Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency.
Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor alpha1-antitrypsin (alpha1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe alpha1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin-8 (IL-8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, alpha1AT and secretory leukoprotease inhibitor (SLPI). Finally serum alpha1AT was measured to determine the degree of protein leakage (sputum sol serum alpha1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL-8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with alpha1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti-proteinase screen with both reduced sputum alpha1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin-8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with alpha1-antitrypsin deficiency had greater inflammation suggesting that alpha1-antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.


The effects of strength training on cognitive performance in elderly women.
Aging is a degenerative process marked by recognized functional, physiological, and metabolic impairments, such as dynapenia and diminished cognitive capacity. Therefore, the search for innovative strategies to prevent/delay these physiological and cognitive disorders is essential to guarantee the independence and life quality of an elderly population. The aim of this work is to verify the effect of a 12-week resistance exercise program on the general physical aptitude and cognitive capacities of elderly and sedentary women. Twenty-nine women (65.87±5.69 years) were divided into two groups. The control group was composed of eight elderly women who met the same inclusion criteria of the study and the strength training group was composed of 29 elderly women who were subjected to a resistance exercise program defined by 12 upper and lower limb exercises combined in 3×10 repetitions with 1-minute interval between repetitions and two resting minutes between exercises (three times/week). Weight loads were fixed between 60% and 75% of the apparent 1 repetition maximum, which was estimated by the test of 10 maximum repetitions. The direct curl was performed for upper body strength evaluation with 2.3 kg dumbbells for 30 seconds, whereas the chair test was used for lower body evaluation (total sit-stand movements in 30 seconds). The cognitive capacities of subjects were evaluated by "The Montreal Cognitive Assessment" questionnaire. After 12 weeks, the elderly group showed significant increases in the average upper body strength (58%), lower body strength (68%), and cognitive capacity (19%). The present study demonstrated that regular resistance exercises could provide significant gains on the upper and lower body strength concomitant to positive improvements on cognitive capacities of elderly women, bringing enhanced life quality.


Finite element analysis of photon density of states for two-dimensional photonic crystals with in-plane light propagation.
In-plane light propagation in two-dimensional (2D) photonic crystals (PCs) has been investigated by using the finite element method (FEM) in frequency domain. Conventionally, the band structures of 2D PCs were calculated by either the plane-wave expansion method (PWEM) or the finite difference time domain method. Here, we solve the eigenvalue equations for the band structures of the 2D PCs using the adaptive FEM in real space. We have carefully examined the convergence of this approach for the desired accuracy and efficiency. The calculated results show some discrepancies when compared to the results calculated by the PWEM. This may be due to the accuracy of the PWEM limited by the discontinuous nature of the dielectric functions. After acquiring the whole information of the dispersion relations within the irreducible Brillouin zone of the 2D PCs, the in-plane photon density of states for both the transverse electric (TE) and transverse magnetic (TM) modes can be calculated, accurately. For the case, the width of the complete band gap predicted by the FEM is much smaller, only about 65 % of that calculated by the PWEM. Therefore, the discrepancy in the prediction of complete band gaps between these two methods can be quite large, although the difference in band structure calculations is only a few percent. These results are relevant to the spontaneous emission by an atom, or to dipole radiation in two-dimensional periodic structures.


Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.
To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.


Increases in Secondhand Smoke After Going Smoke-Free: An Assessment of the Impact of a Mandated Smoke-Free Housing Policy.
The 12-month impact of federally mandated smoke-free housing (SFH) policy adoption (July 2018) was assessed using two markers of ambient secondhand smoke (SHS): airborne nicotine and particulate matter at the 2.5-micrometer threshold (PM2.5). We measured markers of SHS in Norfolk, VA from December 2017 to December 2018 in six federally subsidized multi-unit public housing buildings. Multi-level regression was used to model the following comparisons: (1) the month immediately before SFH implementation versus the month immediately after, and (2) December 2017 versus December 2018. There was a 27% reduction in indoor PM2.5 and a 32% reduction in airborne nicotine in the first month after SFH adoption, compared to the month prior to adoption. However, there was a 33% increase in PM2.5 and a 25% increase in airborne nicotine after 12 months. US Department of Housing and Urban Development (HUD)-mandated SFH can reduce SHS in multi-unit housing. However, SFH could also plausibly increase indoor smoking. Policy approaches adopted by individual properties or housing authorities-for example, property-wide bans versus allowing designated smoking areas-could be driving this potential unintended consequence. Successful implementation of SFH by public housing authorities in response to the HUD rule requires ongoing attention to implementation strategies. In this sense, SFH likely differs from other policies that might be seen as less intrusive. Long-term success of SFH will depend on careful policy implementation, including plans to educate and support housing authority staff, inform and engage residents, and build effective partnerships with community agencies.


The Saccharomyces cerevisiae spindle pole body (SPB) component Nbp1p is required for SPB membrane insertion and interacts with the integral membrane proteins Ndc1p and Mps2p.
The spindle pole body (SPB) in Saccharomyces cerevisiae functions to nucleate and organize spindle microtubules, and it is embedded in the nuclear envelope throughout the yeast life cycle. However, the mechanism of membrane insertion of the SPB has not been elucidated. Ndc1p is an integral membrane protein that localizes to SPBs, and it is required for insertion of the SPB into the nuclear envelope during SPB duplication. To better understand the function of Ndc1p, we performed a dosage suppressor screen using the ndc1-39 temperature-sensitive allele. We identified an essential SPB component, Nbp1p. NBP1 shows genetic interactions with several SPB genes in addition to NDC1, and two-hybrid analysis revealed that Nbp1p binds to Ndc1p. Furthermore, Nbp1p is in the Mps2p-Bbp1p complex in the SPB. Immunoelectron microscopy confirmed that Nbp1p localizes to the SPB, suggesting a function at this location. Consistent with this hypothesis, nbp1-td (a degron allele) cells fail in SPB duplication upon depletion of Nbp1p. Importantly, these cells exhibit a "dead" SPB phenotype, similar to cells mutant in MPS2, NDC1, or BBP1. These results demonstrate that Nbp1p is a SPB component that acts in SPB duplication at the point of SPB insertion into the nuclear envelope.


Evaluation of Person-Centredness in Rehabilitation for People Living with Dementia Is Needed: A Review of the Literature.
With an expected increase in the prevalence of dementia, change in care policies and healthcare systems worldwide is needed. Rehabilitation is increasingly recognised as contributing to dementia care. Rehabilitation subscribes to person-centredness, and thus, evaluations of person-centredness in rehabilitation for people living with dementia are relevant in order for healthcare professionals to know how best to practice person-centredness. The aim of this study was to identify methods of evaluating person-centeredness in rehabilitation for people living with dementia. Review of the literature using the search terms dementia, person-centredness, and rehabilitation or occupational therapy. Databases searched included: CINAHL, PubMed, Embase, PsycINFO, OTseeker, and SveMed+. The study included peer-reviewed articles from year 2000 to 2018 in Danish, English, Norwegian, or Swedish. Only one academic article met the inclusion criteria. In that article, person-centred practice was evaluated using observation and interview as well as analytical frameworks from person-centred care and occupational therapy. Evaluations of person-centred practice in rehabilitation for people living with dementia in peer-reviewed literature are lacking. Evaluations are needed to identify effective strategies to pursue and uphold person-centred care. Given the dearth of research on evaluations of person-centredness in rehabilitation, this article included research in person-centred dementia care in the discussion, which potentially can inspire practice and research of rehabilitation for people living with dementia. To understand the complex nature of person-centredness, a variety of research methodologies of qualitative and quantitative characters are recommended for evaluations.


Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught in the act".
Sessile serrated adenomas (SSAs) show serrations typical of hyperplastic polyps but display architectural differences and lack traditional dysplasia. SSAs with foci of low- (LGD) or high-grade dysplasia (HGD) or early invasive carcinoma are seldom biopsied and, thus, are not well studied. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 (mismatch repair gene products) was performed on colon biopsy specimens from 11 patients (age range, 54-87 years; 4 men and 7 women) showing SSA with LGD (n = 1), HGD (n = 5), or focal invasive carcinoma (n = 5). All 11 cases showed intact nuclear staining for MSH2 and MSH6 in the SSA component; in foci of LGD, HGD, or carcinoma; and in background normal mucosa. In contrast, there was tandem loss of MLH1 and PMS2 in zones of LGD (1/1) or HGD (3/5) and early carcinoma (2/4; with concordant loss in associated HGD) but retention in SSA areas (11/11) and normal mucosa (11/11). No patient was known to have hereditary nonpolyposis colorectal cancer/Lynch syndrome. This study offers additional strong evidence that SSA is truly a precursor to at least a subset of sporadic microsatellite-unstable colorectal cancer.


Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver.
Hepatitis B virus (hepadnavirus) infections are maintained by the presence of a small and regulated number of episomal viral genomes [covalently closed circular DNA (cccDNA)] in the nuclei of infected cells. Although a number of studies have measured the mean copy number of cccDNA molecules in hepadnaviral-infected cells, the distribution of individual copy numbers have not been reported. Using a PCR-based assay, we examined the number of cccDNA molecules of the duck hepatitis B virus in single nuclei isolated from the liver of a chronically infected duck over the course of 131 days of infection. Nuclei were isolated from frozen serial biopsies and individually deposited into PCR microplates by flow sorting. Each nucleus was assayed by nested PCR for cccDNA and for cellular IFN-alpha genes as an internal control. We found that 90% of the nuclei assayed contained between 1 and 17 cccDNA molecules, with the remaining 10% containing more (90% confidence), and that differences in the mean number of copies and distribution of copy numbers occurred within the same animal at different times postinfection. Overall, the data suggest (i) that the number of cccDNA molecules per cell may fluctuate over time, and (ii) that, according to these fluctuations, a substantial fraction of cells may contain only one or a few copies. We infer from the results that infected hepatocytes express virus at different levels and that during cell division it is possible to segregate cells containing no cccDNA.


Interactions and self-organization in the soil-microbe complex.
Soil is the most complicated biomaterial on the planet. As with any material, the physical habitat is of prime importance in determining and regulating biological activity. However, until recently the opaque nature of soil has meant that any interrogation of its interior architecture has been relatively rudimentary, restricted to simple qualitative expressions of the physical heterogeneity that fail to relate to any specific function. However, new techniques and insights into the biophysical and biochemical processes of this inner space are leading to the developments of theoretical frameworks and experimental approaches that will allow us to sustainably manage Earth's most important resource. We introduce the concept that the soil-microbe system is self-organized and suggest new priorities for research based on an integrative approach that combines biochemistry and biophysics.


Identification and analysis of transcriptional regulatory signals for the kil and kor loci of Streptomyces plasmid pIJ101.
Four regulated promoters that direct the transcription of genes (i.e., korA, tra, kilB, and korB) involved in the transfer of the Streptomyces plasmid pIJ101 were isolated following the in vitro fusion of plasmid DNA fragments to a promoterless gene encoding the S. lividans extracellular enzyme beta-galactosidase. Introduction of pIJ101 into cells carrying each of these promoter-lac fusions resulted in decreased lac expression. The sites of initiation of transcription by the promoter sequences were identified by primer extension experiments, and the DNA sequences specifically required for promoter activity and regulation by pIJ101-encoded functions were determined by deletion analysis. The data obtained indicate that the korB locus encodes a repressor that regulates its own transcription, as well as transcription of the kilB promoter; korA and tra are transcribed from overlapping divergent promoters that are coregulated by the korA gene product. Common DNA sequence domains within coregulated promoters allowed the identification of putative binding sites for each of the kor gene products.


Identification of yeast tRNA Um(44) 2'-O-methyltransferase (Trm44) and demonstration of a Trm44 role in sustaining levels of specific tRNA(Ser) species.
A characteristic feature of tRNAs is the numerous modifications found throughout their sequences, which are highly conserved and often have important roles. Um(44) is highly conserved among eukaryotic cytoplasmic tRNAs with a long variable loop and unique to tRNA(Ser) in yeast. We show here that the yeast ORF YPL030w (now named TRM44) encodes tRNA(Ser) Um(44) 2'-O-methyltransferase. Trm44 was identified by screening a yeast genomic library of affinity purified proteins for activity and verified by showing that a trm44-delta strain lacks 2'-O-methyltransferase activity and has undetectable levels of Um(44) in its tRNA(Ser) and by showing that Trm44 purified from Escherichia coli 2'-O-methylates U(44) of tRNA(Ser) in vitro. Trm44 is conserved among metazoans and fungi, consistent with the conservation of Um(44) in eukaryotic tRNAs, but surprisingly, Trm44 is not found in plants. Although trm44-delta mutants have no detectable growth defect, TRM44 is required for survival at 33 degrees C in a tan1-delta mutant strain, which lacks ac(4)C12 in tRNA(Ser) and tRNA(Leu). At nonpermissive temperature, a trm44-delta tan1-delta mutant strain has reduced levels of tRNA(Ser(CGA)) and tRNA(Ser(UGA)), but not other tRNA(Ser) or tRNA(Leu) species. The trm44-delta tan1-delta growth defect is suppressed by addition of multiple copies of tRNA(Ser(CGA)) and tRNA(Ser(UGA)), directly implicating these tRNA(Ser) species in this phenotype. The reduction of specific tRNA(Ser) species in a trm44-delta tan1-delta mutant underscores the importance of tRNA modifications in sustaining tRNA levels and further emphasizes that tRNAs undergo quality control.


Antiamoebic chemoprophylaxis using quinfamide in children: a comparative study.
This study sought to examine whether the administration of quinfamide at 3- or 6-month intervals diminished the frequency of Entamoeba histolytica cysts in stool samples compared to controls. The prospective, longitudinal, randomized, single-blind study examined children from six primary schools in Celaya and Neutla, Guanajuato. Of the 1,524 students in these schools, we selected participants for the study as follows: Children were included in the study if their parents agreed in writing to the study and if the children demonstrated evidence of E. histolytica cysts after a parasitoscopic analysis by concentration (PSC) in three samples over consecutive days using Faust"s method. Those included in the study received a single 4.3-g/kg dose of quinfamide, and we performed PSC on days 5, 6, and 7 following dose administration to examine whether quinfamide had affected the presence of the cysts. The study participants who tested negative for cysts were divided into three groups: Group 1 had 102 patients who underwent quinfamide treatment and three CPS analyses after the 12 months of the study; Group 2 had 98 subjects who underwent the quinfamide treatment and three CPS analyses at months 3, 6, 9, and 12 after their entrance into the study; and Group 3 had 102 patients, who underwent the quinfamide treatment and series of three CPS analyses at months 6 and 12 of the study. All participants received the dose of quinfamide after providing stool samples and after a clinical gastrointestinal history was obtained. Further clinical gastrointestinal data were collected 5 days after the quintamide dose was administered. We used EpiInfo 6.0 for statistical analysis, calculating c2 and p values for the clinical data and the CPS data after the 12 months concluded. Of the initial samples of 1,524 subjects, 308 (20.2%) had Entamoebic cysts. Of these, six were further eliminated because they did not meet the inclusion requirements. At the conclusion of the study, Group 1 presented with 37.6% of subjects still testing positive for cysts; of Group 2, 12.5% tested positive; and in Group 3, 23.5% of participants tested positive for cysts (chi2 = 16.8; df = 2; p = 0.0002). For comparisons of groups 1 and 2 and 1 and 3, p < 0.05; for the comparison of groups 2 and 3, p > 0.05. We conclude that antiamoebic chemoprophylaxis can be a choice for control of amoebic infection where personal hygiene and food consumption habits are not improving.


An injectable method for noninvasive spine fusion.
Bone morphogenetic proteins (BMPs) induce bone formation but are difficult to localize, and subsequent diffusion from the site of interest and short half-life reduce the efficacy of the protein. Currently, spine fusion requires stripping, decortications of the transverse processes, and an autograft harvest procedure. Even in combination with BMPs, clinical spinal fusion has a high failure rate, presumably because of difficulties in localizing sufficient levels of BMP. The goal was to achieve reliable spine fusion through a single injection of a cell-based gene therapy system without the need for any surgical intervention. Eighty-seven immunodeficient (n=44) and immune-competent (n=43) mice were injected along the paraspinous musculature to achieve rapid induction of heterotopic ossification (HO) and ultimately spinal arthrodesis. Immunodeficient and immune-competent mice were injected with fibroblasts, transduced with an adenoviral vector to express BMP2, along the paraspinous musculature. Bone formation was evaluated via radiographs, microcomputed tomography, and biomechanical analysis. ew bridging bone between the vertebrae and the fusion to adjacent skeletal bone was obtained as early as 2 weeks. Reduction in spine flexion-extension also occurred as early as 2 weeks after injection of the gene therapy system, with greater than 90% fusion by 4 weeks in all animals regardless of their genetic background. Injection of our cell-based system into the paraspinous musculature induces spinal fusion that is dependent neither on the cell type nor on the immune status. These studies are the first to harness HO in an immune-competent model as a noninvasive injectable system for clinically relevant spinal fusion and may one day impact human spinal arthrodesis.


Chronotropic response of beta-adrenergic-, muscarinic-, and calcitonin gene-related peptide-receptor agonists in right atria from neonatal capsaicin-treated rats.
We evaluated the potency of isoproterenol, carbachol, pilocarpine and calcitonin gene-related peptide (CGRP) in the rat right atria at 30, 60 and 90 days after neonatal capsaicin treatment. Neonatal rats were pretreated on the second day of life with capsaicin (50 mg/kg). The capsaicin pretreatment caused a five-fold rightward shift at the pEC(50) level on the concentration-response curves to isoproterenol in 30-day-old rats. Propranolol (10 mg/kg, given 15 min prior to capsaicin treatment) prevented this subsensitivity. No changes in the potency of isoproterenol were observed at 60 and 90 days after capsaicin pretreatment. The potency and maximal responses of CGRP in the right atria in 30-day-old rats were significantly higher than in 60- and 90-day-old rats; however, no differences were found between control and capsaicin groups. The potency and maximal responses to carbachol and pilocarpine were not changed in all groups. The neonatal capsaicin treatment reduced by about 74% the CGRP content in the heart in all groups. In summary, capsaicin treatment in newborn rats produces a desensitization of chronotropic response mediated by beta-adrenoceptors in isolated right atria from 30-day-old rats possibly due to a massive release of catecholamines.


Structure-activity relationships in gold nanoparticle dimers and trimers for surface-enhanced Raman spectroscopy.
Understanding the detailed relationship between nanoparticle structure and activity remains a significant challenge for the field of surface-enhanced Raman spectroscopy. To this end, the structural and optical properties of individual plasmonic nanoantennas comprised of Au nanoparticle assemblies that are coated with organic reporter molecules and encapsulated by a SiO(2) shell have been determined using correlated transmission electron microscopy (TEM), dark-field Rayleigh scattering microscopy, surface-enhanced Raman scattering (SERS) microscopy, and finite element method (FEM) calculations. The distribution of SERS enhancement factors (EFs) for a structurally and optically diverse set of nanoantennas is remarkably narrow. For a collection of 30 individual nanoantennas ranging from dimers to heptamers, the EFs vary by less than 2 orders of magnitude. Furthermore, the EFs for the hot-spot-containing nanoparticles are uncorrelated to aggregation state and localized surface plasmon resonance (LSPR) wavelength but are crucially dependent on the size of the interparticle gap. This study demonstrates that the creation of hot spots, where two particles are in subnanometer proximity or have coalesced to form crevices, is paramount to achieving maximum SERS enhancements.


Stress-induced cognition among radiologic technologists in COVID-19 quarantine centres in Palestine.
The outbreak of COVID-19 brought high mortality rate from the viral infection and caused a huge psychological stress for healthcare staff who work under great pressure during the pandemic. The purpose of this study is to assess the level of stress-induced cognition among radiologic technologists (RTs) in COVID-19 quarantine centres in Palestine after the outbreak of COVID-19. Stress-induced cognition was assessed using Stress-induced Cognition Scale (SCS) questionnaire. The validity and stability of the measuring tool was verified. The sample consisted of 61 RTs who are working currently at various quarantine centres in Palestine. Cognition-induced stress was higher than average. There was a statistically significant difference between RTs working directly with COVID-19 patient compared with RTs working indirectly. Additionally, results show an increased level of stress for RTs having children compared with single or non-parent RTs. Also, RTs who dealt with COVID-19 patients for prolonged periods over a month had higher level of stress-induced cognition. Other variables did not show significant differences among RTs. It is recommended to provide psychological support for RTs who dealt and are currently involved in COVID-19 quarantine centres to alleviate stress-induced cognition.


Single-atom single-photon quantum interface.
A major challenge for a scalable quantum computing architecture is the faithful transfer of information from one node to another. We report on the realization of an atom-photon quantum interface based on an optical cavity, using it to entangle a single atom with a single photon and then to map the quantum state of the atom onto a second single photon. The latter step disentangles the atom from the light and produces an entangled photon pair. Our scheme is intrinsically deterministic and establishes the basic element required to realize a distributed quantum network with individual atoms at rest as quantum memories and single flying photons as quantum messengers.


Irritable bowel syndrome: a clinical review.
Irritable bowel syndrome (IBS) affects 7% to 21% of the general population. It is a chronic condition that can substantially reduce quality of life and work productivity. To summarize the existing evidence on epidemiology, pathophysiology, and diagnosis of IBS and to provide practical treatment recommendations for generalists and specialists according to the best available evidence. A search of Ovid (MEDLINE) and Cochrane Database of Systematic Reviews was performed for literature from 2000 to December 2014 for the terms pathophysiology, etiology, pathogenesis, diagnosis, irritable bowel syndrome, and IBS. The range was expanded from 1946 to December 2014 for IBS, irritable bowel syndrome, diet, treatment, and therapy. The database search yielded 1303 articles, of which 139 were selected for inclusion. IBS is not a single disease but rather a symptom cluster resulting from diverse pathologies. Factors important to the development of IBS include alterations in the gut microbiome, intestinal permeability, gut immune function, motility, visceral sensation, brain-gut interactions, and psychosocial status. The diagnosis of IBS relies on symptom-based criteria, exclusion of concerning features (symptom onset after age 50 years, unexplained weight loss, family history of selected organic gastrointestinal diseases, evidence of gastrointestinal blood loss, and unexplained iron-deficiency anemia), and the performance of selected tests (complete blood cell count, C-reactive protein or fecal calprotectin, serologic testing for celiac disease, and age-appropriate colorectal cancer screening) to exclude organic diseases that can mimic IBS. Determining the predominant symptom (IBS with diarrhea, IBS with constipation, or mixed IBS) plays an important role in selection of diagnostic tests and treatments. Various dietary, lifestyle, medical, and behavioral interventions have proven effective in randomized clinical trials. The diagnosis of IBS relies on the identification of characteristic symptoms and the exclusion of other organic diseases. Management of patients with IBS is optimized by an individualized, holistic approach that embraces dietary, lifestyle, medical, and behavioral interventions.


Difference of seasonal variation between glycated albumin and glycated haemoglobin.
Background Glycated albumin reflects 2-3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = -0.359, P < 0.001, rs = -0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.


Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections.
Neuropilin-1 and neuropilin-2 bind differentially to different class 3 semaphorins and are thought to provide the ligand-binding moieties in receptor complexes mediating repulsive responses to these semaphorins. Here, we have studied the function of neuropilin-2 through analysis of a neuropilin-2 mutant mouse, which is viable and fertile. Repulsive responses of sympathetic and hippocampal neurons to Sema3F but not to Sema3A are abolished in the mutant. Marked defects are observed in the development of several cranial nerves, in the initial central projections of spinal sensory axons, and in the anterior commissure, habenulo-interpeduncular tract, and the projections of hippocampal mossyfiber axons in the infrapyramidal bundle. Our results show that neuropilin-2 is an essential component of the Sema3F receptor and identify key roles for neuropilin-2 in axon guidance in the PNS and CNS.


Disturbing-Free Determination of Yeast Concentration in DI Water and in Glucose Using Impedance Biochips.
Deionized water and glucose without yeast and with yeast (Saccharomyces cerevisiae) of optical density OD600 that ranges from 4 to 16 has been put in the ring electrode region of six different types of impedance biochips and impedance has been measured in dependence on the added volume (20, 21, 22, 23, 24, 25 µL). The measured impedance of two out of the six types of biochips is strongly sensitive to the addition of both liquid without yeast and liquid with yeast and modelled impedance reveals a linear relationship between the impedance model parameters and yeast concentration. The presented biochips allow for continuous impedance measurements without interrupting the cultivation of the yeast. A multiparameter fit of the impedance model parameters allows for determining the concentration of yeast (cy) in the range from cy = 3.3 × 107 to cy = 17 × 107 cells/mL. This work shows that independent on the liquid, i.e., DI water or glucose, the impedance model parameters of the two most sensitive types of biochips with liquid without yeast and with liquid with yeast are clearly distinguishable for the two most sensitive types of biochips.


Probing the role of a mobile loop in substrate binding and enzyme activity of human salivary amylase.
Mammalian amylases harbor a flexible, glycine-rich loop 304GHGAGGA(310), which becomes ordered upon oligosaccharide binding and moves in toward the substrate. In order to probe the role of this loop in catalysis, a deletion mutant lacking residues 306-310 (Delta306) was generated. Kinetic studies showed that Delta306 exhibited: (1) a reduction (>200-fold) in the specific activity using starch as a substrate; (2) a reduction in k(cat) for maltopentaose and maltoheptaose as substrates; and (3) a twofold increase in K(m) (maltopentaose as substrate) compared to the wild-type (rHSAmy). More cleavage sites were observed for the mutant than for rHSAmy, suggesting that the mutant exhibits additional productive binding modes. Further insight into its role is obtained from the crystal structures of the two enzymes soaked with acarbose, a transition-state analog. Both enzymes modify acarbose upon binding through hydrolysis, condensation or transglycosylation reactions. Electron density corresponding to six and seven fully occupied subsites in the active site of rHSAmy and Delta306, respectively, were observed. Comparison of the crystal structures showed that: (1) the hydrophobic cover provided by the mobile loop for the subsites at the reducing end of the rHSAmy complex is notably absent in the mutant; (2) minimal changes in the protein-ligand interactions around subsites S1 and S1', where the cleavage would occur; (3) a well-positioned water molecule in the mutant provides a hydrogen bond interaction similar to that provided by the His305 in rHSAmy complex; (4) the active site-bound oligosaccharides exhibit minimal conformational differences between the two enzymes. Collectively, while the kinetic data suggest that the mobile loop may be involved in assisting the catalysis during the transition state, crystallographic data suggest that the loop may play a role in the release of the product(s) from the active site.


Comprehensive Analyses of Nitric Oxide-Induced Plant Stem Cell-Related Genes in Arabidopsis thaliana.
Plant stem cells are pluripotent cells that have diverse applications in regenerative biology and medicine. However, their roles in plant growth and disease resistance are often overlooked. Using high-throughput RNA-seq data, we identified approximately 20 stem cell-related differentially expressed genes (DEGs) that were responsive to the nitric oxide (NO) donor S-nitrosocysteine (CySNO) after six hours of infiltration. Among these DEGs, the highest number of positive correlations (R ≥ 0.8) was observed for CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) 12. Gene ontology (GO) terms for molecular function showed DEGs associated with signal transduction and receptor activity. A promoter study of these DEGs showed the presence of cis-acting elements that are involved in growth as well as the regulation of abiotic and biotic stress. Phylogenetic analysis of the Arabidopsis stem cell-related genes and their common orthologs in rice, soybean, poplar, and tomato suggested that most soybean stem cell-related genes were grouped with the Arabidopsis CLE type of stem cell genes, while the rice stem cell-related genes were grouped with the Arabidopsis receptor-like proteins. The functional genomic-based characterization of the role of stem cell DEGs showed that under control conditions, the clv1 mutant showed a similar phenotype to that of the wild-type (WT) plants; however, under CySNO-mediated nitrosative stress, clv1 showed increased shoot and root length compared to WT. Furthermore, the inoculation of clv1 with virulent Pst DC3000 showed a resistant phenotype with fewer pathogens growing at early time points. The qRT-PCR validation and correlation with the RNA-seq data showed a Pearson correlation coefficient of >0.8, indicating the significantly high reliability of the RNA-seq analysis.


DESIGN OF VACCINE TRIALS DURING OUTBREAKS WITH AND WITHOUT A DELAYED VACCINATION COMPARATOR.
Conducting vaccine efficacy trials during outbreaks of emerging pathogens poses particular challenges. The "Ebola ça suffit" trial in Guinea used a novel ring vaccination cluster randomized design to target populations at highest risk of infection. Another key feature of the trial was the use of a delayed vaccination arm as a comparator, in which clusters were randomized to immediate vaccination or vaccination 21 days later. This approach, chosen to improve ethical acceptability of the trial, complicates the statistical analysis as participants in the comparison arm are eventually protected by vaccine. Furthermore, for infectious diseases, we observe time of illness onset and not time of infection, and we may not know the time required for the vaccinee to develop a protective immune response. As a result, including events observed shortly after vaccination may bias the per protocol estimate of vaccine efficacy. We provide a framework for approximating the bias and power of any given analysis period as functions of the background infection hazard rate, disease incubation period, and vaccine immune response. We use this framework to provide recommendations for designing standard vaccine efficacy trials and trials with a delayed vaccination comparator. Briefly, narrower analysis periods within the correct window can minimize or eliminate bias but may suffer from reduced power. Designs should be reasonably robust to misspecification of the incubation period and time to develop a vaccine immune response.


Adapting the Index of Relative Rurality (IRR) to Estimate Rurality at the ZIP Code Level: A Rural Classification System in Health Services Research.
Accurate analysis of health problems facing rural residents depends on how rurality is defined. Health services research relies frequently on the rural urban commuting area (RUCA) codes to estimate rurality at the small area level. We modified the county-level Index of Relative Rurality (IRR) to the ZIP code level (IRRZIP ) to create an alternative small-area-level rural classification system. We then compared how the 2 rural classification systems differ in how rural areas and populations are defined and in methodological analysis. We linked data for veterans (n = 37,466) who attended the VA Pittsburgh Healthcare System to 2000 United States Census and the US Department of Agriculture's Economic Research Service data. The RUCA and the IRRZIP do not consistently classify the same ZIP code areas and populations as rural. Using the IRRZIP , each 10th increment in increased rurality was associated with a 2.6 increased odds of receiving primary care at a satellite clinic. The IRRZIP is a straightforward measure that is easy to use and interpret and may be a relevant alternative rural classification system that can be used in health services research.


Associations between sports participation, adiposity and obesity-related health behaviors in Australian adolescents.
The purpose of this study was to examine the relationship between organized sports participation, weight status, physical activity, screen time, and important food habits in a large nationally representative sample of Australian adolescents. Nationally representative cross-sectional study of 12,188 adolescents from 238 secondary schools aged between 12 and 17 years (14.47 ± 1.25 y, 53% male, 23% overweight/obese). Participation in organized sports, compliance with national physical activity, screen time, and fruit and vegetable consumption guidelines, and consumption of sugar-sweetened beverages and high-fat foods were self-reported. Weight status and adiposity (BMI, waist circumference) were measured. Organized sports participation was higher among males and those residing in rural/remote areas. Underweight adolescents reported the lowest levels of participation. Higher levels of participation were associated with an increased likelihood of complying with national physical activity (OR = 2.07 [1.67-2.58]), screen time (OR = 1.48 [1.19-1.84]), and fruit and vegetable consumption guidelines (OR = 1.32 [1.05-1.67]). There was no association between organized sport participation and weight status, adiposity, consumption of sugar-sweetened beverages or high-fat foods. Participation in organized sports was associated with a greater likelihood to engage in a cluster of health behaviors, including meeting physical activity guidelines, electronic screen time recommendations, and fruit and vegetable consumption guidelines. However, participation in organized sports was not associated with unhealthy dietary behaviors including the consumption of sugar-sweetened beverages and high-fat foods. There is no association between participation in organized sports and likelihood to be overweight or obese. The role of sports in promoting healthy weight and energy balance is unclear.


Do English NHS Microbiology laboratories offer adequate services for the diagnosis of UTI in children? Healthcare Quality Improvement Partnership (HQIP) Audit of Standard Operational Procedures.
The National Institute of Care Excellence (NICE) 2007 guidance CG54, on urinary tract infection (UTI) in children, states that clinicians should use urgent microscopy and culture as the preferred method for diagnosing UTI in the hospital setting for severe illness in children under 3 years old and from the GP setting in children under 3 years old with intermediate risk of severe illness. NICE also recommends that all 'infants and children with atypical UTI (including non-Escherichia coli infections) should have renal imaging after a first infection'. We surveyed all microbiology laboratories in England with Clinical Pathology Accreditation to determine standard operating procedures (SOPs) for urgent microscopy, culture and reporting of children's urine and to ascertain whether the SOPs facilitate compliance with NICE guidance. We undertook a computer search in six microbiology laboratories in south-west England to determine urine submissions and urine reports in children under 3 years. Seventy-three per cent of laboratories (110/150) participated. Enterobacteriaceae that were not E. coli were reported only as coliforms (rather than non-E. coli coliforms) by 61% (67/110) of laboratories. Eighty-eight per cent of laboratories (97/110) provided urgent microscopy for hospital and 54% for general practice (GP) paediatric urines; 61% of laboratories (confidence interval 52-70%) cultured 1 μl volume of urine, which equates to one colony if the bacterial load is 106 c.f.u. l(-1). Only 22% (24/110) of laboratories reported non-E. coli coliforms and provided urgent microscopy for both hospital and GP childhood urines; only three laboratories also cultured a 5 μl volume of urine. Only one of six laboratories in our submission audit had a significant increase in urine submissions and urines reported from children less than 3 years old between the predicted pre-2007 level in the absence of guidance and the 2008 level following publication of the NICE guidance. Less than a quarter of laboratories were providing a service that would allow clinicians to fully comply with the first line recommendations in the 2007 NICE UTI in children guidance. Laboratory urine submission report figures suggest that the guidance has not led to an increase in diagnosis of UTI in children under 3 years old.


Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: III. Impact of drug nanoparticle loading.
Polymer strip films have emerged as a robust platform for poorly water-soluble drug delivery. However, the common conception is that films cannot exceed low drug loadings, mainly due to poor drug stability, slow release, and film brittleness. This study explores the ability to achieve high loadings of poorly water-soluble drug nanoparticles in strip films while retaining good mechanical properties and enhanced dissolution rate. Aqueous suspensions containing up to 30wt% griseofulvin nanoparticles were prepared via wet stirred media milling and incorporated into hydroxypropyl methylcellulose (HPMC) films. Griseofulvin loading in films was adjusted to be between 9 and 49wt% in HPMC-E15 films and 30 and 73wt% in HPMC-E4M films by varying the mixing ratio of HPMC solution-to-griseofulvin suspension. All films exhibited good content uniformity and nanoparticle redispersibility up to 50wt% griseofulvin, while E4M films above 50wt% griseofulvin had slightly worse content uniformity and poor nanoparticle redispersibility. Increasing drug loading in films generally required more time to achieve 100% release during dissolution, although polymer-drug clusters dispersed from E4M films above 50wt% griseofulvin, resulting in similar dissolution profiles. While all films exhibited good tensile strength, a significant decrease in percent elongation was observed above 40-50wt% GF, resulting in brittle films.


Packed red cell transfusion does not compromise chromosome analysis in newborns.
Critically ill neonates are frequently transfused with packed red cells. Some of these transfused neonates also need chromosome analysis. There is a long-standing tradition in pediatrics of not performing chromosome analysis after transfusion. We wished to determine whether transfusion with packed red cells affect the cytogenetic results in neonates. The medical records of all neonates at the Medical College of Georgia who had had chromosome analysis between June 1995 and June 1998 were reviewed. Ten neonates had received transfusion prior to cytogenetic testing. Of these 10 infants, two had been transfused two or more times. Routine cytogenetic analysis of 20 metaphases at 550-band level had been performed on all 10 patients. Heteromorphic markers were compared in 10 randomly selected metaphases for any discrepancy. To determine whether there were theoretical reasons to delay chromosome analysis in transfused neonates, samples of irradiated, and/or filtered, and nonfiltered blood were obtained from the blood bank and analyzed for the presence of lymphocytes. Prior transfusion did not affect karyotype results. A nonmosaic abnormal karyotype was found in 3 of the 10 patients. A fourth patient's karyotype was 45,X/47,XXX. This mosaicism was constitutive and consistent as demonstrated by a follow-up chromosome analysis. All other abnormal karyotypes were consistent with the dysmorphic phenotype. Randomly selected metaphases did not show any differences in the identifiable heteromorphic markers in all 10 patients. Although there was a 50% chance of patients receiving blood from a donor of opposite sex, there were no instances in which cells with a karyotype of the opposite sex were found in the patients' blood. The irradiated and filtered cultured donor blood samples did not show any metaphases. However, metaphases were seen in the cultures from nonfiltered and nonirradiated donor blood. Based on these results one does not need to delay karyotyping babies who have had blood transfusions. Packed red cell transfusion in newborns does not compromise the accuracy of chromosome analysis in our study even with multiple transfusions.


Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells.
Methylglyoxal is a reactive dicarbonyl compound generated as an intermediate of glycolysis during the physical glycation in the diabetic condition. It is considered to be a potent precursor of advanced glycation end products (AGEs) formation. Methylglyoxal itself and methylglyoxal-derived AGEs have been commonly implicated in the development of diabetic neuropathy. Our previous study indicated that vanillic acid showed an inhibitory effect against methylglyoxal-mediated Neuro-2A cell apoptosis, suggesting that vanillic acid might possess cytoprotective properties in the prevention of diabetic neuropathy complication. In this study, the effects of vanillic acid on the methylglyoxal-mediated glycation system involved in the progression of Neuro-2A cell apoptosis were further investigated. Our findings indicated that methylglyoxal-induced Neuro-2A cell apoptosis was mediated through the possible glycation mechanism of oxidative stress, activation of the MAPK signaling pathway (p38 and JNK) and oxidation-sensitive protein expression (PKC and p47(phox)) and methylglyoxal-derived N-epsilon-(carboxymethyl)lysine (CML) formation. Vanillic acid, however, suppressed methylglyoxal-induced Neuro-2A cell apoptosis via inhibition of glycation mechanisms including ROS, p38 and JNK, PKC and p47(phox), and methylglyoxal-derived CML formation. In the present study, we established the first evidence that vanillic acid might contribute to the prevention of the development of diabetic neuropathy by blocking the methylglyoxal-mediated intracellular glycation system.


How Can Hospital Programs be Strengthened to Enhance Achievement of VISION 2020 Objectives?
The global initiative, "VISION 2020 - The Right to Sight" aims to eliminate avoidable blindness by year 2020. Avoidable blindness by definition are those conditions for which we already have a treatment or a surgical procedure and often a proven strategy to either prevent or cure the condition. Thus, the challenge to realize this goal would be designing the right service delivery systems specific to the local context, organizing the required resources, coordination, and implementing and monitoring these. The key "discipline" that is required to ensure successful implementation is "Management." To be holistic, such management inputs are required both in a program as well as the hospital setting. From a program perspective, the focus will need to be on reaching the unreached, ensuring equity, creating an enabling environment, putting in place the required infrastructure, including that for developing all cadres of the eye care team, and functionally integrating eye care into the general health system and other developmental activities. From a hospital perspective, the management process should manage the internal and external ecosystems as well as all the interfaces to the hospital. It should also put in place systems for ensuring an adequate patient flow, high productivity, quality, sustainability, and accountability. Since in many countries the notion of management in health care or more specifically in eye care is at an early stage or nonexistent, a proactive effort is required to build the management capacity quickly through a structured process.


The Relationship Between School Dropout and Pregnancy Among Adolescent Girls and Young Women in South Africa: A HPTN 068 Analysis.
Background. Prevention of both school dropout and teen pregnancy represent clear public health priorities for South Africa, yet their complex and potentially cyclical relationship has not been fully explored. Objective. To further understand how this relationship operates, we analyzed data from a randomized trial of young women aged 13 to 20 years enrolled in school in rural South Africa to estimate the association between pregnancy and subsequent dropout and between dropout and subsequent pregnancy. Method. We examined inverse probability (IP) of exposure-weighted survival curves for school dropout by pregnancy and for pregnancy by school dropout. We used weighted curves to calculate 1-, 2-, and 3-year risk differences and risk ratios. Additionally, we used an IP-weighted marginal structural cox model to estimate a hazard ratio (HR) for each relationship. Results. Dropout from school was associated with subsequent pregnancy (HR 3.58; 95% confidence interval [CI] [2.04, 6.28]) and pregnancy was associated with subsequent school dropout (HR 2.36; 95% CI [1.29, 4.31]). Young women who attended school but attended fewer days had a higher hazard of pregnancy than those who attended more school (HR 3.64; 95% CI [2.27, 5.84]). Conclusion. Pregnancy is both a cause and a consequence of school dropout. Consideration of school attendance and academic performance could ultimately enhance pregnancy prevention efforts in this population. Programs should be tailored differently for (1) girls who have dropped out of school, (2) those who are in school and at risk for pregnancy, and (3) those who are in school and become pregnant.


CD8+ T cells circumvent immune privilege in the eye and mediate intraocular tumor rejection by a TNF-alpha-dependent mechanism.
Although intraocular tumors reside in an immune-privileged environment, T cells can circumvent immune privilege and mediate tumor rejection without inducing damage to normal ocular tissue. In this study, we used a well-characterized tumor, Ad5E1 (adenovirus type 5 early region 1), to analyze the role of CD8+ T cells in the pristine rejection of intraocular tumors. It has been previously documented that Ad5E1 tumor rejection can occur in the absence of CD8+ T cells. However, here we find that CD8+ T cells infiltrated intraocular Ad5E1 tumors in C57BL/6 mice. Surprisingly, CD8+ T cells from tumor-rejector mice could mediate intraocular tumor rejection following adoptive transfer to SCID mice. In determining the mechanisms behind CD8+ T cell-mediated tumor rejection, we discovered that antitumor CTL activity was neither observed nor necessary for rejection of the intraocular tumors. CD8+ T cells from rejector mice did not produce IFN-gamma in response to Ad5E1 tumor Ags or use FasL to mediate intraocular tumor rejection. Also, CD8+ T cells did not use perforin or TRAIL, as CD8+ T cells from perforin knockout (KO) and TRAIL KO mice conferred protection to SCID recipient mice following adoptive transfer. We discovered that CD8+ T cells used TNF-alpha to mediate tumor rejection, because Ad5E1 tumor cells were highly sensitive to TNF-alpha-induced apoptosis and CD8+ T cells from TNF-alpha KO mice did not protect SCID mice from progressive Ad5E1 tumor growth. The results indicate that CD8+ T cells circumvent immune privilege and mediate intraocular tumor rejection by a TNF-alpha-dependent manner while leaving the eye intact and vision preserved.


Consensus statement of the international summit on intellectual disability and Dementia related to post-diagnostic support.
Post diagnostic support (PDS) has varied definitions within mainstream dementia services and different health and social care organizations, encompassing a range of supports that are offered to adults once diagnosed with dementia until death. An international summit on intellectual disability and dementia held in Glasgow, Scotland in 2016 identified how PDS applies to adults with an intellectual disability and dementia. The Summit proposed a model that encompassed seven focal areas: post-diagnostic counseling; psychological and medical surveillance; periodic reviews and adjustments to the dementia care plan; early identification of behaviour and psychological symptoms; reviews of care practices and supports for advanced dementia and end of life; supports to carers/ support staff; and evaluation of quality of life. It also explored current practices in providing PDS in intellectual disability services. The Summit concluded that although there is limited research evidence for pharmacological or non-pharmacological interventions for people with intellectual disability and dementia, viable resources and guidelines describe practical approaches drawn from clinical practice. Post diagnostic support is essential, and the model components in place for the general population, and proposed here for use within the intellectual disability field, need to be individualized and adapted to the person's needs as dementia progresses. Recommendations for future research include examining the prevalence and nature of behavioral and psychological symptoms (BPSD) in adults with an intellectual disability who develop dementia, the effectiveness of different non-pharmacological interventions, the interaction between pharmacological and non-pharmacological interventions, and the utility of different models of support.


Cytomegalovirus persistence in macrophages and endothelial cells.
Although human cytomegalovirus (HCMV) rarely causes overt disease in healthy individuals, the virus can be a serious, even life-threatening problem in immunosuppressed or immune-deficient patients and in the setting of maternofetal primary infection. In recent years knowledge about HCMV pathogenesis has increased significantly. Identification of the cell types infected by HCMV in vivo has demonstrated that monocytes/macrophages and endothelial cells are key elements both in latent and acute infection with HCMV. Both cell types can be involved in systemic spread of virus and specific organ disease. While it has been demonstrated that differentiation of monocytes into macrophages renders these cells permissive to productive HCMV infection, there is presently limited knowledge about the pathogenesis of HCMV in endothelial cells (ECs). These cells represent the physiological interface between blood and tissues, display heterologous phenotypes, and are functionally variable, depending on their respective microanatomic environment. Microvascular ECs are the site of monocyte transmigration into organ tissues and therefore are likely to regulate the activation state of infected monocytes. Recently, macrovascular endothelium is receiving increasing attention due to its possible involvement in atherogenesis. In this overview we present recent findings on the role of monocytes/macrophages and endothelial cells in HCMV infection.


Simvastatin Therapy for Drug Repositioning to Reduce the Risk of Prostate Cancer Mortality in Patients With Hyperlipidemia.
Prostate cancer (PCa) is one of the most commonly diagnosed cancers in the western world, and the mortality rate from PCa in Asia has been increasing recently. Statins are potent inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase and are commonly used for treating hyperlipidemia, with beneficial effects for cardiovascular disease and they also exhibit anti-cancer activity. However, the protective effects of statins against PCa are controversial. In this study, we investigated the effect of two types of statins (simvastatin and lovastatin) and the mortality rate of PCa patients by using the Taiwan National Health Insurance Research Database (NHIRD). A total of 15,264 PCa patients with hyperlipidemia records and medical claims from the Registry of Catastrophic Illness were enrolled. The patients were divided into two cohorts based on their statin use before the diagnosis of PCa: statin users (n = 1,827) and non-statin users (n = 1,826). The results showed that patients who used statins exhibited a significantly reduced risk of mortality from PCa [adjusted hazard ratio (HR) = 0.84, 95% CI = 0.73-0.97]. Analysis of the cumulative defined daily dose (DDD) indicated that patients who were prescribed simvastatin ≥ 180 DDD had a dramatically decreased risk of death from PCa (adjusted HR = 0.63; 95% CI = 0.51-0.77). This population-based cohort study demonstrated that statin use significantly decreased the mortality of PCa patients, and that this risk was inversely associated with the cumulative DDD of simvastatin therapy. The results of this study revealed that statins may be used for drug repositioning and in the development of a feasible approach to prevent death from PCa.


The contextual malleability of approach-avoidance training effects: approaching or avoiding fear conditioned stimuli modulates effects of approach-avoidance training.
Previous research showed that the repeated approaching of one stimulus and avoiding of another stimulus typically leads to more positive evaluations of the former stimuli. In the current study, we examined whether approach and avoidance training (AAT) effects on evaluations of neutral stimuli can be modulated by introducing a regularity between the approach-avoidance actions and a positive or negative (feared) stimulus. In an AAT task, participants repeatedly approached one neutral non-word and avoided another neutral non-word. Half of the participants also approached a negative fear-conditioned stimulus (CS+) and avoided a conditioned safe stimulus (CS-). The other half of the participants avoided the CS+ and approached the CS-. Whereas participants in the avoid CS+ condition exhibited a typical AAT effect, participants in the approach CS+ condition exhibited a reversed AAT effect (i.e. they evaluated the approached neutral non-word as more negative than the avoided non-word). These findings provide evidence for the malleability of the AAT effect when strongly valenced stimuli are approached or avoided. We discuss the practical and theoretical implications of our findings.


Diagnostic validation of a portable whole slide imaging scanner for lymphoma diagnosis in resource-constrained setting: A cross-sectional study.
Telepathology utilizing high-throughput static whole slide image scanners is proposed to address the challenge of limited pathology services in resource-restricted settings. However, the prohibitive equipment costs and sophisticated technologies coupled with large amounts of space to set up the devices make it impractical for use in resource-limited settings. Herein, we aimed to address this challenge by validating a portable whole slide imaging (WSI) device against glass slide microscopy (GSM) using lymph node biopsies from suspected lymphoma cases from Sub-Saharan Africa. This was part of a multicenter prospective case-control head-to-head comparison study of liquid biopsy against conventional pathology. For the portable WSI scanner validation, the study pathologists evaluated 105 surgical lymph node specimens initially confirmed by gold-standard pathology between February and December 2021. The tissues were processed according to standard protocols for Hematoxylin and Eosin (H&E) and Immunohistochemistry (IHC) staining by well-trained histotechnicians, then digitalized the H& E and IHC slides at each center. The digital images were anonymized and uploaded to a HIPAA-compliant server by the histotechnicians. Three study pathologists independently accessed and reviewed the images after a 6-week washout. The agreement between diagnoses established on GSM and WSI across the pathologists was described and measured using Cohens' kappa coefficient (κ). On GSM, 65.5% (n=84) of specimens were lymphoma; 25% were classified as benign, while 9.5% were metastatic. Morphological quality assessment on GSM and WSI established that 79.8% and 53.6% of cases were of high quality, respectively. When diagnoses by GSM were compared to WSI, the overall concordance for various diagnostic categories was 93%, 100%, and 86% for lymphoma, metastases, and benign conditions respectively. The sensitivity and specificity of WSI for the detection of lymphoma were 95.2% and 85.7%, respectively, with an overall inter-observer agreement (κ) of 0.86; 95% CI (0.70-0.95). We demonstrate that mobile whole slide imaging (WSI) is non-inferior to conventional glass slide microscopy (GSM) for the primary diagnosis of malignant infiltration of lymph node specimens. Our results further provide proof of concept that mobile WSI can be adapted to resource-restricted settings for primary surgical pathology and would significantly improve patient outcomes.


All talk and no action: a transcranial magnetic stimulation study of motor cortex activation during action word production.
A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a word's sensorimotor features. In the present study, we used single- and paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category.


Dual liquid crystal alignment configuration based on nanoparticle-doped polymer films.
This paper proposes an approach for producing dual liquid crystal (LC) alignment configuration based on nanoparticle-doped polymer films. Experimental results indicate that illuminating a nanoparticle-doped pre-polymer film, coated onto a substrate with a homogeneous alignment layer, with unpolarized UV light through a photomask causes the polymerization of pre-polymer, ultimately generating homogeneous and vertical alignment layers in unpolymerized and polymerized regions, respectively. The dual LC alignment configuration of the homogeneous (vertical) and hybrid alignments can be achieved by combining the treated substrate with another substrate that has a homogeneous (vertical) alignment layer. Additionally, the applications of the dual LC alignment layer in phase gratings and transflective LC displays are demonstrated.


Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses.
IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM-antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.


Variables associated with unplanned general adult ICU admission in hospitalised patients: protocol for a systematic review.
Failure to promptly identify deterioration in hospitalised patients is associated with delayed admission to intensive care units (ICUs) and poor outcomes. Existing vital sign-based Early Warning Score (EWS) algorithms do not have a sufficiently high positive predictive value to be used for automated activation of an ICU outreach team. Incorporating additional patient data might improve the predictive power of EWS algorithms; however, it is currently not known which patient data (or variables) are most predictive of ICU admission. We describe the protocol for a systematic review of variables associated with ICU admission. MEDLINE, EMBASE, CINAHL and the Cochrane Library, including Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched for studies that assess the association of routinely recorded variables associated with subsequent unplanned ICU admission. Only studies involving adult patients admitted to general ICUs will be included. We will extract data relating to the statistical association between ICU admission and predictor variables, the quality of the studies and the generalisability of the findings. The results of this review will aid the development of future models which predict the risk of unplanned ICU admission. PROSPERO: CRD42015029617.


SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma.
Recently, analysis of DNA methylation of the SHOX2 locus was shown to reliably identify lung cancer in bronchial aspirates of patients with disease. As a plasma-based assay would expand the possible applications of the SHOX2 biomarker, this study aimed to develop a modified SHOX2 assay for use in a blood-based test and to analyze the performance of this optimized SHOX2 methylation assay in plasma. Quantitative real-time polymerase chain reaction was used to analyze DNA methylation of SHOX2 in plasma samples from 411 individuals. A training study (20 stage IV patients with lung cancer and 20 controls) was performed to show the feasibility of detecting the SHOX2 biomarker in blood and to determine a methylation cutoff for patient classification. The resulting cutoff was verified in a testing study composed of 371 plasma samples from patients with lung cancer and controls. DNA methylation of SHOX2 could be used as a biomarker to distinguish between malignant lung disease and controls at a sensitivity of 60% (95% confidence interval: 53-67%) and a specificity of 90% (95% confidence interval: 84-94%). Cancer in patients with stages II (72%), III (55%), and IV (83%) was detected at a higher sensitivity when compared with stage I patients. Small cell lung cancer (80%) and squamous cell carcinoma (63%) were detected at the highest sensitivity when compared with adenocarcinomas. SHOX2 DNA methylation is a biomarker for detecting the presence of malignant lung disease in blood plasma from patients with lung cancer.


Chest and breast MRI: the added value of a fast imaging for a new diagnostic approach in the planning of augmentation surgery in patients with thoracic asymmetries.
In breast augmentation surgery, breast symmetry depends on the breast tissue, implants and chest wall. Any asymmetry of the anterior thoracic wall can influence the breast shape. If breast asymmetry is detected in the preoperative evaluation, a chest wall deformity should be suspected. Until now, very few reports describe the use of MRI to objectively assess breast and chest measurements with the aim of providing customized augmentation. This study describes the use of MRI to evaluate breast and chest wall asymmetry, and considers the feasibility of preoperative measurements which are useful for performing an objective preoperative evaluation. Between April 2012 and February 2013, 13 patients underwent chest/breast MRI scan. Scans were performed on a 1.5 T scanner using a single T1 FSE non-suppressed axial sequence, without contrast administration. Acquisitions included the breast and chest wall. Specific measurements were obtained to assess the overall shape of the chest wall and breast, as well as any asymmetry. All patients showed some degree of left-right side asymmetry on specific thoracic, breast and implant measurements. MRI provided detailed and objective data. Preliminary findings revealed the value of breast/chest wall MRI in the planning of augmentation surgery. MRI is a valuable technique in young women because there is no use of ionizing radiation. Scans allow surgeons to determine the best surgical approach and obtain reproducible and better aesthetic results.


Prenatal ambient air exposure to polycyclic aromatic hydrocarbons and the occurrence of respiratory symptoms over the first year of life.
The purpose of the study was to test the hypothesis that infants with higher levels of prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) from fossil fuel combustion may be at greater risk of developing respiratory symptoms. The study was carried out in a cohort of 333 newborns in Krakow, Poland, followed over the first year of life, for whom data from prenatal personal air monitoring of mothers in the second trimester of pregnancy were available. The relative risks of respiratory symptoms due to prenatal PAHs exposure were adjusted for potential confounders (gender of child, birth weight, maternal atopy, maternal education as a proxy for the socio-economic status, exposure to postnatal environmental tobacco smoke, and moulds in households) in the Poisson regression models. Increased risk related to prenatal PAH exposure was observed for various respiratory symptoms such as barking cough (RR = 4.80; 95% CI: 2.73-8.44), wheezing without cold (RR = 3.83; 95% CI: 1.18-12.43), sore throat (RR = 1.96; 95% CI: 1.38-2.78), ear infection (RR = 1.82; 95% CI: 1.03-3.23), cough irrespective of respiratory infections (RR=1.27; 95% CI: 1.07-1.52), and cough without cold (RR = 1.72; 95% CI: 1.02-2.92). The exposure to PAHs also had impact on the duration of respiratory symptoms. The effect of PAHs exposure on the occurrence of such symptoms as runny nose or cough was partly modified by the simultaneous exposure to postnatal passive smoking. The analysis performed for the duration of respiratory symptoms confirmed significant interaction between PAHs exposure and postnatal ETS for runny or stuffy nose (RR = 1.82; 95% CI: 1.57-2.10), cough (RR = 1.18; 95% CI: 0.99-1.40), difficulty in breathing (RR = 1.39; 95% CI: 1.01-1.92) and sore throat (RR = 1.74; 1.26-2.39). Obtained results support the hypothesis that prenatal exposure to immunotoxic PAHs may impair the immune function of the fetus and subsequently may be responsible for an increased susceptibility of newborns and young infants to respiratory infections.


Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria.
Eculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of paroxysmal nocturnal hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce. We designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. Of the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to be increased. Low-molecular-weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Twenty cord-blood samples were examined for the presence of eculizumab; the drug was detected in 7 of the samples. A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples. Eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications. (ClinicalTrials.gov number, NCT01374360.).


Group-based cognitive behavioral therapy program for improving poor sleep quality and quality of life in people with epilepsy: A pilot study.
Sleep difficulties are commonly reported by patients with epilepsy and can have a detrimental impact on overall quality of life. The purpose of this pilot study was to assess the efficacy of a psychotherapeutic approach, namely Cognitive Behavioral Therapy for Insomnia (CBT-I), in improving sleep quality in patients with epilepsy. Twenty outpatients with epilepsy who reported poor sleep quality were randomized to either a control or CBT-I treatment group, which involved four group-based CBT-I sessions, delivered on a weekly basis. In addition to completing a range of standardized measures related to sleep quality and quality of life, participants also monitored their sleep with a self-completed sleep diary over a two-week period, on two separate occasions. Following CBT-I treatment, no between-group difference was found on any sleep or quality of life measure. However, both the treatment and control groups improved on measures of sleep quality, quality of life, sleep hygiene behaviors, and dysfunctional beliefs about sleep. These findings suggest that sleep monitoring alone may have the potential for prompting healthy behavior change in this clinical population.


Differential diagnosis and mutation stratification of desmoid-type fibromatosis on MRI using radiomics.
Diagnosing desmoid-type fibromatosis (DTF) requires an invasive tissue biopsy with β-catenin staining and CTNNB1 mutational analysis, and is challenging due to its rarity. The aim of this study was to evaluate radiomics for distinguishing DTF from soft tissue sarcomas (STS), and in DTF, for predicting the CTNNB1 mutation types. Patients with histologically confirmed extremity STS (non-DTF) or DTF and at least a pretreatment T1-weighted (T1w) MRI scan were retrospectively included. Tumors were semi-automatically annotated on the T1w scans, from which 411 features were extracted. Prediction models were created using a combination of various machine learning approaches. Evaluation was performed through a 100x random-split cross-validation. The model for DTF vs. non-DTF was compared to classification by two radiologists on a location matched subset. The data included 203 patients (72 DTF, 131 STS). The T1w radiomics model showed a mean AUC of 0.79 on the full dataset. Addition of T2w or T1w post-contrast scans did not improve the performance. On the location matched cohort, the T1w model had a mean AUC of 0.88 while the radiologists had an AUC of 0.80 and 0.88, respectively. For the prediction of the CTNNB1 mutation types (S45 F, T41A and wild-type), the T1w model showed an AUC of 0.61, 0.56, and 0.74. Our radiomics model was able to distinguish DTF from STS with high accuracy similar to two radiologists, but was not able to predict the CTNNB1 mutation status.


Consensus summary report for CEPI/BC March 12-13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines.
A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.


Incidence of and Neurodevelopmental Outcomes After Late-Onset Meningitis Among Children Born Extremely Preterm.
Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm. To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age. This cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks' gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers. Culture-confirmed LOM. Incidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021). Among 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection. In this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.


Processing Relative Clause Extractions in Swedish.
Relative clauses are considered strong islands for extraction across languages. Swedish comprises a well-known exception, allegedly allowing extraction from relative clauses (RCE), raising the possibility that island constraints may be subject to "deep variation" between languages. One alternative is that such exceptions are only illusory and represent "surface variation" attributable to independently motivated syntactic properties. Yet, to date, no surface account has proven tenable for Swedish RCEs. The present study uses eyetracking while reading to test whether the apparent acceptability of Swedish RCEs has any processing correlates at the point of filler integration compared to uncontroversial strong island violations. Experiment 1 tests RCE against licit that-clause extraction (TCE), illicit extraction from a non-restrictive relative clause (NRCE), and an intransitive control. For this, RCE was found to pattern similarly to TCE at the point of integration in early measures, but between TCE and NRCE in total durations. Experiment 2 uses RCE and extraction from a subject NP island (SRCE) to test the hypothesis that only non-islands will show effects of implausible filler-verb dependencies. RCE showed sensitivity to the plausibility manipulation across measures at the first potential point of filler integration, whereas such effects were limited to late measures for SRCE. In addition, structural facilitation was seen across measures for RCE relative to SRCE. We propose that our results are compatible with RCEs being licit weak island extractions in Swedish, and that the overall picture speaks in favor of a surface rather than a deep variation approach to the lack of island effects in Swedish RCEs.


Single Dose Corticosteroid Therapy After Surgical Repair of Fallot's Tetralogy; A Randomized Controlled Clinical Trial.
Inflammatory reaction can produce several complications after cardiac surgery. Many attempts have been made to reduce these complications; perioperative corticosteroid therapy is one of the simplest methods. We conducted a randomized study to evaluate the efficacy of single dose methylprednisolone, prescribed after surgery, for reducing the complications. Repair of Tetralogy of Fallot was chosen as a homogenous large group for the study. One hundred children who underwent total repair of Tetralogy of Fallot were enrolled in this study. After the surgery, all patients were transferred to pediatric ICU and were randomized (in a double-blind fashion) in 2 groups (A and B); a single dose of methylprednisolone (30 mg/kg of body weight) was injected to participants of group "A" just at the time of ICU entrance. Group "B" received no drug. Then, clinical outcomes and laboratory data were compared between the two groups. The only significant differences were lower incidence of bacteremia and higher incidence of hyperglycemia in the group who were used methylprednisolone. Using a single postsurgical dose of methylprednisolone does not significantly alter the clinical outcome after repairing Tetralogy of Fallot.


Generalist-feeding subterranean mites as potential biological control agents of immature corn rootworms.
Predatory mites are important components of subterranean food webs and may help regulate densities of agricultural pests, including western corn rootworms (Chrysomelidae: Diabrotica virgifera virgifera). Implementing conservation and/or classical biocontrol tactics could enhance densities of specialist or generalist predatory mites and lead to pest suppression, but first relevant mite species must be identified and their predatory capabilities evaluated. We conducted lab assays to quantify consumption of immature rootworms and oviposition rates of various mite species. Our study indicates that rootworms are a sub-optimal food source for the mite taxa tested. However, all mite species fed upon rootworms to some degree, although consumption by nematophagous Eviphis ostrinus was extremely low. Predators consumed more rootworm larvae than eggs, and mite size was correlated with prey consumption, with larger predators eating more prey. Four mite taxa (Gaeolaelaps sp., S. miles, Gl. americana, and G. aculeifer) had detrimental effects on survival of rootworm larvae, and the latter two species also had negative impacts on densities of pest eggs. Although it is unlikely that any of these mite species by itself has a major impact on rootworm control, the community of generalist soil-dwelling mites may play an important role in regulating immature rootworm populations in the field.


Architectural approach to the role of optics in monoprocessor and multiprocessor machines.
The relevance of introducing optical interconnects (OI's) in monoprocessors and multiprocessors is studied from an architectural point of view. We show that perhaps the major explanation for why optical technologies have nearly been unable to penetrate into computers is that OI's generally do not shorten the memory-access time, which is the most critical issue for today's stored-program machines. In monoprocessors the memory-access time is dominated by the electronic latency of the memory itself. Thus implementing OI's inside the memory hierarchy without changing the memory architecture cannot dramatically improve the global performance. In strongly coupled multiprocessors the node-bypass latency dominates. Therefore the higher the connectivity (possibly with optics), the shorter the path to another node, but the more expensive the network and the more complex the structure of electronic nodes. This relation leaves the choice of the best network open in terms of simplicity and latency reduction. The bottlenecks resulting from and the benefits of implementing OI's are discussed with respect to symmetric multiprocessors, rings, and distributed shared-memory supercomputers.


Ten-Year Trends In Treatment Services For Children With Attention Deficit Hyperactivity Disorder Enrolled In Medicaid.
Closing the gap between evidence-based clinical practice standards and their inclusion in routine practice continues to be a major goal of health policy reforms. This gap is especially large for the care of children with psychiatric disorders-especially those from low-income families, many of whom are insured through Medicaid. To address this gap, we analyzed trends over ten years (2001-10) from Medicaid claims data describing changes over time in medication, psychotherapy, and combined treatment services for children diagnosed with attention deficit hyperactivity disorder (ADHD). Over this time, more children received treatments that conformed to practice standards, including the use of combination treatments of medication and psychotherapy. Rates of combined treatment increased by 74 percent, rates of psychotherapy alone more than doubled, and rates of medication alone decreased by 18 percent. Rates of diagnoses without any reimbursed treatment decreased by 39 percent. These trends suggest increasing adherence to clinical practice standards by providers serving children with ADHD in the Medicaid population, although the quality of those services is unknown.


Analysis of the Effect of the Elderly's Labor Status on Care Cost at the End of Life.
This study quantitatively analyzes the effects of employment patterns at the time of death of the elderly on the utilization of medical care before death using the cohort data from the National Health Insurance Corporation, controlling mortality to obtain more accurate results. Gender was coded as 0 for males and 1 for females, and average monthly household income was taken as a logarithm to approximate a normal distribution. Care cost at the end of life was defined as the sum of the national health insurance contributions and statutory self-contributions. To measure proximity to death, deceased elderly were divided by the period from last hospital visit to death (except any hospital visit at time of death). We distinguished regular workers, irregular workers, self-employed and employers, unpaid family workers, and unemployed. The data used in this study are sample cohort data from the National Health Insurance Corporation. We examined the relationships between variables through 4 models using negative binomial regression. The effects of employment status on health status were analyzed and adjusted for demographic characteristics, socioeconomic status, and proximity to death. As the dependent variable, medical expenses were taken for 1 year before death. In this study, care costs at end of life were higher when children were economically independent and when the respondent was more educated, had high economic level, and had high average monthly household income. In addition, employment security also had a significant impact on care cost at end of life: Irregular workers spent significantly less than regular workers. The fact that care cost at end of life is differentiated according to employment status suggests that individuals' health exists within a social context, which may also constrain it: There is a risk that people's health status will become determined by socioeconomic status.


Taccalonolide binding to tubulin imparts microtubule stability and potent in vivo activity.
The taccalonolides are highly acetylated steroids that stabilize cellular microtubules and overcome multiple mechanisms of taxane resistance. Recently, two potent taccalonolides, AF and AJ, were identified that bind to tubulin directly and enhance microtubule polymerization. Extensive studies were conducted to characterize these new taccalonolides. AF and AJ caused aberrant mitotic spindles and bundling of interphase microtubules that differed from the effects of either paclitaxel or laulimalide. AJ also distinctly affected microtubule polymerization in that it enhanced the rate and extent of polymerization in the absence of any noticeable effect on microtubule nucleation. In addition, the resulting microtubules were found to be profoundly cold stable. These data, along with studies showing synergistic antiproliferative effects between AJ and either paclitaxel or laulimalide, suggest a distinct binding site. Direct binding studies demonstrated that AJ could not be displaced from microtubules by paclitaxel, laulimalide, or denaturing conditions, suggesting irreversible binding of AJ to microtubules. Mass spectrometry confirmed a covalent interaction of AJ with a peptide of β-tubulin containing the cyclostreptin-binding sites. Importantly, AJ imparts strong inter-protofilament stability in a manner different from other microtubule stabilizers that covalently bind to tubulin, consistent with the distinct effects of the taccalonolides as compared with other stabilizers. AF was found to be a potent and effective antitumor agent that caused tumor regression in the MDA-MB-231 breast cancer xenograft model. The antitumor efficacy of some taccalonolides, which stabilize microtubules in a manner different from other microtubule stabilizers, provides the impetus to explore the therapeutic potential of this site.