The COVID-19 pandemic as experienced by adults with congenital heart disease from Belgium, Norway, and South Korea: impact on life domains, patient-reported outcomes, and experiences with care.
The coronavirus disease-2019 (COVID-19) pandemic poses significant challenges to many groups within societies, and especially for people with chronic health conditions. It is, however, unknown whether and how the pandemic has thus far affected the physical and mental health of patient populations. Therefore, we investigated how the pandemic affected the lives of adults with congenital heart disease (CHD), compared pre- and peri-pandemic patient-reported outcome measures (PROMs) and a patient-reported experience measure (PREM), and investigated whether having had COVID-19 impacted pre-/peri-pandemic differences of the PROMs and PREM. As part of the ongoing APPROACH-IS II project, we longitudinally surveyed 716 adults with CHD from Belgium, Norway, and South Korea. Pre-pandemic measures were administered from August 2019 to February 2020 and the peri-pandemic surveys were completed September 2020-April 2021. The majority of patients indicated that their social lives (80%), mental health (58%), and professional lives/education (51%) were negatively impacted by the pandemic. Patients felt worried (65%), were afraid (55%), reported the pandemic felt 'close' to them (53%), and were stressed (52%). However, differences between pre- and peri-pandemic scores on the PROMs and PREM were negligibly small (Cohen's d < 0.20). Across measures, 5.8-15.8% of patients demonstrated changes (improved or worsened scores) that exceeded the minimal clinically important difference. There were no difference-in-differences for PROMs and PREM between patients who did vs. did not have COVID-19. Although the COVID-19 pandemic has been disruptive in many ways, pre- to peri-pandemic changes in PROMs and PREM of adults with CHD were negligibly small.


Evaluation and Characterization of Ultrathin Poly(3-hydroxybutyrate) Fibers Loaded with Tetraphenylporphyrin and Its Complexes with Fe(III) and Sn(IV).
The effect of small additions (1-5 wt.%) of tetraphenylporphyrin (TPP) and its complexes with Fe (III) and Sn (IV) on the structure and properties of ultrathin fibers based on poly(3-hydroxybutyrate) (PHB) has been studied. A comprehensive study of biopolymer compositions included X-ray diffraction (XRD), differential scanning calorimetry (DSC), spin probe electron paramagnetic resonance method (EPR), and scanning electron microscopy (SEM). It was demonstrated that the addition of these dopants to the PHB fibers modifies their morphology, crystallinity and segmental dynamics in the amorphous regions. The annealing at 140 °C affects crystallinity and molecular mobility in the amorphous regions of the fibers, however the observed changes exhibit multidirectional behavior, depending on the type of porphyrin and its concentration in the fiber. Fibers exposure to an aqueous medium at 70 °C causes a nonlinear change in the enthalpy of melting and challenging nature of a change of the molecular dynamics.


Absence of a coding region for the helper component-proteinase in the genome of cucumber vein yellowing virus, a whitefly-transmitted member of the Potyviridae.
The complete nucleotide sequence of isolates of Cucumber vein yellowing virus (CVYV) has been determined. The viral genome comprises 9734 nucleotides, excluding a 3'-terminal poly(A) sequence. The genome of CVYV has a 5'-non coding and a 3' non coding region of respectively 67 and 240 nucleotides. The RNA of CVYV encodes a single polyprotein of 3148 amino acid residues and has a deduced genome organization and motifs typical for a member of the family Potyviridae. However, CVYV is atypical because it lacks a coding sequence region for the putative helper-component as well as conserved helper-component-proteinase motifs which may account for its vector relations. All the present coding regions were compared to those from several members of the Potyviridae family. CVYV is most closely related to Sweetpotato mild mottle virus confirming its assignation to the genus Ipomovirus, despite similarities with tritimoviruses.


Chlorogenic acid suppresses lipopolysaccharide‑induced nitric oxide and interleukin‑1β expression by inhibiting JAK2/STAT3 activation in RAW264.7 cells.
Chlorogenic acid (CA) is a phenolic compound purified from coffee, fruits and their associated beverages, which possess various biological properties, such as antioxidant and anticarcinogenic activities. The present study evaluated the effects of CA on lipopolysaccharide (LPS)‑induced inflammation in RAW264.7 cells and the associated intracellular signaling pathways using reverse transcription‑quantitative polymerase chain reaction, western blotting and enzyme‑linked immunosorbent assays. CA pretreatment inhibited LPS‑induced expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and pro‑inflammatory mediators including interleukin (IL)‑6, tumor necrosis factor‑α (TNF‑α), macrophage inflammatory protein‑2 (MIP‑2) and IL‑1β in RAW264.7 cells. In addition, phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) with LPS was inhibited by CA pretreatment. CA and STAT3 inhibitor (STAT3i) pretreatment inhibited LPS‑induced nuclear translocation of phosphorylated STAT3. In addition, STAT3i inhibited the LPS‑induced expression of iNOS, NO and IL‑1β similar to the results of CA pretreatment. By contrast, STAT3i did not inhibit the LPS‑induced increase in IL‑6, TNF‑α and MIP‑2 expression. These results indicate that CA may suppress LPS‑induced NO and IL‑1β expression by inhibiting JAK2/STAT3 activation in RAW264.7 cells.


Phosphate binder therapy for attainment of K/DOQI bone metabolism guidelines.
Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca x P) product less than 55 mg(2)/dL(2), intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO(3)) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca x P product, and HCO(3) in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis.


Host-dependent transposon Tn5-mediated streptomycin resistance.
Transposon Tn5 encodes streptomycin resistance in addition to kanamycin-neomycin resistance. This resistance was not detectable in Escherichia coli but was efficiently expressed in Rhizobium meliloti and certain other strains. By analysis of cloned Tn5 restriction endonuclease fragments, the streptomycin resistance (str) gene was located in the right-hand side of the central region as the transposon is conventionally drawn. Transcription of str appeared to originate at pL, the promoter for the neo gene (neomycin phosphotransferase type II). Expression of streptomycin resistance in E. coli was obtained after cloning of the neo-str region downstream of a strong E. coli promoter. A construct in which PL was deleted also showed differential expression of streptomycin resistance.


Enhancing relationships in long-term care: through story sharing.
Relationships between staff and residents in long-term care (LTC) are foundational to quality of life and high standards of care. Although nurse aides (NAs) provide more than 80% of personal care to nursing home residents, little research has focused on the NA-resident relationship or how NAs come to know and connect with their residents. This interpretive phenomenological study explored how a Story Sharing intervention initiates and enhances this relationship. Following the Story Sharing intervention, 84 volunteer NAs and 54 residents in six nursing homes were interviewed over a 6-month period. Analysis of these interviews revealed 9 patterns and 25 themes that describe how NAs and residents interact every day, along with innovative NA best practices. One theme, exemplifying a best practice, Restoring the Reciprocity of Care, is given. The findings have been incorporated into an extended Story Sharing Program for all LTC staff.


APE1 and XRCC3 polymorphisms and myocardial infarction.
In most cells, DNA is regularly damaged by mutagens. Different DNA repair mechanisms operate on specific types of damaged DNA. When DNA damage resulting from free radicals is not repaired, it might lead to deteriorated gene expression, the development of a number of diseases such as cancer, diabetes, vascular diseases, and aging. In the present study, APE1 and XRCC3 gene polymorphisms were investigated in patients with myocardial infarction. Forty-five first time elective coronary artery bypass grafting (CABG) patients with cardiopulmonary bypass (CPB) and 40 healthy individuals were studied. Gene polymorphisms were determined by a polymerase chain reaction-restriction fragment length polymorphism method. For the APE1 gene, the AG genotype was significantly higher in the patient group than in the control group. The patient group had significantly more G carriers but there was no statistically significant difference between patient and control groups the A allele. The XRCC3 TT genotype was found to be significantly more frequent in the patient group than it was in the control group. The results of our study suggested that the XRCC3 gene TT genotype and the APE1 gene AG genotype might increase the risk of myocardial infarcts.


Deleterious effects of osteoarthritis on the structure and function of the meniscal enthesis.
The ability of menisci to prevent osteoarthritis (OA) is dependent on the integrity of the complex meniscal entheses, the attachments of the menisci to the underlying subchondral bone (SB). The goal of this study was to determine mechanical and structural changes in meniscal entheses after the onset of OA. Healthy and osteoarthritic meniscal entheses were evaluated for changes in histomorphological characteristics, mineralization, and mechanical properties. Glycosaminoglycans (GAG) and calcium in the insertion were evaluated with histological staining techniques. The extent of calcium deposition was assessed and tidemark (TM) integrity was quantified. Changes in the mineralized zone of the insertion were examined using micro-computed tomography (μCT) to determine bone mineral density, cortical zone thickness, and mineralization gradient. Mechanical properties of the entheses were measured using nano-indentation techniques to obtain material properties based on viscoelastic analysis. GAG thickness in the calcified fibrocartilage (CFC) zone and calcium content were significantly greater in osteoarthritic anterior meniscal entheses. TM integrity was significantly decreased in OA tissue, particularly in the medial anterior (MA) enthesis. The mineralized zone of osteoarthritic meniscal entheses was significantly thicker than in healthy entheses and showed decreased bone mineral density. Fitting of mineralization data to a sigmoidal Gompertz function revealed a lower rate of increase in mineralization in osteoarthritic tissue. Analysis of viscoelastic mechanical properties revealed increased compliance in osteoarthritic tissue. These data suggest that significant changes occur at meniscal enthesis sites with the onset of OA. Mechanical and structural changes in meniscal entheses may contribute to meniscal extrusion, which has been shown to increase the progression of OA.


Peripheral motor nerve conduction studies in patients with chronic Chagas' disease.
A comprehensive investigation of nerve motor conduction velocity was carried out in the ulnar nerve of 70 patients in the chronic stage of Chagas disease. It was found that 2.6% of them, had slowness of the large motor axons at distal segments and 14% at proximal segments. Twenty seven percent of them had also slowness of conduction at the smallest motor fibers. These observations signal that some patients in the chronic stage of the infection may develop a motor neuropathy.


Lack of effect of atriopeptin II on rabbit glomerular arterioles in vitro.
This study was designed to determine if atriopeptin II (AP II) has any direct action on glomerular arterioles in vitro. Single superficial afferent or efferent arterioles were dissected from rabbit kidney, cannulated with micropipettes, and changes in lumen diameter were measured. The effect of AP II (10-(12)-10(-7) M) was tested alone or in arterioles precontracted with norepinephrine (3 X 10(-7) M, afferent) or angiotensin II (10(-10) M, efferent). By itself, AP II had no effect on lumen diameter in afferent or efferent arterioles, but both arterioles responded to 3 X 10(-7) M norepinephrine with 74 and 54% reductions in lumen diameter, respectively. Similarly, in norepinephrine-contracted afferent arterioles and angiotensin II-contracted efferent arterioles, AP II did not alter lumen diameter although acetylcholine (10(-6) M) produced near maximal relaxation of both arterioles. Furthermore, luminal addition of AP II (10(-7) M) had no effect on control lumen diameter or on the response to norepinephrine or angiotensin II. The preparation of AP II was biologically active since it caused dose-dependent increases in guanosine 3',5'-cyclic monophosphate levels in isolated rat glomeruli. These results suggest that the renal vascular effects of AP II observed in vivo are not due to a direct action on superficial glomerular arterioles but rather to an, as yet, unidentified indirect action of this peptide.


Cloning of human purine-nucleoside phosphorylase cDNA sequences by complementation in Escherichia coli.
We have obtained cDNA clones that contain the entire coding region of the human purine-nucleoside phosphorylase (PNP; EC 18.104.22.168) mRNA. The cDNA sequences were generated by reverse transcription of PNP-enriched mRNA obtained by immunoadsorption of HeLa cell polyribosomes with monospecific antibody to human PNP. cDNA molecules that were close in length to PNP mRNA were separated by agarose gel electrophoresis and inserted into the Pst I site of the plasmid pBR322. Plasmid DNA from the pooled clones was used to transform PNP-deficient Escherichia coli cells, and those transformants that phenotypically expressed PNP were isolated on selective media. The presence of human PNP in the selected bacterial cells was detected by immunoprecipitation with human PNP antibody.


Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.


Parametric bootstrap for testing model fitting of threshold and grouped data models: an application to the analysis of calving ease of Bruna dels Pirineus beef cattle.
The aim of this study was to compare the goodness of fit of the threshold models with homoscedasticity or heteroscedasticity and the grouped data model for the analysis of calving ease in beef cattle by using a parametric bootstrap procedure. Field data included 8,205 records of the Bruna dels Pirineus beef cattle breed in the Pyrenean mountain areas of Catalonia (Spain). The actual distribution was 81.81% of calvings without assistance, 11.02% slightly assisted by the farmer, 5.12% strongly assisted by the farmer, 0.89% assisted by the veterinarian, and 1.16% cesarean, but these percentages were very different in the different herds. This can be explained partially by the different subjective way of scoring of each farmer. Primiparous cows had a greater (P < 0.001) difficulty calving than cows with 5 or more parities (11.74 vs. 4.49% of calvings strongly assisted by the farmer or the veterinarian and 2.8 vs. 0.65% cesarean). Male calves caused greater (P < 0.001) calving difficulty than females (7.71% of male calvings strongly assisted by the farmer or the veterinarian vs. 4.25% of females and 1.83% cesarean in males vs. 0.47% in females). The month and year of calving also had a strong influence on calving ease. These data were analyzed using 3 different models: the threshold models with homoscedasticity or heteroscedasticity and the grouped data model. The bootstrap comparison among models suggested that the threshold models, even allowing for heteroscedasticity, did not fit the herd effects well. In contrast, fitting deficiencies were not observed for the grouped data model in any factor. The variance of direct effect of the calf was estimated using the 3 models, and the heritability estimate ranged from 0.165 for the grouped data model to 0.185 for the hereroscedastic threshold model. This heritability was moderate, but it would justify the inclusion of direct effects of the calf on calving ease in the breeding objective. Overall, results highlighted the flexibility of the grouped data model for the analysis of discrete traits, like calving ease of beef calves.


An investigation of collisional processes in a Dicke narrowed transition of water vapor in the 7.8 microm spectral region by frequency down-chirped quantum cascade laser spectroscopy.
Information about intermolecular potentials is usually obtained through the analysis of the absorption line shapes recorded in the frequency domain. This approach is also adopted to study the effects of motional narrowing and speed dependence of the pressure broadening coefficients. On the other hand, time domain measurements are directly related to molecular collisions and are therefore frequently employed to study molecular relaxation rates, as well as the effects of velocity changing collisions and the speed dependence of the absorption cross sections. Intrapulse quantum cascade laser spectrometers are able to produce both saturation and molecular alignment of the gas sample. This is due to the rapid sweep of the radiation through the absorption features. In the present work the frequency down-chirped radiation emitted by an intrapulsed quantum cascade laser operating near 7.8 mum is employed to investigate the collisional relaxation processes, and the collisional narrowing, in the 15(0,15)<--16(1,16) and 15(1,15)<--16(0,16) doublet in the water vapor nu(2) band. The effects of He, Ne, Ar, N(2), and CO(2) as collisional partners are investigated. The experimental results clearly indicate the dependence of the collisional cross sections upon the chirp rate. They also demonstrate that by using different chirp rates it is possible to gain information about the intermolecular processes driving the molecular collisions and the related energy transfer.


[Changes in blood pressure and cardiac contraction frequency in diabetes mellitus patients in an orthostatic posture and under physical load].
The author studied the character of changes in arterial pressure (AP) and rate of cardiac contractions (RCC) in the orthostatic position and during physical exercise in 93 patients with diabetes mellitus. A considerable decrease in systolic AP was noted in the orthostatic position, particularly in the first minutes and in individuals of the older age group, while the diastolic pressure showed no essential changes. The RCC at rest and its gradual increase in the orthostatic position were higher in patients with diabetes mellitus than in healthy individuals. In patients with neuro- and nephropathy the diastolic and systolic AP decreased in the orthostatic position; the RCC in patients with neuropathy hardly changed in this case. The capacity for physical exertion in diabetic patients, particularly in those with neuropathy was low. The degree of growth in RCC and in systolic AP was less in the patients than in healthy individuals. The increase in systolic AP and RCC in patients with neuropathy, however, was greater than that in the other groups of patients. The disorders in cardiovascular regulations which were revealed in some of the patients suggest that affections of the vegetative nervous system may also develop in the absence of affection of the peripheral nerves.


Measurement of the Optic Nerve Sheath Diameter in Children: Comparison Between Transbulbar Sonography and Magnetic Resonance Imaging.
To evaluate the accuracy of measurements of the optic nerve sheath diameter (ONSD) in children by comparing transbulbar sonography with magnetic resonance imaging (MRI). 65 children (age: 3 mo- 17y; mean age: 11.3y) underwent MR imaging of the brain including a heavily T 2-w sequence of the orbit and transbulbar sonography using a 17 MHz linear array transducer. Measurements of the ONSD were performed retrospectively by two experienced readers and all images were evaluated regarding the image quality. Bland-Altman Plots were produced to assess the accuracy of measurements. The correlation between readers and between MR imaging and transbulbar sonography was calculated by the concordance correlation coefficient (CCC). Overall the mean values of the ONSD for MRI (5.86 ± 0.66 mm) and transbulbar sonography (5.86 ± 0.71 mm) were identical. There was a high correlation between readers for measurements of the ONSD both for transbulbar sonography (CCC = 0.93) as well as for MRI (CCC = 0.9). Comparing the measurement values between transbulbar sonography and MRI, the correlation of ONSD values was good to moderate with a high dependency on image quality (CCC [0.31, 0.68]). We were able to demonstrate that the ONSD values of transbulbar sonography in children correlate well with MRI if the relevant anatomic structures are depicted and the measuring points are set correctly. Based on the findings of our study, it seems necessary to define normal and cut-off values for the ONSD in children again to finally assess the clinical relevance of the ONSD as a noninvasive parameter for the evaluation of intracranial pressure.


The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice.
During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. SIGNIFICANCE STATEMENT: Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.


Two distinct modes of guidance signalling during collective migration of border cells.
Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells, whereas cells of the fish lateral line, Drosophila tracheal tubes and border-cell clusters migrate as more coherent groups. Here we use Drosophila border cells to examine how collective guidance is performed. We report that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cgamma are used redundantly, and we find that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group.


C-terminal peptides modelling constitutive PrPC processing demonstrate ameliorated toxicity predisposition consequent to α-cleavage.
Misfolding of PrPC (cellular prion protein) to β-strand-rich conformations constitutes a key event in prion disease pathogenesis. PrPC can undergo either of two constitutive endoproteolytic events known as α- and β-cleavage, yielding C-terminal fragments known as C1 and C2 respectively. It is unclear whether C-terminal fragments generated through α- and β-cleavage, especially C2, influence pathogenesis directly. Consequently, we compared the biophysical properties and neurotoxicity of recombinant human PrP fragments recapitulating α- and β-cleavage, namely huPrP-(112-231) (equating to C1) and huPrP-(90-231) (equating to C2). Under conditions we employed, huPrP-(112-231) could not be induced to fold into a β-stranded isoform and neurotoxicity was not a feature for monomeric or multimeric assemblies. In contrast, huPrP-(90-231) easily adopted a β-strand conformation, demonstrated considerable thermostability and was toxic to neurons. Synthetic PrP peptides modelled on α- and β-cleavage of the unique Y145STOP (Tyr145→stop) mutant prion protein corroborated the differential toxicity observed for recombinant huPrP-(112-231) and huPrP-(90-231) and suggested that the persistence of soluble oligomeric β-strand-rich conformers was required for significant neurotoxicity. Our results additionally indicate that α- and β-cleavage of PrPC generate biophysically and biologically non-equivalent C-terminal fragments and that C1 generated through α-cleavage appears to be pathogenesis-averse.


Phase-Engineered WS2 Monolayer Quantum Dots by Rhenium Doping.
Transition metal dichalcogenides (TMDs) occur in the thermodynamically stable trigonal prismatic (2H) phase or the metastable octahedral (1T) phase. Phase engineering of TMDs has proven to be a powerful tool for applications in energy storage devices as well as in electrocatalysis. However, the mechanism of the phase transition in TMDs and the synthesis of phase-controlled TMDs remain challenging. Here we report the synthesis of Re-doped WS2 monolayer quantum dots (MQDs) using a simple colloidal chemical process. We find that the incorporation of a small amount of electron-rich Re atoms in WS2 changes the metal-metal distance in the 2H phase initially, which introduces strain in the structure (strained 2H (S2H) phase). Increasing the concentration of Re atoms sequentially transforms the S2H phase into the 1T and 1T' phases to release the strain. In addition, we performed controlled experiments by doping MoS2 with Re to distinguish between Re and Mo atoms in scanning transmission electron microscopy images and quantified the concentration range of Re atoms in each phase of MoS2, indicating that phase engineering of WS2 or MoS2 is possible by doping with different amounts of Re atoms. We demonstrate that the 1T' WS2 MQDs with 49 at. % Re show superior catalytic performance (a low Tafel slope of 44 mV/dec, a low overpotential of 158 mV at a current density of 10 mA/cm2, and long-term durability up to 5000 cycles) for the hydrogen evolution reaction. Our findings provide understanding and control of the phase transitions in TMDs, which will allow for the efficient manufacturing and translation of phase-engineered TMDs.


Turtle origins: insights from phylogenetic retrofitting and molecular scaffolds.
Adding new taxa to morphological phylogenetic analyses without substantially revising the set of included characters is a common practice, with drawbacks (undersampling of relevant characters) and potential benefits (character selection is not biased by preconceptions over the affinities of the 'retrofitted' taxon). Retrofitting turtles (Testudines) and other taxa to recent reptile phylogenies consistently places turtles with anapsid-grade parareptiles (especially Eunotosaurus and/or pareiasauromorphs), under both Bayesian and parsimony analyses. This morphological evidence for turtle-parareptile affinities appears to contradict the robust genomic evidence that extant (living) turtles are nested within diapsids as sister to extant archosaurs (birds and crocodilians). However, the morphological data are almost equally consistent with a turtle-archosaur clade: enforcing this molecular scaffold onto the morphological data does not greatly increase tree length (parsimony) or reduce likelihood (Bayesian inference). Moreover, under certain analytic conditions, Eunotosaurus groups with turtles and thus also falls within the turtle-archosaur clade. This result raises the possibility that turtles could simultaneously be most closely related to a taxon traditionally considered a parareptile (Eunotosaurus) and still have archosaurs as their closest extant sister group.


Heritable variation in courtship patterns in Drosophila melanogaster.
Little is known about the genetic basis of naturally occurring variation for sexually selected behavioral traits. Drosophila melanogaster, with its rich repertoire of courtship behavior and genomic and genetic resources, is an excellent model organism for addressing this question. We assayed a genetically diverse panel of lines with full genome sequences, the Drosophila Genetic Reference Panel, to assess the heritability of variation in courtship behavior and mating progression. We subsequently used these data to quantify natural variation in transition probabilities between courtship behaviors. We found heritable variation along the expected trajectory for courtship behaviors, including the tendency to initiate courtship and rate of progression through courtship, suggesting a genetic basis to male modulation of courtship behavior based on feedback from unrelated, outbred, and genetically identical females. We assessed the genetic basis of variation of the transition with the greatest heritability--from copulation to no engagement with the female--and identified variants in Serrate and Furin 1 as well as many other polymorphisms on the chromosome 3R associated with this transition. Our findings suggest that courtship is a highly dynamic behavior with both social and genetic inputs, and that males may play an important role in courtship initiation and duration.


Interactions of small molecules with DNA junctions.
The four natural DNA bases (A, T, G and C) associate in base pairs (A=T and G≡C), allowing the attached DNA strands to assemble into the canonical double helix of DNA (or duplex-DNA, also known as B-DNA). The intrinsic supramolecular properties of nucleobases make other associations possible (such as base triplets or quartets), which thus translates into a diversity of DNA structures beyond B-DNA. To date, the alphabet of DNA structures is ripe with approximately 20 letters (from A- to Z-DNA); however, only a few of them are being considered as key players in cell biology and, by extension, valuable targets for chemical biology intervention. In the present review, we summarise what is known about alternative DNA structures (what are they? When, where and how do they fold?) and proceed to discuss further about those considered nowadays as valuable therapeutic targets. We discuss in more detail the molecular tools (ligands) that have been recently developed to target these structures, particularly the three- and four-way DNA junctions, in order to intervene in the biological processes where they are involved. This new and stimulating chemical biology playground allows for devising innovative strategies to fight against genetic diseases.


You never transition alone! Exploring the experiences of youth with chronic health conditions, parents and healthcare providers on self-management.
Recent evidence suggests that fostering strategies to enable youth with chronic health conditions to work towards gradual self-management of their health is key in successful transition to adult healthcare. To date, there is limited research on self-management promotion for youth. The purpose of this study is to explore self-management from the perspectives of youth, parents and healthcare providers in transition to adult healthcare. Part of a larger longitudinal transition (TRACE-2009-2013) study, interpretive phenomenology was used to explore the meaning of the lived experiences and perceptions of youth, parents, and healthcare providers about transition to adult healthcare. Purposeful sampling was utilized to select youth with a range of chronic health conditions from the TRACE cohort (spanning 20 diagnoses including developmental disabilities and chronic conditions), their parents and healthcare providers. The emerging three themes were: increasing independence of youth; parents as safety nets and healthcare providers as enablers and collaborators. The findings indicate that the experiences of transitioning youth, parents and service providers are interconnected and interdependent. Results support a dynamic and developmentally appropriate approach when working with transitioning youth and parents in practice. As youth depend on parents and healthcare providers for support in taking charge of their own health, parents and healthcare providers must work together to enable youth for self-management. At a policy level, adequate funding, institutional support and accreditation incentives are recommended to allow for designated time for healthcare providers to foster self-management skills in transitioning youth and parents.


Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.
DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease. However, no information on the induction and processing of DSBs after physiologically relevant radiation doses is available. Many of the methods used to measure DSB repair inadvertently introduce this form of damage as part of the methodology, and hence are limited in their sensitivity. Here we present evidence that foci of gamma-H2AX (a phosphorylated histone), detected by immunofluorescence, are quantitatively the same as DSBs and are capable of quantifying the repair of individual DSBs. This finding allows the investigation of DSB repair after radiation doses as low as 1 mGy, an improvement by several orders of magnitude over current methods. Surprisingly, DSBs induced in cultures of nondividing primary human fibroblasts by very low radiation doses (approximately 1 mGy) remain unrepaired for many days, in strong contrast to efficient DSB repair that is observed at higher doses. However, the level of DSBs in irradiated cultures decreases to that of unirradiated cell cultures if the cells are allowed to proliferate after irradiation, and we present evidence that this effect may be caused by an elimination of the cells carrying unrepaired DSBs. The results presented are in contrast to current models of risk assessment that assume that cellular responses are equally efficient at low and high doses, and provide the opportunity to employ gamma-H2AX foci formation as a direct biomarker for human exposure to low quantities of ionizing radiation.


Adrenergic signaling and oxidative stress: a role for sirtuins?
The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure.


Assessment of prenatal exposure to persistent organohalogen compounds from cord blood serum analysis in two Mediterranean populations (Valencia and Menorca).
Prenatal levels of organohalogen compounds (OHCs), including polybromodiphenyl ethers (PBDEs), polychlorobiphenyls (PCBs), hexachlorobenzene (HCB), hexachlorocyclohexanes and DDTs, have been investigated in two different cohorts from the Spanish Mediterranean area, Valencia and Menorca, by analysis of cord blood serum. Comparison of the observed median concentrations to other cohorts shows low PBDE levels (2.8-6.5 ng g(-1) lipid) but high values of HCB (0.68 ng ml(-1), 260 ng g(-1) lipid) and PCBs (0.65 ng ml(-1), 240 ng g(-1) lipid) in the cohort of Menorca indicating that Mediterranean areas, and not only high latitude regions, may contain population groups highly exposed to some of these pollutants. Significant differences in the concentrations of these compounds have been found between the two cohorts. Differences in maternal population such as age or body mass index cannot explain this variation. One possible cause of variability is the seven year time period elapsed between the two cohort recruitments but the strong differences observed do not allow exclusion of local diet differences. Thus, the different average PCB congener distributions between the two cohorts suggest an influence from materials containing diverse PCB mixtures. The congener mixtures found in Menorca could reflect a diet contribution from some western Mediterranean fish species. These results provide baseline information on prenatal OHC background levels in the Mediterranean area.


Adrenal and Hepatic Venous Sampling in a Case of Aldosterone-Producing Adrenocortical Carcinoma with Hepatic Metastasis.
Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. ACCs often secrete adrenal steroid hormones including cortisol and androgens; however, aldosterone-producing ACC is very rare. Although adrenal production of aldosterone is assessed by adrenal venous sampling, the use of sampling from the relevant vein to assess aldosterone production from a tumor arising from ACC metastasis has not been previously reported. Case Presentation. We report the case of a 69-year-old Japanese man with aldosterone-producing ACC with hepatic metastasis. He presented with a history of treatment-resistant hypertension and hypokalemia. Endocrinological examination showed markedly increased plasma aldosterone concentration and suppressed plasma renin activity. Serum cortisol concentration was not suppressed by administration of dexamethasone 1 mg, and normal circadian variation of cortisol secretion was disrupted. Abdominal computed tomography showed a large tumor in the left adrenal gland and multiple tumors in the liver. Together, these results strongly suggested ACC with multiple liver metastases causing primary aldosteronism and subclinical Cushing syndrome. Adrenal and hepatic venous sampling showed markedly increased aldosterone concentration in the left adrenal vein but no increase in the hepatic vein, despite a pathological diagnosis of ACC with hepatic metastasis, with immunohistochemical investigation showing both primary and secondary tumors to have synthetic capability for aldosterone. The patient received mitotane but declined combination chemotherapy and died 2 months later. This is the first report of adrenal and hepatic venous sampling in a case of aldosterone-producing ACC with hepatic metastasis. The case suggests that hepatic venous sampling is unable to detect aldosterone production from liver metastases arising from ACC.


Post-transplant persistent lymphopenia is a strong predictor of late survival in isolated intestine and multivisceral transplantation.
Absolute lymphocyte count (ALC) has been identified as a prognostic factor in liver transplantation. We hypothesized that a lower ALC may be linked to poor outcomes in isolated intestinal/multivisceral transplantation (IIT/MVT). The aim of this study was to investigate the prognostic impact of ALC in IIT/MVT. A total 141 IIT/MVT patients were eligible for the study. Post-transplant ALCs (at 3, 6, and 12 months) were evaluated, and prognostic impact of trend of ALC during the first year was investigated. Of these 141 patients, 108 patients survived in the first year (1-year survivors). One-year survivors were categorized according to post-transplant ALC at each time point. When ALC was decreased throughout the first year (post-transplant persistent lymphopenia: <500/μl at 3, 6, and 12 months), patient survival (P < 0.001, hazard ratio = 5.09) and graft survival (P < 0.001, hazard ratio = 5.15) after the first year was significantly worse, and this remained to be an independent risk factor. Negative impact of persistent lymphopenia on patient and graft survival was significant regardless of type of intestinal graft. Infection leading to mortality occurred more frequently in the persistent lymphopenia group (43% vs. 24%). Trend of post-transplant ALC may be a strong predictive marker for long-term outcome in 1-year survivors after IIT/MVT.


Identification of Behavior Change Techniques From Successful Web-Based Interventions Targeting Alcohol Consumption, Binge Eating, and Gambling: Systematic Review.
Web-based interventions are thought to overcome barriers to treatment, such as accessibility and geographical location, which can undermine the effectiveness of traditional face-to-face interventions. Owing to these features, researchers are increasingly testing the efficacy of web-based interventions as ways to reduce alcohol misuse, binge eating, and gambling. However, many web-based interventions have poorly defined mechanisms of action; therefore, it is often uncertain how they propose to bring about behavior change. This systematic review aims to identify effective behavior change techniques (BCTs) present in web-based interventions aimed at reducing alcohol consumption, binge eating, or gambling. This systematic review covered research conducted in the last 20 years. Inclusion criteria for interventions were web-based administration; targeting alcohol use, binge eating, and/or gambling; and reporting on baseline and postintervention measures of behavior. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were followed. We coded intervention effectiveness, study quality, and BCTs present in the interventions. Following removal of 4152 ineligible articles, 45 were included in the review: 32 (71%) targeted alcohol misuse, 6 (13%) targeted binge eating, and 7 (16%) targeted gambling. In total, 5 frequency counts were performed to identify the most commonly used BCTs: all studies, effective interventions, high-quality studies at 2 thresholds, and both high quality and effective studies. The results obtained from this were integrated to identify 7 BCTs. These 7 BCTs were problem solving, feedback on behavior, self-monitoring of behavior, self-monitoring of outcomes, instruction on how to perform a behavior, information about social and health consequences, and social comparison. A total of 4 BCTs were found in all frequency counts: feedback on behavior, self-monitoring of behavior, instruction on how to perform a behavior, and social comparison. Self-monitoring of outcomes of behavior was found in 3 of the 5 frequency counts, problem solving was found in 2 frequency counts, and information about social and health consequences was found in 1 frequency count. This systematic review identified 7 of the most frequently used BCTs used in web-based interventions focused on alcohol misuse, binge eating, and gambling. These results can inform the development of evidence-based eHealth interventions that have the potential to lead to effective, positive behavior changes in all 3 areas.


Development of flight and foraging behaviour in a juvenile seabird with extreme soaring capacities.
The early life of animals is a period of high mortality, when foraging capacities are assumed to be improved progressively. In birds, this critical period involves the improvement of the flight. How do young birds gain these capacities has rarely been studied in natural conditions especially in seabirds that spend most of their life at sea. We used detailed GPS and body acceleration data on 37 great frigatebirds (Fregata minor), to test the hypothesis that juveniles starting their first flights have lower flying capacities than adults, but that these capacities will improve during a long learning period, before independence from parents, specific to this seabird that can spend months on the wing at sea. We found that most flight components improved over time to tend towards those of adults, especially the travel speed, range, duration and maximum altitude of trips. However, unexpectedly, juveniles had higher ascent rates, soaring and gliding capacities above the sea than adults. Moreover, energy expenditure of juveniles was similar to adults during low cost travelling movements and during active foraging, but juveniles spent more time foraging actively than adults. Our results suggest that flight tactics based on long-distance effortless movements specific to this family are acquired during a long period, but soaring and gliding capacities are already inherited by juveniles and possibly favoured by morphological adaptations specific to juveniles. These adaptations might explain the extreme dispersive capacities of juveniles.


Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.
Cyclin-dependent kinase-6 (CDK6) is the earliest inducible member of the CDK family in human T lymphocytes, involved in growth factor stimulation and cell cycle progression. CDK6 is one of the targets of p16 and p15, CDK inhibitors encoded by MTS1 and MTS2, two tumor suppressor genes that are frequently deleted in T-cell leukemia. In this study we have investigated CDK6 expression in normal and neoplastic lymphoid tissues using immunohistochemistry and flow cytometry. In normal (six samples) and hyperplastic (four samples) thymuses, strong CDK6 expression was observed in a discrete proportion of cortical thymocytes (10 to 15%), mainly located in the peripheral (subcapsular) zone of the cortex. All tested cases of T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) showed strong CDK6 expression in the majority (up to 100%) of neoplastic lymphoid cells. Western blot analysis confirmed the expected CDK6 protein size (40 kd). According to Southern blot analysis, CDK6 overexpression in neoplastic T lymphoblasts was not due to gene amplification. In all other lymphomas investigated (28 peripheral T-cell non-Hodgkin's lympohomas (T-NHLs), 7 CD30+ anaplastic NHLs, 22 high-grade B-NHLs, 15 low-grade B-NHLs, 25 B-cell precursor ALLs), CDK6 was not expressed or expressed at low levels, with the only exception of three nasal angiocentric T-NHLs, all exhibiting CDK6 immunoreactivity comparable to that observed in T-LBL/ALL. These data provide evidence that CDK6 is abnormally expressed in T-LBL/ALL and may be involved in the pathogenesis of this malignancy. In addition, the quantitative difference of CDK6 expression between neoplastic and non-neoplastic cortical thymocytes can be potentially useful in the differential diagnosis of thymic neoplasms on histological and cytological specimens.


Limitations on space flight due to cosmic radiations.
These conclusions (10) may be summarized as follows: 1) Flight below the Van Allen belts seems reasonably safe without radiation shielding. 2) It is probably impractical to shield a rocket sufficiently to permit a man to remain in the inner Van Allen belt for more than about an hour, but it should be possible for him to go through it without serious harm. 3) Shielding for the outer Van Allen belt is possible but would have to be quite heavy if a stay of more than a few hours were contemplated. 4) The primary cosmic radiation is not intense enough to deliver a serious radiation dose, even for exposures of a few weeks, and the heavy cosmic ray primaries do not seem to present an unusual hazard.


Alpha-lipoic acid induces adipose triglyceride lipase expression and decreases intracellular lipid accumulation in HepG2 cells.
Non-alcoholic fatty liver disease can be attributed to the imbalance between lipogenesis and lipolysis in the liver. Alpha-lipoic acid has been shown to activate the 5'-AMP-activated protein kinase (AMPK) signalling pathway and to effectively inhibit the lipogenesis pathway in liver. However, whether alpha-lipoic acid stimulates lipolysis remains unclear. Recently, adipose triglyceride lipase (ATGL) was shown to be responsible for triacylglycerol hydrolase activity in cells. In the present study, we established a fatty liver cell model by incubating HepG2 cells in a high glucose (30mM glucose) and high fat (0.1mM palmitate) medium. We found that the activation of the AMPK signalling pathway induced ATGL protein expression and enhanced lipid hydrolysis. Similarly, treatment of the fatty liver cell model with alpha-lipoic acid reduced intracellular lipid accumulation in HepG2 cells, increased AMPK phosphorylation, and induced ATGL expression. We showed that insulin phosphorylates the transcription factor forkhead box O1 (FOXO1), which regulates ATGL expression and inhibits FOXO1 translocation into the nucleus. In contrast, alpha-lipoic acid dephosphorylated FOXO1 and reversed the nuclear exclusion of FOXO1. These data suggest that alpha-lipoic acid can effectively ameliorate intracellular lipid accumulation and induce ATGL expression through the FOXO1/ATGL pathway in liver cells. Thus, alpha-lipoic acid may be a potential therapeutic agent for treating fatty liver disease.


Memories of being injured and patients' care trajectory after physical trauma.
The purpose of this study was to acquire a deeper understanding of patients' memories of being injured and the trajectory of care before, during and after their Intensive Care Unit (ICU) stay. Interviews were conducted with eighteen informants who after physical trauma had been cared for in the ICU. The interviews were analyzed by using a phenomenological hermeneutical method. The memories of injury during the trajectory of care are illustrated in a figure in which the injured informants have memories from five scenes; the scene of the accident, emergency unit, ICU, nursing ward and of coming home. Twelve subthemes were abstracted and four themes emerged; a surrealistic world, an injured body, care, and gratitude for life. After the accident, a "surrealistic world" appeared along with bad memories of being in a floating existence where plans had to be changed. This world was unfamiliar, sometimes including delusional and fragmentary memories from the ICU, and it was experienced as uncontrollable. They felt connected to an "injured body", experiencing bad memories from the ICU of being injured, from the nursing ward of simply enduring and of being in a No Man's Land when coming home; their lives had become limited. At the same time they were "connected to care" with good memories of receiving attention from others at the scene of the accident, being taken cared of at the emergency unit and cared for in the ICU. This care made them realise that people are responsible for each other, and they felt comforted but also vulnerable. Finally, they experienced "gratitude for life". This included good memories of being loved together with support from their families at the ICU, wanting to win life back at the nursing ward and acceptance when returning home. The support from their families made them realise that they fit in just as they are. When bad memories of a surrealistic world and of being injured are balanced by good ones of care and love with a gratitude for life, there are more possibilities to move on despite an uncertain future following the injury.


Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta.
Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b(-/-) mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b(-/-) mice are not yet clear, we have reported that Cbl-b(-/-) CD4(+)CD25(-) effector T cells (Teffs) are resistant to CD4(+)CD25(+) regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b(-/-) Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b(-/-) Teffs. Additionally, we show that Cbl-b(-/-) Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b(-/-) mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-beta sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b(-/-) mice are able to mount a normal Th17 response in vivo. As Cbl-b(-/-) Teffs have been shown to be insensitive to the suppressive effects of TGF-beta in other in vivo models, the present results suggest that Cbl-b(-/-) Teffs demonstrate a context-dependent sensitivity to TGF-beta in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b(-/-) mice offer unique approaches for studying the interrelationships between Treg function, TGF-beta-mediated responses, and the development of autoimmunity.


Age of first self-harm act in childhood and adolescence: A scoping review protocol.
Self-harm in youth is associated with adverse outcomes for many. The age of first self-harm is not often reported in the literature and there is considerable heterogeneity in how it is reported and in the methods used to estimate it. The objective of this study will be to examine the age of first self-harm act in childhood and adolescence and to identify the research methods used to assess this. This scoping review will follow JBI guidance. Five electronic databases, Medline, PsycInfo, CINAHL Plus, Embase, and Web of Science will be searched from inception. Grey literature will be searched via Google Scholar. Studies reporting the age of first act of self-harm in young people aged 17 years and younger are of interest. Any study design and methodology will be eligible for inclusion. Included studies may use any self-harm definition, any measures used to assess self-harm and the age of the first act. The focus can be in any context, including health services presenting or community samples. Title and abstract screening and full text screening will be carried out by two reviewers independently. The data extraction tool will be piloted by two reviewers independently, included studies will undergo data extraction by one reviewer and this will be checked by a second, independent reviewer. The resulting data will be presented using descriptive statistics, in tabular format, and accompanied with a narrative presentation of results. The results of this study will be distributed by publication in an academic journal.


Tuning the magnetism of gold nanoparticles by changing the thiol coating.
Room-temperature ferromagnetic behaviour has been reported in nanoscale materials expected to be diamagnetic, including gold. However, it is yet unclear which factors (size, shape, surface coating) predominantly influence the magnitude of the magnetic response. In this work, we study the magnetic and electronic properties of similarly-sized gold nanoparticles (Au NPs) coated with four different n-alkanethiols, as well as hydroxyl- and carboxyl-functionalized alkanethiols using superconducting quantum interference device (SQUID) magnetometry and ultraviolet photoelectron spectroscopy (UPS). We find room-temperature behaviour (hysteresis in magnetization vs. field strength loops) in all samples, as well as large effective magnetic anisotropy. Importantly, we find the nanoparticles coated with polar chain end-groups (-OH and -COOH) show markedly higher magnetization; this increased magnetization correlates with a higher work function. This work establishes chemical handles to enhance magnetism in nanoscale gold particles.


Mechanical activation and cement formation of beta-tricalcium phosphate.
The reactivity of acid base cements forming hydroxyapatite (HA) such as, tetracalcium phosphate, and dicalcium phosphate anhydride or dicalcium phosphate dihydrate, is normally adjusted by altering the particle size and hence the specific surface area of the compounds. Amorphous calcium phosphates, prepared by precipitation from supersaturated solutions, can also react to form apatitic cements since they are thermodynamic unstable with respect to HA and have a setting reaction more independent of particle size. In this report we show for the first time that prolonged high-energy ball milling of beta-tricalcium phosphate (beta-TCP), led to mechanically induced phase transformation from the crystalline to the amorphous state. The process increased the thermodynamic solubility of the beta-TCP compared to the unmilled material by up to nine times and accelerated the normally slow reaction with water. By using a 2.5% Na(2)HPO(4) solution setting times were reduced to 5-16min rather than hours. X-ray diffraction analyses indicated that the amorphous fraction within the materials was responsible for the primary setting reaction and hardening of the cements, while the crystalline fraction remained unreacted and converted only slowly to HA. Mechanically activated beta-TCP cements were produced with compressive and diametral tensile strengths of up to 50 and 7MPa respectively. The effect of preparation and setting parameters on the physical and chemical properties of mechanically activated beta-TCP cement was investigated.


High-Resolution Optical Coherence Tomography in the Differentiation of Inflammatory Versus Noninflammatory Peripheral Corneal Thinning.
To evaluate whether high-resolution optical coherence tomography (HR-OCT) can aid in differentiation of inflammatory versus noninflammatory causes of peripheral corneal thinning. Retrospective chart review of 10 patients with peripheral corneal thinning and their respective slit-lamp photographs and HR-OCT images. Ten patients were identified who had peripheral corneal thinning and HR-OCT images. Five had a clinical history consistent with Terrien marginal degeneration (TMD), whereas 5 had thinning believed to be inflammatory in origin. In the eyes with presumed TMD, patients denied pain or inflammation. HR-OCT images demonstrated stromal thinning in the presence of an intact epithelium. The stroma underneath the epithelium in the area of thinning had a similar reflectivity pattern as the nonaffected cornea. There was epithelial marsupialization evident in 2 of the 5 images. In the 4 patients with a clinical history of inflammation (bulbar hyperemia and pain), and in the 1 patient with active inflammation at the time of HR-OCT imaging, HR-OCT also demonstrated thinning with an intact epithelium. In contrast to the TMD group, in the group with signs of inflammation, a dense hyperreflective band was noted in the stroma directly below the epithelium in the area of thinning, suggestive of scarring and/or cellular infiltration. In patients with a clinical history of inflammation and corneal thinning, HR-OCT revealed a hyperreflective band directly under the epithelium in the area of thinning, which was not seen in patients with presumed noninflammatory melts and thinning.


[Minimally invasive extraction and immediate implant placement with single-stage surgical procedure: a clinical observation of 21 cases].
To evaluate the clinical results of minimally invasive extraction without flap reflection and immediate implant placement with single-stage surgical procedure. Twenty-one patients (23 single-tooth implants) were included in the study. Eight fractured teeth and 15 residual roots in the maxillary anterior region were extracted without flap reflection and implants placed immediately. Special gingival former was connected at the same time of implant placement with single-stage surgical procedure, final prostheses were restored after 6 months. The follow-up time was from 13 months to 51 months (mean: 27.6 months) after final restoration. Clinical and radiographic study were conducted, the interproximal papillae were analyzed according to Jemt's classification and the level of soft-tissue margin and buccal soft tissue color were evaluated according to Fürhauser's method. All 23 implants acquired osseointegration, and the level of marginal bone at the mesial and distal aspects of all implants were stable. The mesial and distal papilla index score of 3 were observed in 18 implant sites, the papilla index score of 2 in 5 implant sites. Harmonious relationship of gingival margin between peri-implant restorations and adjacent natural teeth was observed in 15 implant sites. The color of buccal soft tissue matched that of the adjacent natural teeth in 18 implant sites, 5 sites showed minor discrepancies. All the patients were satisfied with the final restoration. Minimally invasive extraction without flap reflection and immediate implant placement with single-stage surgical procedure is a sensitive technique. Many factors may affect the final results and the strict control of indication is the key factor.


Short-Term Change in Measures of Glycemia in Obese Youth Meeting Criteria for Prediabetes: A Retrospective Chart Review.
The prevalence of youth diagnosed with prediabetes is increasing, yet there is a lack of guidelines on how to manage this condition clinically. The aim was to determine the short-term outcomes of patients referred with prediabetes and to determine predictors of worsening dysglycemia in youth. This is a retrospective chart review of patients referred to our Youth Diabetes Prevention Clinic (YDPC) with laboratory tests indicating an increased risk for type 2 diabetes (T2D). We defined glycemic categories by HbA1c with normoglycemia as HbA1c <5.7%, prediabetes I (P1) as HbA1c 5.7 to <6.0%, and prediabetes II (P2) as HbA1c 6.0 to <6.5%. We compared HbA1c at the time of referral (screening HbA1c) and at the YDPC visit (YDPC HbA1c) to assess for improvement or worsening. Multinomial logistic regression was used to assess predictors of prediabetes. Among 562 patients seen, 336 had both screening and YDPC HbA1c values. Race (p < 0.001) and screening glycemic category (p < 0.001) were significantly associated with dysglycemia at the YDPC visit, while sex (p = 0.50), BMI z-score change (p = 0.27), and days from referral (p = 0.83) were not. As compared to those who reverted to normoglycemia, patients with prediabetes at YDPC were 7 times more likely to have a higher screening HbA1c (both P1 and P2). The majority of patients referred with prediabetes had lower HbA1c at the YDPC (75.4-82.6%). Patients with screening HbA1c <6% might benefit from a 4-month follow-up at primary care while recommending lifestyle changes. Patients of minority race and screening HbA1c ≥6% are more likely to have a persistent elevation of HbA1c.


Metal Dependence of the Xylose Isomerase from Piromyces sp. E2 Explored by Activity Profiling and Protein Crystallography.
Xylose isomerase from Piromyces sp. E2 (PirXI) can be used to equip Saccharomyces cerevisiae with the capacity to ferment xylose to ethanol. The biochemical properties and structure of the enzyme have not been described even though its metal content, catalytic parameters, and expression level are critical for rapid xylose utilization. We have isolated the enzyme after high-level expression in Escherichia coli, analyzed the metal dependence of its catalytic properties, and determined 12 crystal structures in the presence of different metals, substrates, and substrate analogues. The activity assays revealed that various bivalent metals can activate PirXI for xylose isomerization. Among these metals, Mn2+ is the most favorable for catalytic activity. Furthermore, the enzyme shows the highest affinity for Mn2+, which was established by measuring the activation constants (Kact) for different metals. Metal analysis of the purified enzyme showed that in vivo the enzyme binds a mixture of metals that is determined by metal availability as well as affinity, indicating that the native metal composition can influence activity. The crystal structures show the presence of an active site similar to that of other xylose isomerases, with a d-xylose binding site containing two tryptophans and a catalytic histidine, as well as two metal binding sites that are formed by carboxylate groups of conserved aspartates and glutamates. The binding positions and conformations of the metal-coordinating residues varied slightly for different metals, which is hypothesized to contribute to the observed metal dependence of the isomerase activity.


Plasticity of the different neuropeptide-containing nerve fibres in the tongue of the diabetic rat.
Common oral complications of diabetes mellitus are xerostomia, impairment of taste, atrophic lesions of the tongue, leukoplakia, lichen oris planus, and tumours, which might be the consequence of chronic inflammation and changes in innervation. In this work, we examined the density of different neuropeptide-containing nerve fibres immunohisto- and immunocytochemically in the root of the control and diabetic rat's tongue. Quantitative analysis showed that the number of immunoreactive (IR) nerve fibres was decreased after 1 week of the streptozotocin treatment, which was prevented by immediate insulin treatment. However, after 4 weeks duration of diabetes, the number of all investigated IR nerve fibres increased significantly (p<0.05), which was further enhanced by the delayed insulin treatment. The numbers of substance P (SP) and vasoactive intestinal polypeptide IR perikarya were also increased by insulin treatment. The electron-microscopic investigations showed that some of the nerve terminals from diabetic animals were found in degeneration. After 4 weeks duration of diabetes, the number of inflammatory cells as well as the mast cell/nerve fibre contacts was also increased. The immunocells also showed IR for SP and neuropeptide Y in the diabetic rats. The insulin treatment decreased both the number and the immunoreactivity of these cells. The increased synthesis and/or regeneration of neuropeptide-containing nerves might indicate the plasticity of nerve fibres in diabetes mellitus, which might happen as a consequence of the changes in the level of neurotrophic factors released by increased number of inflammatory cells or as an effect of insulin.


Large scale studies with vitamin C.
The combination of a regular daily supplement of vitamin C with extra dosage at the time of illness has been shown to reduce the disability due to common colds and other winter illness, but we have seen little effect on frequency of infections, sense of (well-being), or levels of serum cholesterol. The variable results that have been obtained from some other trials of vitamin C may be due in part to variation in the initial nutritional state of the subjects, with the greatest effects to be expected where there is most room for improvement. Because of the great variation in individual susceptibility to infection large numbers of subjects are required in these trials and they must be strictly double-blind. Although we have seen no clear evidence of harmful side-effects, occasional sensitivity to large doses of vitamin C cannot be ruled out, and the withdrawal depression of blood levels could conceivably interfere with a patient's ability to handle stress.


TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation.
TSG-6 is an inflammation-induced protein that is produced at pathological sites, including arthritic joints. In animal models of arthritis, TSG-6 protects against joint damage; this has been attributed to its inhibitory effects on neutrophil migration and plasmin activity. Here we investigated whether TSG-6 can directly influence bone erosion. Our data reveal that TSG-6 inhibits RANKL-induced osteoclast differentiation/activation from human and murine precursor cells, where elevated dentine erosion by osteoclasts derived from TSG-6(-/-) mice is consistent with the very severe arthritis seen in these animals. However, the long bones from unchallenged TSG-6(-/-) mice were found to have higher trabecular mass than controls, suggesting that in the absence of inflammation TSG-6 has a role in bone homeostasis; we have detected expression of the TSG-6 protein in the bone marrow of unchallenged wild type mice. Furthermore, we have observed that TSG-6 can inhibit bone morphogenetic protein-2 (BMP-2)-mediated osteoblast differentiation. Interaction analysis revealed that TSG-6 binds directly to RANKL and to BMP-2 (as well as other osteogenic BMPs but not BMP-3) via composite surfaces involving its Link and CUB modules. Consistent with this, the full-length protein is required for maximal inhibition of osteoblast differentiation and osteoclast activation, although the isolated Link module retains significant activity in the latter case. We hypothesize that TSG-6 has dual roles in bone remodeling; one protective, where it inhibits RANKL-induced bone erosion in inflammatory diseases such as arthritis, and the other homeostatic, where its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts.


Characteristics and outcomes of patients with pT4 urothelial carcinoma at radical cystectomy: a retrospective international study of 583 patients.
We describe cancer specific outcomes in patients with pT4 bladder urothelial carcinoma at radical cystectomy in a large international cohort. We reviewed the records of 4,257 patients treated with radical cystectomy for bladder urothelial carcinoma at 12 centers. No patient received any preoperative systemic chemotherapy or radiotherapy. Of the 4,257 patients 583 (14%) had pT4 bladder urothelial carcinoma, of whom 83.7% were male, 85.2% had substage pT4a disease, 24.9% had positive soft tissue surgical margins, 57.8% had lymphovascular invasion and 53.5% had lymph node metastasis. Median followup was 55.0 months. Overall estimated 5-year recurrence-free and cancer specific survival was 29% (95% CI 22-32) and 31% (95% CI 25-36), respectively. On multivariate analysis female gender (p = 0.005 and p = 0.001), positive soft tissue surgical margins (p = 0.014 and p <0.001), lymphovascular invasion (p = 0.016 and p = 0.005), pT4b substage (p = 0.041 and p = 0.002, respectively) and lymph node involvement (each p <0.001) were independently associated with disease recurrence and cancer specific mortality. Patients with pT4 bladder urothelial carcinoma have highly variable outcomes. Features associated with metastatic tumor dissemination (ie lymph node invasion and lymphovascular invasion) and local disease burden (ie soft tissue surgical margins and pT4 substage) are associated with poor outcomes in patients with pT4 bladder urothelial carcinoma. Further research is needed to understand why female patients with pT4 bladder urothelial carcinoma have a worse outcome than their male counterparts.


Levodopa and pramipexole effects on presynaptic dopamine PET markers and estimated dopamine release.
Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson's disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [Δ(DA)]. Twenty-three unilaterally 6-OHDA lesioned rats underwent an 11C-dihydrotetrabenazine (DTBZ, VMAT2 marker), an 11C-methylphenidate (MP, DAT marker), and a double 11C-raclopride (RAC, D2-type receptor marker) scan. They were assigned to three treatment groups: saline (N=7), pramipexole (N=8), and levodopa (N=8). After 4 weeks of treatment, imaging was repeated. Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on Δ(DA). These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level.


It Does Not Follow: Evaluating the One-Off Publication Bias Critiques by Francis (2012a, 2012b, 2012c, 2012d, 2012e, in press).
Francis (2012a, 2012b, 2012c, 2012d, 2012e, in press) attacks individual papers through critiques that apply faulty logic to analyses ironically biased by cherry picking. However well intentioned, the critiques are probably counterproductive to their stipulated goal and certainly unfair to the targeted authors.


Phylogenetic placement of the enigmatic parasite, Polypodium hydriforme, within the Phylum Cnidaria.
Polypodium hydriforme is a parasite with an unusual life cycle and peculiar morphology, both of which have made its systematic position uncertain. Polypodium has traditionally been considered a cnidarian because it possesses nematocysts, the stinging structures characteristic of this phylum. However, recent molecular phylogenetic studies using 18S rDNA sequence data have challenged this interpretation, and have shown that Polypodium is a close relative to myxozoans and together they share a closer affinity to bilaterians than cnidarians. Due to the variable rates of 18S rDNA sequences, these results have been suggested to be an artifact of long-branch attraction (LBA). A recent study, using multiple protein coding markers, shows that the myxozoan Buddenbrockia, is nested within cnidarians. Polypodium was not included in this study. To further investigate the phylogenetic placement of Polypodium, we have performed phylogenetic analyses of metazoans with 18S and partial 28S rDNA sequences in a large dataset that includes Polypodium and a comprehensive sampling of cnidarian taxa. Analyses of a combined dataset of 18S and partial 28S sequences, and partial 28S alone, support the placement of Polypodium within Cnidaria. Removal of the long-branched myxozoans from the 18S dataset also results in Polypodium being nested within Cnidaria. These results suggest that previous reports showing that Polypodium and Myxozoa form a sister group to Bilateria were an artifact of long-branch attraction. By including 28S rDNA sequences and a comprehensive sampling of cnidarian taxa, we demonstrate that previously conflicting hypotheses concerning the phylogenetic placement of Polypodium can be reconciled. Specifically, the data presented provide evidence that Polypodium is indeed a cnidarian and is either the sister taxon to Hydrozoa, or part of the hydrozoan clade, Leptothecata. The former hypothesis is consistent with the traditional view that Polypodium should be placed in its own cnidarian class, Polypodiozoa.


Reaching High Piezoelectric Performance with Rotating Directional-Field-Aligned PVDF-MoS2 Piezo-Polymer Applicable for Large-Area Flexible Electronics.
Wearable electronics and smart harvesting textile studies require a material system that resists physical stimulation. Such applications require receptive piezo-polymers, and their activation-free preparation that can translate into a continuous large-area film. In this work, it is discussed whether the β-content of piezo-polymer is extended with no use of any activation (i.e. poling), and if the β-content increases, it can be processed over a wide range of surfaces like large-area piezo-film. Such prerequisites within polyvinylidene fluoride-molybdenum disulfide ((PVDF)-MoS2 ) piezo-polymer are thoroughly experimented here to develop a high-performance piezo-film. A MoS2 -mediated PVDF piezo-polymer (termed as P+ -MoS2 ) is introduced, in which no extra β-enhancement activation step is required after spin coating. Experimental results record β ≧ 80% which allows to harvest the voltage and current in the level of ≈17 V and 1 µA, respectively which satisfies 5 V supply voltage requirement of the current microelectronics, and internet of things (IoT). In addition, the capacitors having different capacities are charged using the developed nanogenerator to check its practical applicability. Therefore, the transition process of P-MoS2 to aligned P+ -MoS2 due to passive interlocking (PiL) through rotating directional field is novel and found to be a principal reason for β-enhancement in fabricated devices.


[Morpho-functional features of the myocardium and coronary microvasculature in experimental embolism of the pulmonary artery branches].
Functional parameters of the heart ventricles, subendocardial morphology of anterior and posterior walls (AW and PW) of the right and left ventricles (RV and LV) and the state of coronary microvasculature were studied in experimental research on chinchilla mature rabbits at early (1, 2, 3 days) and late (after 7 and 30 days) stages after pulmonary artery branches embolism (PABE) which had been established by means of vaseline oil injection (0.3 ml/kg) in marginal ear vein. It was found that the heart muscle responded as a whole to the RV overload in PABE, with the structural and functional changes of both ventricles. LV damage develops in parallel with the restoration of the RV reserve possibilities and is more significant and prolonged in the LV PW. Positive correlation exists between the blood supply level of both ventricles PW and the interventricular pressure changes.


Chemotherapy administration directly into the fourth ventricle in a new piglet model. Laboratory Investigation.
The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.


[Clinical characteristics of non-invasive ventilation treatment in children with spinal muscular atrophy and sleep disordered breathing].
Objective: To study the short-term and long-term efficacy of the non-invasive ventilation treatment in children with spinal muscular atrophy (SMA) and sleep-disordered breathing. Methods: This was a prospective research to study the effect of night-time non-invasive ventilation in children with SMA and moderate to severe sleep-disordered breathing during March 2016 to January 2018, from the Pulmonary Department of Capital Institute of Pediatrics Affiliated Children's Hospital. Patients were divided into the treated group (with night-time non-invasive ventilation) and the control group (without ventilator). Sleep breathing pressure titration was suggested to the patients who were prepared to receive non-invasive ventilation. All cases were followed up for one year. Parameters'changes in polysomnography were assessed (paired t-test) in titration patients. Frequency of respiratory tract infection during the next year in the patients with and without ventilation was collected and compared (Mann-Whitney U-test). Results: Seventeen cases were recruited. The average age was (5.1±2.9) years, 10 cases were boys and 7 cases were girls. In the titration group (8 patients), after non-invasive ventilation, the average apnea hypopnea index was (3.8±2.5) times/h (t=4.086, P=0.005), hypopnea index was (2.4±1.2) times/h (t=2.779, P=0.027), average oxygen saturation during total sleep time was 0.966±0.007 (t=-5.292, P=0.001), and the minimum oxygen saturation was 0.906±0.023 (t=-3.938, P=0.006). All the above parameters were significantly improved after treatment. Than before, which was (16.6±9.7) times/h, (7.2±4.7) times/h, 0.946±0.015, 0.786±0.092 respectively. Ventilator mode for the 9 children with long time non-invasive ventilation at home was Bi-level positive airway pressure S/T. The positive airway pressure was set at 8-14 cmH(2)O (1 cmH(2)O=0.098 kPa) in inspiratory phase and 4-6 cmH(2)O in expiratory phase. In the treated group (9 patients), the average frequency of upper respiratory tract infection was 1.0 (0, 3.0) times/year (Z=-2.245, P=0.023), the lower respiratory tract infection was 0 (0, 0) times/year (Z=-3.189, P=0.001), hospitalization was 0 (0, 0) times/year (Z=-3.420, P<0.01), and admission to intensive care unit was 0 (0, 0) times/year (Z=-3.353, P=0.029). All the above indexes were significantly decreased compared with the control group (8 patients), which was 3.0 (2.3, 7.0) times/year, 2.0 (1.3, 4.5) times/year, 1.0 (1.0, 4.3) times/year, 0.5 (0, 1.0) times/year respectively. Conclusion: Non-invasive ventilation is efficient to SMA children with sleep-disordered breathing, and also can reduce the incidence of respiratory tract infections for children with SMA.


"Do Their Own Thing": Radical Health Care and the Fair Haven Community Health Center.
Radical health reform movements of the 1960s inspired two widely adopted alternative health care models in the United States: free clinics and community health centers. These groundbreaking institutions attempted to realize bold ideals but faced financial, bureaucratic, and political obstacles. This article examines the history of Fair Haven Community Health Care (FHCHC) in New Haven, Connecticut, an organization that spanned both models and typified innovative aspects of each while resisting the forces that tempered many of its contemporaries' progressive practices. Motivated by a tradition of independence and struggling to address medical neglect in their neighborhood, FHCHC leaders chose not to affiliate with the local academic hospital, a decision that led many disaffected community members to embrace the clinic. The FHCHC also prioritized grant funding over fee-for-service revenue, thus retaining freedom to implement creative programs. Furthermore, the center functioned in an egalitarian manner, enthusiastically employing nurse practitioners and whole-staff meetings, and was largely able to avoid the conflicts that strained other community-controlled organizations. The FHCHC proved unusual among free clinics and health centers and demonstrated strategies similar institutions might employ to overcome common challenges. (Am J Public Health. 2021;111(10): 1806-1814. https://doi.org/10.2105/AJPH.2021.306417).


Issues and problems in remedial education.
Children with reading and other education problems present for help to a wide variety of professionals from different disciplines. At present there appears to be a wide gulf between sophisticated assessments and effective remedial intervention. This paper examines some of the issues involed in providing and evaluating remedial education, and the issues of definition, measurement and prevalence; it is concluded that as many as 20 per cent of 10-year-olds in inner cities in the United Kingdom may require extra help with reading. The evidence suggests that, over-all, remedial help is not at present very effective. A concerted research programme is needed to identify effective approaches. Constructive suggestions are advanced whereby such a research programme would make a significant contribution to services for children with educational problems.


Platelet-rich fibrin ensures hemostasis after single-tooth removal under factor Xa inhibitors - a clinical prospective randomized split-mouth study.
In this prospective, double-blinded, randomized split-mouth study, the local hemostatic effect of platelet-rich fibrin (PRF) inserted into the extraction socket in patients taking factor Xa (FXa) inhibitors (apixaban, rivaroxaban, edoxaban) was compared to a hemostatic gelatine sponge (GS) as the "therapeutic gold standard" without withdrawal of oral anticoagulant therapy. Single-tooth extraction was conducted under local anesthesia in n = 21 patients using a split-mouth design (42 teeth). Using a double-blind approach, the extraction socket on one side of the jaw was filled with PRF and on the other with a GS. Bleeding was assessed immediately after surgery, in 30 min, 1 h, 1.5 h, and on follow-up appointments in 24 h and on the 7th day. In 67% of cases, mild postoperative oozing could be stopped 30-90 min after tooth extraction via gauze pressure without any delayed bleeding. Concerning bleeding events, there was no difference among the PRF and GS groups and no significant difference among rivaroxaban, apixaban, and edoxaban (all p > 0.15). PRF and GS are reliable hemostatic methods in postextraction sockets of patients taking FXa inhibitors. Consequently, there is no need to discontinue FXa inhibitors because of a single-tooth removal, eliminating the risk of thrombus formation.


Prevalence of vitamin D insufficiency in an adult normal population.
The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43 degrees and 51 degrees N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant 'sun' effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D values < or = 30 nmol/l (12 ng/ml), which represents the lower limit (< 2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p < 0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.


The relationship between flow, sleepiness and cognitive performance: the effects of short afternoon nap and bright light exposure.
"Flow" is a positive emotional state which typically occurs when a person perceives a balance between the challenges associated with a situation and his or her capabilities to accomplish these demands. While flow often occurs along with positive feelings and high introspective performance, only a few studies have investigated how it is associated with cognitive performance (i.e., objective performance). In the present study, we investigated the relationship between flow, emotions, and cognitive performance. A short nap (20 min) and bright light (>2,000 lux) techniques were used as experimental manipulations to enhance flow. Fifteen participants (31.3 ± 7.19 yr old) took part in four experimental conditions: rest, short nap, bright light, and nap and bright light. Pearson's correlation coefficients were calculated for flow and other indices using standardized data. Results showed that flow scores significantly increased after a short nap and under bright light exposure. The correlations between flow and reaction time were also significant. Flow was significantly associated with positive emotion and sleepiness. These results suggest that a short nap and bright light can be employed as a flow facilitator and that flow status can be used as an indicator in evaluating work efficiency and occupational mental health.


Understanding hospital admissions close to the end of life (ACE) study.
Palliative care is a policy priority internationally. In England, policymakers are seeking to develop high quality care for all by focusing on reducing the number of patients who die in acute hospitals. It is argued that reducing 'inappropriate' hospital admissions will lead to an improvement in the quality of care and provide cost savings.Yet what is meant by an 'inappropriate' admission is unclear and is unlikely to be shared by all stakeholders. The decision process that leads to hospital admission is often challenging, particularly when patients are frail and elderly. The ACE study reopens the idea of 'inappropriate' hospital admissions close to the end of life. We will explore how decisions that result in inpatient admissions close to death are made and valued from the perspective of the decision-maker, and will consider the implications of these findings for current policy and practice. The study focuses on the admission of patients with advanced dementia, chest disease or cancer who die within 72 hours of admission to acute hospitals. The study uses mixed methods with three data collection phases. Phase one involves patient case studies of admissions with interviews with clinicians involved in the admission and next-of-kin. Phase two uses vignette-based focus groups with clinical professionals and patients living with the conditions of interest. Phase three uses questionnaires distributed to clinical stakeholders. Qualitative data will be explored using framework analysis whilst the questionnaire data will be examined using descriptive statistical analysis. Findings will be used to evaluate current policy and literature. Significant ethical and validity issues arise due to the retrospective nature of phase one of the study. We are not able to gain consent from patients who have died, and the views of the deceased patients cannot be included directly, which risks privileging professional views. This phase also relies on the memories of the participants which may be unreliable. Later phases of the study attempt to compensate for the "absent voices" of the deceased patients by including next-of-kin and patient focus groups.