lipid membrane.


Nessys: A new set of tools for the automated detection of nuclei within intact tissues and dense 3D cultures.
Methods for measuring the properties of individual cells within their native 3D environment will enable a deeper understanding of embryonic development, tissue regeneration, and tumorigenesis. However, current methods for segmenting nuclei in 3D tissues are not designed for situations in which nuclei are densely packed, nonspherical, or heterogeneous in shape, size, or texture, all of which are true of many embryonic and adult tissue types as well as in many cases for cells differentiating in culture. Here, we overcome this bottleneck by devising a novel method based on labelling the nuclear envelope (NE) and automatically distinguishing individual nuclei using a tree-structured ridge-tracing method followed by shape ranking according to a trained classifier. The method is fast and makes it possible to process images that are larger than the computer's memory. We consistently obtain accurate segmentation rates of >90%, even for challenging images such as mid-gestation embryos or 3D cultures. We provide a 3D editor and inspector for the manual curation of the segmentation results as well as a program to assess the accuracy of the segmentation. We have also generated a live reporter of the NE that can be used to track live cells in 3 dimensions over time. We use this to monitor the history of cell interactions and occurrences of neighbour exchange within cultures of pluripotent cells during differentiation. We provide these tools in an open-access user-friendly format.


Advancements in Life Cycle Human Exposure and Toxicity Characterization.
The Life Cycle Initiative, hosted at the United Nations Environment Programme, selected human toxicity impacts from exposure to chemical substances as an impact category that requires global guidance to overcome current assessment challenges. The initiative leadership established the Human Toxicity Task Force to develop guidance on assessing human exposure and toxicity impacts. Based on input gathered at three workshops addressing the main current scientific challenges and questions, the task force built a roadmap for advancing human toxicity characterization, primarily for use in life cycle impact assessment (LCIA). The present paper aims at reporting on the outcomes of the task force workshops along with interpretation of how these outcomes will impact the practice and reliability of toxicity characterization. The task force thereby focuses on two major issues that emerged from the workshops, namely considering near-field exposures and improving dose–response modeling. The task force recommended approaches to improve the assessment of human exposure, including capturing missing exposure settings and human receptor pathways by coupling additional fate and exposure processes in consumer and occupational environments (near field) with existing processes in outdoor environments (far field). To quantify overall aggregate exposure, the task force suggested that environments be coupled using a consistent set of quantified chemical mass fractions transferred among environmental compartments. With respect to dose–response, the task force was concerned about the way LCIA currently characterizes human toxicity effects, and discussed several potential solutions. A specific concern is the use of a (linear) dose–response extrapolation to zero. Another concern addresses the challenge of identifying a metric for human toxicity impacts that is aligned with the spatiotemporal resolution of present LCIA methodology, yet is adequate to indicate health impact potential. Further research efforts are required based on our proposed set of recommendations for improving the characterization of human exposure and toxicity impacts in LCIA and other comparative assessment frameworks. https://doi.org/10.1289/EHP3871.


People with chronic facial pain perform worse than controls at a facial emotion recognition task, but it is not all about the emotion.
Alexithymia, or a lack of emotional awareness, is prevalent in some chronic pain conditions and has been linked to poor recognition of others' emotions. Recognising others' emotions from their facial expression involves both emotional and motor processing, but the possible contribution of motor disruption has not been considered. It is possible that poor performance on emotional recognition tasks could reflect problems with emotional processing, motor processing or both. We hypothesised that people with chronic facial pain would be less accurate in recognising others' emotions from facial expressions, would be less accurate in a motor imagery task involving the face, and that performance on both tasks would be positively related. A convenience sample of 19 people (15 females) with chronic facial pain and 19 gender-matched controls participated. They undertook two tasks; in the first task, they identified the facial emotion presented in a photograph. In the second, they identified whether the person in the image had a facial feature pointed towards their left or right side, a well-recognised paradigm to induce implicit motor imagery. People with chronic facial pain performed worse than controls at both tasks (Facially Expressed Emotion Labelling (FEEL) task P < 0·001; left/right judgment task P < 0·001). Participants who were more accurate at one task were also more accurate at the other, regardless of group (P < 0·001, r(2) = 0·523). Participants with chronic facial pain were worse than controls at both the FEEL emotion recognition task and the left/right facial expression task and performance covaried within participants. We propose that disrupted motor processing may underpin or at least contribute to the difficulty that facial pain patients have in emotion recognition and that further research that tests this proposal is warranted.


The burden of unintentional drowning: global, regional and national estimates of mortality from the Global Burden of Disease 2017 Study.
Drowning is a leading cause of injury-related mortality globally. Unintentional drowning (International Classification of Diseases (ICD) 10 codes W65-74 and ICD9 E910) is one of the 30 mutually exclusive and collectively exhaustive causes of injury-related mortality in the Global Burden of Disease (GBD) study. This study's objective is to describe unintentional drowning using GBD estimates from 1990 to 2017. Unintentional drowning from GBD 2017 was estimated for cause-specific mortality and years of life lost (YLLs), age, sex, country, region, Socio-demographic Index (SDI) quintile, and trends from 1990 to 2017. GBD 2017 used standard GBD methods for estimating mortality from drowning. Globally, unintentional drowning mortality decreased by 44.5% between 1990 and 2017, from 531 956 (uncertainty interval (UI): 484 107 to 572 854) to 295 210 (284 493 to 306 187) deaths. Global age-standardised mortality rates decreased 57.4%, from 9.3 (8.5 to 10.0) in 1990 to 4.0 (3.8 to 4.1) per 100 000 per annum in 2017. Unintentional drowning-associated mortality was generally higher in children, males and in low-SDI to middle-SDI countries. China, India, Pakistan and Bangladesh accounted for 51.2% of all drowning deaths in 2017. Oceania was the region with the highest rate of age-standardised YLLs in 2017, with 45 434 (40 850 to 50 539) YLLs per 100 000 across both sexes. There has been a decline in global drowning rates. This study shows that the decline was not consistent across countries. The results reinforce the need for continued and improved policy, prevention and research efforts, with a focus on low- and middle-income countries.


State anxiety impairs attentional control when other sources of control are minimal.
Research suggests anxiety impairs attentional control; however, this effect has been unreliable. We argue that anxiety's impairment of attentional control is subtle, and can be obscured by other non-emotional sources of control. We demonstrate this by examining conflict adaptation, an enhancement in attentional control following a trial with high conflict between distracter and target stimuli. Participants completed a Stroop task featuring incongruent (e.g. RED in green font; high-conflict) and control (e.g. +++ in green font; low-conflict) trials. More state-anxious participants showed greater Stroop interference following control trials, but interference was uniformly low following incongruent trials. This suggests state anxiety can impair attention, but other sources of top-down control - such as conflict adaptation - can easily overcome this impairment. This is consistent with recent theories of anxious cognition and shows that anxiety researchers must attend to the dynamics and sources of attentional control.


Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.


Outcomes of patients with alcohol use disorders experiencing healthcare-associated infections.
Healthcare-associated infections (HAI) affect 1.7 million patients annually in the United States, and patients with alcohol use disorders (AUD) are at increased risk of developing HAI. HAI have been shown to substantially increase the hospital length of stay, mortality, and cost. In a cohort of patients with HAI, we sought to determine mortality, cost, and hospital length of stay attributable to AUD. Using the Nationwide Inpatient Sample for the year 2007, the largest all-payer database of hospitalized patients comprising approximately 1,000 hospitals, we performed a retrospective cohort study of all patients who developed healthcare-associated pneumonia or sepsis. We excluded patients who were transferred from another healthcare facility, who were diagnosed with community-acquired infections, immunosuppression, or cancer. Logistic regression was computed to calculate attributable mortality. Linear regression analyses were computed to determine cost and hospital length of stay α = 10(-10) . A total of 149,892 patients developed HAI, and 8,830 (5.9%) had a co-diagnosis of AUD. Patients with AUD were younger, more likely to be men, less likely to be Asian, and more likely to be Hispanic. Patients with AUD were more likely to have tobacco dependence, less likely to be electively admitted to the hospital, and less likely to undergo surgery. They also had lower severity of illness, lower income, and were more likely to be in academic medical centers. Logistic regression revealed that AUD was an independent predictor of increased mortality: Odds ratio = 1.71, 95% confidence interval (CI) [1.626; 1.799], p < 10(-10) . Linear regression demonstrated that AUD independently predicted increased hospital length of stay by 2 days: Patients with AUD had a length of stay of 13 days, 95% CI [12.4; 13.6] compared with 11 days, 95% CI [11.1; 11.4] for patients without AUD, p < 10(-10) . Linear regression also revealed that patients with AUD had a higher hospital cost: $34,826, 95% CI [32,415.71; 37,416.52] for patients with AUD compared with $27,167, 95% CI [25,703.18; 28,714.05] for patients without AUD, p < 10(-10) . Patients with AUD who experience HAI have worse outcomes compared with patients without AUD. Patients with AUD have higher mortality, longer hospital length of stay, and higher costs. Studies aimed at decreasing the morbidity and mortality of HAI in patients with AUD are warranted.


A pilot study to examine the feasibility and acceptability of a coordinated intervention design to address treatment engagement challenges in school mental health services.
Treatment engagement is a significant challenge in school mental health services. Despite a growing evidence base on effective interventions for treatment engagement, attempts to address these challenges rarely leverage the available relevant research. To close this gap, this pilot study examined the feasibility, acceptability, and initial implementation outcomes of a coordinated knowledge system (CKS) designed to support the efforts of school mental health (SMH) professionals to address treatment engagement challenges. A sample of four supervisors and their supervisees (n = 17) with master's of social work degrees serving youth within an urban SMH program were randomly assigned to either (a) a CKS condition that offered a unified set of resources to structure decisions about treatment engagement or (b) a survey plus practice guidelines (SPG) condition, in which resources were provided without an explicit model for their coordinated use. Feasibility was assessed quantitatively, acceptability was assessed quantitatively and qualitatively, and initial implementation outcomes were evaluated using a behavioral observation coding system. Results provided strong support for the feasibility and acceptability of the study design, instrumentation, and interventions. It appears that the CKS can be feasibly implemented with good acceptability. Patterns of initial implementation strongly suggested that, relative to the SPG, the CKS supports identification of engagement problems as well as intervention selection and planning. Findings also identified modifications to study procedures that would be necessary in a future study. A larger trial using similar methodology and instrumentation could yield important findings about the effectiveness of the CKS in clinical practice and could articulate the mechanisms by which it operates.


Relationship between push phase and final race time in skeleton performance.
The aim of this study was to examine the relationship between push-time and final race time in skeleton participants during a series of major international competitions to determine the importance of the push phase in skeleton performance. Correlations were computed from the first and second heat split data measured during 24 men and 24 women skeleton competitions. Body mass, height, age, and years of experience of the first 30 men and women athletes of the skeleton, bobsleigh and luge 2003-2004 World Cup ranking were used for the comparison between sliding sports. Moderate but significant correlations (p < 0.05) were found between push-time and final race time in men (r(mean) = 0.48) and women (r(mean) = 0.63). No correlations were found between changes in the individual push-time between the first and second heat with the corresponding changes in final race time. The bobsleigh sliders are heavier than the athletes of the other sliding disciplines. Luge athletes have more experience and are younger than bobsleigh and skeleton sliders. The results of this study suggest that a fast push phase is a prerequisite to success in competition and confirms that the selection of skeleton athletes based on the ability to accelerate to a maximum speed quickly could be valid. However, a good or improved push-time does not ensure a placement in the top finishing positions. On the basis of these results, we suggest that strength and power training is necessary to maintain a short push-time but additional physical training aimed to enhance the push phase might not reflect performance improvements. The recruitment of younger athletes and an increase of youthful competitive activity may be another effective way to reach international competitive results.


Angiogenesis inhibitors in the treatment of prostate cancer.
Prostate cancer remains a significant public health problem, with limited therapeutic options in the setting of castrate-resistant metastatic disease. Angiogenesis inhibition is a relatively novel antineoplastic approach, which targets the reliance of tumor growth on the formation of new blood vessels. This strategy has been used successfully in other solid tumor types, with the FDA approval of anti-angiogenic agents in breast, lung, colon, brain, and kidney cancer. The application of anti-angiogenic therapy to prostate cancer is reviewed in this article, with attention to efficacy and toxicity results from several classes of anti-angiogenic agents. Ultimately, the fate of anti-angiogenic agents in prostate cancer rests on the eagerly anticipated results of several key phase III studies.