Hypercalcemia and Unilateral Ovarian Mass in a Young Adult: A Case Report of Small Cell Ovarian Carcinoma.
BACKGROUND Small cell ovarian carcinoma, hypercalcemic type is an uncommon malignant ovarian tumor entity with an unfavorable prognosis and a short overall survival rate. It mainly affects women of childbearing age. CASE REPORT We report a case in which a 31-year-old woman with small cell ovarian carcinoma, hypercalcemic type presented with unspecific symptoms. We emphasize the importance of treatment planning and address fertility-sparing surgical procedures, which remain a therapeutic dilemma. CONCLUSIONS The occurrence of unspecific abdominal symptoms, unilateral tumor masses, and hypercalcemia may indicate the presence of malignant ovarian neoplasm in young adults. Histopathological examination of the mass should be performed by an experienced gynecological pathologist. A misdiagnosis can lead to inadequate surgical and adjuvant treatment. Adjuvant multi-agent chemotherapy and high-dose chemotherapy with autologous stem cell rescue may prolong the progression-free interval and overall survival.


Optimal Collision Energies and Bioinformatics Tools for Efficient Bottom-up Sequence Validation of Monoclonal Antibodies.
Rigorous validation of amino acid sequence is fundamental in the characterization of original and biosimilar protein biopharmaceuticals. Widely accepted workflows are based on bottom-up mass spectrometry, and they often require multiple techniques and significant manual work. Here, we demonstrate that optimization of a set of tandem mass spectroscopy (MS/MS) collision energies and automated combination of all available information in the measurements can increase the sequence validated by one technique close to the inherent limits. We created a software (called "Serac") that consumes results of the Mascot database search engine and identifies the amino acids validated by bottom-up MS/MS experiments using the most rigorous, industrially acceptable definition of sequence coverage (we term this "confirmed sequence coverage"). The software can combine spectra at the level of amino acids or fragment ions to exploit complementarity, provides full transparency to justify validation, and reduces manual effort. With its help, we investigated collision energy dependence of confirmed sequence coverage of individual peptides and full proteins on trypsin-digested monoclonal antibody samples (rituximab and trastuzumab). We found the energy dependence to be modest, but we demonstrated the benefit of using spectra taken at multiple energies. We describe a workflow based on 2-3 LC-MS/MS runs, carefully selected collision energies, and a fragment ion level combination, which yields ∼85% confirmed sequence coverage, 25%-30% above that from a basic proteomics protocol. Further increase can mainly be expected from alternative digestion enzymes or fragmentation techniques, which can be seamlessly integrated to the processing, thereby allowing effortless validation of full sequences.


Evolutionary toxicology: population-level effects of chronic contaminant exposure on the marsh frogs (Rana ridibunda) of Azerbaijan.
We used molecular methods and population genetic analyses to study the effects of chronic contaminant exposure in marsh frogs from Sumgayit, Azerbaijan. Marsh frogs inhabiting wetlands in Sumgayit are exposed to complex mixtures of chemical contaminants, including petroleum products, pesticides, heavy metals, and many other industrial chemicals. Previous results documented elevated estimates of genetic damage in marsh frogs from the two most heavily contaminated sites. Based on mitochondrial DNA (mtDNA) control region sequence data, the Sumgayit region has reduced levels of genetic diversity, likely due to environmental degradation. The Sumgayit region also acts as an ecological sink, with levels of gene flow into the region exceeding gene flow out of the region. Additionally, localized mtDNA heteroplasmy and diversity patterns suggest that one of the most severely contaminated sites in Sumgayit is acting as a source of new mutations resulting from an increased mutation rate. This study provides an integrated method for assessing the cumulative population impacts of chronic contaminant exposure by studying both population genetic and evolutionary effects.


PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins.
Most available information on endoplasmic reticulum (ER)-plasma membrane (PM) contacts in cells of higher eukaryotes concerns proteins implicated in the regulation of Ca(2+) entry. However, growing evidence suggests that such contacts play more general roles in cell physiology, pointing to the existence of additionally ubiquitously expressed ER-PM tethers. Here, we show that the three extended synaptotagmins (E-Syts) are ER proteins that participate in such tethering function via C2 domain-dependent interactions with the PM that require PI(4,5)P2 in the case of E-Syt2 and E-Syt3 and also elevation of cytosolic Ca(2+) in the case of E-Syt1. As they form heteromeric complexes, the E-Syts confer cytosolic Ca(2+) regulation to ER-PM contact formation. E-Syts-dependent contacts, however, are not required for store-operated Ca(2+) entry. Thus, the ER-PM tethering function of the E-Syts (tricalbins in yeast) mediates the formation of ER-PM contacts sites, which are functionally distinct from those mediated by STIM1 and Orai1.


Multiple analysis of three common genetic alterations associated with thrombophilia.
We have previously reported the use of a novel mini-sequencing protocol for detection of the factor V Leiden variant, the first nucleotide change (FNC) technology. This technology is based on a single nucleotide extension of a primer, which is hybridized immediately adjacent to the site of mutation. The extended nucleotide that carries a reporter molecule (fluorescein) has the power to discriminate the genotype at the site of mutation. More recently, the prothrombin 20210 and thermolabile methylene tetrahydrofolate reductase (MTHFR) 677 variants have been identified as possible risk factors associated with thrombophilia. This study describes the use of the FNC technology in a combined assay to detect factor V, prothrombin and MTHFR variants in a population of Australian blood donors, and describes the objective numerical methodology used to determine genotype cut-off values for each genetic variation. Using FNC to test 500 normal blood donors, the incidence of Factor V Leiden was 3.6% (all heterozygous), that of prothrombin 20210 was 2.8% (all heterozygous) and that of MTHFR was 10% (homozygous). The combined FNC technology offers a simple, rapid, automatable DNA-based test for the detection of these three important mutations that are associated with familial thrombophilia.


Laser scanning cytometry quantification of estrogen receptors in breast cancer.
To describe the laser scanning cytometry (LSC) processing and analysis developed for the quantitative analysis of estrogen receptor (ER) content in routine paraffin sections of breast carcinomas. Histologic sections of archival, paraffin-embedded tissues from 30 breast carcinomas were labeled for ER with fluoresceinated monoclonal antibody. ER expression was quantified by LSC and expressed as percent positive tumor cells and as histogram distributions of receptor expression per cell. Duplicate sections of the same tumors were stained for ER by a conventional immunoperoxidase reaction and percent positive tumor cells counted visually. Percent ER-positive tumor cells by LSC of immunofluorescence-stained sections correlated well with conventional (visual) counts of immunoperoxidase-stained duplicate sections when the latter were categorized as low, intermediate or high percent of positive cells. In addition, the marked variation in relative number of ER binding sites per cell could be quantified by LSC and displayed in histogram distribution. LSC measurements are fast and objective and can be carried out on sections of paraffin-embedded tissue after routine processing in the pathology laboratory. In addition, LSC data provide the relative number of ER binding sites per unit of DNA; that may reveal clinically significant skewed distributions or subpopulations of tumor cells.


Speciation versus phenotypic plasticity in coral inhabiting barnacles: Darwin's observations in an ecological context.
Speciation and phenotypic plasticity are two extreme strategic modes enabling a given taxon to populate a broad ecological niche. One of the organismal models which stimulated Darwin's ideas on speciation was the Cirripedia (barnacles), to which he dedicated a large monograph. In several cases, including the coral-inhabiting barnacle genera Savignium and Cantellius (formerly Pyrgoma and Creusia, respectively), Darwin assigned barnacle specimens to morphological "varieties" (as opposed to species) within a genus. Despite having been the subject of taxonomic investigations and revisions ever since, the significance of these varieties has never been examined with respect to host-associated speciation processes. Here we provide evidence from molecular (12S mt rDNA sequences) and micromorphological (SEM) studies, suggesting that these closely related barnacle genera utilize opposite strategies for populating a suite of live-coral substrates. Cantellius demonstrates a relatively low genetic variability, despite inhabiting a wide range of corals. The species C. pallidus alone was found on three coral families, belonging to distinct higher-order classification units. In contrast, Savignium barnacles exhibit large between- and within-species variations with respect to both micromorphology and DNA sequences, with S. dentatum "varieties" clustering phylogenetically according to their coral host species (all of which are members of a single family). Thus, whereas Savignium seems to have undergone intense host-associated speciation over a relatively narrow taxonomic range of hosts, Cantellius shows phenotypic plasticity over a much larger range. This dichotomy correlates with differences in life-history parameters between these barnacle taxa, including host-infestation characteristics, reproductive strategies, and larval trophic type.


Changing crops in response to climate: virtual Nang Rong, Thailand in an agent based simulation.
The effects of extended climatic variability on agricultural land use were explored for the type of system found in villages of northeastern Thailand. An agent based model developed for the Nang Rong district was used to simulate land allotted to jasmine rice, heavy rice, cassava, and sugar cane. The land use choices in the model depended on likely economic outcomes, but included elements of bounded rationality in dependence on household demography. The socioeconomic dynamics are endogenous in the system, and climate changes were added as exogenous drivers. Villages changed their agricultural effort in many different ways. Most villages reduced the amount of land under cultivation, primarily with reduction in jasmine rice, but others did not. The variation in responses to climate change indicates potential sensitivity to initial conditions and path dependence for this type of system. The differences between our virtual villages and the real villages of the region indicate effects of bounded rationality and limits on model applications.


Multi-omics insights into the biological mechanisms underlying statistical gene-by-lifestyle interactions with smoking and alcohol consumption.
Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium's Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment interactions, yet accessing and harmonizing individual-level genetic and 'omics data is challenging. Here, we demonstrate the coordinated use of summary-level data for gene-lifestyle interaction associations on up to 600,000 individuals, differential methylation data, and gene expression data for the characterization and prioritization of loci for future follow-up analyses. Using this approach, we identify 48 genes for which there are multiple sources of functional support for the identified gene-lifestyle interaction. We also identified five genes for which differential expression was observed by the same lifestyle factor for which a gene-lifestyle interaction was found. For instance, in gene-lifestyle interaction analysis, the T allele of rs6490056 (ALDH2) was associated with higher systolic blood pressure, and a larger effect was observed in smokers compared to non-smokers. In gene expression studies, this allele is associated with decreased expression of ALDH2, which is part of a major oxidative pathway. Other results show increased expression of ALDH2 among smokers. Oxidative stress is known to contribute to worsening blood pressure. Together these data support the hypothesis that rs6490056 reduces expression of ALDH2, which raises oxidative stress, leading to an increase in blood pressure, with a stronger effect among smokers, in whom the burden of oxidative stress is greater. Other genes for which the aggregation of data types suggest a potential mechanism include: GCNT4×current smoking (HDL), PTPRZ1×ever-smoking (HDL), SYN2×current smoking (pulse pressure), and TMEM116×ever-smoking (mean arterial pressure). This work demonstrates the utility of careful curation of summary-level data from a variety of sources to prioritize gene-lifestyle interaction loci for follow-up analyses.


Association of herpetic encephalitis with acute retinal necrosis syndrome.
Bilateral acute retinal necrosis syndrome developed shortly after a severe acute encephalitis in two previously healthy adults. The clinical and laboratory data suggested that herpes simplex virus was the cause of the encephalitis and acute retinal necrosis in these patients. To the authors' knowledge, this is the first report of an association of herpetic encephalitis with acute retinal necrosis in the literature.


Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy.
Endometrial lymphocytes were studied at all stages throughout the menstrual cycle and early pregnancy by flow cytometry to examine different lymphocyte subpopulations and the expression of the T- and NK-cell activation markers. After pregnancy, CD8+CD3+ lymphocytes were decreased in the decidua. In both endometrium and decidua, more T cells expressed CD69, CD71, HLA-DR, and CD38 antigens than in peripheral blood. After pregnancy, CD71+CD3+ lymphocytes were further increased. CD25+CD3+ lymphocytes decreased significantly in the endometrium and decidua of ectopic pregnancies, but not in the decidua of normal pregnancies. These findings indicate that T cells are regionally activated in the first trimester, and it may be the result of the stimulation by fetal antigens. NK cells were the most abundant cell type in the decidua, which expressed the phenotype CD16- CD56+, and CD57-CD56+. The proportion of activated decidual NK cells was increased in anembryonic pregnancies more than in normal pregnancies, although the total NK subpopulation was similar in both groups. This might result in increased NK cytotoxicity in anembryonic pregnancies. In conclusion, T cells are activated, but NK cytotoxicity is decreased in the decidua of early normal pregnancies. This might be important in the control of trophoblast growth and placental development.


The base of the proteasome regulatory particle exhibits chaperone-like activity.
Protein substrates of the proteasome must apparently be unfolded and translocated through a narrow channel to gain access to the proteolytic active sites of the enzyme. Protein folding in vivo is mediated by molecular chaperones. Here, to test for chaperone activity of the proteasome, we assay the reactivation of denatured citrate synthase. Both human and yeast proteasomes stimulate the recovery of the native structure of citrate synthase. We map this chaperone-like activity to the base of the regulatory particle of the proteasome, that is, to the ATPase-containing assembly located at the substrate-entry ports of the channel. Denatured but not native citrate synthase is bound by the base complex. Ubiquitination of citrate synthase is not required for its binding or refolding by the base complex of the proteasome. These data suggest a model in which ubiquitin-protein conjugates are initially tethered to the proteasome by specific recognition of their ubiquitin chains; this step is followed by a nonspecific interaction between the base and the target protein, which promotes substrate unfolding and translocation.


Protective effects of anthocyanins against brain ischemic damage.
Anthocyanins are considered as bioactive components of plant-based diets that provide protection against ischemic cardiovascular pathologies by mechanisms dependent on their antioxidant and reductive capacities. However, it is not clear whether similar anthocyanin-mediated mechanisms can provide protection against ischemia-induced brain mitochondrial injury and cell death. In this study, we compared effects of three cyanidin-3-glycosides - glucoside (Cy3G), galactoside (Cy3Gal) and rutinoside (Cy3R), with pelargonxidin-3-glucoside (Pg3G) and found that at 10-20 μM concentrations they have no direct effect on respiratory functions of mitochondria isolated from normal or ischemia-damaged rat brain slices. However, intravenous injection of Cy3Gal and Cy3G (0,025 mg/kg or 0,05 mg/kg what matches 10 μM or 20 μM respectively) but not Cy3R in rats protected against ischemia-induced caspase activation and necrotic cell death, and reduced infarct size in cerebral cortex and cerebellum. These effects correlated with cytochrome c reducing capacity of cyanidin-3-glycosides. In contrast, intravenous injection of 0,025 mg/kg Pg3G which has the lowest cytochrome c reducing capacity among investigated anthocyanins, had no effect on ischemia-induced caspase activation and necrosis but reduced brain infarct size whereas intravenous injection of 0,05 mg/kg of Pg3G slightly promoted necrosis in the brain. Our data suggest that reductive rather than antioxidant capacities of anthocyanins may be important components in providing protection against ischemic brain damage.


Analyses of associations between reactive oxygen metabolites and antioxidant capacity and related factors among healthy adolescents.
Evidence based on epidemiologic investigations using biochemical parameter is meaningful for health promotion and administration among adolescents. We conducted Reactive Oxygen Metabolites (ROM) and Biological Antioxidant Potentials (BAP) tests, along with a questionnaire survey, for a sample of 74 high school students (16.51±0.11 years of aged mean±SE), to investigate the associations between ROM, BAP, and related factors, including BMI and blood biochemical data. Venous blood samples (approximately 7cc) were collected. At the same time, each individual's information was obtained from the questionnaire. The mental health status was investigated using the Center for Epidemiologic Study Depression scale (CES-D) included in the same questionnaire. The mean values and standard errors of all variables were calculated. In addition, the relationships between ROM and BAP with these factors were analyzed. The results revealed the preferred levels of ROM (261.95 ± 9.52 U.CARR) and, BAP (2429.89±53.39 µmol/L) and blood biochemical data. Few significant relationships between two markers and related factors were found. So, we detected a cluster with an imbalance between ROM and BAP, which means low antioxidant ability, whereas the other clusters had conditions with moderate balance or good balance between them. Moreover, we determined the Oxidative stress-Antioxidant capacity ratio (OAR), using the ROM and BAP values, in order to clarify the characteristic of the detected clusters.However, comparative analyses across the three clusters did not yield significant differences in all related factors. No correlations between ROM, BAP and related factors were indicated, although significant association between ROM and BAP was observed (R2=0.1156, R=0.340, P=0.013). The reason for these results can be explained by the influences of good health and young age. On the other hand, present study suggests that some latent problems among adolescents may be related to unhealthy conditions in the future. Also, this study indicated that ROM and BAP may be useful as markers of the oxidative stress status. After this, further investigations using biomarkers based on epidemiologic design should be conducted, to reveal the reliability of the present results.


Neuropsychological outcome at adolescence of very preterm birth and its relation to brain structure.
Neuropsychological outcome at 14 to 15 years of age of a cohort of 75 participants (39 male, 36 female) born at <33 weeks' gestation was investigated. Research was conducted parallel to a recent MRI study by Stewart and colleagues which reported that 55% of this cohort had evidence of brain abnormality. One aim of the study was to compare neuropsychological function in those very preterm children with and without MRI abnormality. Compared to a control sample of term adolescents, very preterm participants had impairment only on a measure of word production. On measures of attention, memory, perceptual skill, and visuomotor and executive function, the adolescents born very preterm performed in the normal range, whether or not they had evidence of MRI abnormality. Our findings are encouraging as the neuropsychological consequences of damage to the very preterm brain, still evident on MRI at 14 to 15 years of age, appear to be minor.


Gut microbiota and probiotics in maternal and infant health.
The interplay between both heredity and environmental factors seems to affect every stage of development from conception to the early postnatal period with potential long-term effects on child and adult health. During pregnancy, immune and metabolic functions of the fetus are dependent on the mother; moreover, the refinement of these functions seems to commence inside the uterus and to be diet sensitive. The microbiota inhabiting the intestinal tract develop an array of physiologic roles within the human body, which influences both metabolic and immune functions, particularly during early neonatal life and possibly even in utero. Transmission of bacteria from the mother to the neonate through direct contact with maternal microbiota during birth and through breast milk during lactation also seems to influence the infant's gut colonization, with potential health consequences. In this context, intentional modulation of microbiota composition through the use of probiotics during the perinatal and early postnatal period has been proposed as a possible dietary strategy to reduce risk of disease. Herein, studies are reviewed on the composition of the intestinal microbiota during pregnancy and clinical trials evaluating the effects of perinatal administration of probiotics on different clinical outcomes.


Habitat type determines herbivory controls over CO2 fluxes in a warmer Arctic.
High-latitude ecosystems store large amounts of carbon (C); however, the C storage of these ecosystems is under threat from both climate warming and increased levels of herbivory. In this study we examined the combined role of herbivores and climate warming as drivers of CO2 fluxes in two typical high-latitude habitats (mesic heath and wet meadow). We hypothesized that both herbivory and climate warming would reduce the C sink strength of Arctic tundra through their combined effects on plant biomass and gross ecosystem photosynthesis and on decomposition rates and the abiotic environment. To test this hypothesis we employed experimental warming (via International Tundra Experiment [ITEX] chambers) and grazing (via captive Barnacle Geese) in a three-year factorial field experiment. Ecosystem CO2 fluxes (net ecosystem exchange of CO2, ecosystem respiration, and gross ecosystem photosynthesis) were measured in all treatments at varying intensity over the three growing seasons to capture the impact of the treatments on a range of temporal scales (diurnal, seasonal, and interannual). Grazing and warming treatments had markedly different effects on CO2 fluxes in the two tundra habitats. Grazing caused a strong reduction in CO2 assimilation in the wet meadow, while warming reduced CO2 efflux from the mesic heath. Treatment effects on net ecosystem exchange largely derived from the modification of gross ecosystem photosynthesis rather than ecosystem respiration. In this study we have demonstrated that on the habitat scale, grazing by geese is a strong driver of net ecosystem exchange of CO2, with the potential to reduce the CO2 sink strength of Arctic ecosystems. Our results highlight that the large reduction in plant biomass due to goose grazing in the Arctic noted in several studies can alter the C balance of wet tundra ecosystems. We conclude that herbivory will modulate direct climate warming responses of Arctic tundra with implications for the ecosystem C balance; however, the magnitude and direction of the response will be habitat-specific.


Immunohistochemical localization of advanced glycation end products in pinguecula.
Advanced glycation end products (AGEs) are known to be deposited in the target organ of ageing. In addition, the deposition of AGEs accelerate the process of ageing. We investigated the immunohistochemical localization of AGEs in pinguecula, one of the ocular changes related with ageing process. Surgical specimens of conjunctiva with or without pinguecula were prepared from nine patients, respectively. Immunohistochemical localization of AGEs was investigated using monoclonal antibodies to N(epsilon)-(carboxymethyl)lysine, pentosidine, imidazolone, and pyrraline. Moderate to strong immunoreactivities to AGEs were detected in the subepithelial amorphous deposits of all the surgical specimens with pinguecula. In contrast, no or weak immunoreactivities to AGEs were detected in the surgical specimens without pinguecula. Pinguecula is an aggregation of AGEs-modified proteins. The presence of pinguecula would be an index of local irradiation of ultraviolet rays and decreased antioxidant activities.


["Simulanten des Irrsinns auf dem Vortragspult": dada, war and psychiatry--'active dynamics of trauma'].
This paper relates stage performances of dada artists to war neurosis and shell shock as sociocultural phenomena. The leitmotif of this investigation is the notion of simulation, as dada artists were referred to as malingerers (simulators) of madness by the press at the time. I hypothesize that the performers imitate/simulate with drums, shouting and 'bruitist' sound poems, the noises of war, staging themselves as war neurotics in a kind of shocking clinical demonstration. Both discourses intersect in the fact that many dadaists try to dodge the draft by simulating madness. The scandalizing anti-art of dada will be understood as contagious anti-pedagogy, trying to vaccinate against the madness of the era.


Adapting a perinatal empathic training method from South Africa to Germany.
Maternal mental health conditions are prevalent across the world. For women, the perinatal period is associated with increased rates of depression and anxiety. At the same time, there is widespread documentation of disrespectful care for women by maternity health staff. Improving the empathic engagement skills of maternity healthcare workers may enable them to respond to the mental health needs of their clients more effectively. In South Africa, a participatory empathic training method, the "Secret History" has been used as part of a national Department of Health training program with maternity staff and has showed promising results. For this paper, we aimed to describe an adaptation of the Secret History empathic training method from the South African to the German setting and to evaluate the adapted training. The pilot study occurred in an academic medical center in Germany. A focus group (n = 8) was used to adapt the training by describing the local context and changing the materials to be relevant to Germany. After adapting the materials, the pilot training was conducted with a mixed group of professionals (n = 15), many of whom were trainers themselves. A pre-post survey assessed the participants' empathy levels and attitudes towards the training method. In adapting the materials, the focus group discussion generated several experiences that were considered to be typical interpersonal and structural challenges facing healthcare workers in maternal care in Germany. These experiences were crafted into case scenarios that then formed the basis of the activities used in the Secret History empathic training pilot. Evaluation of the pilot training showed that although the participants had high levels of empathy in the pre-phase (100% estimated their empathic ability as high or very high), 69% became more aware of their own emotional experiences with patients and the need for self-care after the training. A majority, or 85%, indicated that the training was relevant to their work as clinicians and trainers, that it reflected the German situation, and that it may be useful ultimately to address emotional distress in mothers in the perinatal phase. Our study suggests that it is possible to adapt an empathic training method developed in a South African setting and apply it to a German setting, and that it is well received by participants who may be involved in healthcare worker training. More research is needed to assess adaptations with other groups of healthcare workers in different settings and to assess empathic skill outcomes for participants and women in the perinatal period.


Differences in duration discrimination of filled and empty auditory intervals as a function of base duration.
In the present experiments, participants were presented with two time intervals that were marked by auditory signals, and their task was to decide which of the two was longer in duration. In Experiment 1, the base durations were 50 and 1,000 msec, whereas in Experiment 2, seven different base durations ranging from 50 to 1,000 msec were employed. It was found that filled intervals (continuous tones) were discriminated more accurately than empty intervals (with onset and offset marked by clicks) at the 50-msec base duration, whereas no performance differences could be shown for longer ones. The findings are consistent with the notion of a unitary timing mechanism that governs the timing of both filled and empty auditory intervals, independent of base durations. A likely conceptual framework that could explain better performance with filled as compared with empty intervals represents an information-processing model of interval timing that evolved from scalar timing theory. According to this account, a performance decrement observed with empty intervals may be due to a misassignment of pulses generated by an internal pacemaker.


Effect-based monitoring of the Danube River using mobile passive sampling.
Many aquatic pollutants can be present at low concentrations, but their mixtures can still affect health or behavior of exposed organisms. In this study, toxicological and chemical analyses were combined for spatial contamination profiling using an innovative passive sampling approach. A novel Dynamic Passive Sampler (DPS) was employed as a mobile sampler from a ship cruising along 2130km of the Danube river during the Joint Danube Survey 3 (JDS3). The sampling was performed in eight subsequent river stretches with two types of complementary passive samplers: silicone rubber sheets (SR) used for non-polar chemicals and SDB-RPS Empore™ disks (ED) for more hydrophilic compounds. Besides extensive chemical analyses, the bioactivity of samples was characterized by a battery of reporter gene bioassays. Cross-calibration of the employed passive samplers enabled robust estimation of water concentrations applicable for compounds with a wide range of physicochemical properties. DPS was suitable for sampling of water contaminants even at pgL-1 levels, with 209 of 267 analyzed compounds detected in the samples. Biological effects were detected in both ED and SR extracts across all river stretches by bioassays focused on xenobiotic metabolism mediated by the aryl hydrocarbon and pregnane X receptors, endocrine disruptive potential mediated by estrogen and androgen receptors and the oxidative stress response. The bioassay responses expressed as bioanalytical equivalent concentrations (BEQbio) were comparable with data obtained from large volume active sampling. The extracts of the ED samplers were more biologically active than extracts of SR samplers. Except of estrogenicity, where the analyzed chemicals explained on average 62% of the effects in ED samples, the detected chemicals explained <8% of BEQbio values. The study shows the utility of the combination of the innovative passive sampling approach with effect-based tools for efficient and fast monitoring even in water bodies with relatively low levels of contamination.


[Reactions of N-quaternary 1-phenyl-3,4-dihydroisoquinolinium compounds with nucleophiles--products and their isomerism--part 2].
A series of substituted 1-phenyl-3,4-dihydroisoquinolinium compounds was treated with O-, C- and N-nucleophilic agents in order to study ring-chain isomerism of the products. With methanolate carbinolamine ethers and with cyanide pseudocyanides as cyclic species resulted from these iminium salts. Electronic and steric differently substituted dihydroisoquinoline compounds reacted with hydroxylamine under ring opening generally to amine oximes predominantly in their Z-configuration. A cyclic isomer substituted with a hydroxylamine group--also in equilibrium in solution--could be excluded. With O-methylhydroxylamine a similar reaction gave rise to amine oxime methyl ethers only. 4-Phenylsemicarbazide and 4-nitrophenylhydrazine in pyridine produced the ring opened hydrazone derivatives.


Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.
Aberrant activation of Ras and Raf in mitogen-activated protein kinase (MAPK) signaling has been linked with cancer. However, the role of MAPK kinases (MAPKKs or MEKs) in cancer is unclear, although constitutively activated MEK1, which does not exist in nature, is "oncogenic." Herein, we found that T-cell-originated protein kinase (TOPK), a member of the MAPKK protein family, is highly expressed in human colorectal cancer tissues and cell lines and plays an important role in the transformation of colorectal cancer. The biologic consequences of overexpression or knockdown of TOPK in JB6 Cl41 and HCT116 colorectal cancer cells were studied in vitro and in vivo, respectively. Kinase assay or transient transfection experiments were performed to study the bidirectional signaling pathway between TOPK and extracellular signal-regulated kinase (ERK). TOPK was shown to promote transformation in vitro and in vivo, and knockdown of TOPK in HCT116 colorectal cancer cells reduced this cell lines' tumorigenic properties in vitro and in vivo. Furthermore, a positive feedback loop between TOPK and ERK2 was identified. With epidermal growth factor treatment, knockdown of either TOPK or ERK2 in HCT116 cells resulted in a decreased phosphorylation of ERK2 or TOPK, respectively, and knockdown of TOPK in HCT116 colorectal cancer cells blocked the phosphorylation of downstream substrates of ERK2. The positive feedback loop between TOPK and ERK2 increases tumorigenesis properties of HCT116 colorectal cancer cells, and TOPK-regulated signaling may serve as a potential therapeutic target in colorectal cancer.


Pharmacotherapeutic options for the treatment of menopausal symptoms.
Introduction: Menopausal symptoms can be very overwhelming for women. Over the years, many pharmacotherapeutic options have been tested, and others are still being developed. Hormone therapy (HT) is the most efficient therapy for managing vasomotor symptoms and related disturbances. The term HT comprises estrogens and progestogens, androgens, tibolone, the tissue-selective estrogen complex (TSEC), a combination of bazedoxifene and conjugated estrogens, and the selective estrogen receptor modulators, such as ospemifene. Estrogens and progestogens and androgens may differ significantly for chemical structure and can be delivered through different routes, thereby displaying various pharmacological and clinical properties. Tibolone, TSEC and SERM also exhibit unique pharmacodynamics that can be exploited to obtain distinctive therapeutic effects. Non-hormonal options fall mainly into the selective serotonin reuptake inhibitor (SSRI) and selective noradrenergic reuptake inhibitor (SNRI), GABA-analogue drug classes.Areas covered: Herein, the authors describe the pharmacokinetics and pharmacodynamics of hormonal (androgens, estrogens, progestogens, tibolone, TSEC, SERMs) and non-hormonal (SSRIs, SNRIs, Gabapentin, Pregabalin, Oxybutynin, Neurokinin antagonists) treatments for menopausal symptoms and report essential clinical trial data in humans.Expert opinion: Patient tailoring of treatment is key to managing symptoms of menopause. Physicians must have in-depth knowledge of the pharmacology of compounds to tailor therapy to the individual patient's characteristics and needs.


Vision Impairment and Productivity Among Female Garment Workers in Bangladesh: A Cohort Study.
To assess the prevalence of near and correctable distance visual impairment among screened participants in the garment industry and to explore associations with income, age, and urban versus rural residence. Vision screenings were conducted at 4 garment factories, 2 urban and 2 rural locations during September and October 2019. Distance vision impairment was the presence of uncorrected vision of <6/12 in either eye, correctable to ≥6/7.5 with distance refraction. Near vision impairment was defined as 1 or more of the following: 1) either eye with presenting near vision <N8 at 40 cm with distance visual acuity >6/12 in the same eye; 2) having been prescribed near add spectacle power in examination records; and/or 3) clinical diagnosis of presbyopia at the time of screening. Demographic information and monthly income were self-reported by questionnaire completion. Among 915 participating workers (100% female, 18 to 70 years), 29.2% (n = 267) and 26.8% (n = 245) had correctable distance and near vision impairment respectively. Prevalence of near vision impairment was significantly higher among rural residents (34.2%, n = 160), compared to urban (19.0%, n = 85, P < 0.0001) with the largest differences in the 35 to 39 (68.2% vs 44.2%, P = 0.0019) and 40+ (85.9 vs 48.9%, P < 0.0001) year age ranges. Prevalence of near vision impairment was already high among urban (20.4%, n = 20) and rural (23.0%, n = 17) workers aged 30 to 34 years. In simple linear regression models, participants with near vision impairment earned $13.3 [standard error (SE) 2.44, P < 0.0001] less per month than those without, while urban residents earned $40.6 (SE 1.74, P < 0.0001) more than rural dwellers. In the final multivariate linear model, both near vision impairment ($6.51 lower monthly earnings, SE 1.84, P = 0.0004) and urban residence ($43.2 higher monthly earnings, SE 2.39, P < 0.0001) remained significantly associated with income. This study found high rates of near vision impairment among female garment workers, particularly rural dwellers, and at a younger age than expected. The high prevalence and association between near vision impairment and lower income suggest that focusing on industries with a high proportion of female workers, such as readymade garments, may be effective in addressing gender disparities in vision impairment and its economic impact.


Improved adenoviral vectors for gene therapy of Duchenne muscular dystrophy.
We have been exploring the feasibility of gene therapy for Duchenne muscular dystrophy by characterizing parameters important for the design of therapeutic protocols. These studies have used transgenic mice to analyze expression patterns of multiple dystrophin vectors, and have been accompanied by the development of viral vectors for gene transfer to dystrophic mdx mouse muscle. Analysis of transgenic mdx mice indicates that greater than 50% of the fibers in a muscle group must express dystrophin to prevent development of a significant dystrophy, and that low-level expression of truncated dystrophins can function very well. These results suggest that gene therapy of DMD will require methods to transduce the majority of fibers in critical muscle groups with vectors that express moderate levels of dystrophin proteins. Strategies for the development of viral vectors able to deliver dystrophin genes to muscle include the use of muscle specific regulatory sequences coupled with deletion of viral gene sequences to limit virus-induced immune rejection of transduced tissues. These strategies should enable production of adenoviral vectors expressing full-length dystrophin proteins in muscle.


Measurement of leukocyte-platelet aggregates (LPA) by FACS: a comparative analysis.
In addition to their role in hemostasis and coagulation platelets bear critical roles in modulation of the innate and adaptive immune system. Upon platelet activation in response to tissue injury, bacterial or viral infections, they secrete many soluble factors or directly interact with leukocytes. An increase of leukocyte-platelet aggregates (LPA) has been described for many pathological conditions. Nevertheless, a standardized method for the reliable measurement of PLAs is not securely established. This methodical study provides a comparison of four different protocols from the literature and summarizes major pitfalls of measuring and interpreting leukocyte-platelet aggregates. The different techniques vary in the workup of the blood samples, applying variable washing and centrifugation steps or the use of erythrocyte lysis. All samples were finally analyzed by flow cytometry. Leukocyte subsets were stained with specific antibodies and platelet aggregates were identified by additional expression of CD41. The different procedures generated very heterogeneous data from the same blood sample which highlight the abundance of error measuring LPA. The most reproducible technique turned out to be a two-color whole blood flow cytometry assay with erythrocyte lysis and without washing or centrifugation steps avoiding platelet activation and artificial aggregate formation to achieve data mirroring the true situation in peripheral blood.


Psychosocial pathways to inconsistent condom use among male sex workers: personality, drug misuse and criminality.
This research compared street male sex workers in Santo André, Brazil, that reported consistent condom use with those that revealed inconsistent condom use with their clients, concerning personality aspects, impulsiveness, alcohol and drug consumption, depressive symptoms, sociodemographic data and criminal involvement. Eighty-six male sex workers were evaluated in face-to-face interviews at their place of work. A 'snowball' sampling procedure was used to access this hard-to-reach population. Male sex workers with inconsistent condom use showed greater involvement with criminal activities, higher reward dependence level and more frequent self-report of being HIV-positive. Conceptualisation of male sex workers' psychological characteristics may be required where HIV risk is not only attributed to sex work per se, but to other aspects such as personality-related factors and negative identity.


Diagnostic accuracy of three screening questions (3Q/TMD) in relation to the DC/TMD in a specialized orofacial pain clinic.
To determine the diagnostic accuracy of three screening questions (3Q/TMD) in relation to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), in a specialized clinic. Consecutive patients, >18 years, referred with a possible TMD complaint to the Orofacial Pain and Dysfunction clinic, Academic Centre for Dentistry Amsterdam, the Netherlands, were included in the study. All patients (n = 449; mean age 44 years; 72% females), answered the 3Q/TMD and the DC/TMD questionnaire before a DC/TMD examination. The 3Q/TMD constitutes of two questions on weekly pain from the jaw, face and temple region (Q1), and on function (Q2), and one function-related question on weekly catching and/or locking of the jaw (Q3). Q1 and Q2 were evaluated in relation to a DC/TMD pain diagnosis and Q3 in relation to a subgroup of DC/TMD intra-articular diagnosis, referred to as the reference standard. In total, 44% of patients received a pain-related DC/TMD diagnosis and 33% an intra-articular reference DC/TMD diagnosis. Sensitivity for the two pain screening questions was high (0.83-0.94), whereas specificity was low (0.41-0.55). For the function-related question, sensitivity was low (0.48), whereas specificity was high (0.96). In a specialized pain clinic, the two pain questions (Q1, Q2) are positive in most patients with pain-related TMD. Therefore, in case of a positive response, further diagnostic procedures for TMD pain are warranted. For the functional screening question (Q3), a positive response is indicative for an intra-articular DC/TMD diagnosis, while in case of a negative outcome, an intra-articular TMD might still be present.


Using the Grubbs and Cochran tests to identify outliers.
In a previous Technical Brief (TB No. 39) three approaches for tackling suspect results were summarised. Median-based and robust methods respectively ignore and down-weight measurements at the extremes of a data set, while significance tests can be used to decide if suspect measurements can be rejected as outliers. This last approach is perhaps still the most popular one, and is used in several standards, despite possible drawbacks. Here significance testing for identifying outliers is considered in more detail with the aid of some typical examples.


Ketamine as a promising prototype for a new generation of rapid-acting antidepressants.
The discovery of ketamine's rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild-to-moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment are not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders.


Cyclophosphamide in the treatment of pulmonary diseases: survey of use, training, and practitioner knowledge base.
To assess pulmonologists' use, training in the use, and knowledge base of the drug cyclophosphamide. Survey through questionnaire. Testing of knowledge base before and after instructional conference. Pulmonologists (94 attendings, 31 fellows), selected randomly at the 1996 and 1997 annual meetings of The American Thoracic Society, completed surveys of their use and training in the use of cyclophosphamide. Thirty-five attending at the 1998 meeting completed a test of knowledge base of the drug. Members of the pulmonary teaching service at The University of Chicago Hospitals completed the test before and after a case-based conference designed to educate pulmonologists in the use of the drug. Forty-three percent of the attending pulmonologists and 55% of the fellows were currently using the drug in the management of their patients; 77% of the attending pulmonologists had prescribed the drug in the past. Nonmalignant diseases for which the drug was prescribed included usual interstitial pneumonitis/desquamative interstitial pneumonitis, vasculitis, collagen vascular disease, constrictive bronchiolitis, sarcoid, and Goodpasture's disease. Sixty-eight percent of attending pulmonologists and 81% of fellows had no training in the drug's use. Of the attending pulmonologists who made use of the drug, 64% were prescribing and managing its use themselves. Of those who prescribed and managed the drug's use themselves, 65% had had no training in its use. Of those fellows who prescribed and managed the drug's use themselves, 73% had had no training in the drug's use. On knowledge-based testing, the average correct score was 30 +/- 10%. With an educational conference, average pre- and post-test scores rose from 40 +/- 10% to 80 +/- 10% (p < 0.001). Cyclophosphamide had been used by the vast majority of pulmonologists, either currently or in the past, for a wide variety of lung diseases. Its use is commonly managed by physicians who have no specific training relevant to this agent. Practitioner knowledge base of the drug is poor, and case-based conferences in fellowship may be an effective means of imparting information concerning this drug.


Mechanisms of ADRF release from rat aortic adventitial adipose tissue.
Blood vessels are surrounded by variable amounts of adipose tissue. We showed earlier that adventitial adipose tissue inhibits rat aortic contraction by release of a transferable factor, adventitium-derived relaxing factor (ADRF), which activates smooth muscle K(+) channels. However, little is known about the mechanisms of ADRF release. Using isolated rat aortic rings and isometric contraction measurements, we show that ADRF release depends on extracellular [Ca(2+)] (EC(50) approximately 4.7 mM). ADRF effects do not involve neuronal presynaptic N-type Ca(2+) and Na(+) channels or vanilloid, cannabinoid, and CGRP receptors. ADRF release is strongly inhibited by the protein tyrosine kinase inhibitors genistein and tyrphostin A25. In contrast, daidzein, an inactive genistein analog, and the protein tyrosine kinase inhibitor ST638 had no effect. Protein kinase A inhibition by H89 also inhibited ADRF release, whereas the protein kinase G inhibitor KT-5823 had no effect. We propose that ADRF release is Ca(2+) dependent and is regulated by intracellular signaling pathways involving tyrosine kinase and protein kinase A. Furthermore, ADRF release does not depend on perivascular nerve endings.


Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.
Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3'-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50-6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.


Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression.


The psychological profiles of internet, contact, and mixed internet/contact sex offenders.
A sample of 526 contact offenders, 459 internet offenders, and 143 mixed contact/internet offenders was compared on a range of self-report psychological measures assessing offense-supportive beliefs, socioaffective functioning, emotional management, and socially desirable responding. A multivariate general linear model found a mixed offender profile that was similar to internet offenders rather than contact offenders. The contact group demonstrated lower victim empathy, a greater level of pro-offending attitudes, an externalized locus of control, more assertiveness, a diminished ability to relate to fictional characters, and greater impulsivity than the internet and mixed offender groups. The mixed offender group demonstrated a higher level of empathic concern than the other two groups. The mixed offender group could also be distinguished from the internet group by increased personal distress and perspective-taking ability. A discriminant function analysis highlighted the key linear factor distinguishing between the groups to be one relating to offense-supportive attitudes and identification with fictional characters. A second factor was related to higher levels of empathic concern and poor self-management. These findings are discussed in the context of the potential pathways between internet and contact sexual offenses.


The value of preplacement screening radiography of the low back.
Because there has not been a randomized controlled trial on the validity of preplacement screening radiography of the low back, the author assesses this procedure indirectly by reviewing empirical evidence concerning its usefulness in industrial settings and by evaluating it against the basic requirements of a successful screening test.


UV treatment and air quality in a pool facility.
We investigated how UV treatment of indoor pool water affects the concentration of trihalomethanes (THMs) and chloramines (NCl3) in the air above one therapy pool. One-hundred and sixty-two samples of tTHMs (sum of the four most common THMs in swimming facilities) and thirty-six samples of NCl3 were collected simultaneously at poolside and in the extract channel in a room with one therapy pool for 2 days a week over a period of 5 weeks. When the UV lamp was on, the concentration of combined chlorine in the water decreased 58%, the concentration of tTHMs in the air increased 37%, and the concentration of NCl3 in the air decreased 15%. Between 42% and 56% of the gases in the air are recirculated back into the poolroom along with the recycled air. The correlation between NCl3 and THMs in the air was stronger when the UV treatment was on (r2 = 0.963) compared to when the UV treatment was off (r2 = 0.472). Using a linear mixed model, 30% of the variability in THMs was attributed to UV treatment. For NCl3, the number of bathers was the most important predictor variable. UV treatment has a limited effect on airborne NCl3 but increases the air concentration of tTHMs.


NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor.
The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. Several studies have shown that the DNA-PKcs inhibitor NU7441 is a highly potent radiosensitizer, however, the mechanism of NU7441's anti-proliferation effect has not been fully elucidated. In this study, the combined effect of NU7441 and ionizing radiation (IR) in a panel of non-small cell lung cancer cell lines (A549, H460 and H1299) has been investigated. We found that NU7441 significantly enhances the effect of IR in all cell lines. The notable findings in response to this combined treatment are (i) prolonged delay in IR-induced DNA DSB repair, (ii) induced robust G2/M checkpoint, (iii) increased aberrant mitosis followed by mitotic catastrophe specifically in H1299, (iv) dramatically induced autophagy in A549 and (v) IR-induced senescence specifically in H460. H1299 cells show greater G2 checkpoint adaptation after combined treatment, which can be attributed to higher expression level of Plk1 compared to A549 and H460. The enhanced autophagy after NU7441 treatment in A549 is possibly due to the higher endogenous expression of pS6K compared to H1299 and H460 cells. In conclusion, choice of cell death pathway is dependent on the mutation status and other genetic factors of the cells treated.


Does exposure to noise pollution influence the incidence and severity of COVID-19?
Research that analyzes the effect of different environmental factors on the impact of COVID-19 focus primarily on meteorological variables such as humidity and temperature or on air pollution variables. However, noise pollution is also a relevant environmental factor that contributes to the worsening of chronic cardiovascular diseases and even diabetes. This study analyzes the role of short-term noise pollution levels on the incidence and severity of cases of COVID-19 in Madrid from February 1 to May 31, 2020. The following variables were used in the study: daily noise levels averaged over 14 days; daily incidence rates, average cumulative incidence over 14 days; hospital admissions, Intensive Care Unit (ICU) admissions and mortality due to COVID-19. We controlled for the effect of the pollutants PM10 and NO2 as well as for variables related to seasonality and autoregressive nature. GLM models with Poisson regressions were carried out using significant variable selection (p < 0.05) to calculate attributable RR. The results of the modeling using a single variable show that the levels of noise (leq24 h) were related to the incidence rate, the rate of hospital admissions, the ICU admissions and the rate of average cumulative incidence over 14 days. These associations presented lags, and the first association was with incidence (lag 7 and lag 10), then with hospital admissions (lag 17) and finally ICU admissions (lag 22). There was no association with deaths due to COVID-19. In the results of the models that included PM10, NO2, Leq24 h and the control variables simultaneously, we observed that only Leq24 h went on to become a part of the models using COVID-19 variables, including the 14-day average cumulative incidence. These results show that noise pollution is an important environmental variable that is relevant in relation to the incidence and severity of COVID-19 in the Province of Madrid.


Patients with multiple morphological abnormalities of the sperm flagella due to DNAH1 mutations have a good prognosis following intracytoplasmic sperm injection.
Does DNAH1 status influence intracytoplasmic sperm injection (ICSI) outcomes for patients with multiple morphological abnormalities of the sperm flagella (MMAF)? Despite a highly abnormal morphology, sperm from MMAF patients with DNAH1 mutations have a low aneuploidy rate and good nuclear quality, leading to good embryonic development following ICSI and a high pregnancy rate. Teratozoospermia represents a heterogeneous group including a wide range of phenotypes. Among all these qualitative defects, a flagellar phenotype called MMAF is characterized by a mosaic of morphological abnormalities of the flagellum, including coiled, bent, irregular, short or/and absent flagella, mainly due to the absence of the axonemal central pair microtubules. We previously demonstrated that homozygous mutations in the DNAH1 gene, encoding an inner arm heavy chain dynein, are frequently found in patients with MMAF (28% of the patients from the initial cohort). Numerous studies have reported an increased rate of aneuploidy and a poor sperm nuclear quality related to sperm flagellar abnormalities, which could impede ICSI outcome. Moreover, success rates after ICSI may be influenced by the type of ultrastructural flagellar defects and/or by the gene defects carried by the patients. This retrospective cohort study included 6 infertile males with MMAF due to deleterious homozygous DNAH1 mutations and their respective spouses, who underwent 9 ISCI cycles, with 16 embryos being transferred. ICSI results were compared with two control populations of 13 MMAF men without DNAH1 mutations and an aged-matched control group of 1431 non-MMAF couples. All ICSI attempts took place between 2000 and 2012. Clinical and biological data were collected from patients treated for infertility at the CPSR les Jasmins in Tunis (Tunisia). We compared the ICSI outcomes obtained with couples including DNAH1 mutated and nonmutated patients and non-MMAF couples. For the analysis of the chromosomal status, fluorescence in situ hybridization (FISH) analyses were performed on sperm cells from 3 DNAH1-mutated patients and from 29 fertile control subjects. Sperm chromatin condensation and DNA fragmentation were evaluated using aniline blue staining and TUNEL assays, respectively, on sperm cells from 3 DNAH1-mutated men and 6 fertile controls. There was a significantly increased proportion of disomy XY and 18 in sperm from DNAH1 mutated patients compared with fertile controls (1.52 versus 0.28%, P = 0.0001 and 0.64 versus 0.09%, P = 0.0001). However, there were no statistically significant differences among sperm from the two groups in their frequencies of either 13, 21, XX or YY disomy or diploidy. Measures of DNA compaction and fragmentation demonstrated a good nuclear sperm quality among DNAH1 mutated men. The overall fertilization, pregnancy and delivery rates of couples including DNAH1 mutated men were of 70.8, 50.0 and 37.5%, respectively. There were no statistically significant differences in any of these parameters compared with the two control groups (P > 0.05). A limitation of this study is the small number of DNAH1-mutated patients available and the low number of genes identified in MMAF. Further genetic studies are warranted to identify other MMAF-inducing genes to better characterize the genetic etiology of the MMAF phenotype and to improve the management of patients diagnosed with flagellar defects. MMAF patients with DNAH1 mutations have low aneuploidy rates and good nuclear sperm quality, explaining the high pregnancy rate obtained with these patients. Good ICSI results were obtained for both MMAF groups (DNAH1 mutated and nonmutated), suggesting that patients presenting with asthenozoospermia due to flagellar defects have a good ICSI prognosis irrespective of their genotype. The majority of MMAF cases currently remain idiopathic with no genetic cause yet identified. In depth genetic analysis of these patients using next generation sequencing should reveal new causal genes. Subsequent genotype phenotype analyses could improve advice and care provided to MMAF patients. None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)', funded by the program GENOPAT 2009 from the French Research Agency (ANR) and the MAS-Flagella project, financed by the French ANR and the Direction Générale de l'Offre de Soins (DGOS).


Sagittal splitting of the temporalis muscle for encephalo-myo-synangiosis to prevent ischemic complications due to a swollen temporalis muscle without inhibiting collateral developments in patients with moyamoya disease.
OBJECTIVEEncephalo-myo-synangiosis (EMS) is an effective revascularization procedure for the treatment of moyamoya disease (MMD). However, the temporalis muscle used for EMS sometimes swells and causes ischemic complications by compressing the underlying brain. This study aimed to elucidate the effect of sagittal splitting (SS) of the muscle for prevention of ischemic complications and its impact on the postoperative development of collateral vessels.METHODSIn this historical case-control study, we analyzed 60 hemispheres in adult patients with MMD who underwent EMS using the temporalis muscle from December 1998 to November 2017. The muscle was divided anteroposteriorly by coronal splitting, and the anterior, posterior, or both parts of the muscle were used for EMS in 17, 4, and 39 hemispheres, respectively. In cases performed after 2006, the muscle was halved by SS, and the medial half was used for EMS to reduce the muscle volume (n = 47). The degree of postoperative muscle swelling was evaluated by measuring the maximum thickness of the muscle on CT scans obtained 3 to 7 days after surgery. The collateral developments of the anterior deep temporal artery (aDTA), posterior deep temporal artery (pDTA), and middle temporal artery (MTA) were assessed using digital subtraction angiography and MR angiography performed 6 months or more after surgery.RESULTSSS significantly reduced the temporalis muscle thickness from 12.1 ± 5.0 mm to 7.1 ± 3.0 mm (p < 0.01). Neurological deterioration due to the swollen temporalis muscle developed in 4 of the 13 hemispheres without SS (cerebral infarction in 1, reversible neurological deficit in 2, and convulsion in 1) but in none with SS. There were no significant differences in the postoperative collateral developments of the aDTA, pDTA, and MTA between hemispheres with and without SS. The MTA more frequently developed in hemispheres with EMS in which the posterior part of the muscle was used (30/37) than those in which this part was not used (4/16) (p < 0.01).CONCLUSIONSSS of the temporalis muscle might prevent neurological deterioration caused by the swollen temporalis muscle by reducing its volume without inhibiting the development of the collateral vessels.


Adipose tissue homeostasis orchestrates the oxidative, energetic, metabolic and endocrine disruption induced by binge drinking in adolescent rats.
Binge drinking (BD) is the most common alcohol consumption model for adolescents, and has recently been related to the generation of high oxidation and insulin resistance (IR). White adipose tissue (WAT) is a target organ for insulin action that regulates whole-body metabolism by secreting adipokines. The present study aimed to analyse the oxidative, inflammatory, energetic and endocrine profile in the WAT of BD-exposed adolescent rats, to obtain an integrative view of insulin secretion and WAT in IR progression. Two groups of male adolescent rats were used: control (n = 8) and BD (n = 8). An intermittent i.p. BD model (20% v/v) was used during 3 consecutive weeks. BD exposure led to a pancreatic oxidative imbalance, which was joint to high insulin secretion by augmenting deacetylase sirtuin-1 (SIRT-1) pancreatic expression and serum adipsin levels. However, BD rats had hyperglycaemia and high homeostasis model assessment of insulin resistance value (HOMA-IR). BD exposure in WAT increased lipid oxidation, as well as decreased insulin receptor substrate 1 (IRS-1) and AKT expression, sterol regulatory element-binding protein 1 (SREBP1), forkhead box O3A (FOXO3a) and peroxisome proliferator-activated receptor γ (PPARγ), and adipocyte size. BD also affected the expression of proteins related to energy balance, such as SIRT-1 and AMP activated protein kinase (AMPK), affecting the adipokine secretion profile (increasing resistin/adiponectin ratio). BD altered the entire serum lipid profile, increasing the concentration of free fatty acids. In conclusion, BD led to an oxidative imbalance and IR process in WAT, which modified the energy balance in this tissue, decreasing the WAT lipogenic/lipolytic ratio, affecting adipokine secretion and the systemic lipid profile, and contributing to the progression of IR. Therefore, WAT is key in the generation of metabolic and endocrine disruption after BD exposure during adolescence in rats. KEY POINTS: Adolescent rat binge drinking (BD) exposure leads to hepatic and systemic oxidative stress (OS) via reactive oxygen species generation, causing hepatic insulin resistance (IR) and altered energy metabolism. In the present study, BD exposure in adolescent rats induces OS in the pancreas, with increased insulin secretion despite hyperglycaemia, indicating a role for IR in white adipose tissue (WAT) homeostasis. In WAT, BD produces IR and an oxidative and energetic imbalance, triggering an intense lipolysis where the serum lipid profile is altered and free fatty acids are increased, consistent with liver lipid accumulation and steatosis. BD exposure heightens inflammation in WAT, elevating pro-inflammatory and reducing anti-inflammatory adipokines, favouring cardiovascular damage. This research provides a comprehensive view of how adolescent BD in rats impacts liver, WAT and pancreas homeostasis, posing a risk for future cardiometabolic complications in adulthood.


Epidemiology and the global burden of stroke.
Stroke remains one of the most devastating of all neurological diseases, often causing death or gross physical impairment or disability. As numerous countries throughout the world undergo the epidemiological transition of diseases, trends in the prevalence of stroke have dramatically changed. All major international epidemiological articles published during the past 20 years addressing the global burden of stroke were reviewed. A focus was placed upon better defining current and future trends in surveillance, incidence, burden of disease, mortality, and costs associated with stroke internationally. Despite the fact that various surveillance systems are used to identify stroke and its sequela around the world, it is clear that stroke remains one of the top causes of mortality and disability-adjusted life-years (DALYs) lost globally. Concerning trends include the increase of stroke mortality and lost DALYs in low- and middle-income countries. The global economic impact of stroke may be dire if effective preventive measures are not implemented to help decrease the burden of this disease. The global burden of stroke is high, inclusive of increasing incidence, mortality, DALYs, and economic impact, particularly in low- and middle-income countries. The implementation of better surveillance systems and prevention programs are needed to help track current trends as well as to curb the projected exponential increase in stroke worldwide.


Putative function of cytochrome b559 as a plastoquinol oxidase.
The function of cytochrome b559 (cyt b559) in photosystem II (PSII) was studied in a tobacco mutant in which the conserved phenylalanine at position 26 in the beta-subunit was changed to serine. Young leaves of the mutant showed no significant difference in chloroplast ultra structure or in the amount and activity of PSII, while in mature leaves the size of the grana stacks and the amount of PSII were significantly reduced. Mature leaves of the mutant showed a higher susceptibility to photoinhibition and a higher production of singlet oxygen, as shown by spin trapping electron paramagnetic resonance (EPR) spectroscopy. Oxygen consumption and superoxide production were studied in thylakoid membranes in which the Mn cluster was removed to ensure that all the cyt b559 was present in its low potential form. In thylakoid membranes, from wild-type plants, the larger fraction of superoxide production was 3-(3,4-dichlorophenyl)-1,1-dimethylurea-sensitive. This type of superoxide formation was absent in thylakoid membranes from the mutant. The physiological importance of the plastoquinol oxidation by cyt b559 for photosynthesis is discussed.


The osmotic stress response of split influenza vaccine particles in an acidic environment.
Oral influenza vaccine provides an efficient means of preventing seasonal and pandemic disease. In this work, the stability of envelope-type split influenza vaccine particles in acidic environments has been investigated. Owing to the fact that hyper-osmotic stress can significantly affect lipid assembly of vaccine, osmotic stress-induced morphological change of split vaccine particles, in conjunction with structural change of antigenic proteins, was investigated by the use of stopped-flow light scattering (SFLS), intrinsic fluorescence, transmission electron microscopy (TEM), and hemagglutination assay. Split vaccine particles were found to exhibit a step-wise morphological change in response to osmotic stress due to double-layered wall structure. The presence of hyper-osmotic stress in acidic medium (0.3 osmolarity, pH 2.0) induced a significant level of membrane perturbation as measured by SFLS and TEM, imposing more damage to antigenic proteins on vaccine envelope than can be caused by pH-induced conformational change at acidic iso-osmotic condition. Further supports were provided by the intrinsic fluorescence and hemagglutinin activity measurements. Thus, hyper-osmotic stress becomes an important factor for determining stability of split vaccine particles in acidic medium. These results are useful in better understanding the destabilizing mechanism of split influenza vaccine particles in gastric environment and in designing oral influenza vaccine formulations.


Toxicity of synthetic chelators and metal availability in poultry manure amended Cd, Pb and As contaminated agricultural soil.
Chelating agents added to contaminated soils may increase solubility and phytoextraction efficiency of soil metals. However, they can create negative effects on soil biological quality. A 90-day incubation experiment was conducted to evaluate mixed effects of chelating agents and poultry manure on changes in available Cd, Pb and As, CO2-C efflux, microbial biomass C, dissolved organic C (DOC), and N mineralization in metal-polluted agricultural soil. Application of poultry manure resulted in a considerable increase in soil pH, DOC, CO2-C efflux, net N mineralization, net N nitrification, and microbial biomass C compared to those in unmanured soil. Availability of arsenic increased twice in manure amended soil due to changes in pH and DOC. However, adding poultry manure did not affect the concentrations of available Pb and Cd compared to those in control soil. Chelating agents increased CO2-C efflux, DOC, and metal availability but decreased microbial biomass C and net N mineralization. Maximum decrease in microbial biomass C, net N mineralization, and net N nitrification, was observed in EDTA applied soil possibly due to high metal availability to soil microorganisms. Overall results revealed that the application of synthetic chelators in combination with poultry manure enhances available As and demonstrates better environment for soil biota.


Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical Practice: A Nationwide Cohort Study From Sweden.
Considering the widespread and increasing use of biological immunomodulators (biological disease-modifying antirheumatic drugs [bDMARDs]) to treat chronic inflammatory conditions, and the concern that immunomodulation may alter cancer risk and progression, the limited available data on use of these therapies as used in clinical practice and cancer risks are a concern. To assess the risk of incident malignant neoplasms in patients with rheumatoid arthritis (RA) treated with bDMARDs. This was a national register-based prospective cohort study of the public health care system in Sweden from 2006 to 2015. Cohorts of patients with RA initiating treatment with tocilizumab (n = 1798), abatacept (n = 2021), and rituximab (n = 3586), a tumor necrosis factor inhibitor (TNFi) as first-ever (n = 10 782) or second-ever (n = 4347) bDMARD, a biologics-naive cohort treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (n = 46 610), and a general population comparator cohort (n = 107 491). Treatment with tocilizumab, abatacept, rituximab, or TNFi. Outcomes included a first invasive solid or hematologic malignant neoplasm, or skin cancer. Hazard ratios were calculated using Cox-regression, adjusted for age, sex, disease and treatment characteristics, and educational level. We identified a total of 15 129 initiations of TNFi as the first or second bDMARD, 7405 initiations of other bDMARDs, and 46 610 csDMARD users. The mean age varied from 58 to 64 years, and the proportion of female patients varied from 71% to 80%, across the 7 cohorts under study. The observed numbers of events (crude incidence per 100 000 person-years) for a first invasive solid or hematologic malignant neoplasm were 50 (959) for tocilizumab, 61 (1026) for abatacept, 141 (1074) for rituximab, 478 (978) for initiators of TNFi as first bDMARD, and 169 (917) for TNFi as second bDMARD. There were no statistically significant differences between initiators of a first or second TNFi, or other bDMARDs, and bDMARD-naive RA for any of a total of 25 drug- and outcome-specific comparisons, with 1 exception (abatacept and increased risk of squamous cell skin cancer). The overall risk of cancer among patients with RA initiating TNFi as first or second bDMARD, tocilizumab, abatacept, or rituximab does not differ substantially from that of biologic drug-naive, csDMARD-treated patients with RA, although altered risks for specific cancer types, or those with longer latency, cannot be excluded.


Direct thrombin inhibitors in cardiac disease.
Most acute coronary syndromes (ACS) are triggered by platelet-rich thrombus superimposed on disrupted atherosclerotic plaque. Thrombin and platelets both play a role in this process. Whereas unfractionated heparin and aspirin have served as cornerstones in the treatment of ACS, several limitations of heparin provide the impetus to seek out better anticoagulants. Direct thrombin inhibitors such as bivalirudin, hirudin, and argatroban offer several pharmacologic advantages over heparin. Additionally, bivalirudin also appears to provide clinical advantages over unfractionated heparin therapy in ACS patients and those undergoing percutaneous coronary intervention.


Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN).
To evaluate the safety and efficacy of a once-daily gastroretentive formulation of gabapentin (G-GR; 1800 mg). This was an 11-week, double-blind, randomized, placebo-controlled Phase 3 clinical trial in patients with postherpetic neuralgia. Patients underwent a 2-week dose titration, 8 weeks of stable dosing, and 1 week of dose tapering. The primary endpoint was the change in average daily pain intensity score from Baseline to Week 10 using Baseline Observation Carried Forward (BOCF) imputation. Four-hundred and fifty-two patients (mean age 65.6 y, BMI 29 Kg/m) were randomized. Baseline average daily pain intensity score during the week prior to randomization was 6.6 and 6.5 for the G-GR and placebo treatment groups, respectively. Three hundred and seventy-seven patients completed the study (84% G-GR, 83% placebo). G-GR significantly reduced BOCF change in average daily pain intensity compared with placebo (-2.1 vs. -1.6; G-GR vs. placebo, P=0.013). Compared with placebo, more G-GR-treated patients reported "much" or "very much" improvement (patient global impression of change, 43% vs. 34%; P<0.0434), and G-GR reduced sleep interference (-2.3 vs. -1.59; P<0.0001), although neither endpoint was considered statistically significant based on a stringent hierarchical statistical paradigm. Other secondary endpoints showed similar trends. The most common adverse events were dizziness (G-GR, 11.3% vs. placebo, 1.7 %) and somnolence (G-GR, 5.4% vs. placebo, 3.0%). Once-daily G-GR 1800 mg was effective and well tolerated for the relief of pain in patients with postherpetic neuralgia.


Numerical simulations of internal wave generation by convection in water.
Water's density maximum at 4°C makes it well suited to study internal gravity wave excitation by convection: an increasing temperature profile is unstable to convection below 4°C, but stably stratified above 4°C. We present numerical simulations of a waterlike fluid near its density maximum in a two-dimensional domain. We successfully model the damping of waves in the simulations using linear theory, provided we do not take the weak damping limit typically used in the literature. To isolate the physical mechanism exciting internal waves, we use the spectral code dedalus to run several simplified model simulations of our more detailed simulation. We use data from the full simulation as source terms in two simplified models of internal-wave excitation by convection: bulk excitation by convective Reynolds stresses, and interface forcing via the mechanical oscillator effect. We find excellent agreement between the waves generated in the full simulation and the simplified simulation implementing the bulk excitation mechanism. The interface forcing simulations overexcite high-frequency waves because they assume the excitation is by the "impulsive" penetration of plumes, which spreads energy to high frequencies. However, we find that the real excitation is instead by the "sweeping" motion of plumes parallel to the interface. Our results imply that the bulk excitation mechanism is a very accurate heuristic for internal-wave generation by convection.


Effect of lipid head groups on double-layered two-dimensional crystals formed by aquaporin-0.
Aquaporin-0 (AQP0) is a lens-specific water channel that also forms membrane junctions. Reconstitution of AQP0 with dimyristoyl phosphatidylcholine (DMPC) and E. coli polar lipids (EPL) yielded well-ordered, double-layered two-dimensional (2D) crystals that allowed electron crystallographic structure determination of the AQP0-mediated membrane junction. The interacting tetramers in the two crystalline layers are exactly in register, resulting in crystals with p422 symmetry. The high-resolution density maps also allowed modeling of the annular lipids surrounding the tetramers. Comparison of the DMPC and EPL bilayers suggested that the lipid head groups do not play an important role in the interaction of annular lipids with AQP0. We now reconstituted AQP0 with the anionic lipid dimyristoyl phosphatidylglycerol (DMPG), which yielded a mixture of 2D crystals with different symmetries. The different crystal symmetries result from shifts between the two crystalline layers, suggesting that the negatively charged PG head group destabilizes the interaction between the extracellular AQP0 surfaces. Reconstitution of AQP0 with dimyristoyl phosphatidylserine (DMPS), another anionic lipid, yielded crystals that had the usual p422 symmetry, but the crystals showed a pH-dependent tendency to stack through their cytoplasmic surfaces. Finally, AQP0 failed to reconstitute into membranes that were composed of more than 40% dimyristoyl phosphatidic acid (DMPA). Hence, although DMPG, DMPS, and DMPA are all negatively charged lipids, they have very different effects on AQP0 2D crystals, illustrating the importance of the specific lipid head group chemistry beyond its mere charge.


One man's tall is another man's small: how the framing of portion size influences food choice.
Labels such as 'Large' or 'Super-size' are often used to describe portion sizes. How do these normative labels influence consumer choice and how much they ultimately either consume or waste? Although one might believe that firms use normative labels to impact choice behavior through loss aversion, a field experiment shows consumer's willingness to pay is inconsistent with a loss aversion explanation. Although portions were clearly visible, individuals appeared to use the labels as objective information about their size. Importantly, a second study showed these labels also led people to eat less when food was given a larger sounding name than a smaller name (double vs. regular; regular vs. half-size). If labels are used as size information, policies governing normative names could help reduce food consumption or reduce waste.


16-Epiestriol, a novel anti-inflammatory nonglycogenic steroid, does not inhibit IFN-gamma production by murine splenocytes.
All the steroidal anti-inflammatory drugs currently available are glucocorticoids. The desired anti-inflammatory activities of glucocorticoids frequently are accompanied by adverse side effects, notably glycogenic activities and profound immunosuppression, that can limit clinical use. We recently identified 16-epiestriol, a naturally occurring steroid, as exhibiting significant anti-inflammatory activity without glycogenic activity. In the present study, we compared the effects of 16-epiestriol and hydrocortisone on the capacity of murine splenocytes to produce interferon-y (IFN-y). We injected young adult male BDF1 mice once with 20 mg/kg hydrocortisone or 20, 5, or 1 mg/kg 16-epiestriol and 4 h later harvested the splenocytes. Flow cytometric analysis confirmed that 16-epiestriol did not alter the number of CD3+ T cells in the spleen. In contrast to the suppressive effects of hydrocortisone, none of the 16-epiestriol concentrations inhibited concanavalin A-stimulated IFN-gamma production by spleen cells, as determined by ELISA. Incubating spleen cells from untreated mice in concentrations of 16-epiestriol ranging from 1 mg/ml to 100 pg/ml did not alter profiles of IFN-gamma production, in contrast to the suppressive dose-response effects of hydrocortisone. Collectively, these results support the contention that 16-epiestriol may be a clinically useful safe anti-inflammatory steroid without profound immunosuppressive activities.


Fast random bit generation with bandwidth-enhanced chaos in semiconductor lasers.
We experimentally demonstrate random bit generation using multi-bit samples of bandwidth-enhanced chaos in semiconductor lasers. Chaotic fluctuation of laser output is generated in a semiconductor laser with optical feedback and the chaotic output is injected into a second semiconductor laser to obtain a chaotic intensity signal with bandwidth enhanced up to 16 GHz. The chaotic signal is converted to an 8-bit digital signal by sampling with a digital oscilloscope at 12.5 Giga samples per second (GS/s). Random bits are generated by bitwise exclusive-OR operation on corresponding bits in samples of the chaotic signal and its time-delayed signal. Statistical tests verify the randomness of bit sequences obtained using 1 to 6 bits per sample, corresponding to fast random bit generation rates from 12.5 to 75 Gigabit per second (Gb/s) ( = 6 bit x 12.5 GS/s).


Methodological quality, completeness of reporting and use of systematic reviews as evidence in clinical practice guidelines for paediatric overweight and obesity.
Paediatric obesity rates remain high despite extensive efforts to prevent and treat obesity in children. We investigated the quality of the methodology and reporting within systematic reviews (SRs) underpinning paediatric content in US clinical practice guidelines (CPGs). In June 2016 we searched guideline clearinghouses and professional organization websites for guidelines published by national or professional organizations in the United States from January 2007 onwards. In our primary, a priori analysis, we used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) instruments to score SRs and meta-analyses that included paediatric populations and were cited by included CPGs. In a secondary, post hoc analysis, we determined the extent to which US CPGs use available, relevant SRs and meta-analyses compared with non-US CPGs. Eight US-based CPGs with 27 references to 22 unique SRs were found. AMSTAR and PRISMA scores were low overall, with only three SRs having 'high' methodological quality. Items dealing with bias assessments and search strategies had especially low scores. US CPGs were also older on average and cited fewer SRs than their international counterparts. Low quality scores and dated guidelines should be a cause for concern among practicing clinicians and a call to action for future guideline developers, publishers and research institutions.


Multidirectional Planar Motion Transmission on a Single-Motor Actuated Robot via Microscopic Galumphing.
Insect-scale mobile robots can execute diverse arrays of tasks in confined spaces. Although most self-contained crawling robots integrate multiple actuators to ensure high flexibility, the intricate actuators restrict their miniaturization. Conversely, robots with a single actuator lack the requisite agility and precision for planar movements. Herein, a novel eccentric rotation-dependent multidirectional transmission is presented using a tilted eccentric motor and a simplistic two-legged structural configuration for planar locomotion. The speed of the eccentric motor is modulated to enable alternating microscopic jumps to propel the system, creating a mode of motion analogous to galumphing of seals. Upon modeling the motion dynamics and conducting experiments, the effectiveness of direct motion transmission is substantiated through microscopic galumphing encompassing left/right crawling and straight-forward crawling. Finally, a 1.2 g untethered robot is developed, which demonstrates enhanced straight crawling and spot turning, traverses narrow tunnels, and achieves precise movements. Therefore, the proposed motion-transmission technique provides a comprehensive set of innovative solutions of underactuated agile robots.


Lung regional stress and strain as a function of posture and ventilatory mode.
During positive-pressure ventilation parenchymal deformation can be assessed as strain (volume increase above functional residual capacity) in response to stress (transpulmonary pressure). The aim of this study was to explore the relationship between stress and strain on the regional level using computed tomography in anesthetized healthy pigs in two postures and two patterns of breathing. Airway opening and esophageal pressures were used to calculate stress; change of gas content as assessed from computed tomography was used to calculate strain. Static stress-strain curves and dynamic strain-time curves were constructed, the latter during the inspiratory phase of volume and pressure-controlled ventilation, both in supine and prone position. The lung was divided into nondependent, intermediate, dependent, and central regions: their curves were modeled by exponential regression and examined for statistically significant differences. In all the examined regions, there were strong but different exponential relations between stress and strain. During mechanical ventilation, the end-inspiratory strain was higher in the dependent than in the nondependent regions. No differences between volume- and pressure-controlled ventilation were found. However, during volume control ventilation, prone positioning decreased the end-inspiratory strain of dependent regions and increased it in nondependent regions, resulting in reduced strain gradient. Strain is inhomogeneously distributed within the healthy lung. Prone positioning attenuates differences between dependent and nondependent regions. The regional effects of ventilatory mode and body positioning should be further explored in patients with acute lung injury.


Posttraumatic cognitions, childhood sexual abuse characteristics, and posttraumatic stress disorder in men who have sex with men.
High rates of experience of childhood sexual abuse (CSA) among in men who have sex with men (MSM) place this population at increased risk for posttraumatic stress disorder (PTSD). This study explores how specific characteristics of CSA relate to posttraumatic cognitions (PTCs) and explores the role that specific PTCs play in the relationship between CSA and PTSD in MSM. Two-hundred and ninety MSM completed a CSA interview, the Davidson Trauma Scale, and the Posttraumatic Cognitions Inventory. Controlling for sociodemographic factors, CSA involving physical injury and CSA with intense fear were associated with higher levels of PTCs about the self and world, but not with self-blame. We did not find significant associations for CSA involving a family member, CSA with penetration, or duration or frequency of CSA with any subscale on the PTCI. Experiencing CSA for the first time during adolescence was associated with higher self-blame. Analyses revealed that physical injury and intense fear each had indirect effects on PTSD symptoms through negative cognitions about the self and world. First CSA episode during adolescence had an indirect effect on PTSD symptoms through self-blame. CSAs accounted for 16.7% and PTCs accounted for 31.7% of the variance in PTSD, underlining the importance of PTCs. Assessing for physical injury, intense fear, and age at first CSA are particularly relevant to PTCs and of critical importance to advancing assessment and treatment strategies for PTSD in MSM.


Direct carbon-carbon bond formation via soft enolization: a biomimetic asymmetric Mannich reaction of phenylacetate thioesters.
An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonyl-activating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives.


Carotid intima-media thickness is increased not only in non-alcoholic fatty liver disease patients but also in alcoholic fatty liver patients.
There are many reports of non-alcoholic fatty liver disease (NAFLD) patients with increased carotid intima-media thickness (IMT). However, there is little information about carotid IMT in alcoholic fatty liver disease (AFLD) patients. We aimed to compare the carotid IMT of NAFLD patients and AFLD patients. The medical records of individuals who underwent carotid IMT measurement and abdominal ultrasonography between January 2006 and December 2008 at Korea University Ansan Hospital were retrospectively reviewed. The patients were divided into group A (no fatty liver without alcohol history), group B (NAFLD), group C (AFLD) and group D (no fatty liver with alcohol history). The carotid IMT results were compared across all groups. The mean carotid IMT was 0.55 ± 0.1 mm for group A, 0.6 ± 0.1 mm for group B, 0.59 ± 0.1 mm for group C, and 0.54 ± 0.1 mm for group D. There were significant differences between groups A and B, groups A and C, and groups C and D (p < 0.05), but there were no differences between groups B and C (p = 0.736). We determined that patients with fatty livers have an increased carotid IMT both in NAFLD and AFLD patients.


Genomic Epidemiology and Active Surveillance to Investigate Outbreaks of Hantaviruses.
Emerging and re-emerging RNA viruses pose significant public health, economic, and societal burdens. Hantaviruses (genus Orthohantavirus, family Hantaviridae, order Bunyavirales) are enveloped, negative-sense, single-stranded, tripartite RNA viruses that are emerging zoonotic pathogens harbored by small mammals such as rodents, bats, moles, and shrews. Orthohantavirus infections cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome in humans (HCPS). Active targeted surveillance has elucidated high-resolution phylogeographic relationships between patient- and rodent-derived orthohantavirus genome sequences and identified the infection source by temporally and spatially tracking viral genomes. Active surveillance of patients with HFRS entails 1) recovering whole-genome sequences of Hantaan virus (HTNV) using amplicon (multiplex PCR-based) next-generation sequencing, 2) tracing the putative infection site of a patient by administering an epidemiological questionnaire, and 3) collecting HTNV-positive rodents using targeted rodent trapping. Moreover, viral genome tracking has been recently performed to rapidly and precisely characterize an outbreak from the emerging virus. Here, we reviewed genomic epidemiological and active surveillance data for determining the emergence of zoonotic RNA viruses based on viral genomic sequences obtained from patients and natural reservoirs. This review highlights the recent studies on tracking viral genomes for identifying and characterizing emerging viral outbreaks worldwide. We believe that active surveillance is an effective method for identifying rodent-borne orthohantavirus infection sites, and this report provides insights into disease mitigation and preparedness for managing emerging viral outbreaks.