Transcriptional synergy between LIM-homeodomain proteins and basic helix-loop-helix proteins: the LIM2 domain determines specificity.
LIM-homeodomain proteins direct cellular differentiation by activating transcription of cell-type-specific genes, but this activation requires cooperation with other nuclear factors. The LIM-homeodomain protein Lmx1 cooperates with the basic helix-loop-helix (bHLH) protein E47/Pan-1 to activate the insulin promoter in transfected fibroblasts. In this study, we show that two proteins originally called Lmx1 are the closely related products of two distinct vertebrate genes, Lmx1.1 and Lmx1.2. We have used yeast genetic systems to delineate the functional domains of the Lmx1 proteins and to characterize the physical interactions between Lmx1 proteins and E47/Pan-1 that produce synergistic transcriptional activation. The LIM domains of the Lmx1 proteins, and particularly the second LIM domain, mediate both specific physical interactions and transcriptional synergy with E47/Pan-1. The LIM domains of the LIM-homeodomain protein Isl-1, which cannot mediate transcriptional synergy with E47/Pan-1, do not interact with E47/Pan-1. In vitro studies demonstrate that the Lmx1.1 LIM2 domain interacts specifically with the bHLH domain of E47/Pan-1. These studies provide the basis for a model of the assembly of LIM-homeodomain-containing complexes on DNA elements that direct cell-type-restricted transcription in differentiated tissues.


Comparative genomics reveals contraction in olfactory receptor genes in bats.
Gene loss and gain during genome evolution are thought to play important roles in adaptive phenotypic diversification. Among mammals, bats possess the smallest genomes and have evolved the unique abilities of powered flight and laryngeal echolocation. To investigate whether gene family evolution has contributed to the genome downsizing and phenotypic diversification in this group, we performed comparative evolutionary analyses of complete proteome data for eight bat species, including echolocating and non-echolocating forms, together with the proteomes of 12 other laurasiatherian mammals. Our analyses revealed extensive gene loss in the most recent ancestor of bats, and also of carnivores (both >1,000 genes), although this gene contraction did not appear to correlate with the reduction in genome size in bats. Comparisons of highly dynamic families suggested that expansion and contraction affected genes with similar functions (immunity, response to stimulus) in all laurasiatherian lineages. However, the magnitude and direction of these changes varied greatly among groups. In particular, our results showed contraction of the Olfactory Receptor (OR) gene repertoire in the last common ancestor of all bats, as well as that of the echolocating species studied. In contrast, non-echolocating fruit bats showed evidence of expansion in ORs, supporting a "trade-off" between sensory modalities.


Incidence of tuberculosis in HIV-infected adults on first- and second-line antiretroviral therapy in India.
Programmatic data on the baseline risk of tuberculosis in people living with HIV (PLHIV) are needed to evaluate long-term effectiveness of the ongoing isoniazid preventive therapy (IPT) roll-out in India. We estimated the incidence rate and risk factors of tuberculosis disease in adult PLHIV initiating first- and second-line anti-retroviral therapy (ART) prior to widespread IPT in a public ART center in Pune, India. 4067 participants contributing 5205.7 person-years of follow-up on first-line ART and 871 participants contributing 1031.7 person-years of follow-up on second-line ART were included in the analysis. The incidence rate of tuberculosis was 4.39 cases (95%CI 3.86-5.00) per 100 person-years on first-line ART and 1.64 cases (95%CI 1.01-2.63) per 100 person-years on second-line ART (p < 0.001). After adjusting for competing risks, male sex (aSHR = 1.33, 95%CI 1.02-1.74, p = 0.03), urban residence (aSHR = 1.53, 95%CI 1.13-2.07, p = 0.006) and CD4+ counts < 350 cells/mm3 (aSHR = 3.06 vs CD4 > 350 cells/mm3, 95%CI 1.58-5.94, p < 0.001) at ART initiation were associated with higher risk of tuberculosis independent of ART regimen. Risk of tuberculosis was lower in PLHIV receiving second-line ART compared to first-line ART. Prioritizing IPT in PLHIV with low CD4+ counts, urban residence and in males may further mitigate the risk of tuberculosis during ART.


Arabidopsis root K+-efflux conductance activated by hydroxyl radicals: single-channel properties, genetic basis and involvement in stress-induced cell death.
Reactive oxygen species (ROS) are central to plant stress response, signalling, development and a multitude of other processes. In this study, the plasma-membrane hydroxyl radical (HR)-activated K(+) channel responsible for K(+) efflux from root cells during stress accompanied by ROS generation is characterised. The channel showed 16-pS unitary conductance and was sensitive to Ca(2+), tetraethylammonium, Ba(2+), Cs(+) and free-radical scavengers. The channel was not found in the gork1-1 mutant, which lacks a major plasma-membrane outwardly rectifying K(+) channel. In intact Arabidopsis roots, both HRs and stress induced a dramatic K(+) efflux that was much smaller in gork1-1 plants. Tests with electron paramagnetic resonance spectroscopy showed that NaCl can stimulate HR generation in roots and this might lead to K(+)-channel activation. In animals, activation of K(+)-efflux channels by HRs can trigger programmed cell death (PCD). PCD symptoms in Arabidopsis roots developed much more slowly in gork1-1 and wild-type plants treated with K(+)-channel blockers or HR scavengers. Therefore, similar to animal counterparts, plant HR-activated K(+) channels are also involved in PCD. Overall, this study provides new insight into the regulation of plant cation transport by ROS and demonstrates possible physiological properties of plant HR-activated K(+) channels.


Invasive intraductal papillary mucinous neoplasm: predictors of survival and role of adjuvant therapy.
Adjuvant treatment for pancreatic adenocarcinoma has been shown to improve survival. An increasingly recognized 'subtype' of pancreatic adenocarcinoma is invasive intraductal papillary mucinous neoplasm (IPMN). It is unclear whether adjuvant treatment for invasive IPMN improves survival. This study aimed to determine the impact of adjuvant treatment in invasive IPMN. We conducted a retrospective analysis of merged clinical databases including 412 patients undergoing resection for IPMN at two academic institutions between 1989 and 2006. Of 412 patients with IPMN who underwent pancreatectomy, 98 had invasive carcinoma. Median survival in invasive IPMN was 32 months. Adjuvant treatment did not affect median survival in node-positive or node-negative invasive IPMN. Biopsy-proven recurrence of invasive IPMN occurred in 45 patients (46%). The median disease-free interval from resection to recurrence was 27 months. Treatment of recurrences with chemotherapy or radiation therapy was not associated with a difference in survival; however, a subgroup of patients with recurrence in the remnant pancreas who underwent re-resection appeared to have more favourable outcomes. An invasive component measuring >2 cm and lymph node involvement are associated with poorer prognosis. Adjuvant therapy in invasive IPMN appears to confer no survival benefit. In selected patients with recurrence of invasive IPMN in the remnant pancreas, re-resection should be considered.


Downy mildew resistance induced by Trichoderma harzianum T39 in susceptible grapevines partially mimics transcriptional changes of resistant genotypes.
Downy mildew, caused by Plasmopara viticola, is one of the most severe diseases of grapevine and is commonly controlled by fungicide treatments. The beneficial microorganism Trichoderma harzianum T39 (T39) can induce resistance to downy mildew, although the molecular events associated with this process have not yet been elucidated in grapevine. A next generation RNA sequencing (RNA-Seq) approach was used to study global transcriptional changes associated with resistance induced by T39 in Vitis vinifera Pinot Noir leaves. The long-term aim was to develop strategies to optimize the use of this agent for downy mildew control. More than 14.8 million paired-end reads were obtained for each biological replicate of T39-treated and control leaf samples collected before and 24 h after P. viticola inoculation. RNA-Seq analysis resulted in the identification of 7,024 differentially expressed genes, highlighting the complex transcriptional reprogramming of grapevine leaves during resistance induction and in response to pathogen inoculation. Our data show that T39 has a dual effect: it directly modulates genes related to the microbial recognition machinery, and it enhances the expression of defence-related processes after pathogen inoculation. Whereas several genes were commonly affected by P. viticola in control and T39-treated plants, opposing modulation of genes related to responses to stress and protein metabolism was found. T39-induced resistance partially inhibited some disease-related processes and specifically activated defence responses after P. viticola inoculation, causing a significant reduction of downy mildew symptoms. The global transcriptional analysis revealed that defence processes known to be implicated in the reaction of resistant genotypes to downy mildew were partially activated by T39-induced resistance in susceptible grapevines. Genes identified in this work are an important source of markers for selecting novel resistance inducers and for the analysis of environmental conditions that might affect induced resistance mechanisms.


Novel method for early signs of clinical shock detection by monitoring blood capillary/vessel spatial pattern.
The ability to monitor capillary/vessel spatial patterns and local blood volume fractions is critical in clinical shock detection and its prevention in Intensive Care Units (ICU). Although the causes of shock might be different, the basic abnormalities in pathophysiological changes are the same. To detect these changes, we have developed a novel method based on both spectrally and spatially resolved diffuse reflectance spectra. The preliminary study has shown that this method can monitor the spatial distribution of capillary/vessel spatial patterns through local blood volume fractions of reduced hemoglobin and oxyhemoglobin. This method can be used as a real-time and non-invasive tool for the monitoring of shock development and feedback on the therapeutic intervention.


First marine cryptotephra in Antarctica found in sediments of the western Ross Sea correlates with englacial tephras and climate records.
We report the discovery of an important new cryptotephra within marine sediments close to Cape Hallett (northern Victoria Land), in the western Ross Sea, Antarctica. The cryptotephra is fully characterized for its texture, mineralogy and major- and trace-element data obtained on single glass shards. On the basis of geochemical composition, the cryptotephra is unequivocally correlated with the proximal deposits of an explosive eruption of the poorly known Mount Rittmann volcano, situated in northern Victoria Land. The cryptotephra is also correlated with a widespread tephra layer, which was erupted in 1254 C.E. and is present in numerous ice-cores and blue ice fields across East and West Antarctica. The characteristics of the tephra indicate that it was produced by a prolonged, moderate energy, mostly hydromagmatic eruption. This is the first time that a cryptotephra has been identified in marine sediments of the Ross Sea and in ice cores. It provides an important new and widespread stratigraphical datum with which the continental cryosphere and marine sedimentological records in Antarctica can be correlated. Moreover, from a purely volcanological point of view, the discovery further confirms the occurrence of a long-lasting, significant explosive eruption from Mount Rittmann in historical times that produced abundant widely dispersed fine ash. The study also highlights the inadequacy of current hazard assessments for poorly known volcanoes such as Mount Rittmann, located at high southern latitudes.


Effects of Allergic Sensitization on Antiviral Immunity: Allergen, Virus, and Host Cell Mechanisms.
Multiple clinical and epidemiological studies demonstrate links between allergic sensitization and virus-induced atopic disease exacerbations. This review summarizes the recent findings regarding allergen, viral, and host cellular mechanisms relevant to these observations. Recent studies have focused on the molecular pathways and genetic influences involved in allergen-mediated inhibition of innate antiviral immune responses. Multiple tissue and cell types from atopic individuals across the atopy spectrum exhibit deficient interferon responses to a variety of virus infections. Impairment in barrier function, viral RNA and DNA recognition by intracellular sensing molecules, and dysregulation of signaling components are broadly affected by allergic sensitization. Finally, genetic predisposition by numerous nucleotide polymorphisms also impacts immune pathways and potentially contributes to virus-associated atopic disease pathogenesis. Allergen-virus interactions in the setting of atopy involve complex tissue and cellular mechanisms. Future studies defining the pathways underlying these interactions could uncover potential therapeutic targets. Available data suggest that therapies tailored to restore specific components of antiviral responses will likely lead to improved clinical outcomes in allergic disease.


Attaching-effacing lesions associated with Escherichia coli O157:H7 and other bacteria in experimentally infected conventional neonatal goats.
Four conventionally reared goats aged 6 days were inoculated orally with approximately 10(10) colony-forming units (cfu) of a non-verotoxigenic strain of Escherichia coli O157:H7. All remained clinically normal. Tissues were sampled under terminal anaesthesia at 24 (two animals), 48 and 72 h post-inoculation (hpi). E. coli O157:H7 was cultured from the ileum, caecum, colon and rectum of all animals, but the number of bacteria recovered at these sites varied between animals. Attaching-effacing (AE) lesions associated with O157 organisms, as confirmed by immunolabelling, were observed in the ileum of one of the two animals examined at 24 hpi, and in the ileum, caecum and proximal colon of an animal examined at 72 hpi. E. coli O157 organisms were detected at > or =10(5) cfu/g of tissue at these sites. In addition, AE lesions associated with unidentified bacteria were observed at various sites in the large bowel of the same animals. Lesions containing both E. coli O157 and unidentified bacteria (non-O157) were not observed. Non-O157 AE lesions were also observed in the large bowel of one of two uninoculated control animals. This indicated that three (one control and two inoculated) animals were colonized with an unidentified AE organism before the commencement of the experiment. The O157-associated AE lesions were observed only in animals colonized by non-O157 AE organisms and this raises questions about individual host susceptibility to AE lesions and whether non-O157 AE organisms influence colonization by E. coli O157.


The Opioid/Overdose Crisis as a Dialectics of Pain, Despair, and One-Sided Struggle.
The opioid/overdose crisis in the United States and Canada has claimed hundreds of thousands of lives and has become a major field for research and interventions. It has embroiled pharmaceutical companies in lawsuits and possible bankruptcy filings. Effective interventions and policies toward this and future drug-related outbreaks may be improved by understanding the sociostructural roots of this outbreak. Much of the literature on roots of the opioid/overdose outbreak focuses on (1) the actions of pharmaceutical companies in inappropriately promoting the use of prescription opioids; (2) "deaths of despair" based on the deindustrialization of much of rural and urban Canada and the United States, and on the related marginalization and demoralization of those facing lifetimes of joblessness or precarious employment in poorly paid, often dangerous work; and (3) increase in occupationally-induced pain and injuries in the population. All three of these roots of the crisis-pharmaceutical misconduct and unethical marketing practices, despair based on deindustrialization and increased occupational pain-can be traced back, in part, to what has been called the "one-sided class war" that became prominent in the 1970s, became institutionalized as neo-liberalism in and since the 1980s, and may now be beginning to be challenged. We describe this one-sided class war, and how processes it sparked enabled pharmaceutical corporations in their misconduct, nurtured individualistic ideologies that fed into despair and drug use, weakened institutions that created social support in communities, and reduced barriers against injuries and other occupational pain at workplaces by reducing unionization, weakening surviving unions, and weakening the enforcement of rules about workplace safety and health. We then briefly discuss the implications of this analysis for programs and policies to mitigate or reverse the opioid/overdose outbreak.


Determination of the precise location and orientation of the Escherichia coli dnaE gene.
The minimal region required for expression of the dnaE gene of Escherichia coli has been determined relative to a detailed restriction endonuclease map. This has been accomplished by analysis of Bal 31 exonuclease-generated deletions from the termini of the E. coli DNA contained in plasmid pMWE303 , a plasmid that we have previously demonstrated to contain the dnaE gene (M. M. Welch and C. S. McHenry , J. Bacteriol . 152:351-356, 1982). The competence of these deletion-containing plasmids in expressing the alpha subunit of DNA polymerase III holoenzyme has been determined by their ability both to complement a dnaE mutant and to direct the synthesis of a complete alpha subunit. The carboxyl-terminal coding region of dnaE has been identified through the detection of partial alpha polypeptides encoded by plasmids containing deletions from one end of the gene. This approach has permitted the precise determination of both termini of the dnaE gene and the determination of the orientation of the gene within the E. coli chromosome.


Orangutan pantomime: elaborating the message.
We present an exploratory study of forest-living orangutan pantomiming, i.e. gesturing in which they act out their meaning, focusing on its occurrence, communicative functions, and complexities. Studies show that captive great apes may elaborate messages if communication fails, and isolated reports suggest that great apes occasionally pantomime. We predicted forest-living orangutans would pantomime spontaneously to communicate, especially to elaborate after communication failures. Mining existing databases on free-ranging rehabilitant orangutans' behaviour identified 18 salient pantomimes. These pantomimes most often functioned as elaborations of failed requests, but also as deceptions and declaratives. Complexities identified include multimodality, re-enactments of past events and several features of language (productivity, compositionality, systematicity). These findings confirm that free-ranging rehabilitant orangutans pantomime and use pantomime to elaborate on their messages. Further, they use pantomime for multiple functions and create complex pantomimes that can express propositionally structured content. Thus, orangutan pantomime serves as a medium for communication, not a particular function. Mining cases of complex great ape communication originally reported in functional terms may then yield more evidence of pantomime.


mfSBA: Multifractal analysis of spatial patterns in ecological communities.
Multifractals have been applied to characterize complex communities in a spatial context. They were developed for nonlinear systems and are particularly suited to capture multiplicative processes observed in ecological systems. Multifractals characterize variability in a scale-independent way within an experimental range. I have developed an open-source software package to estimate multifractals using a box-counting algorithm (available from https://github.com/lsaravia/mfsba and permanently available at doi: 10.5281/zenodo.7659). The software is specially designed for two dimensional (2D) images such as the ones obtained from remote sensing, but other 2D data types can also be analyzed. Additionally I developed a new metric to analyze multispecies spatial patterns with multifractals: spatial rank surface, which is included in the software.


Molecular phylogenetic perspective on evolution of lizards of the Anolis grahami series.
We report the results of phylogenetic analyses of 1447 bases of mitochondrial DNA sequence for 21 populations representing seven species of the Anolis grahami series (A. conspersus, A. garmani, A. grahami, A. lineatopus, A. opalinus, A. reconditus, and A. valencienni), six of which occur on Jamaica. These data include 705 characters that are phylogenetically informative according to parsimony. A parsimony analysis of these data combined with previously published allozymic data yields a single most parsimonious tree with strong support for monophyly of the A. grahami series, the sister-group relationship between Anolis lineatopus and A. reconditus and a clade composed of Anolis garmani, A. grahami, and A. opalinus. Based on DNA data alone, A. conspersus is nested within A. grahami. Haplotypes sampled from geographic populations of A. grahami, A. lineatopus, and A. opalinus are highly divergent (approximately 12-15% sequence difference on average for each species) and show similar phylogeographic patterns, suggesting that each of these currently recognized species may be a complex of species. Anolis valencienni also shows high sequence divergence among haplotypes from different geographic populations (approximately 8% sequence difference) and may contain cryptic species. Divergence among haplotypes within A. garmani is substantially lower (approximately 3% sequence difference), and phylogeographic patterns are significantly different from those observed in A. grahami, A. lineatopus and A. opalinus.


Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy.
The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R(2) = 0.91, p < 0.001, and R(2) = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R(2) = 0.7, p = 0.009). No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT.


A major outer membrane protein of Moraxella catarrhalis is a target for antibodies that enhance pulmonary clearance of the pathogen in an animal model.
A murine immunoglobulin G monoclonal antibody (MAb) raised against outer membrane vesicles of Moraxella catarrhalis 035E was shown to bind to a surface-exposed epitope of a major outer membrane protein of this organism. This outer membrane protein, which had an apparent molecular weight of approximately 80,000 in sodium dodecyl sulfate-polyacrylamide gels, was designated CopB. MAb 10F3, reactive with CopB, bound to a majority (70%) of M. catarrhalis strains tested. More importantly, mice passively immunized with MAb 10F3 exhibited an enhanced ability to clear a bolus challenge of M. catarrhalis from their lungs, a result which suggested that CopB might have potential as a vaccine candidate. The M. catarrhalis gene encoding CopB was cloned in Escherichia coli, and nucleotide sequence analysis of the copB gene indicated that the CopB protein was synthesized with a leader peptide, a finding confirmed by N-terminal amino acid sequence analysis of the mature CopB protein purified from M. catarrhalis 035E. Southern blot analysis showed that chromosomal DNA from seven different M. catarrhalis strains hybridized with a probe comprising the majority of the copB structural gene from strain 035E. Additional data emphasizing the extent of conservation of the CopB protein among M. catarrhalis strains were obtained from Western immunoblot analyses with polyclonal antisera raised against CopB proteins from different M. catarrhalis strains used to probe the recombinant form of the CopB protein from strain 035E. The ability of the CopB protein to function as a target for biologically active antibodies and its apparent conservation among M. catarrhalis strains warrant further investigation of this outer membrane protein as a potential vaccine candidate.


Accurate deep neural network inference using computational phase-change memory.
In-memory computing using resistive memory devices is a promising non-von Neumann approach for making energy-efficient deep learning inference hardware. However, due to device variability and noise, the network needs to be trained in a specific way so that transferring the digitally trained weights to the analog resistive memory devices will not result in significant loss of accuracy. Here, we introduce a methodology to train ResNet-type convolutional neural networks that results in no appreciable accuracy loss when transferring weights to phase-change memory (PCM) devices. We also propose a compensation technique that exploits the batch normalization parameters to improve the accuracy retention over time. We achieve a classification accuracy of 93.7% on CIFAR-10 and a top-1 accuracy of 71.6% on ImageNet benchmarks after mapping the trained weights to PCM. Our hardware results on CIFAR-10 with ResNet-32 demonstrate an accuracy above 93.5% retained over a one-day period, where each of the 361,722 synaptic weights is programmed on just two PCM devices organized in a differential configuration.


Baseline Survey of the Neuroradiology Work Environment in the United States with Reported Trends in Clinical Work, Nonclinical Work, Perceptions of Trainees, and Burnout Metrics.
Neuroradiologists have faced continuously increasing clinical workloads. Our aim was to establish and report a baseline survey of the current neuroradiology work environment in the United States and of experiential changes in recent years. A voluntary survey was sent to practicing and out-of-training members of the American Society of Neuroradiology in the United States. Selected measures included workday volume and length, burnout symptoms, participation in academic and practice-building duties; effects on perceived interpretation quality, communication of abnormal results, and consideration of early retirement or career changes, among others. Four hundred thirty-two respondents across a broad range of experience reported the following: 52.8% (224/424) with teaching responsibilities; 93% (399/430) with workdays extending at least 1 hour past expected, in 45% (193/430) frequently or always; 71.9% (309/430) reading more cases per hour compared to previous years; 79.5% (341/429) sometimes-to-always interpreting cases faster than comfortable for optimal interpretation; and 67.8% (292/431) sometimes or more often with inadequate time to discuss abnormal results. Burnout symptoms ranged between 49% and 75% (211/428 to 322/428) across 4 indices. For academic activities of teaching, mentoring, and research/publications, a mean of 94.3% reported cut-backs during the past few years. For practice-building activities, 92% reported cut-backs, 51.6% (222/429) considered early retirement, and 38.8% (167/429) considered changing careers. Increasing clinical demands have coincided with destructive effects in the work environment and the ability and desire of neuroradiologists in the United States to perform academic or practice-building duties with a substantial incidence of burnout symptoms. While this survey does not prove causation, the trends and the correlations should be concerning to the leaders of radiology and warrant further monitoring.


18F-Fluoroform: a 18F-trifluoromethylating agent for the synthesis of SCF218F-aromatic derivatives.
Herein the synthesis of various SCF218F-containing derivatives is reported by a transition metal-free process. By using HCF218F, readily generated from a bench-stable difluoromethyl sulfonium salt, various aromatic disulfides were easily converted into the desired radiolabelled trifluoromethylthiolated compounds in the presence of a base. This protocol allowed the formation of the SCF218F-containing aromatic derivatives in good to excellent radiochemical yields. This process was also extended to the corresponding selenium derivative.


Acetaminophen-induced hepatotoxicity in a glutathione synthetase-deficient patient.
We report a patient with glutathione synthetase (GS) deficiency who developed acetaminophen-induced hepatotoxicity after a two-day treatment with regular doses of acetaminophen. A nine-month-old female was referred because of intractable metabolic acidosis. She was given acetaminophen at therapeutic doses over a 48-hour period. She was hospitalized because of confusion and metabolic acidosis. Liver function tests were abnormal with normal bilirubin levels. The urine gas chromatography-mass spectrometry (GC/MS) showed massive excretion of 5-oxoproline. She improved and liver function tests normalized in the next six days, but compensated metabolic acidosis and massive 5-oxoprolinuria persisted. The analysis of GS in erythrocytes revealed 5% of normal enzyme activity, and the patient had 491G > A mutation on both alleles in the GS gene. In this report it can be assumed that patients, even if heterozygous for a mutation of the GS gene, are at risk for acetaminophen toxicity.


The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells.
The ability to withstand mitochondrial damage is especially critical for the survival of postmitotic cells, such as neurons. Likewise, cancer cells can also survive mitochondrial stress. We found that cytochrome c (Cyt c), which induces apoptosis upon its release from damaged mitochondria, is targeted for proteasome-mediated degradation in mouse neurons, cardiomyocytes, and myotubes and in human glioma and neuroblastoma cells, but not in proliferating human fibroblasts. In mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevented the proteasome-dependent degradation of Cyt c in response to induced mitochondrial stress. An RNA interference screen in U-87 MG glioma cells identified p53-associated Parkin-like cytoplasmic protein (PARC, also known as CUL9) as an E3 ligase that targets Cyt c for degradation. The abundance of PARC positively correlated with differentiation in mouse neurons, and overexpression of PARC reduced the abundance of mitochondrially-released cytosolic Cyt c in various cancer cell lines and in mouse embryonic fibroblasts. Conversely, neurons from Parc-deficient mice had increased sensitivity to mitochondrial damage, and neuroblastoma or glioma cells in which PARC or ubiquitin was knocked down had increased abundance of mitochondrially-released cytosolic Cyt c and decreased viability in response to stress. These findings suggest that PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress.


Determination of urine melamine by validated isotopic ultra-performance liquid chromatography/tandem mass spectrometry.
Little is known about melamine (MEL) analysis in children's urine. In this study, an isotopic ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed and systematically validated for the analysis of MEL in urine. The method is easily performed and comprises acidification, solid-phase extraction (SPE) and UPLC/MS/MS analysis. (13)C(3)N(3)((15)NH(2))(3) was used as the internal standard (IS) for calibration. Transition ions m/z 127 > 85 of MEL and m/z 133 > 89 of the IS were used for quantification and m/z 127 > 68 of MEL was used for quantitative confirmation. Recovery and precision were assessed to guarantee the applicability of the method. The limit of quantification (LOQ) was 0.01 microg/mL while the calculated method detection limit was 0.006 microg/mL. The mean recoveries ranged from 96-99%. The method was then applied to analyze urine samples from children who had potentially consumed MEL-tainted dairy products during screening in Taiwan. Ten nephrolithiasis cases and 20 age- and gender-matched controls were selected for this study. Three out of the 10 nephrolithiasis cases had elevated levels of MEL. Comparatively, twenty age- and gender-matched non-nephrolithiasis controls consuming Taiwan brand milk powder all showed MEL levels lower than the detection limit except for two children with background levels of 0.02 microg/mL. The background level in these children urine samples was established by UPLC/MS/MS analysis. Positive results of urine MEL tests might be associated with nephrolithiasis in these candidates. Measurement of urine MEL concentration can be helpful in confirming MEL-related nephrolithiasis, but its clinical application needs further clarification.


Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
Psoriasis is a common inflammatory skin disease with a prevalence of 2-3% in individuals of European ancestry. In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster. The absence of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated (P = 1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P = 5.4E-04). LCE3C_LCE3B-del is tagged by rs4112788 (r(2) = 0.93), which is also strongly associated with psoriasis (P < 6.6E-09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.


Screening for red flag symptoms of cancer: A community-based cross-sectional study from urban Puducherry, India.
Patients with cancer often delay seeking medical advice in developing countries. In India, only 20%-30% of cancers are being diagnosed in Stages I and II. Screening for red flag symptoms of cancer can be used to identify high-risk individuals in the community. A community-based cross-sectional study was conducted in February 2017 among 302 participants in one of the service areas of Jawaharlal Institute of Postgraduate Medical Education and Research urban health center selected by universal sampling. Data on the presence of red flag symptoms of cancer (persistent cough, persistent change in bowel/bladder habits, nonhealing ulcer, persistent difficulty in swallowing, unexplained weight loss, unexplained lump, persistent unexplained pain, unexplained bleeding, and change in the appearance of mole) and presence of risk factors were collected through interviews. The collected data were entered using EpiData version 3.0. The mean (standard deviation) age of the study participants was 44 (11) years and 50.6% of them were male. At least one red flag symptom of cancer was present in 22 (7.3%) individuals; 9 (2.8%) had unexplained pain, 4 (1.3%) had change in bowel habits, 4 (1.3%) had change in bladder habits, 3 (1%) had cough, 3 (1%) had nonhealing ulcer, 2 (0.6%) had unexplained bleeding, 1 (0.3%) had difficulty in swallowing, 1 (0.3%) had weight loss, 1 (0.3%) had lump, and 1 (0.3%) had change in the appearance of mole. Screening for red flag symptoms of cancer is an easy tool that can be used in the community to identify high-risk individuals, which will facilitate early diagnosis of cancer.


The role of selective attention in matching observed and executed actions.
Substantial evidence suggests that observed actions can engage their corresponding motor representations within the observer. It is currently believed that this process of observation-execution matching occurs relatively automatically, without the need for top-down control. In this study we tested the susceptibility of the observation-execution matching process to selective attention. We used a Go/NoGo paradigm to investigate the phenomenon of 'automatic imitation', in which participants are faster to initiate a hand movement that is congruent with a concurrently observed action, relative to one that is incongruent. First, we replicated previous findings of automatic imitation, and excluded the possibility that spatial compatibility effects might explain these results (Experiment 1). We then presented participants with the same goal-directed actions while directing their attention to an imperative stimulus that spatially overlapped, but was distinct from, the observed actions (Experiment 2). Crucially, automatic imitation no longer occurred when participants directed their attention away from the displayed actions and towards the spatially overlapping stimulus. In a final experiment, we examined whether the automatic imitation of grasp persists when participants attend to an irrelevant feature of the observed action, such as whether it is performed by a left or right hand (Experiment 3). Here we found that automatic imitation is contingent on participants attending to the feature of the observed hand that was relevant to their responses. Together these findings demonstrate the importance of selective mechanisms in the filtering of task-irrelevant actions, and indicate a role for top-down control in limiting the motoric simulation of observed actions.


Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting.
Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.


In vitro down-regulation of antigen-induced IL-5 gene expression and protein production by cAMP-specific phosphodiesterase type 4 inhibitor.
The effects of cAMP-elevating agents on antigen-induced IL-5 (interleukin-5) messenger RNA expression and protein production were examined in vitro in an antigen-driven system of splenocytes from ovalbumin sensitized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 10(-5) M) and by dibutyryl-cAMP (db-cAMP) (3 x 10(-4) M), but not by the type 3 and type 5 PDE inhibitors milrinone and zaprinast (10(-5) M), respectively. Forskolin (10(-5) M), an adenylate cyclase activator, was noninhibitory alone but potentiated inhibition by rolipram. Inhibition was associated with a decrease in IL-5 mRNA expression. Cycloheximide 10(-6) M and actinomycin 2 micrograms/ml abolished IL-5 production and mRNA expression. We conclude that in splenocytes from sensitized mice, IL-5 production and mRNA expression depend on antigen stimulation. The time course of IL-5 protein production is closely related to IL-5 mRNA expression and depends on de novo protein synthesis. db-cAMP and a selective PDE4 inhibitor, alone or in combination with forskolin, are the only cAMP-elevating agents that dose-dependently inhibited antigen-induced IL-5 mRNA expression and protein production. These results are in agreement with in vivo inhibition by a selective PDE4 inhibitor of antigen-induced pulmonary eosinophil infiltration and IL-5 production in sensitized mice, and they suggest that PDE4 inhibitors have potential for treating respiratory allergy.


Essential thrombocythemia: a review of the clinical features, diagnostic challenges, and treatment modalities in the era of molecular discovery.
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that is associated with diminished quality of life, thrombohemorrhagic complications, and transformation to myelofibrosis (MF) and acute leukemia (AML). The important recent discoveries of driver mutations, including the calreticulin gene in addition to JAK2 and MPL, have led to a greater understanding of disease pathogenesis and set the stage for the advent of more sophisticated prognostic, diagnostic, and therapeutic strategies. In this paper we summarize recent studies describing the molecular basis of ET. We review the prognostic importance of establishing a 'true' ET diagnosis, as well as risk factors for the development of adverse outcomes including thrombosis, AML (2% risk at 15 years), and MF (9% risk at 15 years). Finally, we discuss the decision to initiate treatment and assess the quality of evidence supporting the use of established, available therapies as well as novel treatments. Special situations, such as pregnancy, familial ET, and extreme thrombocytosis will also be discussed.


Pneumococcal conjugate vaccines for preventing acute otitis media in children.
Prior to introducing pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae was most commonly isolated from middle ear fluid of children with acute otitis media (AOM). Reducing nasopharyngeal colonisation of this bacterium by PCVs may lead to a decline in AOM. The effects of PCVs deserve ongoing monitoring since studies from the post-PCV era report a shift in causative otopathogens towards non-vaccine serotypes and other bacteria. This updated Cochrane Review was first published in 2002 and updated in 2004, 2009, and 2014. The review title was changed (to include the population, i.e. children) for this update. To assess the effect of PCVs in preventing AOM in children up to 12 years of age. We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and trials registers (ClinicalTrials.gov and WHO ICTRP) to 29 March 2019. Randomised controlled trials of PCV versus placebo or control vaccine. We used the standard methodological procedures expected by Cochrane. The primary outcomes were frequency of all-cause AOM and adverse effects. Secondary outcomes included frequency of pneumococcal AOM and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year). We used GRADE to assess the quality of the evidence. We included 14 publications of 11 trials (60,733 children, range 74 to 37,868 per trial) of 7- to 11-valent PCVs versus control vaccines (meningococcus type C vaccine in three trials, and hepatitis A or B vaccine in eight trials). We included two additional trials for this update. We did not find any relevant trials with the newer 13-valent PCV. Most studies were funded by pharmaceutical companies. Overall, risk of bias was low. In seven trials (59,415 children) PCVs were administered in early infancy, while four trials (1318 children) included children aged one year and over who were either healthy or had a history of respiratory illness. There was considerable clinical heterogeneity across studies, therefore we did not perform meta-analyses.Adverse eventsNine trials reported on adverse effects (77,389 children; high-quality evidence). Mild local reactions and fever were common in both groups, and occurred more frequently in PCV than in control vaccine groups: redness (< 2.5 cm): 5% to 20% versus 0% to 16%; swelling (< 2.5 cm): 5% to 12% versus 0% to 8%; and fever (< 39 °C): 15% to 44% versus 8% to 25%. More severe redness (> 2.5 cm), swelling (> 2.5 cm), and fever (> 39 °C) occurred less frequently (0% to 0.9%, 0.1% to 1.3%, and 0.4% to 2.5%, respectively in children receiving PCV) and did not differ significantly between PCV and control vaccine groups. Pain or tenderness, or both was reported more frequently in PCV than in control vaccine groups: 3% to 38% versus 0% to 8%. Serious adverse events judged causally related to vaccination were rare and did not differ significantly between groups, and no fatal serious adverse event judged causally related to vaccination was reported.PCV administered in early infancyPCV7The effect of a licenced 7-valent PCV with CRM197 as carrier protein (CRM197-PCV7) on all-cause AOM varied from -5% (95% confidence interval (CI) -25% to 12%) relative risk reduction (RRR) in high-risk infants (1 trial; 944 children; moderate-quality evidence) to 6% (95% CI -4% to 16%; 1 trial; 1662 children) and 6% (95% CI 4% to 9%; 1 trial; 37,868 children) RRR in low-risk infants (high-quality evidence). PCV7 with the outer membrane protein complex of Neisseria meningitidis serogroup B as carrier protein (OMPC-PCV7), was not associated with a reduction in all-cause AOM (RRR -1%, 95% CI -12% to 10%; 1 trial; 1666 children; high-quality evidence).CRM197-PCV7 and OMPC-PCV7 were associated with 20% (95% CI 7% to 31%) and 25% (95% CI 11% to 37%) RRR in pneumococcal AOM, respectively (2 trials; 3328 children; high-quality evidence) and CRM197-PCV7 with 9% (95% CI -12% to 27%) to 10% (95% CI 7% to 13%) RRR in recurrent AOM (2 trials; 39,530 children; high-quality evidence).PHiD-CV10/11The effect of a licenced 10-valent PCV conjugated to protein D, a surface lipoprotein of Haemophilus influenzae, (PHiD-CV10) on all-cause AOM varied from 6% (95% CI -6% to 17%; 1 trial; 5095 children) to 15% (95% CI -1% to 28%; 1 trial; 7359 children) RRR in healthy infants (moderate-quality evidence). PHiD-CV11 was associated with 34% (95% CI 21% to 44%) RRR in all-cause AOM (1 trial; 4968 children; high-quality evidence).PHiD-CV10 and PHiD-CV11 were associated with 53% (95% CI 16% to 74%) and 52% (95% CI 37% to 63%) RRR in pneumococcal AOM (2 trials; 12,327 children; high-quality evidence) and PHiD-CV11 with 56% (95% CI -2% to 80%) RRR in recurrent AOM (1 trial; 4968 children; moderate-quality evidence).PCV administered at later agePCV7We found no evidence of a beneficial effect on all-cause AOM of administering CRM197-PCV7 in children aged 1 to 7 years with a history of respiratory illness or frequent AOM (2 trials; 457 children; high-quality evidence) and CRM197-PCV7 combined with a trivalent influenza vaccine in children aged 18 to 72 months with a history of respiratory tract infections (1 trial; 597 children; high-quality evidence).CRM197-PCV9In 1 trial including 264 healthy day-care attendees aged 1 to 3 years, CRM197-PCV9 was associated with 17% (95% CI -2% to 33%) RRR in parent-reported all-cause OM (low-quality evidence). Administration of the licenced CRM197-PCV7 and PHiD-CV10 during early infancy is associated with large relative risk reductions in pneumococcal AOM. However, the effects of these vaccines on all-cause AOM is far more uncertain. We found no evidence of a beneficial effect on all-cause AOM of administering PCVs in high-risk infants, after early infancy (i.e. in children one year and above), and in older children with a history of respiratory illness. Compared to control vaccines, PCVs were associated with an increase in mild local reactions (redness, swelling), fever, and pain and/or tenderness. We found no evidence of a difference in more severe local reactions, fever, or serious adverse events judged causally related to vaccination.


Feasibility and Acceptability of Instructions of Daily Care in Overweight and Obese Knee Osteoarthritis Participants.
Knee Osteoarthritis (OA) is a weight-bearing joint disease and is more common in overweight and obese persons. The objective of the study was to assess the feasibility and acceptability of Instructions of Daily Care (IDC) on pain, mobility, and Body Mass Index (BMI) among knee OA participants who are overweight or obese. The study was an open-label randomized controlled trial of six weeks. Forty overweight and obese participants with knee OA were randomly divided into two groups by a computer-generated number. The participants in the Instruction Group (IG) were provided with leaflets explaining IDC for the duration of six weeks. Both groups were instructed to take low doses of the non-steroid anti-inflammatory drug (NSAIDs) on alternate days. The outcome measures were pain, mobility and BMI. The feasibility and acceptability of knee pain and mobility were assessed using a questionnaire designed by experts in rehabilitation. Participants in the IG reported more statistically significant pain relief as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index score (p=0.001) and improvement in mobility (p=0.000) assessed by the Timed Up and Go test score after six weeks compared to the Control Group (CG). Both groups did not demonstrate any significant change in BMI (p-value > 0.05). The results of descriptive statistics showed a significantly higher satisfaction score for participants who received a combination of IDC and NSAIDs, indicating an acceptable intervention. The IDC is effective and acceptable in terms of improving pain and mobility and should be recommended as the usual care of treatment.


Tactile influences on astronaut visual spatial orientation: human neurovestibular studies on SLS-2.
Human spatial orientation in spaceflight is initially disturbed by the absence of usable graviceptor information from the otolithic organs. Experiments measuring astronaut visually induced motion (vection) strength on various flight days during the first 10 days of the Spacelab Life Sciences-2 mission demonstrated two new phenomena in addition to confirming the initial increased weighting of visual and localized tactile cues. The reliance on tactile and visual noninertial cues apparently declined after a week in space, as the crew became able to utilize their internal reference frame. Subjects also showed that even nondirectional tactile cues served as a direction anchor and inhibited visually induced roll sensation relative to a new loosely tethered test condition. Individual perceptual styles were again revealed among the four astronauts tested. The readaptation to 1 G similarly shows a period of reinterpretation of inertial and visual cues to spatial orientation. The results are discussed in terms of an internal-model representation of body orientation, with time-varying weights applied to extrinsic and intrinsic signals.


The role of MAPT sequence variation in mechanisms of disease susceptibility.
The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse group of neurodegenerative dementias and movement disorders. The genomic architecture in the region spanning the MAPT locus contains a ~1.8 Mb block of linkage disequilibrium characterized by two major haplotypes: H1 and H2. Recent studies have established strong genetic association between the MAPT locus and neurodegenerative disease and uncovered haplotype-specific differences in expression and alternative splicing of MAPT transcripts. Integrating genetic association data and gene expression data to understand how non-coding genetic variation at a gene locus affects gene expression and leads to susceptibility to disease is a high priority in disease genetics, and the MAPT locus provides an excellent paradigm for this. In the absence of protein-coding changes caused by haplotype sequence variation, altered levels of protein expression or altered ratios of isoform expression are excellent candidate mechanisms to link the MAPT genetic disease association with biological function. The use of novel transgenic and endogenous genetic models are required to understand the role of MAPT sequence variation in mechanisms of disease susceptibility.


Correction of projector nonlinearity in multi-frequency phase-shifting fringe projection profilometry.
In fringe projection profilometry, the original purpose of projecting multi-frequency fringe patterns is to determine fringe orders automatically, thus unwrapping the measured phase maps. This paper presents that using the same patterns, simultaneously, allows us to correct the effects of projector nonlinearity on the measured results. As is well known, the projector nonlinearity decreases the measurement accuracies by inducing ripple-like artifacts on the measured phase maps; and, theoretical analysis reveals that these artifacts, depending on the number of phase shifts, have multiplied frequencies higher than the fringe frequencies. Based on this fact, we deduce an error function for modeling the phase artifacts and then suggest an algorithm estimating the function coefficients from a couple of phase maps of fringe patterns having different frequencies. As a result, subtracting out the estimated phase errors yields the accurate phase maps with the effects of the projector nonlinearity on them being suppressed significantly. Experiment results demonstrated that this proposed method offers some advantages over others, such as working without a photometric calibration, being applicable when the projector nonlinearity varies over time, and having satisfied efficiency in implementation.


Improving adherence to surveillance and screening recommendations for people with colorectal cancer and their first degree relatives: a randomized controlled trial.
Colorectal cancer (CRC) is among the leading causes of cancer-related morbidity and mortality worldwide. Despite clinical practice guidelines to guide surveillance care for those who have completed treatment for this disease as well as screening for first degree relatives of people with CRC, the level of uptake of these recommendations remains uncertain. If outcomes for both patients and their families are to be improved, it is important to establish systematic and cost-effective interventions to improve adherence to guideline recommendations for CRC surveillance and screening. A randomized controlled trial will be used to test the effectiveness of a print-based intervention to improve adherence to colonoscopy surveillance among people with CRC and adherence to CRC screening recommendations among their first degree relatives (FDRs). People diagnosed with CRC in the past 10 months will be recruited through a population-based cancer registry. Consenting participants will be asked if their first degree relatives might also be willing to participate in the trial. Information on family history of CRC will be obtained from patients at baseline. Patients and their families will be randomized to either minimal ethical care or the print-based intervention. The print-based intervention for FDRs will be tailored to the participant's level of risk of CRC as determined by the self-reported family history assessment. Follow up data on surveillance and screening participation will be collected from patients and their FDRs respectively at 12, 24 and 36 months' post recruitment. The primary analyses will relate to comparing levels of guideline adherence in usual care group versus print-based group in the patient sample and the FDR sample respectively. Results of this study will provide contribute to the evidence base about effective strategies to a) improve adherence to surveillance recommendation for people with CRC; and b) improve adherence to screening recommendation for FDRs of people with CRC. The use of a population-based cancer registry to access the target population may have significant advantages in increasing the reach of the intervention. This trial is registered with the Australian and New Zealand Clinical Trials Registry Registration Number (ACTRN): ACTRN12609000628246.


Fruit development and diversification.
The evolutionary success of angiosperms depends largely on the unique feature of producing fruits, which protect and nourish the seeds, and at maturity facilitate efficient seed dispersal. Fruits have long been an important energy source for humans, providing us with nutritious proteins and vitamins. Domestication of fruit and seed crops ignited the formation of modern civilisation during the Neolithic Revolution. In the past two decades, the fruit development process has been extensively studied in the model species Arabidopsis thaliana and related Brassicaceae species, and great advances have been made in dissecting the molecular circuit underlying patterning of the fruit into specific tissues. The aim of this Primer is to discuss the molecular network and the inter-connected hormonal signalling events in fruit patterning from an evolutionary and developmental point-of-view. An interesting theme emerging from the studies in leaves and fruits is that tissue polarity, as manifested by anisotropic growth, is tightly associated with local auxin distribution. We further highlight that changes in cell anisotropic growth, possibly directed by the formation of local auxin maxima, may explain fruit-shape diversification in the Brassicaceae.


Statin use and ventricular arrhythmias during clinical treadmill testing.
Premature ventricular complexes (PVCs) during exercise are associated with adverse prognosis, particularly in patients with intermediate treadmill test findings. Statin use reduces the incidence of resting ventricular arrhythmias in patients with coronary artery disease; however, the relationship between statin use and exercise-induced ventricular arrhythmias has not been investigated. We evaluated the association between statin use and PVCs in 1,847 heart-failure-free patients (mean age 58, 95% male) undergoing clinical exercise treadmill testing between 1997 and 2004 in the VA Palo Alto Health Care System. PVCs were quantified in beats per minute and frequent PVCs were defined as PVC rates greater than the median value (0.43 and 0.60 PVCs per minute for exercise and recovery, respectively). Propensity-adjusted logistic regression was used to evaluate the odds of developing PVCs during exercise and recovery periods associated with statin use. There were 431 subjects who developed frequent PVCs during exercise and 284 subjects had frequent recovery PVCs. After propensity score adjustment, subjects treated with statins (n = 145) had 42% lower odds of developing frequent PVCs during exercise (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37-0.93) and 44% lower odds of developing frequent PVCs during recovery (OR 0.56, 95% CI 0.30-0.94). These effects were not modified by age, prior coronary disease, hypercholesterolemia, exercise-induced angina, or exercise capacity. Statin use was associated with reduced odds of frequent PVCs during and after clinical exercise testing in a manner independent of associations with coronary disease or ischemia in our study population.


Human proprioceptive adaptations during states of height-induced fear and anxiety.
Clinical and experimental research has demonstrated that the emotional experience of fear and anxiety impairs postural stability in humans. The current study investigated whether changes in fear and anxiety can also modulate spinal stretch reflexes and the gain of afferent inputs to the primary somatosensory cortex. To do so, two separate experiments were performed on two separate groups of participants while they stood under conditions of low and high postural threat. In experiment 1, the proprioceptive system was probed using phasic mechanical stimulation of the Achilles tendon while simultaneously recording the ensuing tendon reflexes in the soleus muscle and cortical-evoked potentials over the somatosensory cortex during low and high threat conditions. In experiment 2, phasic electrical stimulation of the tibial nerve was used to examine the effect of postural threat on somatosensory evoked potentials. Results from experiment 1 demonstrated that soleus tendon reflex excitability was facilitated during states of height-induced fear and anxiety while the magnitude of the tendon-tap-evoked cortical potential was not significantly different between threat conditions. Results from experiment 2 demonstrated that the amplitudes of somatosensory-evoked potentials were also unchanged between threat conditions. The results support the hypothesis that muscle spindle sensitivity in the triceps surae muscles may be facilitated when humans stand under conditions of elevated postural threat, although the presumed increase in spindle sensitivity does not result in higher afferent feedback gain at the level of the somatosensory cortex.


A framework for mining signatures from event sequences and its applications in healthcare data.
This paper proposes a novel temporal knowledge representation and learning framework to perform large-scale temporal signature mining of longitudinal heterogeneous event data. The framework enables the representation, extraction, and mining of high-order latent event structure and relationships within single and multiple event sequences. The proposed knowledge representation maps the heterogeneous event sequences to a geometric image by encoding events as a structured spatial-temporal shape process. We present a doubly constrained convolutional sparse coding framework that learns interpretable and shift-invariant latent temporal event signatures. We show how to cope with the sparsity in the data as well as in the latent factor model by inducing a double sparsity constraint on the β-divergence to learn an overcomplete sparse latent factor model. A novel stochastic optimization scheme performs large-scale incremental learning of group-specific temporal event signatures. We validate the framework on synthetic data and on an electronic health record dataset.


Editorial Perspective: Rapid responses to understand and address children and young people's mental health in the context of COVID-19.
Prior to the pandemic, we already had good reason to be concerned about the mental health of children and young people. As an example, the 2017 Mental Health of Children and Young People (MHCYP) survey in England, comprising a large, national probability sample, identified that one in nine children had a probable mental health disorder, with a 49% increase in emotional disorders compared to a previous survey in 2004 (Sadler et al., 2018). The pandemic has clearly brought a broad range of challenges to children and young people. These include the direct viral threat to self, friends, and family (with recent estimates of a 17.5%-20.2% increase in parental bereavement in the United States; Kidman et al, 2021), as well as disruptions to school work, social interactions, family pressures, economic impacts, a lack of opportunity and ongoing uncertainty, and reduced access to mental health and other support from outside the home. So how have these experiences affected the mental health of children and young people?


Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly.
Adaptor protein complex 2 alpha and beta-appendage domains act as hubs for the assembly of accessory protein networks involved in clathrin-coated vesicle formation. We identify a large repertoire of beta-appendage interactors by mass spectrometry. These interact with two distinct ligand interaction sites on the beta-appendage (the "top" and "side" sites) that bind motifs distinct from those previously identified on the alpha-appendage. We solved the structure of the beta-appendage with a peptide from the accessory protein Eps15 bound to the side site and with a peptide from the accessory cargo adaptor beta-arrestin bound to the top site. We show that accessory proteins can bind simultaneously to multiple appendages, allowing these to cooperate in enhancing ligand avidities that appear to be irreversible in vitro. We now propose that clathrin, which interacts with the beta-appendage, achieves ligand displacement in vivo by self-polymerisation as the coated pit matures. This changes the interaction environment from liquid-phase, affinity-driven interactions, to interactions driven by solid-phase stability ("matricity"). Accessory proteins that interact solely with the appendages are thereby displaced to areas of the coated pit where clathrin has not yet polymerised. However, proteins such as beta-arrestin (non-visual arrestin) and autosomal recessive hypercholesterolemia protein, which have direct clathrin interactions, will remain in the coated pits with their interacting receptors.


Engineering nanocomposite materials for cancer therapy.
Cancer accounted for 13% of all deaths worldwide in 2005. Although early detection is critical for the successful treatment of many cancers, there are sensitivity limitations associated with current detection methodologies. Furthermore, many traditional anticancer drug treatments exhibit limited efficacy and cause high morbidity. The unique physical properties of nanoscale materials can be utilized to produce novel and effective sensors for cancer diagnosis, agents for tumor imaging, and therapeutics for cancer treatment. Functionalizing inorganic nanoparticles with biocompatible polymers and natural or rationally designed biomolecules offers a route towards engineering responsive and multifunctional composite systems. Although only a few such innovations have reached human clinical trial to date, nanocomposite materials based on functionalized metal and semiconductor nanoparticles promise to transform the way cancer is diagnosed and treated. This review summarizes the current state-of-the-art in the development of inorganic nanocomposites for cancer-related applications.


Morbidity and mortality after use of iliac conduits for endovascular aortic aneurysm repair.
Although placement of an open iliac conduit for endovascular aortic aneurysm repair (EVAR) is generally felt to result in higher morbidity and mortality, published literature is scarce. Our objective was to assess 30-day outcomes after elective EVAR with an open iliac conduit using a multi-institutional database. Patients who underwent elective EVAR (n = 14,339) for abdominal aortic aneurysm were identified from the American College of Surgeons National Surgical Quality Improvement Program 2005 to 2011 database. Univariable and multivariable logistic regression analyses were performed. An open iliac conduit was used in 231 patients (1.6%), and the remainder had femoral exposure or percutaneous EVAR. Women comprised 32% of patients with iliac conduits in contrast to 17% of those without iliac conduits. Patients with iliac conduits were older and had a lower body mass index. Univariable analysis showed patients with open iliac conduits had a higher incidence of postoperative pneumonia (3.0% vs 1.1%), ventilator dependence (4.8% vs 1.0%), renal failure (3.0% vs 0.7%), cardiac arrest or myocardial infarction (5.2% vs 1.1%), return to the operating room (9.1% vs 3.7%), major morbidity (16.0 vs 6.6%), and death (3.0% vs 0.9%). On multivariable analysis, the use of open iliac conduits was associated with higher risk of 30-day mortality (odds ratio, 2.7; 95% confidence interval, 1.2-6.0) and 30-day major morbidity (odds ratio, 2.3; 95% confidence interval, 1.6-3.3). Patients with open iliac conduits for EVAR are more likely to be female and have higher postoperative morbidity and mortality. For patients with complex iliac artery disease, conduits are a viable alternative after EVAR to be performed, albeit at an increased risk. These data do suggest the need for lower-profile grafts and other alternative strategies for navigating complex iliac artery disease.


Epitope specificity delimits the functional capabilities of vaccine-induced CD8 T cell populations.
Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2K(d) epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2D(d) epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2D(d) specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.


Regulation of glucose transporter 4 traffic by energy deprivation from mitochondrial compromise.
Skeletal muscle is the major store and consumer of fatty acids and glucose. Glucose enters muscle through glucose transporter 4 (GLUT4). Upon insufficient oxygen availability or energy compromise, aerobic metabolism of glucose and fatty aids cannot proceed, and muscle cells rely on anaerobic metabolism of glucose to restore cellular energy status. An increase in glucose uptake into muscle is a key response to stimuli requiring rapid energy supply. This chapter analyses the mechanisms of the adaptive regulation of glucose transport that rescue muscle cells from mitochondrial uncoupling. Under these conditions, the initial drop in ATP recovers rapidly, through a compensatory increase in glucose uptake. This adaptive response involves AMPK activation by the initial ATP drop, which elevates cell surface GLUT4 and glucose uptake. The gain in surface GLUT4 involves different signals and routes of intracellular traffic compared with those engaged by insulin. The hormone increases GLUT4 exocytosis through phosphatidylinositol 3-kinase and Akt, whereas energy stress retards GLUT4 endocytosis through AMPK and calcium inputs. Given that energy stress is a component of muscle contraction, and that contraction activates AMPK and raises cytosolic calcium, we hypothesize that the increase in glucose uptake during contraction may also involve a reduction in GLUT4 endocytosis.


Bright spots among the world's coral reefs.
Ongoing declines in the structure and function of the world's coral reefs require novel approaches to sustain these ecosystems and the millions of people who depend on them3. A presently unexplored approach that draws on theory and practice in human health and rural development is to systematically identify and learn from the 'outliers'—places where ecosystems are substantially better ('bright spots') or worse ('dark spots') than expected, given the environmental conditions and socioeconomic drivers they are exposed to. Here we compile data from more than 2,500 reefs worldwide and develop a Bayesian hierarchical model to generate expectations of how standing stocks of reef fish biomass are related to 18 socioeconomic drivers and environmental conditions. We identify 15 bright spots and 35 dark spots among our global survey of coral reefs, defined as sites that have biomass levels more than two standard deviations from expectations. Importantly, bright spots are not simply comprised of remote areas with low fishing pressure; they include localities where human populations and use of ecosystem resources is high, potentially providing insights into how communities have successfully confronted strong drivers of change. Conversely, dark spots are not necessarily the sites with the lowest absolute biomass and even include some remote, uninhabited locations often considered near pristine6. We surveyed local experts about social, institutional, and environmental conditions at these sites to reveal that bright spots are characterized by strong sociocultural institutions such as customary taboos and marine tenure, high levels of local engagement in management, high dependence on marine resources, and beneficial environmental conditions such as deep-water refuges. Alternatively, dark spots are characterized by intensive capture and storage technology and a recent history of environmental shocks. Our results suggest that investments in strengthening fisheries governance, particularly aspects such as participation and property rights, could facilitate innovative conservation actions that help communities defy expectations of global reef degradation.


Alternatives for safe water provision in urban and peri-urban slums.
In response to rapid urbanization throughout the global South, urban and peri-urban slums are expanding at an alarming rate. Owing to inadequate financial and institutional resources at the municipal level, conventional approaches for safe water provision with centralized treatment and distribution infrastructure have been unable to keep pace with rapidly growing demand. In the absence of alternatives to centralized systems, a global public health emergency of infectious water-related diseases has developed. Alternative decentralized water treatment systems have been promoted in recent years as a means of achieving rapid health gains among vulnerable populations. Though much work with decentralized systems, especially in urban environments, has been at the household level, there is also considerable potential for development at the community level. Both levels of approach have unique sets of advantages and disadvantages that, just as with treatment technologies, may make certain options more appropriate than others in a particular setting. Integrating community, government and other relevant stakeholders into the process of systems development and implementation is essential if the outcome is to be appropriate to local circumstances and sustainable in the long term.


IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation.
A recent in vitro study indicates that IGOB131, a novel seed extract of the traditional West African food plant Irvingia gabonensis, favorably impacts adipogenesis through a variety of critical metabolic pathways including PPAR gamma, leptin, adiponectin, and glycerol-3 phosphate dehydrogenase. This study was therefore aimed at evaluating the effects of IGOB131, an extract of Irvingia gabonensis, on body weight and associated metabolic parameters in overweight human volunteers. The study participants comprised of 102 healthy, overweight and/or obese volunteers (defined as BMI > 25 kg/m2) randomly divided into two groups. The groups received on a daily basis, either 150 mg of IGOB131 or matching placebo in a double blinded fashion, 30-60 minutes before lunch and dinner. At baseline, 4, 8 and 10 weeks of the study, subjects were evaluated for changes in anthropometrics and metabolic parameters to include fasting lipids, blood glucose, C-reactive protein, adiponectin, and leptin. Significant improvements in body weight, body fat, and waist circumference as well as plasma total cholesterol, LDL cholesterol, blood glucose, C-reactive protein, adiponectin and leptin levels were observed in the IGOB131 group compared with the placebo group. Irvingia gabonensis administered 150 mg twice daily before meals to overweight and/or obese human volunteers favorably impacts body weight and a variety of parameters characteristic of the metabolic syndrome. This is the first double blind randomized placebo controlled clinical trial regarding the anti-obesity and lipid profile modulating effects of an Irvingia gabonensis extract. The positive clinical results, together with our previously published mechanisms of gene expression modulation related to key metabolic pathways in lipid metabolism, provide impetus for much larger clinical studies. Irvingia gabonensis extract may prove to be a useful tool in dealing with the emerging global epidemics of obesity, hyperlipidemia, insulin resistance, and their co-morbid conditions.


Exoplanet orbital eccentricities derived from LAMOST-Kepler analysis.
The nearly circular (mean eccentricity [Formula: see text]) and coplanar (mean mutual inclination [Formula: see text]) orbits of the solar system planets motivated Kant and Laplace to hypothesize that planets are formed in disks, which has developed into the widely accepted theory of planet formation. The first several hundred extrasolar planets (mostly Jovian) discovered using the radial velocity (RV) technique are commonly on eccentric orbits ([Formula: see text]). This raises a fundamental question: Are the solar system and its formation special? The Kepler mission has found thousands of transiting planets dominated by sub-Neptunes, but most of their orbital eccentricities remain unknown. By using the precise spectroscopic host star parameters from the Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) observations, we measure the eccentricity distributions for a large (698) and homogeneous Kepler planet sample with transit duration statistics. Nearly half of the planets are in systems with single transiting planets (singles), whereas the other half are multiple transiting planets (multiples). We find an eccentricity dichotomy: on average, Kepler singles are on eccentric orbits with [Formula: see text] 0.3, whereas the multiples are on nearly circular [Formula: see text] and coplanar [Formula: see text] degree) orbits similar to those of the solar system planets. Our results are consistent with previous studies of smaller samples and individual systems. We also show that Kepler multiples and solar system objects follow a common relation [[Formula: see text](1-2)[Formula: see text]] between mean eccentricities and mutual inclinations. The prevalence of circular orbits and the common relation may imply that the solar system is not so atypical in the galaxy after all.


Evaluation of left ventricular functions in patients with primary hyperparathyroidism: is there any effect of parathyroidectomy?
Our aim was to evaluate left ventricular (LV) systolic and diastolic functions of primary hyperparathyroidism (pHPT) patients with detailed echocardiographic analysis and investigate the effect of parathyroidectomy on echocardiographic parameters. A total of 22 eligible consecutive patients with pHPT who underwent parathyroidectomy operation were recruited to the study. Another 22 subjects with similar age, gender and frequency of cardiovascular risk factors compared to patients were used as a control group. Echocardiographic parameters of patients scheduled for parathyroidectomy were compared to healthy matched controls. Echocardiographic parameters measured 6 months after the operation were also compared with preoperative values for each patient. Patients had higher LV mass index compared with controls. There were no significant differences between groups regarding 2D echocardiographic parameters reflecting LV systolic function and tissue Doppler velocities; however, 2D echocardiographic parameters demonstrated impairment in LV diastolic functions compared with controls. Speckle tracking echocardiography (STE) demonstrated similar LV global longitudinal systolic strain; however, left atrial conduit and reservoir functions were significantly reduced in patients with pHPT. In general, there were no significant differences between baseline and postoperative state regarding parameters reflecting LV systolic and diastolic functions; however, STE demonstrated significantly increased LV global longitudinal strain after surgery (22.3 ± 3.3% vs 20.3 ± 2.9%, p = 0.026). Patients with pHPT displayed higher LV mass and impairment in LV diastolic function compared with controls. Parathyroidectomy did not lead to significant improvements in LV mass or LV diastolic function; however, subtle but not apparent increases in LV systolic function were observed 6 months after surgery.


HySAR: Hybrid Material Rendering by an Optical See-Through Head-Mounted Display with Spatial Augmented Reality Projection.
Spatial augmented reality (SAR) pursues realism in rendering materials and objects. To advance this goal, we propose a hybrid SAR (HySAR) that combines a projector with optical see-through head-mounted displays (OST-HMD). In an ordinary SAR scenario with co-located viewers, the viewers perceive the same virtual material on physical surfaces. In general, the material consists of two components: a view-independent (VI) component such as diffuse reflection, and a view-dependent (VD) component such as specular reflection. The VI component is static over viewpoints, whereas the VD should change for each viewpoint even if a projector can simulate only one viewpoint at one time. In HySAR, a projector only renders the static VI components. In addition, the OST-HMD renders the dynamic VD components according to the viewer's current viewpoint. Unlike conventional SAR, the HySAR concept theoretically allows an unlimited number of co-located viewers to see the correct material over different viewpoints. Furthermore, the combination enhances the total dynamic range, the maximum intensity, and the resolution of perceived materials. With proof-of-concept systems, we demonstrate HySAR both qualitatively and quantitatively with real objects. First, we demonstrate HySAR by rendering synthetic material properties on a real object from different viewpoints. Our quantitative evaluation shows that our system increases the dynamic range by 2.24 times and the maximum intensity by 2.12 times compared to an ordinary SAR system. Second, we replicate the material properties of a real object by SAR and HySAR, and show that HySAR outperforms SAR in rendering VD specular components.


Cyclic sciatica from extrapelvic endometriosis affecting the sciatic nerve.
Sciatic (catamenial) radiculopathy, waxing and waning with the menstrual cycle, is an uncommon condition typically caused by pelvic endometriosis affecting the lumbosacral plexus or proximal sciatic nerve. The authors describe a woman with catamenial sciatica caused by endometriosis affecting the sciatic nerve trunk in the upper thigh. Symptomatic with leg pain for 5 years, this patient developed gluteal atrophy and sensory loss and decreased strength in the L-5 dermatomyotome, a distribution confirmed by electromyography. Magnetic resonance imaging suggested thickening of the sciatic nerve at and distal to the sciatic notch. At operation the nerve showed extrinsic and intrinsic abnormality, proven to be endometriosis. Her symptoms improved, and she began gonadotropin-releasing hormone agonist therapy for further suppression. This very unusual case shows that endometriosis can affect the sciatic nerve over a range of territory inside and outside the pelvis, and that surgery must be appropriately directed to avoid negative exploration. Surgical decompression achieves good relief of symptoms, and medical therapy also allows sustained suppression of this disease.


Consensus statement on injury definitions and data collection procedures in studies of football (soccer) injuries.
Variations in definitions and methodologies have created differences in the results and conclusions obtained from studies of football injuries; this has made inter-study comparisons difficult. An Injury Consensus Group was established under the auspices of FIFA Medical Assessment and Research Centre. Using a nominal group consensus model approach, a working document that identified the key issues related to definitions, methodology and implementation was discussed by members of the group during a 2-day meeting. Following this meeting, iterative draft statements were prepared and circulated to members of the group for comment before the final consensus statement was produced. Definitions of injury, recurrent injury, severity and training and match exposures in football together with criteria for classifying injuries in terms of location, type, diagnosis and causation are proposed. Proforma for recording players' baseline information, injuries and training and match exposures are presented. Recommendations are made on how the incidence of match and training injuries should be reported and a checklist of issues and information that should be included in published reports of studies of football injuries is presented. The definitions and methodology proposed in the consensus statement will ensure that consistent and comparable results will be obtained from studies of football injuries.


BMP7 improves insulin signal transduction in the liver via inhibition of mitogen-activated protein kinases.
Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.


A primary care specialist genetics service: a cluster-randomised factorial trial.
GPs do not have the confidence to identify patients at increased genetic risk. A specialist primary care clinical genetics service could support GPs with referral and provide local clinics for their patients. To test whether primary care genetic-led genetics education improves both non-cancer and cancer referral rates, and primary care-led genetics clinics improve the patient pathway. Cluster-randomised factorial trial in 73 general practices in the south of England. Practices randomised to receive case scenario based seminar (intervention) or not (control), and referred patients a primary (intervention) or secondary (control) care genetic counsellor (GC)-led appointment. GP referral and clinic attendance rates (primary), appropriate cancer and case scenario referral rates, patient satisfaction, clinic costs, and case management (secondary). Eighty-nine and 68 referrals made by 36 intervention and 37 control practices respectively. There was a trend towards an overall higher referral rate among educated GPs (referral rate ratio [RRR] 1.34, 95% confidence interval [CI] = 0.89 to 2.02; P = 0.161), and they made more appropriate cancer referrals (RRR 2.36, 95% CI = 1.07 to 5.24; P = 0.035). No indication of difference in clinic attendance rates (odds ratio 0.91, 95% CI = 0.43 to 1.95; P = 0.802) or patient satisfaction (P = 0.189). Patients spent 49% less travelling (£3.60 versus £6.62; P<0.001) and took 33% less time (39.7 versus 57.7 minutes; P<0.001) to attend a primary than secondary care appointment; 83% of GC-managed appointments met the 18-week referral to treatment, NHS target. An integrated primary care genetics service both supports GPs in appropriate cancer referral and provides care in the right place by the right person.


A prehospital trauma registry for tactical combat casualty care.
Many combat-related deaths occur in the prehospital environment before the casualty reaches a medical treatment facility. The tenets of Tactical Combat Casualty Care (TCCC) were published in 1996 and integrated throughout the 75th Ranger Regiment in 1999. In order to validate and refine TCCC protocols and procedures, a prehospital trauma registry was developed and maintained. The application of TCCC, in conjunction with validation and refinement of TCCC through feedback from a prehospital trauma registry, has translated to an increase in survivability on the battlefield.


Systematic review of response rates of sarcomatoid malignant pleural mesotheliomas in clinical trials.
Malignant pleural mesothelioma is an almost universally fatal malignancy primarily related to asbestos exposure. Based on the differences in immunologic markers and gene expression between histologic subtypes of mesothelioma, and our clinical impression that response rates vary by histology, we decided to examine the reported response rates of mesothelioma subtypes. Our objective was to compare the response rates of sarcomatoid mesotheliomas to the overall response rates in published clinical trials. We searched PubMed for "mesothelioma" with the clinical trials filter selected. We included articles published between January 1, 2000 and March 20, 2014 in which subjects received first or second line systemic therapy for malignant pleural mesothelioma. Studies investigating multi-modality therapy including surgery were excluded. Response rates [including 95% confidence intervals (95% CI)] were estimated for the entire patient cohort and then separately for subjects with sarcomatoid tumors. We reviewed 544 publications of which 41 trials met our inclusion criteria. Eleven of these trials did not include patients with sarcomatoid mesothelioma (27% of eligible studies). The remaining 30 publications included 1475 subjects, 1011 with epithelioid tumors (68.5%), 203 with biphasic tumors (13.8%), 137 with sarcomatoid tumors (9.3%) and 124 with unknown subtypes (8.4%). In total, there were 323 responses (21.9%, complete and partial responses, 95% CI: 16.3, 28.8) to systemic therapy across all histological subtypes. In patients with sarcomatoid tumors (n=137) 19 responses were observed. This accounted for 5.9% of all responses and yields a 13.9% (95% CI: 8.6, 21.6) response rate for patients with sarcomatoid tumors. Multiple biases likely affected this systematic review. Response rates for different histological subtypes of malignant pleural mesothelioma are infrequently reported. Partial and complete responses to systemic therapies appear to be less common among patients with sarcomatoid tumors.


Accuracy of reporting of methicillin-resistant Staphylococcus aureus in a provincial quality control program: a 9-year study.
We report the results of a province-wide quality control program in which five methicillin-resistant Staphylococcus aureus strains were circulated to all Ontario laboratories (hospital, private, and public health laboratories) on nine occasions between 1980 and 1989. The level of expression of methicillin resistance in each of the isolates was determined by performing viable colony counts on serial dilutions of methicillin in agar, and each isolate was assigned to an expression class according to previous published criteria (A. Tomasz, S. Nachman, and H. Leaf, Antimicrob. Agents Chemother. 35:124-129, 1991). Over this time there was an improvement in the performance of laboratories in the recognition of three strains that were relatively easy to detect (strains B, C, and E). These strains were of expression class II, and 98% of laboratories reported correct identifications in 1986. Performance in identifying two strains (strains A and D) of expression class I remained poor. Strain A was circulated in two surveys in 1987 and 1989, and laboratories were sent a questionnaire requesting details of the methods used in those two surveys. The methods used by the laboratories were classified into three categories: disk diffusion, single-plate screening by agar incorporation, and automated methods, which included premanufactured MIC panels. Between the 1987 and 1989 surveys, there was no change in the performance of the disk diffusion test (60% correct on both occasions), but there was improvement in the sensitivity of the agar incorporation test (36% correct in 1987 and 84% correct in 1989) and in automated methods (43% correct in 1987 and 79% correct in 1989). Over a decade, there was overall improvement in the performance of laboratories in detecting easy-to-detect strains, but there were difficulties in detecting organisms of low expression class, and an organism of very low expression class should be designated as a control organism for routine testing of methicillin-resistant s. aureus isolates.


Biotin Regulates Colonization and Growth of Candida albicans in the Catheter Lumen During Nutrient Infusions.
Bacterial and fungal catheter-related bloodstream infections (CRBSI) cause high fever and blindness due to fungal endophthalmitis. Candidal CRBSI have a particularly high mortality rate and needs attention. In this study, we examined the effect of biotin on the colonization and growth of Candida albicans in the lumen of the catheter used for nutrient infusions. In the current study, nutrient infusion-1: commercially available peripheral parenteral nutrition (PPN) infusion solution with vitamin B1 (control), nutrient infusion-2: biotin added to the PPN infusion, nutrient infusion-3: water-soluble vitamins (B2, B6, B12, C, folic acid, nicotinamide, panthenol) except biotin added to the PPN infusion, and nutrient infusion-4: commercially available PPN infusion with all water soluble vitamins (B1, B2, B6, B12, C, folic acid, nicotinamide, biotin, panthenol) were used. Candida albicans suspension was injected into a Planecta infusion set, which was connected to one of the test solutions, and the infusions flow pass was blocked for approximately 30 minutes. Subsequently, the infusions were resumed, and the test solution was collected at 24 hours, 48 hours, and 72 hours to estimate the Candida albicans colony-forming units in each infusion. We demonstrated that nutrient infusion with biotin promoted colonization and proliferation in the catheter lumen, whereas those without biotin had no effect. These results suggest that biotin may accelerate the colonization and growth of Candida albicans in catheter lumen and using biotin-containing nutrient infusions may increase the risk of CRBSI.


Patient-oriented intervention in addition to centrally organised checkups improves diabetic patient outcome in primary care.
Logistic support to general practitioners improves the care processes for patients with diabetes but is not sufficient to meet all criteria. To introduce patient-oriented interventions by a practice nurse in general practices which already use logistic support to improve the care processes for patients with diabetes. A controlled before-after study with delayed intervention in the control group. 51 practices (n = 23 for the intervention and n = 28 for the control group) in the south of The Netherlands and 900 of their patients with type 2 diabetes. Data were collected on the results of the checkups (fasting blood glucose, glycosylated haemoglobin (HbA1C), cholesterol, cholesterol/high-density lipoprotein ratio, triglycerides, creatinine, blood pressure, fundus photo, foot exam and body mass index), smoking status, physical activity and medication use. The effect of the patient-oriented intervention was analysed in a mixed model with repeated measurement covariance structure. The HbA1C improved in the intervention group (from 7.3 to 7.1), while that of the control group deteriorated (from 7.2 to 7.3). The percentage of patients with an HbA1C >or=8.5 was halved after the intervention (from 13 to 6). Patients in the intervention group started to exercise more besides their daily activities compared with the control group. The need for medication increased more in the control group than in the intervention group (more changes to insulin and more defined daily dose (DDD) oral medication). Patient-oriented interventions in addition to logistic support have a positive effect on diabetic patient outcomes.