Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy.
Various imaging modalities have been used to explore pathogenic mechanisms and stratify the severity of hepatic encephalopathy (HE). The hypothesis of this meta-analysis was that there is a progressive identifiable derangement of imaging measures using magnetic resonance spectroscopy (MRS) related to the severity of the HE. Studies with more than 10 cases and HE diagnosis were identified from the electronic databases PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Literatura Latino Americana em Ciências da Saúde (LILACS), and Cochrane Central Register of Controlled Trials (CENTRAL) through July 25, 2018. Participants were stratified into healthy controls and patients with non-HE (NHE) (cirrhosis without HE), minimal HE (MHE), and overt HE (OHE). Analyses were organized by metabolite studied and brain region examined. Statistical meta-analysis was performed using the metafor package in R (v3.4.1). Pooled standardized mean differences between patient groups were calculated using a random effects model. We identified 31 studies (1,481 patients) that included data for cirrhosis-related HE. We found the parietal region to be the most reliable in differentiating between patients with and without MHE, with standard mean differences of +0.82 (95% confidence interval [CI] +0.49 to +1.15, p < 0.0001, I 2 = 37.45%) for glutamine/glutamate, -0.36 (95% CI -0.61 to -0.10, p = 0.007, I 2 = 20.00%) for choline, and-0.77 (95% CI -1.19 to -0.34, p = 0.0004, I 2 = 67.48%) for myo-inositol. We also found that glutamine/glutamate was the metabolite that reliably correlated with HE grade in all brain regions. The meta-analysis reveals that MRS changes in glutamine/glutamate, choline, and myo-inositol, particularly in the parietal lobe, correlate with the severity of HE. MRS may be of value in the assessment of HE.


Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.
There are limited data about the effect of maternal influenza infection on fetuses and newborns. We performed a secondary analysis of data from the Mother's Gift project, a randomized study designed to test the effectiveness of inactivated influenza and pneumococcal vaccines during pregnancy. In the Mother's Gift project, 340 pregnant women in Bangladesh received either inactivated influenza vaccine or 23-valent pneumococcal polysaccharide vaccine (control). This study was performed from August 2004 through December 2005. We performed a secondary analysis of outcomes following maternal influenza immunization during two periods: when influenza virus was not circulating (September 2004 through January 2005) and when influenza virus was circulating (February through October 2005). We assessed gestational age, mean birth weight and the proportion of infants who were small for gestational age. During the period with no circulating influenza virus, there were no differences in the incidence of respiratory illness with fever per 100 person-months among mothers and infants in the two groups (influenza vaccine: 3.9; control: 4.0; p > 0.9). The proportion of infants who were small for gestational age and the mean birth weight were similar between groups (small for gestational age: influenza vaccine 29.1%, control 34.3%; mean birth weight: influenza vaccine 3083 g, control 3053 g). During the period with circulating influenza virus, there was a substantial reduction in the incidence per 100 person-months of respiratory illness with fever among the mothers and infants who had received the influenza vaccine (influenza vaccine: 3.7; control: 7.2; p = 0.0003). During this period, the proportion of infants who were small for gestational age was lower in the influenza vaccine group than in the control group (25.9% v. 44.8%; p = 0.03). The mean birth weight was higher among infants whose mothers received the influenza vaccine than among those who received the control vaccine during this period (3178 g v. 2978 g; p = 0.02). During the period with circulating influenza virus, maternal immunization during pregnancy was associated with a lower proportion of infants who were small for gestational age and an increase in mean birth weight. These data need confirmation but suggest that prevention of influenza infection in pregnancy can influence intrauterine growth. ClinicalTrials.gov: NCT 00142389.


Do different clinical evidence bases lead to discordant health-technology assessment decisions? An in-depth case series across three jurisdictions.
Health-technology assessment (HTA) plays an important role in informing drug-reimbursement decision-making in many countries. HTA processes for the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia, the Common Drug Review (CDR) in Canada, and the National Institute for Health and Clinical Excellence (NICE) in England and Wales are among the most established in the world. In this study, we performed nine in-depth case studies to assess whether different clinical evidence bases may have influenced listing recommendations made by PBAC, CDR, and NICE. Nine drugs were selected for which the three agencies had provided listing recommendations for the same indication between 2007 and 2010. We reviewed the evidence considered for each listing recommendation, identified the similarities and differences among the clinical evidence bases considered, and evaluated the extent to which different clinical evidence bases could have contributed to different decisions based on HTA body comments and public assessment of the evidence. HTA agencies reached the same recommendation for reimbursement (recommended for listing) for four drugs and different recommendations for five drugs. In all cases, each agency used different evidence bases in their recommendations. The agencies considered overlapping sets of clinical comparators and trials when evaluating the same drug. While PBAC and NICE considered indirect and/or mixed-treatment comparisons, CDR did not. In some cases, CDR and/or NICE excluded trials from review if the drug and/or the comparator were not administered according to the relevant marketing authorization. In the listing recommendations reviewed, considerable variability exists in the clinical evidence considered by PBAC, CDR, and NICE for drug-listing recommendations. Differences in evidence resulted from differences in the consideration of indirect and mixed-treatment comparison data and differences in medical practice in each jurisdiction.


Differential responses to x-irradiation of subpopulations of two heterogeneous human carcinomas in vitro.
The responses of two heterogeneous human cancer cell lines and their derivative clones to graded single doses of X-rays were examined in vitro. One system consisted of the human colon carcinoma line DLD-1 and two subpopulations (clones A and D). The second system consisted of the human lung carcinoma line (LX1) and four subpopulations (LX1-1, LX1-2, LX1-3, and LX1-9). These subpopulations have previously been shown to be markedly heterogeneous in terms of such characteristics as karyotype, morphology, drug sensitivity, tumorigenicity, and expression of membrane glycoproteins (such as carcinoembryonic antigen and tumor colonic mucoprotein antigen). Exponentially growing cultures were irradiated with graded single doses of 100-kVp X-rays. Survival was assessed using colony formation as the end point, and responses from multiple experiments were fitted to the single-hit, multitarget equation of cell survival. Values for the mean lethal dose (D0, grays), quasithreshold dose (Dq, grays), and extrapolation number (n) were obtained. For the human colon adenocarcinoma system, these values for the three tumor lines were: DLD-1, 0.95, 2.34, and 11.7; clone A, 1.06, 2.23 and 8.20; and clone D, 1.08, 1.89, and 5.80. For the human lung carcinoma system, these values for the five sublines were: LX1, 1.14, 0.19, and 1.20; LX1-1, 0.96, 2.06, and 8.54; LX1-2, 0.98, 0.88, and 2.48; LX1-3, 0.68, 2.05, and 20.3; and LX1-9, 1.12, 0.00, and 1.00. These two human tumor systems therefore exhibit variability in their intrinsic sensitivity to X-irradiation. The data indicate that failure of some human carcinomas to respond to physical treatment modalities can be due to preexisting resistant subpopulations.


The costs of delivering human papillomavirus vaccination to Grade 4 learners in KwaZulu-Natal, South Africa.
The national human papillomavirus (HPV) vaccination roll-out in South Africa provides two doses of Cervarix to all female Grade 4 learners in state schools. This study estimated the costs of vaccinating all learners in KwaZulu-Natal Province (females or males and females) using either the two- or three-dose strategies for both the bivalent and quadrivalent vaccines. To determine costs of the HPV vaccination programme in KwaZulu-Natal. Costs were determined adapting World Health Organization vaccination costing guidelines. The 2014 current cost of delivering three doses of Gardasil was ZAR510 per learner. The projected cost of delivering Cervarix to female learners at two or three doses over the period 2014 - 2018, adjusted for inflation, was ZAR172 717 342 and ZAR250 048 426, respectively. Similarly, the cost for Gardasil at these doses was ZAR197 482 200 and ZAR287 194 361, respectively. For male and female learners the cost for Cervarix over this period at two or three doses was ZAR337 101 132 and ZAR540 150 713, respectively. Similarly, the cost for Gardasil at these doses was ZAR426 597 971 and ZAR620 392 784, respectively. Accounting for population variation for females over 5 years, the cost of two doses of Cervarix ranged from ZAR168 888 677 to ZAR 176 545 977 at the lower and upper 95% confidence intervals (CIs), respectively. For three doses the cost ranged from ZAR244 505 544 to ZAR255 591 263 at the lower and upper 95% CIs, respectively. Similarly, the cost for two doses of Gardasil ranged from ZAR193 104 566 to ZAR201 859 798. For three doses the cost ranged from ZAR280 828 057 to ZAR293 560 614. This study gives decision makers a basis for structured planning and cost apportionment to ensure effective roll-out of the HPV vaccination programme.


Organochlorine pesticides in placentas from Southern Spain and some related factors.
During pregnancy, lipophilic xenobiotics stored in maternal adipose tissue can be mobilized and enter her blood circulation and reach the placenta. This study measured residues of oestrogen-mimicking organochlorine pesticides (OCs) in 150 placenta samples from women in Southern Spain. OCs were extracted from placenta by solid-liquid technique and purified by preparative liquid chromatography. Gas chromatography/electron-capture detection and mass spectrometry were used to identify and quantify p,p'-DDT and congeners/metabolites, endosulphan and congeners/metabolites, lindane, aldrin/dieldrin/endrin, hexachlorobenzene, methoxychlor and mirex. A mean of eight pesticides per placenta were detected (range, 3-15 pesticides). Endosulphan-ether, endosulphan-diol, endosulphan-I, p,p'-DDE, o,p'-DDD, p,p'-DDT, o,p'-DDT and lindane were detected in >or=50% of samples; p,p'-DDE was the most frequent (96.03%), followed by endosulphan-diol (76.86%) and lindane (74.17%). Presence of more pesticides was significantly associated with lower birth weight. Mean concentration of p,p'-DDE was 2.37+/-2.80 ng/g of placenta or 76.62+/-104.85 ng/g of lipid. Higher maternal body mass index was significantly associated with higher endosulphan concentrations in placenta, and greater maternal weight gain was significantly associated with higher p,p'-DDE concentrations. Prenatal exposure to OC xenoestrogens may be a causative factor in adverse reproductive health trends, and further studies are required to identify and describe pathways of this exposure to enhance preventive measures.


Probing the self-assembly dynamics and internal structure of amphiphilic hyaluronic acid conjugates by fluorescence spectroscopy and molecular dynamics simulations.
Polymeric nanoparticles are increasingly used as biocompatible carriers for drugs and imaging agents. Understanding their self-assembly dynamics and morphology is of ultimate importance to develop nanoformulations with optimal characteristics. To achieve better performance, it is vital to account for cargo-carrier interactions at the molecular level. The self-assembly dynamics were studied and the internal structure of nanoparticles derived from a series of hydrophobically modified hyaluronic acid was revealed. Environment-sensitive ratiometric fluorescent probes provide valuable information about the nanoparticle's interior morphology, and molecular dynamics simulations complement the overall picture with insights into intramolecular and intermolecular interactions of the polymer, as well as its interactions with the small-molecule load. van der Waals and π-π interactions of the hydrophobic side fragments play a leading role in self-assembly and loading of hydrophobic small molecules. Aliphatic substituents form more extensive hydrophobic domains, while aromatic moieties allow more interaction of the loaded small molecules with the surrounding solvent.


Homogenous Population Genetic Structure of the Non-Native Raccoon Dog (Nyctereutes procyonoides) in Europe as a Result of Rapid Population Expansion.
The extent of gene flow during the range expansion of non-native species influences the amount of genetic diversity retained in expanding populations. Here, we analyse the population genetic structure of the raccoon dog (Nyctereutes procyonoides) in north-eastern and central Europe. This invasive species is of management concern because it is highly susceptible to fox rabies and an important secondary host of the virus. We hypothesized that the large number of introduced animals and the species' dispersal capabilities led to high population connectivity and maintenance of genetic diversity throughout the invaded range. We genotyped 332 tissue samples from seven European countries using 16 microsatellite loci. Different algorithms identified three genetic clusters corresponding to Finland, Denmark and a large 'central' population that reached from introduction areas in western Russia to northern Germany. Cluster assignments provided evidence of long-distance dispersal. The results of an Approximate Bayesian Computation analysis supported a scenario of equal effective population sizes among different pre-defined populations in the large central cluster. Our results are in line with strong gene flow and secondary admixture between neighbouring demes leading to reduced genetic structuring, probably a result of its fairly rapid population expansion after introduction. The results presented here are remarkable in the sense that we identified a homogenous genetic cluster inhabiting an area stretching over more than 1500km. They are also relevant for disease management, as in the event of a significant rabies outbreak, there is a great risk of a rapid virus spread among raccoon dog populations.


Haptic perception of texture gradients.
To pick up 3-D aspects of pictures is arguably the most difficult problem concerning tactile pictorial perception by the blind. The aim of the experiments reported was to examine the potential utility of texture gradients in this context. Since there is no theoretical basis for predicting absolute values of 3-D properties from 2-D patterns read by the finger pads, the abilities of participants to perceive gradients lying between known maxima and minima were assessed. Experiment 1 involved blindfolded sighted participants making verbal magnitude estimations of texture-gradient magnitudes corresponding to plane surfaces at different slants. In experiment 2 the participants' task was to orient a surface at a slant corresponding to the texture gradients depicted tactually, and experiment 3 required early-blind participants to attempt the same task. The results revealed that participants can scale the magnitudes of texture gradients with high precision and that they can also accurately produce surface slants from depictions, providing the extreme conditions are clearly defined and there are opportunities for learning. Texture gradients appear as informative to the blind as they do to the sighted. To what extent these data can be generalised to other gradients and textures or to other projections of 3-D scenes remains to be investigated.


Effects of isoflavone and exercise on BMD and fat mass in postmenopausal Japanese women: a 1-year randomized placebo-controlled trial.
The combined intervention of isoflavone intake and walking exercise over 1 year in postmenopausal Japanese women exhibited a trend for a greater effect on prevention of bone loss at the total hip and Ward's triangle regions. The additive effects of isoflavones and exercise on bone and lipid metabolism have been shown in estrogen-deficient animals. In this study, we determined the effects of isoflavone intake, walking exercise, and their interaction on bone, fat mass, and lipid metabolism over 1 year in postmenopausal Japanese women. A total of 136 postmenopausal women at <5 years after the onset of menopause were randomly assigned to four groups: (1) placebo, (2) walking (45 minutes/day, 3 days/week) with placebo, (3) isoflavone intake (75 mg of isoflavone conjugates/day), and (4) combination of isoflavone plus walking. BMD, fat mass, serum lipid, and serum and urinary isoflavone concentrations were assessed. A significant main effect of isoflavone on the reduction in trunk fat mass was obtained at 12 months. Significant main effects of walking on the reduction in fat mass in the whole body and the trunk were observed at 3, 6, and 12 months and that in the legs and arms at 6 and 12 months. Serum high-density lipoprotein (HDL)-cholesterol concentration significantly increased by 12 months after the walking and the combined intervention. After 12 months, a significant main effect of isoflavone on BMD was observed only at Ward's triangle. Walking prevented bone loss at the total hip and the Ward's triangle to significant degrees. The effect of the combined intervention on BMD at total hip and Ward's triangle regions was greater than that of either alone. No significant interaction was observed between isoflavone and walking in any measurements recorded during the study. Our study suggest that combined intervention of 75 mg/day of isoflavone intake and walking exercise 3 times/week for 1 year showed a trend for a greater effect on BMD at total hip and Ward's triangle regions than either alone. Intervention with isoflavone in postmenopausal Japanese women showed a modest effect on BMD compared with those in Westerners. Further studies over longer treatment duration that include assessment of BMD at various regions are necessary to ascertain the clinical significance of the combined intervention of isoflavone plus walking in postmenopausal women.


Emerging infections in burns.
Patients who suffer severe burns are at higher risk for local and systemic infections. In recent years, emerging resistant pathogens have forced burn care providers world wide to search for alternative forms of treatment. Multidrug-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp., and various fungal strains have been the major contributors to the increase in morbidity and mortality rates. Multi-drug-resistant S. aureus remains the major cause of gram-positive burn wound infections world wide. Treatment strategies include rigorous isolation protocols and new types of antibiotics where necessary. We reviewed 398 severely burned patients (burns >40% total body surface area [TBSA]) admitted to our hospital between 2000 and 2006. Patients who did not contract multi-drug-resistant gram-negative organisms during their hospital course and received our standard antibiotic regimen-vancomycin and piperacillin/tazobactam-served as controls (piperacillin/tazobactam; n = 280). The treatment group consisted of patients who, during their acute hospital stay, developed infections with multi-drug-resistant gram-negative pathogens and were treated with vancomycin and colistin for at least three days (colistin; n = 118). Gram-negative organisms continue to cause the most severe infections in burn patients. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections of burns. Patients who required colistin therapy had a significantly larger average total and full-thickness burn than patients treated with piperacillin/tazobactam and vancomycin, and the mortality rate was significantly higher in the colistin group (p < 0.05). However, there was no significant difference between the colistin and piperacillin/tazobactam groups in the incidence of neurotoxicity, hepatic toxicity, or nephrotoxicity. The main fungal pathogens in burn patients are Candida spp., Aspergillus spp., and Fusarium spp. A definitive diagnosis is more difficult to obtain than in bacterial infections. Amphotericin B and voriconazole remain the two most important anti-fungal substances in our practice. Innovations in fluid management, ventilatory support, surgical care, and antimicrobial therapy have contributed to a significant reduction in morbidity and mortality rates in burn patients. Vancomycin and clindamycin are the two most important reserve antibiotics for methicillin-resistant Staphylococcus aureus infection. Oxazolidinones and streptogramins have showed high effectiveness against gram-positive infections. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections. Current challenges include Candida, Aspergillus, and molds. The development of new agents, prudent and appropriate use of antibiotics, and better infection control protocols are paramount in the ongoing battle against multi-resistant organisms.


Intraguild predation and competitive displacement between Nesidiocoris tenuis and Dicyphus maroccanus, two biological control agents in tomato pests.
Dicyphus maroccanus Wagner and Nesidiocoris tenuis Reuter (Hemiptera: Miridae) are 2 biological control agents in tomatoes. Through the crop seasons, a natural shift in the occurrence of both mirids in favor of N. tenuis has been observed at the end of the cropping cycle in eastern Spain. To better optimize their conservation, the reasons for the observed change, such as intraguild interactions (IGP) or the influence of environmental conditions, are worth elucidating. To do this, we first studied the IGP of adult females on heterospecific nymphs in the laboratory. We next studied exploitative competition between adults and nymphs of each species when feeding on Ephestia kueniella Zeller (Lepidoptera: Pyralidae) eggs in the laboratory. Finally, to analyze the competitive displacement between both mirids, we conducted a semifield experiment in which both predators were released together. All experiments were conducted at 2 temperature regimes (20 and 25°C). Adult-to-nymph intraguild interactions occurred only at 25 ºC at very low levels, showing that N. tenuis attacked and consumed a greater proportion of heterospecific nymphs. Nesidiocoris tenuis was a better competitor than D. maroccanus when feeding on the shared prey in the presence of its heterospecific nymph at 25 ºC. In semifield conditions, N. tenuis showed a competitive advantage over D. maroccanus at both temperatures. We conclude that there is not direct interference between both species, however, N. tenuis has a greater ability to outcompete, since it is best adapted to higher temperatures and it is able to remove food sources for D. maroccanus.


Supplementary oxygen and risk of childhood lymphatic leukaemia.
Childhood leukaemia has been linked to several factors, such as asphyxia and birthweight, which in turn are related to newborn resuscitation. Based on the findings from a previous study a population-based case-control study was performed to investigate the association between childhood leukaemia and exposure to supplementary oxygen and other birth-related factors. Children born in Sweden and diagnosed with lymphatic leukaemia between 1973 and 1989 (578 cases) were individually matched by gender and date of birth to a randomly selected control. Children with Down's syndrome were excluded. Exposure data were blindly gathered from antenatal, obstetric and other standardized medical records. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by conditional logistic regression. Resuscitation with 100% oxygen with a facemask and bag immediately postpartum was significantly associated with an increased risk of childhood lymphatic leukaemia (OR = 2.57, 95% Cl 1.21-6.82). The oxygen-related risk further increased if the manual ventilation lasted for 3 min or more (OR = 3.54, 95% CI 1.16-10.80). Low Apgar scores at 1 and 5 min were associated with a non-significantly increased risk of lymphatic leukaemia. There were no associations between lymphatic leukaemia and supplementary oxygen later in the neonatal period or other birth-related factors. Resuscitation with 100% oxygen immediately postpartum is associated with childhood lymphatic leukaemia, but further studies are warranted to confirm the findings.


Cell Communication, Stochastic Cell Responses, and Anthocyanin Pattern in Mustard Cotyledons.
The role of intercellular signals in plant development was investigated using phytochrome-induced formation of anthocyanin in cotyledons of white mustard as a model system. The problem was approached by irradiating different subregions of the cotyledon with a microbeam. This technique was combined with in situ hybridization of chalcone synthase mRNA after irradiation of the entire cotyledon. Individual cells that exhibited all-or-none responses with a resultant stochastic, patchy pattern were examined during early stages of anthocyanin synthesis. It was demonstrated that the responses of individual cells were subsequently integrated by long-range inhibitory signals. This process led to ordered and gradually developing patterns that could be detected when final stages were analyzed at the whole-organ level. The significance of these findings is discussed in terms of efforts toward a general understanding of photomorphogenesis in plants.


Molecular targets for rapid identification of Brucella spp.
Brucella is an intracellular pathogen capable of infecting animals and humans. There are six recognized species of Brucella that differ in their host preference. The genomes of the three Brucella species have been recently sequenced. Comparison of the three revealed over 98% sequence similarity at the protein level and enabled computational identification of common and differentiating genes. We validated these computational predictions and examined the expression patterns of the putative unique and differentiating genes, using genomic and reverse transcription PCR. We then screened a set of differentiating genes against classical Brucella biovars and showed the applicability of these regions in the design of diagnostic tests. We have identified and tested set of molecular targets that are associated in unique patterns with each of the sequenced Brucella spp. A comprehensive comparison was made among the published genome sequences of B. abortus, B. melitensis and B. suis. The comparison confirmed published differences between the three Brucella genomes, and identified subsets of features that were predicted to be of interest in a functional comparison of B. melitensis and B. suis to B. abortus. Differentiating sequence regions from B. abortus, B. melitensis and B. suis were used to develop PCR primers to test for the existence and in vitro transcription of these genes in these species. Only B. suis is found to have a significant number of unique genes, but combinations of genes and regions that exist in only two out of three genomes and are therefore useful for diagnostics were identified and confirmed. Although not all of the differentiating genes identified were transcribed under steady state conditions, a group of genes sufficient to discriminate unambiguously between B. suis, B. melitensis, and B. abortus was identified. We present an overview of these genomic differences and the use of these features to discriminate among a number of Brucella biovars.


Characterization of gut-homing molecules in non-endstage livers of patients with primary sclerosing cholangitis and inflammatory bowel disease.
The co-occurrence of inflammatory bowel disease (IBD) in up to 80% of patients with primary sclerosing cholangitis (PSC) suggests a relation between the gut and the liver in patients with both PSC and IBD. One hypothesis suggests that aberrantly expressed homing molecules in the liver drive infiltration of gut-homing memory T-cells that are originally primed in intestinal environment. One of the main findings supporting this hypothesis is the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in PSC livers. Expression of homing molecules in early PSC remains unclear. The aim of this study was to investigate expression patterns of homing chemokines and adhesion molecules in PSC-IBD colons and livers, and to study whether changes are already present in early stages of PSC. Needle biopsies from livers of 20 PSC patients with short-term PSC (PSC-IBDST) as well as explant liver biopsies of 8 patients with long-term PSC (PSC-IBDLT) were collected (median disease duration 0 and 22 years, respectively). Only patients with concomitant IBD were included (89% ulcerative colitis and 11% Crohn's disease). Expression and distribution of MAdCAM-1, VAP-1, integrin β7, CCL25, CCL28, CXCL12, αE (CD103) and E-cadherin were assessed in both liver and colon tissue. Liver tissue collected from obstructive cholangitis in resection specimens for Klatskin tumors or resection specimens from hepatic metastasis, liver tissue of patients with hepatitis C virus (HCV) and of patients with primary biliary cholangitis (PBC) served as controls. MAdCAM-1 expression in livers of PSC-IBDLT patients was increased compared to controls. The proportion of CD3+ T-cells expressing integrin β7 did not differ between PSC-IBDST and control groups, but was higher in liver tissue of PSC-IBDLT patients. There was no difference in αE+ T-cells between PSC-IBDLT and control groups. The chemokine CCL28 was highly expressed in biliary epithelial cells. This intense staining pattern was more pronounced in PSC-IBDST, but overall did not significantly differ from controls. We confirm that aberrant gut lymphocyte homing to the liver exists in PSC, linking gut and liver disease pathology in PSC-IBD. Our data suggests that this phenomenon increases over time in later stages of the disease, worsening ongoing inflammation.


Dignity of patients with palliative needs in the Middle East: an integrative review.
Patients with palliative needs experience high psychological and symptom distress that may lead to hopelessness and impaired sense of dignity. Maintaining patient dignity or the quality of being valued is a core aim in palliative care. The notion of dignity is often explained by functionality, symptom relief and autonomy in decision making. However, this understanding and its implications in Middle Eastern countries is not clear. The aim of this review is to 1) explore the understanding of dignity and how dignity is preserved in adult patients with palliative care needs in the Middle East 2) critically assess the findings against the Dignity Model dominant in western literature. Using an integrative review we searched four databases EMBASE, Psych-Info, CINAHL, and PubMed. These databases retrieve a broad literature on palliative care and are often chosen in other palliative care reviews. To enhance the search strategy, three online journals were hand searched, reference lists of review papers scanned, and forward citations sought. No time limits were applied. The retrieved papers were assessed independently by two authors including quality assessment using the Hawker's appraisal tool. Out of the 5113 studies retrieved, 294 full texts were assessed. Sixteen studies were included for synthesis of which fourteen were published in Iran. Seven themes were developed after data analysis: Maintaining Privacy and Secrecy; Gentle communication with a dialogue that preserves hope instead of blunt truth-telling; Abundance characterised by accessibility to medical supplies and financial stability; Family Support where relatives deliver major assistance in care; Physical Fitness; Reliable health care, and Social justice that endorses equal care to all. The results are compatible with the existing evidence from the Dignity Model ascertaining that dignity is socially mediated and influenced by interactions and physical fitness. Nevertheless, the findings highlight that patient dignity is also shaped by the socio-political, cultural, and economic conditions of the country, where family support, gentle communication and accessible health care are essential elements.


Observation and Structure Determination of an Oxide Quasicrystal Approximant.
We report on the first observation of an approximant structure to the recently discovered two-dimensional oxide quasicrystal. Using scanning tunneling microscopy, low-energy electron diffraction, and surface x-ray diffraction in combination with ab initio calculations, the atomic structure and the bonding scheme are determined. The oxide approximant follows a 3^{2}.4.3.4 Archimedean tiling. Ti atoms reside at the corners of each tiling element and are threefold coordinated to oxygen atoms. Ba atoms separate the TiO_{3} clusters, leading to a fundamental edge length of the tiling 6.7 Å.


Lifestyle Risk Factors in Esophageal Cancer: An Integrative Review.
Esophageal cancer (EC) is a prevalent type of cancer, affecting more than 16 000 people annually in the United States. Being a high-burden disease, the comprehensive management of EC is challenging, particularly for older adults. In addition, Asian countries have some of the highest age-standardized incidence rates of EC in the world. Epidemiologic studies have revealed that cigarette and cigar smoking, alcohol drinking, obesity, being overweight, and areca chewing increase the risk of EC. This integrative review aims to elucidate the association between lifestyle factors such dietary habits, smoking, and alcohol consumption and EC among the Asian populations with Chinese, Japanese, and Taiwanese ethnicity. The synthesis of the literature found that environmental factors play an important role in the risk of EC occurrence. Although most of the risk factors showed a positive relationship in increasing the risk, studies included in this review reported inconclusive results on whether tea and coffee are risk factors. The consumption of very hot beverages and low intake of green vegetable are associated with EC. Smoking, alcohol intake, and their interaction with diets were found to be the biggest factor in the development of EC. Registered nurses can educate about esophageal thermal injury among persons who have preference for drinking burning-hot beverages and those with multiple risk factors, such as those who smoke and drink excess alcohol, as well as promoting health behaviors and serving as patient advocates.


Does butyrate protect from colorectal cancer?
Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.


Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus-like particles.
The L1 genes of two human papillomavirus type 16 (HPV16) isolates derived from condylomata acuminata were used to express the L1 major capsid protein in insect cells via recombinant baculoviruses. Both L1 major capsid proteins self-assembled into virus-like particles (VLP) with high efficiency and could be purified in preparative amounts on density gradients. The yield of VLP was 3 orders of magnitude higher than what has been obtained previously, using L1 derived from the prototype HPV16. DNA sequence comparison identified a single nonconserved amino acid change to be responsible for the inefficient self-assembly of the prototype L1. VLP were also obtained by expressing L1 of HPV6, HPV11, and cottontail rabbit papillomavirus, indicating that L1 from a variety of papillomaviruses has the intrinsic capacity to self-assemble into VLP. Coexpression of HPV16 L1 plus L2 by using a baculovirus double-expression vector also resulted in efficient self-assembly of VLP, and the average particle yield increased about fourfold in comparison to when L1 only was expressed. Coimmunoprecipitation of L1 and L2 and cosedimentation of the two proteins in a sucrose gradient demonstrated that L2 was incorporated into the particles. The ability to generate preparative amounts of HPV16 L1 and L1-L2 VLP may have implications for the development of a serological assay to detect anti-HPV16 virion immune responses to conformational epitopes and for immunoprophylaxis against HPV16 infection.


Pancreatic digestive enzyme gene expression: effects of CCK and soybean trypsin inhibitor.
Regulation of pancreatic gene expression by cholecystokinin (CCK) was examined in the rat using cloned cDNA probes to quantify changes in specific mRNAs (amylase, trypsinogen I, chymotrypsinogen B, and ribonuclease). Rats were administered intraduodenally an elemental liquid diet. Plasma CCK levels were raised to levels comparable to physiological postprandial levels either by intraduodenal perfusion with soybean trypsin inhibitor (SBTI) (6.9 +/- 1.0 pM, n = 8) or by continuous intravenous infusion with cholecystokinin octapeptide (CCK-8, 6.0 +/- 0.9 pM, n = 6). SBTI infusion resulted in fivefold increases in trypsinogen I and chymotrypsinogen B mRNA levels after 48 h. In contrast SBTI infusion had no effect on amylase mRNA levels and led to a decrease in ribonuclease mRNA levels to approximately 50% of control after 48 h. Intravenous infusion with CCK-8 for 24 h resulted in plasma levels of CCK comparable to those obtained with SBTI and had similar effects on digestive enzyme mRNA levels. These data suggested that SBTI acted via its ability to raise plasma CCK levels. To further test the specificity of these effects, animals were infused intraduodenally with the specific CCK receptor antagonist L364,718. Although the antagonist itself had no effect on digestive enzyme mRNA levels, antagonist treatment totally abolished the effects of both CCK infusion and SBTI treatment. These data therefore indicate that CCK regulates digestive enzyme gene expression at plasma concentrations comparable to physiological postprandial levels. Furthermore, the ability of SBTI infusion to increase plasma CCK accounts for its effects on pancreatic digestive enzyme mRNA levels.


Factors influencing cancer genetic somatic mutation test ordering by cancer physician.
Clinical whole exome sequencing was introduced in an Australian centre in 2017, as an alternative to Sanger sequencing. We aimed to identify predictors of cancer physicians' somatic mutation test ordering behaviour. A validated instrument assessed somatic mutation test ordering, genomic confidence, perceived utility of tumour molecular profiling, and percent of patients eligible for targeted therapy. A cash incentive was included in 189/244 questionnaires which were mailed to all Queensland cancer specialists in November 2018. 110 participated (response rate 45%); 54.7% oncologists, and the remainder were surgeons, haematologists and pulmonologists. Oncologists were more likely to respond (p = 0.008), and cash incentive improved the response rate (p < 0.001). 67/102 (65.7%) of physicians ordered ≥ 5 somatic mutation tests annually. Oncologists saw 86.75 unique patients monthly and ordered 2.33 somatic mutation tests (2.2%). An average of 51/110 (46.1%) reported having little/no genomic confidence. Logistic regression identified two significant predictors of somatic mutation test ordering: being an oncologist (OR 3.557, CI 1.338-9.456; p = 0.011) and having greater confidence in interpreting somatic results (OR 5.926, CI 2.230-15.74; p < 0.0001). Consistent with previous studies, the majority of cancer physicians ordered somatic mutation tests. However, the percentage of patients on whom tests were ordered was low. Almost half respondents reported low genomic confidence. Somatic mutation test ordering was higher amongst oncologists and those with increased confidence in interpreting somatic variants. It is unclear whether genomically confident individuals ordered more tests or whether ordering more tests increased genomic confidence. Educational interventions could improve confidence and enhance test ordering behaviour.


Bumblebee colony development following chronic exposure to field-realistic levels of the neonicotinoid pesticide thiamethoxam under laboratory conditions.
Neonicotinoid pesticides are used in agriculture to reduce damage from crop pests. However, beneficial insects such as bees can come into contact with these pesticides when foraging in treated areas, with potential consequences for bee declines and pollination service delivery. Honeybees are typically used as a model organism to investigate insecticide impacts on bees, but relatively little is known about impacts on other taxa such as bumblebees. In this experiment, we chronically exposed whole mature bumblebee (Bombus terrestris) colonies to field-realistic levels of the neonicotinoid thiamethoxam (2.4ppb & 10ppb) over four weeks, and compared colony growth under laboratory conditions. We found no impact of insecticide exposure on colony weight gain, or the number or mass of sexuals produced, although colonies exposed to 2.4ppb produced larger males. As previous studies have reported pesticide effects on bumblebee colony growth, this may suggest that impacts on bumblebee colonies are more pronounced for colonies at an earlier stage in the reproductive cycle. Alternatively, it may also indicate that thiamethoxam differs in toxicity compared to previously tested neonicotinoids in terms of reproductive effects. In either case, assessing bumblebee colony development under field conditions is likely more informative for real world scenarios than tests conducted in laboratory conditions.


Sleep extension is a feasible lifestyle intervention in free-living adults who are habitually short sleepers: a potential strategy for decreasing intake of free sugars? A randomized controlled pilot study.
Evidence suggests that short sleep duration may be a newly identified modifiable risk factor for obesity, yet there is a paucity of studies to investigate this. We assessed the feasibility of a personalized sleep extension protocol in adults aged 18-64 y who are habitually short sleepers (5 to <7 h), with sleep primarily measured by wrist actigraphy. In addition, we collected pilot data to assess the effects of extended sleep on dietary intake and quality measured by 7-d food diaries, resting and total energy expenditure, physical activity, and markers of cardiometabolic health. Forty-two normal-weight healthy participants who were habitually short sleepers completed this free-living, 4-wk, parallel-design randomized controlled trial. The sleep extension group (n = 21) received a behavioral consultation session targeting sleep hygiene. The control group (n = 21) maintained habitual short sleep. Rates of participation, attrition, and compliance were 100%, 6.5%, and 85.7%, respectively. The sleep extension group significantly increased time in bed [0:55 hours:minutes (h:mm); 95% CI: 0:37, 1:12 h:mm], sleep period (0:47 h:mm; 95% CI: 0:29, 1:05 h:mm), and sleep duration (0:21 h:mm; 95% CI: 0:06, 0:36 h:mm) compared with the control group. Sleep extension led to reduced intake of free sugars (-9.6 g; 95% CI: -16.0, -3.1 g) compared with control (0.7 g; 95% CI: -5.7, 7.2 g) (P = 0.042). A sensitivity analysis in plausible reporters showed that the sleep extension group reduced intakes of fat (percentage), carbohydrates (grams), and free sugars (grams) in comparison to the control group. There were no significant differences between groups in markers of energy balance or cardiometabolic health. We showed the feasibility of extending sleep in adult short sleepers. Sleep extension led to reduced free sugar intakes and may be a viable strategy to facilitate limiting excessive consumption of free sugars in an obesity-promoting environment. This trial was registered at www.clinicaltrials.gov as NCT02787577.


Eruptive syringoma.
Eruptive syringoma is a rare variant of syringoma that appears on anterior surfaces of the body, including the neck, chest, and arms. Textbooks state that this eccrine-derived tumor arises at puberty. We describe four cases of eruptive syringoma that began in childhood. We review the literature on this entity and suggest that the disorder typically presents between the ages of 4 and 10 years. Eruptive syringoma is a benign tumor that should be considered among the papular dermatoses of childhood.


A Bayesian growth mixture model to examine maternal hypertension and birth outcomes.
Maternal hypertension is a major contributor to adverse pregnancy outcomes, including preterm birth (PTB) and low birth weight (LBW). Although several studies have explored the relationship between maternal hypertension and fetal health, few have examined how the longitudinal trajectory of blood pressure, considered over the course of pregnancy, affects birth outcomes. In this paper, we propose a Bayesian growth mixture model to jointly examine the associations between longitudinal blood pressure measurements, PTB, and LBW. The model partitions women into distinct classes characterized by a mean arterial pressure (MAP) curve and joint probabilities of PTB and LBW. Each class contains a unique mixed effects model for MAP with class-specific regression coefficients and random effect covariances. To account for the strong correlation between PTB and LBW, we introduce a bivariate probit model within each class to capture residual within-class dependence between PTB and LBW. The model permits the association between PTB and LBW to vary by class, so that for some classes, PTB and LBW may be positively correlated, whereas for others, they may be uncorrelated or negatively correlated. We also allow maternal covariates to influence the class probabilities via a multinomial logit model. For posterior computation, we propose an efficient MCMC algorithm that combines full-conditional Gibbs and Metropolis steps. We apply our model to a sample of 1027 women enrolled in the Healthy Pregnancy, Healthy Baby Study, a prospective cohort study of host, social, and environmental contributors to disparities in pregnancy outcomes.


Bright light therapy for symptoms of anxiety and depression in focal epilepsy: randomised controlled trial.
Bright light therapy is an effective treatment for seasonal affective disorder and non-seasonal depression. Depression and anxiety are common psychiatric comorbidities in epilepsy. To examine the efficacy of bright light therapy for symptoms of anxiety and depression in adults with focal epilepsy (trial registration at ClinicalTrials.gov: NCT01028456). We recruited 101 adults with medically intractable focal epilepsy. Participants completed the Hospital Anxiety and Depression Scale (HADS) at the beginning (T1) and end of a 12-week baseline period (T2) and again after 12 weeks of daily light therapy (T3), with 51 participants using a high-intensity light box and 50 using a low-intensity one. Seizure diaries were kept throughout the baseline and trial period. A total of 58 patients completed the trial. Anxiety and depression scores were significantly reduced following the light therapy at T3 in both the high- and low-intensity groups. Light therapy resulted in a significant reduction in symptoms of anxiety and depression but we did not find any differences between high- v. low-intensity treatment. This may, therefore, be an effective treatment for symptoms of low mood in epilepsy at lower intensities than those typically used to treat seasonal affective disorder. Further work is needed to investigate this possibility with an adequate placebo condition.


Energetics of the loop-to-helix transition leading to the coiled-coil structure of influenza virus hemagglutinin HA2 subunits.
Fusion of influenza virus with the endosomal membrane of the host cell is mediated by the homotrimer-organized glycoprotein hemagglutinin (HA). Its fusion activity is triggered by a low pH-mediated conformational change affecting the structure of the HA1 and HA2 subunits. The HA2 subunits undergo a loop-to-helix transition leading to a coiled-coil structure, a highly conserved motif for many fusion mediating viral proteins. However, experimental studies showed that the HA2 coiled-coil structure is stable at neutral and low pH, implying that there is no direct relationship between low pH and the HA2 loop-to-helix transition. To interpret this observation, we used a computational approach based on the dielectric continuum solvent model to explore the influence of water and pH on the free energy change of the transition. The computations showed that the electrostatic interaction between HA2 fragments and water is the major driving force of the HA2 loop-to-helix transition leading to the coiled-coil structure, as long as the HA1 globular domain covering the HA2 subunits in the nonfusion competent conformation is reorganized and thereby allows water molecules to interact with the whole loop segments of the HA2 subunits. Moreover, we show that the energy released by the loop-to-helix transition may account for those energies required for driving the subsequent steps of membrane fusion. Such a water-driven process may resemble a general mechanism for the formation of the highly conserved coiled-coil motif of enveloped viruses.


Theoretical time-domain study of self-imaging properties in a multimode interference coupler.
We report a theoretical and numerical study of self-imaging properties, including time domain and pulse spreading, caused by modal group-delay dispersion in generalized N x N multimode interference devices achieved by using a mode-propagation analysis and finite-difference time-domain method. It was found that the spatial self-imaging condition does not realize temporal self-imaging but lets waveforms separate whose shape depends on input position and input field distribution. Pulse spreading, which is sensitive to beam diameter, has a very large variation (420 fs) among input positions as well as rising to a very high 900 fs in response to a 21 fs and spatially Gaussian pulse for the conveniently smallest size with 10 channels.


Rapid identification of mycobacteria to species level by PCR-restriction fragment length polymorphism analysis of the hsp65 gene and proposition of an algorithm to differentiate 34 mycobacterial species.
PCR-restriction fragment length polymorphism analysis (PRA) of the hsp65 gene (A. Telenti, F. Marchesi, M. Balz, F. Bally, E. C. Böttger, and T. Bodmer, J. Clin. Microbiol. 31:175-178, 1993) was applied to 108 mycobacterial isolates representing 34 species to evaluate its potential as a rapid reference method. A total of 49 distinct patterns were obtained; 25 species were characterized by a single PRA pattern, while 9 species gave more than one specific pattern. An algorithm describing these 34 species (which includes five additional species and new subgroups of Mycobacterium kansasii, M. abscessus, and M. peregrinum) is proposed. A relatively simple and inexpensive method, PRA may be particularly helpful in routine clinical microbiology laboratories.


Genome sequence of the Chinese white wax scale insect Ericerus pela: the first draft genome for the Coccidae family of scale insects.
The Chinese white wax scale insect, Ericerus pela, is best known for producing wax, which has been widely used in candle production, casting, Chinese medicine, and wax printing products for thousands of years. The secretion of wax, and other unusual features of scale insects, is thought to be an adaptation to their change from an ancestral ground-dwelling lifestyle to a sedentary lifestyle on the higher parts of plants. As well as helping to improve its economic value, studies of E. pela might also help to explain the adaptation of scale insects. However, no genomic data are currently available for E. pela. To assemble the E. pela genome, 303.92 Gb of data were generated using Illumina and Pacific Biosciences sequencing, producing 277.22 Gb of clean data for assembly. The assembled genome size was 0.66 Gb, with 1,979 scaffolds and a scaffold N50 of 735 kb. The guanine + cytosine content was 33.80%. A total of 12,022 protein-coding genes were predicted, with a mean coding sequence length of 1,370 bp. Twenty-six fatty acyl-CoA reductase genes and 35 acyltransferase genes were identified. Evolutionary analysis revealed that E. pela and aphids formed a sister group and split ∼241.1 million years ago. There were 214 expanded gene families and 2,219 contracted gene families in E. pela. We present the first genome sequence from the Coccidae family. These results will help to increase our understanding of the evolution of unique features in scale insects, and provide important genetic information for further research.


Molecular genetic and biochemical evidence for adaptive evolution of leaf abaxial epicuticular wax crystals in the genus Lithocarpus (Fagaceae).
Leaf epicuticular wax is an important functional trait for physiological regulation and pathogen defense. This study tests how selective pressure may have forced the trait of leaf abaxial epicuticular wax crystals (LAEWC) and whether the presence/absence of LAEWC is associated with other ecophysiological traits. Scanning Electron Microscopy was conducted to check for LAEWC in different Lithocarpus species. Four wax biosynthesis related genes, including two wax backbone genes ECERIFERUM 1 (CER1) and CER3, one regulatory gene CER7 and one transport gene CER5, were cloned and sequenced. Ecophysiological measurements of secondary metabolites, photosynthesis, water usage efficiency, and nutrition indices were also determined. Evolutionary hypotheses of leaf wax character transition associated with the evolution of those ecophysiological traits as well as species evolution were tested by maximum likelihood. Eight of 14 studied Lithocarpus species have obvious LAEWC appearing with various types of trichomes. Measurements of ecophysiological traits show no direct correlations with the presence/absence of LAEWC. However, the content of phenolic acids is significantly associated with the gene evolution of the wax biosynthetic backbone gene CER1, which was detected to be positively selected when LAEWC was gained during the late-Miocene-to-Pliocene period. Changes of landmass and vegetation type accelerated the diversification of tropical and subtropical forest trees and certain herbivores during the late Miocene. As phenolic acids were long thought to be associated with defense against herbivories, co-occurrence of LAEWC and phenolic acids may suggest that LAEWC might be an adaptive defensive mechanism in Lithocarpus.


Advantages and limitations of different p62-based assays for estimating autophagic activity in Drosophila.
Levels of the selective autophagy substrate p62 have been established in recent years as a specific readout for basal autophagic activity. Here we compared different experimental approaches for using this assay in Drosophila larvae. Similar to the more commonly used western blots, quantifying p62 dots in immunostained fat body cells of L3 stage larvae detected a strong accumulation of endogenous p62 aggregates in null mutants for Atg genes and S6K. Importantly, genes whose mutation or silencing results in early stage lethality can only be analyzed by microscopy using clonal analysis. The loss of numerous general housekeeping genes show a phenotype in large-scale screens including autophagy, and the p62 assay was potentially suitable for distinguishing bona fide autophagy regulators from silencing of a DNA polymerase subunit or a ribosomal gene that likely has a non-specific effect on autophagy. p62 accumulation upon RNAi silencing of known autophagy regulators was dependent on the duration of the knockdown effect, unlike in the case of starvation-induced autophagy. The endogenous p62 assay was more sensitive than a constitutively overexpressed p62-GFP reporter, which showed self-aggregation and large-scale accumulation even in control cells. We recommend western blots for following the conversion of overexpressed p62-GFP reporters to estimate autophagic activity if sample collection from mutant larvae or adults is possible. In addition, we also showed that overexpressed p62 or Atg8 reporters can strongly influence the phenotypes of each other, potentially giving rise to false or contradicting results. Overexpressed p62 aggregates also incorporated Atg8 reporter molecules that might lead to a wrong conclusion of strongly enhanced autophagy, whereas expression of an Atg8 reporter transgene rescued the inhibitory effect of a dominant-negative Atg4 mutant on basal and starvation-induced autophagy.


Systematic analysis of the physiological importance of deubiquitinating enzymes.
Deubiquitinating enzymes (DUBs) are proteases that control the post-translational modification of proteins by ubiquitin and in turn regulate diverse cellular pathways. Despite a growing understanding of DUB biology at the structural and molecular level, little is known about the physiological importance of most DUBs. Here, we systematically identify DUBs encoded by the genome of Drosophila melanogaster and examine their physiological importance in vivo. Through domain analyses we uncovered 41 Drosophila DUBs, most of which have human orthologues. Systematic knockdown of the vast majority of DUBs throughout the fly or in specific cell types had dramatic consequences for Drosophila development, adult motility or longevity. Specific DUB subclasses proved to be particularly necessary during development, while others were important in adults. Several DUBs were indispensable in neurons or glial cells during developmental stages; knockdown of others perturbed the homeostasis of ubiquitinated proteins in adult flies, or had adverse effects on wing positioning as a result of neuronal requirements. We demonstrate the physiological significance of the DUB family of enzymes in intact animals, find that there is little functional redundancy among members of this family of proteases, and provide insight for future investigations to understand DUB biology at the molecular, cellular and organismal levels.


COVID-19 Vaccine Hesitancy Worldwide: A Concise Systematic Review of Vaccine Acceptance Rates.
Utility of vaccine campaigns to control coronavirus 2019 disease (COVID-19) is not merely dependent on vaccine efficacy and safety. Vaccine acceptance among the general public and healthcare workers appears to have a decisive role in the successful control of the pandemic. The aim of this review was to provide an up-to-date assessment of COVID-19 vaccination acceptance rates worldwide. A systematic search of the peer-reviewed English survey literature indexed in PubMed was done on 25 December 2020. Results from 31 peer-reviewed published studies met the inclusion criteria and formed the basis for the final COVID-19 vaccine acceptance estimates. Survey studies on COVID-19 vaccine acceptance rates were found from 33 different countries. Among adults representing the general public, the highest COVID-19 vaccine acceptance rates were found in Ecuador (97.0%), Malaysia (94.3%), Indonesia (93.3%) and China (91.3%). However, the lowest COVID-19 vaccine acceptance rates were found in Kuwait (23.6%), Jordan (28.4%), Italy (53.7), Russia (54.9%), Poland (56.3%), US (56.9%), and France (58.9%). Only eight surveys among healthcare workers (doctors and nurses) were found, with vaccine acceptance rates ranging from 27.7% in the Democratic Republic of the Congo to 78.1% in Israel. In the majority of survey studies among the general public stratified per country (29/47, 62%), the acceptance of COVID-19 vaccination showed a level of ≥70%. Low rates of COVID-19 vaccine acceptance were reported in the Middle East, Russia, Africa and several European countries. This could represent a major problem in the global efforts to control the current COVID-19 pandemic. More studies are recommended to address the scope of COVID-19 vaccine hesitancy. Such studies are particularly needed in the Middle East and North Africa, Sub-Saharan Africa, Eastern Europe, Central Asia, Middle and South America. Addressing the scope of COVID-19 vaccine hesitancy in various countries is recommended as an initial step for building trust in COVID-19 vaccination efforts.


Accuracy of transcranial Doppler ultrasonography and single-photon emission computed tomography in the diagnosis of angiographically demonstrated cerebral vasospasm.
The goal of this study was to assess the accuracy of the routine clinical use of transcranial Doppler (TCD) ultrasonography and SPECT in predicting angiographically demonstrated vasospasm. Following receipt of institutional review board approval, the authors reviewed the records of patients with subarachnoid hemorrhage who had been admitted between 2004 and 2005 and underwent TCD ultrasonography and SPECT evaluations within 24 hours of cerebral angiography. Patients were categorized based on the presence or absence of vasospasm and/or hypoperfusion in the anterior cerebral arteries (ACAs), middle cerebral arteries (MCAs), and basilar arteries (BAs) or posterior cerebral arteries (PCAs) according to each imaging modality. Logistic regression was used to estimate the odds ratio (OR) of an angiographically demonstrated vasospasm also detected on TCD ultrasonography and SPECT. One hundred fifty-two patients (101 women) with a mean age (+/- standard deviation) of 53 +/- 13 years were included in the study. In the ACA, the OR of a vasospasm on TCD ultrasonography was 27 (95% confidence interval [CI] 3-243) and on SPECT 0.97 (95% CI 0.36-2.6); in the MCA, 17 (95% CI 5.4-55) and 2.0 (95% CI 0.71-5.5), respectively; in the BA, 4.4 (95% CI 0.72-27) and 5.6 (95% CI 0.89-36), respectively. There was no substantial change in the relative odds of a vasospasm when the findings on TCD ultrasonography and SPECT were considered jointly. Transcranial Doppler ultrasonography appears to be highly predictive of an angiographically demonstrated vasospasm in the MCA and ACA; however, its diagnostic accuracy was lower with regard to vasospasm in the BA. Single-photon emission computed tomography was not predictive of a vasospasm in any of the vascular territories assessed.


Systematic Review of Community- and Home-Based Interventions to Support Parenting and Reduce Risk of Child Maltreatment Among Families With Substance-Exposed Newborns.
Substance-exposed newborns (SENs) are at increased risk of child maltreatment, out-of-home placement, and poor health and developmental outcomes. The purpose of this systematic review is to synthesize existing research on community- and home-based interventions designed to improve parenting and reduce risk of maltreatment for families with SENs, applying a program logic framework. The review includes studies that used preexperimental, quasi-experimental, and experimental designs. Twelve interventions were identified. Of the nine studies that used more rigorous experimental or quasi-experimental designs, five showed positive effects on at least one parenting or child maltreatment outcome, although some studies showed high risk of bias. Full coherence among the intended participants, theory of change, and program components was observed for only two interventions. The findings suggest a need for more rigorous research to develop and test interventions that are grounded in theory and prior research and that address the unique needs of families with SENs.


trans-Complementation of yellow fever virus NS1 reveals a role in early RNA replication.
Mutational analysis of the nonstructural protein 1 (NS1) of yellow fever virus (YF) has implicated it in viral RNA replication. To further explore this observation, we sought a method for uncoupling NS1 function from NS1 expression and processing as part of the large YF polyprotein. Here we describe a strategy for providing NS1 in trans, utilizing a noncytopathic Sindbis virus vector. Replication of a defective YF genome containing a large in-frame deletion of NS1 was dependent on functional expression of NS1. Recovered mutant virus was shown to contain the deletion and was neutralized by YF-specific antiserum. Complemented mutant virus increased in titer with kinetics similar to those of parental YF 17D but peaked at lower titers. trans-complementation has allowed us to derive high-titer, helper-free stocks of YF defective in NS1 with which to further characterize the role of this gene product in RNA replication. The first cycles of RNA replication were analyzed by using a sensitive strand-specific RNase protection assay. We document these events for mutant and wild-type viruses in the presence or absence of complementation. These data strongly suggest a role for NS1 prior to or at initial minus-strand synthesis.


TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets.
Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.


Isolation and antimicrobial susceptibility of bacteria from external ear canal of cancer patients at Shafa Cancer Hospital-Ahwaz.
A bacteriological study of external ear canal was performed in 52 hospitalized cancer patients and 42 non hospitalized cancer patients at Shafa hospital, Ahwaz. Study was under taken to find out the normal flora changes in the external ear canals and to observe the prevalence of external otitis among these cancer patients. The control group consisted of 40 non-cancer patients. We observed the following bacteria among hospitalized cancer patients. Staphylococcus Coagulase negative (51.9%), Staphylococcus aureus (15.7%) and Streptococcus pneumoniae (11.9%). Similarly, among non hospitalized cancer patients, Staphylococcus Coagulase negative (45.2%), S. aureus (9.5%) and Streptococcus pneumoniae (4.7%). Incidence of Staphylococcus Coagulase negative and Streptococci pneumoniae is higher in control group than that in cancer patients. We have concluded that cancer patients probably suffer from external otitis more frequently because of enhanced colonization by S. aureus (P < 0.05). The antimicrobial susceptibility of these organisms to various antibiotics was determined by disk diffusion method using Muller Hinton agar. In hospitalized cancer patients Staphylococcus Coagulase negative was 25% and 85% resistant to Vancomycin and Penicillin G and in non hospitalized cancer patients, Staphylococcus Coagulase negative were 45% and 80% resistant to Vancomycin and Penicillin G. S. aureus of both the groups (hospitalized & non hospitalized) were resistant to Penicillin G. Similarly, both the groups were 55% and 50% resistance to Vancomycin.


Parametric regression model for survival data: Weibull regression model as an example.
Weibull regression model is one of the most popular forms of parametric regression model that it provides estimate of baseline hazard function, as well as coefficients for covariates. Because of technical difficulties, Weibull regression model is seldom used in medical literature as compared to the semi-parametric proportional hazard model. To make clinical investigators familiar with Weibull regression model, this article introduces some basic knowledge on Weibull regression model and then illustrates how to fit the model with R software. The SurvRegCensCov package is useful in converting estimated coefficients to clinical relevant statistics such as hazard ratio (HR) and event time ratio (ETR). Model adequacy can be assessed by inspecting Kaplan-Meier curves stratified by categorical variable. The eha package provides an alternative method to model Weibull regression model. The check.dist() function helps to assess goodness-of-fit of the model. Variable selection is based on the importance of a covariate, which can be tested using anova() function. Alternatively, backward elimination starting from a full model is an efficient way for model development. Visualization of Weibull regression model after model development is interesting that it provides another way to report your findings.


Rule learning enhances structural plasticity of long-range axons in frontal cortex.
Rules encompass cue-action-outcome associations used to guide decisions and strategies in a specific context. Subregions of the frontal cortex including the orbitofrontal cortex (OFC) and dorsomedial prefrontal cortex (dmPFC) are implicated in rule learning, although changes in structural connectivity underlying rule learning are poorly understood. We imaged OFC axonal projections to dmPFC during training in a multiple choice foraging task and used a reinforcement learning model to quantify explore-exploit strategy use and prediction error magnitude. Here we show that rule training, but not experience of reward alone, enhances OFC bouton plasticity. Baseline bouton density and gains during training correlate with rule exploitation, while bouton loss correlates with exploration and scales with the magnitude of experienced prediction errors. We conclude that rule learning sculpts frontal cortex interconnectivity and adjusts a thermostat for the explore-exploit balance.


Location and behavior of dorsal determinants during first cell cycle in Xenopus eggs.
In Xenopus eggs, removal of small volumes of cytoplasm along with the surface (2-10% of the entire egg volume) causes very severe dorsal reduction (average DAI=1.4) when made at a site ventrally 30 degrees off the vegetal pole at 20% time of first cell cycle (0.2 NT). The greatest dorsal reduction (average DAI=1.1) occurs when removal is done at the vegetal pole at 0.3 NT, and intermediate reductions (average DAI=2.2-2.6) when done at sites dorsally, dorsolaterally or laterally 30 degrees off the vegetal pole at 0.4 NT. Removal at sites dorsally, dorsolaterally or laterally 60 degrees off the vegetal pole provokes slight dorsal reduction (average DAI=3.5-3.9) when made at 0.4-0.5 NT. Removal at all sites after 0.4 NT causes a steady decrease in the extent of dorsal reduction. By contrast, removal of larger volumes of dorsal cytoplasm (16-50% of the entire egg volume) causes a steady increase in the extent of dorsal reduction during first cell cycle with its maximum effect at 1.0 NT (average DAI=3.1). The surgery for the cytoplasmic removal does not affect cortical rotation. We conclude from these results that dorsal determinants are concentrated first in a small region ventrally 30 degrees off the vegetal pole by 0.2 NT, then move toward the vegetal pole during the period 0.2-0.3 NT and disperse to a broad region spanning over both the presumptive dorsal and ventral, but mainly the dorsal, hemispheres during the period 0.3-0.8 NT.


Alternative splicing regulated by butyrate in bovine epithelial cells.
As a signaling molecule and an inhibitor of histone deacetylases (HDACs), butyrate exerts its impact on a broad range of biological processes, such as apoptosis and cell proliferation, in addition to its critical role in energy metabolism in ruminants. This study examined the effect of butyrate on alternative splicing in bovine epithelial cells using RNA-seq technology. Junction reads account for 11.28 and 12.32% of total mapped reads between the butyrate-treated (BT) and control (CT) groups. 201,326 potential splicing junctions detected were supported by ≥ 3 junction reads. Approximately 94% of these junctions conformed to the consensus sequence (GT/AG) while ~3% were GC/AG junctions. No AT/AC junctions were observed. A total of 2,834 exon skipping events, supported by a minimum of 3 junction reads, were detected. At least 7 genes, their mRNA expression significantly affected by butyrate, also had exon skipping events differentially regulated by butyrate. Furthermore, COL5A3, which was induced 310-fold by butyrate (FDR <0.001) at the gene level, had a significantly higher number of junction reads mapped to Exon#8 (Donor) and Exon#11 (Acceptor) in BT. This event had the potential to result in the formation of a COL5A3 mRNA isoform with 2 of the 69 exons missing. In addition, 216 differentially expressed transcript isoforms regulated by butyrate were detected. For example, Isoform 1 of ORC1 was strongly repressed by butyrate while Isoform 2 remained unchanged. Butyrate physically binds to and inhibits all zinc-dependent HDACs except HDAC6 and HDAC10. Our results provided evidence that butyrate also regulated deacetylase activities of classical HDACs via its transcriptional control. Moreover, thirteen gene fusion events differentially affected by butyrate were identified. Our results provided a snapshot into complex transcriptome dynamics regulated by butyrate, which will facilitate our understanding of the biological effects of butyrate and other HDAC inhibitors.


Effects of organic acids and initial solution pH on photocatalytic degradation of bisphenol A (BPA) in a photo-Fenton-like process using goethite (α-FeOOH).
This work investigated the effects of organic acids and initial solution pH on the photodegradation of BPA in a photo-Fenton-like process using α-FeOOH as a catalyst. The results showed that the addition of different organic acids affected the formation of the ferric-carboxylate complexes and free radicals, which in turn varied the photodegradation efficacy. Compared with the other acids, oxalic acid (OA) was found to be the most effective in enhancing the photodegradation of BPA, which strongly depends on the OA concentration. Particularly, the addition of OA could significantly extend the working pH from an acidic to a neutral range for the photocatalytic process and thus the acidification pretreatment may not be needed. A high photocatalytic degradation of BPA occurred at pH 6.0, due to the formation of ferric-oxalate complexes and ˙OH radicals in the synergistic interactions of OA and α-FeOOH. This finding highlights that the oxalate-promoted photo-Fenton-like process using the α-FeOOH catalyst may be used for wastewater treatment without pH adjustment.


The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.
The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.


Interpreting trial results following use of different intention-to-treat approaches for preventing attrition bias: a meta-epidemiological study protocol.
When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses. Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses. This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication. In PROSPERO CRD42013006702, 11. December 2013.


Fracture risk after the diagnosis of Parkinson's disease: Influence of concomitant dementia.
In an inception cohort of 196 Olmsted County, Minnesota, residents with Parkinson's disease (PD) first recognized in 1976 to 1995, we tested whether the increased risk of bone fractures is associated with concomitant dementia. Using the data resources of the Rochester Epidemiology Project, information about PD, dementia, other clinical risk factors for fracture and fracture events was obtained from review of complete inpatient and outpatient medical records spanning each subject's residence in the community. Compared to an equal number of age- and sex-matched non-PD referent subjects from the community, PD patients were at a 2.2-fold increased risk of fractures generally and a 3.2-fold greater risk of hip fractures specifically. Adjusting for age, the independent predictors of overall fracture risk in the PD subjects included female sex (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.1-2.3), dementia (HR, 1.6; 95% CI, 1.1-2.4) and chronic depression, which was associated with a reduced risk (HR, 0.4; 95% CI, 0.2-0.8). Hip fractures were predicted by dementia (HR, 2.2; 95% CI, 1.2-4.1). The increased fracture risk in patients with PD is not entirely explained by concomitant dementia, and additional study is needed to determine the relative contributions to fracture risk of falls versus bone loss in these patients.