Consistency and replicability of a pharmacist-led intervention for asthma patients: Italian Medicines Use Review (I-MUR).
AimThis study aimed to assess the consistency and replicability of these process measures during provision of the Italian Medicines Use Review (I-MUR). Medication review is a common intervention provided by community pharmacists in many countries, but with little evidence of consistency and replicability. The I-MUR utilised a standardised question template in two separate large-scale studies. The template facilitated pharmacists in recording medicines and problems reported by patients, the pharmaceutical care issues (PCIs) they found and actions they took to improve medicines use. Community pharmacists from four cities and across 15 regions were involved in the two studies. Patients included were adults with asthma. Medicines use, adherence, asthma problems, PCIs and actions taken by pharmacists were compared across studies to assess consistency and replicability of I-MUR.FindingsThe total number of pharmacists and patients completing the studies was 275 and 1711, respectively. No statistically significant differences were found between the studies in the following domains: patients' demographic, patients' perceived problems, adherence, asthma medicines used and healthy living advice provided by pharmacists. The proportion of patients in which pharmacists identified PCIs was similar across both studies. There were differences only in the incidence of non-steroidal anti-inflammatory drug use, the frequency of potential drug-disease interactions and in the types of advice given to patients and GPs. The use of a standardised template for the I-MUR may have contributed to a degree of consistency in the issues found, which suggests this intervention could have good replicability.


Digital microfluidics-based digital counting of single-cell copy number variation (dd-scCNV Seq).
Single-cell copy number variations (CNVs), major dynamic changes in humans, result in differential levels of gene expression and account for adaptive traits or underlying disease. Single-cell sequencing is needed to reveal these CNVs but has been hindered by single-cell whole-genome amplification (scWGA) bias, leading to inaccurate gene copy number counting. In addition, most of the current scWGA methods are labor intensive, time-consuming, and expensive with limited wide application. Here, we report a unique single-cell whole-genome library preparation approach based on digital microfluidics for digital counting of single-cell Copy Number Variation (dd-scCNV Seq). dd-scCNV Seq directly fragments the original single-cell DNA and uses these fragments as templates for amplification. These reduplicative fragments can be filtered computationally to generate the original partitioned unique identified fragments, thereby enabling digital counting of copy number variation. dd-scCNV Seq showed an increase in uniformity in the single-molecule data, leading to more accurate CNV patterns compared to other methods with low-depth sequencing. Benefiting from digital microfluidics, dd-scCNV Seq allows automated liquid handling, precise single-cell isolation, and high-efficiency and low-cost genome library preparation. dd-scCNV Seq will accelerate biological discovery by enabling accurate profiling of copy number variations at single-cell resolution.


Application of proximity ligation assays to identify potential plasma biomarkers in oral cavity cancer patients: A case control study.
Practical cancer biomarkers for oral cavity cancer are currently in limited use. We aimed to investigate the differences in soluble E-cadherin between patients with oral cavity cancer and matched healthy participants via Proximity Ligation Assay (PLA). Samples were taken from both patients diagnosed with oral cavity cancer, as well as non-cancerous participants. PLA was used to detect soluble E-cadherin and Cycle threshold (Ct) values derived from qPCR in order to calculate the number of starting amplicons. In total, 74 patients with oral cavity cancer and 55 matched non-cancerous participants were included for final analysis. The Ct value of E-cadherin was found to be lower in oral cavity cancer patients when compared with that of the matched non-cancerous participants (20.72 ± 0.39 versus 21.27 ± 0.45, P< 0.001). Using a Ct value of 20.9 as a cut-off point, the sensitivity and specificity of discriminating patients with oral cavity cancer from the healthy controls was 63.5% and 87.3%, respectively. Plasma soluble E-cadherin levels were significantly higher in patients with oral cavity cancer when compared with those from the matched non-cancerous participants.


Yeast methionine aminopeptidase I can utilize either Zn2+ or Co2+ as a cofactor: a case of mistaken identity?
Yeast methionine aminopeptidase I (MetAP I) is one of two enzymes in Saccharomyces cerevisiae that is responsible for cotranslational cleavage of initiator methionines. It has previously been classified as a Co2+ metalloprotease in all prokaryotic and eukaryotic forms studied. However, treatment of recombinant apo-MetAP I with 12.5 microM Zn2+ produces an enzyme that is as active as that reconstituted with 200 microM Co2+. In the presence of physiological concentrations of reduced glutathione (GSH), Co-MetAP I is inactive, while the activity of Zn-MetAP I is increased more than 1.7-fold over Zn-MetAP I assayed in the absence of GSH. Given that the in vivo concentration of Zn2+ is at least 1,000-fold higher than that of Co2+, and that Co2+ is insoluble in physiological concentrations of GSH, it is probable that yeast MetAP I is actually a Zn2+ metalloprotease. Furthermore, unless there are extraordinary conditions that insulate or sequester them from this reducing milieu, that have yet to be identified, there are not likely to be any cytoplasmic enzymes that use free Co2+.


The cooperative folding of annexin A2 relies on a transient nonnative intermediate.
Annexins (Anxs) are a family of highly homologous proteins that bind and aggregate lipid vesicles in the presence of calcium. All members of the family contain a variable N-terminus determining specific functions, followed by a conserved core region responsible for the general calcium-dependent lipid-binding property. The core structure consists of four homologous domains (DI-DIV), each consisting of a right-handed super-helix of five α-helices. We present data from a combination of site-directed mutagenesis, NMR, and circular dichroism showing that the G25-D34 region of the N-terminus as well as the contacts between residues D38A, R63A, and Q67A of AnxA2-DI are crucial for the autonomous folding and stability of DI of AnxA2. However, we also show that the folding of the full-length protein is very robust in that mutations and truncations that disrupted the folding of AnxA2-DI did not abolish the folding of full-length AnxA2, only lowering its thermal stability. This robustness of the folding of full-length AnxA2 is likely to be mediated by the existence of at least one transient nonnative intermediate as suggested by our kinetic data using stopped-flow fluorescence experiments. We also show that hydrophobic amino acids in AnxA2-DI involved in interfacial contacts with AnxA2-DIV are important for the cooperative folding and stability of the full-length protein. Mutating all of the V57E-V98R-G101Y residues in AnxA2-DI did not affect the folding of the domain, only its stability, but prevented the cooperative folding of the full-length protein. Our collective results favor a highly cooperative and robust folding process mediated by alternative intermediate steps. Since AnxA2 is a multifunctional protein involved in several steps of the progression of cell transformation, these data on structure and folding pathways are therefore crucial to designing anticancer drugs targeting AnxA2.


Posttraumatic neovascularization in a cataractous crystalline lens.
A 73-year-old woman presented with a dense traumatic cataract and intralens angiogenesis. Slitlamp examination showed abundant blood vessels in the lens stroma. Microscopic examination confirmed the presence of blood cells in the lumen. The angiogenesis represented an ingrowth into the lens from posterior synechias. Pathologic angiogenesis is frequently seen in the retina, vitreous, iris, and cornea but is rarely seen in the crystalline lens. This is the first well-documented case of angiogenesis in the lens stroma.


Plant regeneration and stable transformation in the floricultural plant Cleome spinosa, a C₃ plant closely related to the C₄ plant C. gynandra.
Cleome spinosa is widely used as a garden ornamental in many countries. Here we determined the optimal conditions for plant regeneration from different tissue explants grown in vitro. Induction medium containing MS salts, MS vitamins, 3% sucrose, 1 mg l⁻¹ BA, 200 mg l⁻¹ timentin, and 0.8% agar was sufficient for shoot regeneration of all the tissue explants examined, including leaf, hypocotyl, and cotyledon. Subsequently, an Agrobacterium tumefaciens-mediated method was developed to transform the vector pCHS, which carries the transgenes Petunia chalcone synthase (chs) and selection marker neomycin phosphotransferase II (nptII), into C. spinosa. From a total of 368 cotyledon explants, 13 putative transgenic lines were regenerated from selection medium supplemented with 50 mg l⁻¹ kanamycin and 200 mg l⁻¹ timentin, and transferred to the greenhouse. Genomic PCR and Southern blot analyses revealed that the nptII transgene was present in all 13 transgenic plants. Similarly, when the Petunia chs transgene was used as a probe in Southern blot analysis, single or multiple hybridization bands were detected in 12 out of the 13 transgenic plants. In addition, T₁ progeny assay from selected transformants showed that the nptII transgene can be transmitted in a Mendelian manner from transgenic parents into their progeny. This is the first report of stable transformation of the C₃ dicotyledon C. spinosa, which will facilitate functional comparison of cell-type specific genes with counterpart C₄ dicotyledon C. gynandra using transgenic approaches.


Direct cross-linking of heptauridilate to E. coli ribosomes by water-soluble carbodiimide in the complex stabilized by codon-anticodon interaction at both A- and P-sites.
Affinity labelling of E. coli ribosomes is performed by treatment with water-soluble carbodiimide of the complex of ribosomes with (pU)7, tRNAPhe at the P-site and with Phe-tRNAPhe (complex I) and without Phe-tRNAPhe (complex II) at the A-site. The extent of modification is, respectively, 0.06 and 0.026 mol (pU)7 per mol ribosomes. Protein S3 is found as a single labelled protein in complex I, whereas S7, S8, L25 are modified in complex II. Thus, in the absence of a large spacer group within the complex stabilized by codon-anticodon interactions at both A- and P-sites, a highly selective modification occurs.


Effect of 6-hydroxydopamine treatment on TSH secretion in basal and cold-stimulated conditions in the rat.
6-Hydroxydopamine (6-OHDA) (two doses of 200 micrograms each, administered intraventricularly at a 48 h interval) caused a marked decrease of hypothalamic noradrenaline content and blocked the TSH rise elicited by cold exposure. Clonidine (0.4 mg/kg i.p.), a noradrenaline receptor agonist, was able to reverse the 6-OHDA of cold-induced TSH surge. The plasma TSH levels after cold stress in rats treated with 6-OHDA + clonidine were significantly higher than in vehicle + clonidine-injected animals, thus suggesting the presence of noradrenaline receptor supersensitivity in 6-OHDA-pretreated rats. 6-OHDA did not modify the basal concentrations of TSH but the administration of clonidine to 6-OHDA-injected animals caused a significant increase in thyrotropin secretion when compared with the vehicle + clonidine group.


Malignant mesothelioma with minimal asbestos exposure.
The association of malignant mesothelioma and asbestos fibers is well established. The minimal exposure that may produce the tumor is not known. The present report documents the minimal exposure by thorough examination of occupational history and personal hobbies, and counting of the number of asbestos fibers in the lungs. The evidence for the elemental composition of asbestos fibers by electron probe (EDAX) is also presented.


Caffeine injection raises brain tryptophan level, but does not stimulate the rate of serotonin synthesis in rat brain.
Acute caffeine injection (100 mg/kg) elevates brain levels of tryptophan (TRP), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA). Experiments were performed to determine if the increases in 5HT and 5HIAA result from a stimulation of the rate of 5HT synthesis. Both the rate of 5-hydroxytryptophan (5HTP) accumulation following NSD-1015 injection, and the rate of 3H-5-hydroxyindole synthesis from 3H-tryptophan were measured in vivo following caffeine administration and found to be normal. Tryptophan hydroxylase activity, as measured in vitro in brain homogenates, was also unaffected by caffeine. The results suggest that the elevations in brain 5HT and 5HIAA levels produced by caffeine do not reflect enhanced 5HT synthesis, despite significant elevations in brain TRP level. Some other mechanism(s) must therefore be responsible for these elevations in brain 5-hydroxyindole levels.


Scoring of brain magnetic resonance imaging and neurodevelopmental outcomes in infants with congenital heart disease.
Advances in surgical techniques to tackle critical congenital heart diseases (CHD) have enhanced the survival rates and life expectancy of children born with heart disease. Studies to better acknowledge their neurodevelopmental trajectory have paramount implications. The aim of this study is to examine the nature of brain MRI findings in infants born with critical congenital heart diseases needing intervention in the first 6 months of life, with the help of an MRI scoring system and correlation with long term neurodevelopmental outcomes. Brain MRI scans of eligible infants were extracted from database, reexamined to categorize, and score them into three main functional areas: cognitive/grey matter, motor/white matter, and visual. The scoring system also included stage of myelination and presence of punctate hemorrhages. The correlation of individual and total MRI scores with neurodevelopmental assessment using Bayley Scales for Infant and Toddler Development- version 3 (BSID III) were examined via logistic regression models while controlling for confounding variables. Median (IQR) MRI score was 6 (4-7) with grey matter score of 2 (1-4). Initial BSID III scores were 80 ± 15, 80 ± 18, and 81 ± 19 for cognitive, motor and language components, respectively. The MRI cognitive score had direct correlation with respiratory index prior to surgery (cc = 0.47, p = 0.03) and cross-clamping time (cc = 0.65, p = 0.001). It displayed a significant inverse correlation with language scores for BSID III at 9 months (R = -0.42, p = 0.04) which lost significance in subsequent visits. This pilot study proved the feasibility of correlating structural brain abnormalities in MRI with later brain developmental deficits in infants with CHD. We envision establishing a standardized MRI scoring system to be performed on a large multi-center cohort that would help better predict and measure brain injury in infants with CHDs.


The effects of abdominal-based early progressive mobilisation on gastric motility in endotracheally intubated intensive care patients: A randomised controlled trial.
To examine whether an abdominal-based early progressive mobilisation program improves gastric motility and reduces feeding intolerance in critically ill patients with endotracheal intubation. A randomised controlled trial was designed. Adult patients admitted to the intensive care unit who were intubated and had an order for enteral nutrition were randomly assigned to partake in an three stages of abdominal-based progressive mobilisation program (passive abdominal massage, bed-side bicycle and ambulating) or standard of care. Gastric antral motility was measured by bedside ultrasound. A total of 83 critically ill patients were included in the study. The intervention group displayed a statistically significant improvement in the antral motility index than the control group (p < .001), as well as in complications of feeding intolerance, including the incidence of abdominal distention (9.8% vs 33.3%, p = .009), vomiting (0% vs 16.7%, p = .019) and diarrhoea (22% vs 50%, p = .008). However, no significant difference for the full enteral feeding rate on the third day was observed between the groups.Furthermore, time on mechanical ventilation (4.52 ± 2.77 days vs 6.24 ± 3.90 days, p = .023) was shorter in intervention group, but no significant difference of length of intensive care unit stay was observed between the groups. Implementation of an abdominal-based early progressive mobilisation program can improve gastric motility and feeding intolerance in critically ill patients with an endotracheal tube.


Toll-like receptor 9, what o'clock is it?
In this issue of Immunity, Silver et al. (2012) provide evidence that murine Toll-like receptor 9 (TLR9) expression and function in innate and adaptive immunity is controlled by the circadian cycle.


Speciation analysis of inorganic arsenic by microchip capillary electrophoresis coupled with hydride generation atomic fluorescence spectrometry.
A novel method for speciation analysis of inorganic arsenic was developed by on-line hyphenating microchip capillary electrophoresis (chip-CE) with hydride generation atomic fluorescence spectrometry (HG-AFS). Baseline separation of As(III) and As(V) was achieved within 54 s by the chip-CE in a 90 mm long channel at 2500 V using a mixture of 25 mmol l(-1) H3BO3 and 0.4 mmol l(-1) CTAB (pH 8.9) as electrolyte buffer. The precisions (RSD, n=5) ranged from 1.9 to 1.4% for migration time, 2.1 to 2.7% for peak area, and 1.8 to 2.3% for peak height for the two arsenic species at 3.0 mg l(-1) (as As) level. The detection limits (3sigma) for As(III) and As(V) based on peak height measurement were 76 and 112 microg l(-1) (as As), respectively. The recoveries of the spikes (1 mg l(-1) (as As) of As(III) and As(V)) in four locally collected water samples ranged from 93.7 to 106%.


Comprehensive analysis of IncC plasmid conjugation identifies a crucial role for the transcriptional regulator AcaB.
The IncC family of broad-host-range plasmids enables the spread of antibiotic resistance genes among human enteric pathogens1-3. Although aspects of IncC plasmid conjugation have been well studied4-9, many roles of conjugation genes have been assigned based solely on sequence similarity. We applied hypersaturated transposon mutagenesis and transposon-directed insertion-site sequencing to determine the set of genes required for IncC conjugation. We identified 27 conjugation genes, comprising 19 that were previously identified (including two regulatory genes, acaDC) and eight not previously associated with conjugation. We show that one previously unknown gene, acaB, encodes a transcriptional regulator that has a crucial role in the regulation of IncC conjugation. AcaB binds upstream of the acaDC promoter to increase acaDC transcription; in turn, AcaDC activates the transcription of IncC conjugation genes. We solved the crystal structure of AcaB at 2.9-Å resolution and used this to guide functional analyses that reveal how AcaB binds to DNA. This improved understanding of IncC conjugation provides a basis for the development of new approaches to reduce the spread of these multi-drug-resistance plasmids.


A preliminary study of the effects of tooth guidance on working-side condylar movement.
Clinical observations have indicated that lateral working-side tooth contacts can produce a posterior shift of the working-side condyle, resulting in pain in the temporomandibular joint. This study examined the influence of lateral retrusive and lateral protrusive tooth guidance on the movements of working condyles of the lateral pole. Four patients with lateral retrusive natural tooth contacts and four patients with lateral protrusive natural tooth contacts were studied. Movement of the lateral pole of the working condyle was recorded under the following conditions: (1) natural teeth in contact, (2) wearing of a mandibular acrylic resin splint that created lateral protrusive or lateral retrusive tooth guidance, and (3) a central bearing screw and bearing plate separating the teeth. The results indicated that the condition of the patient's temporomandibular joints was a crucial factor in consistency of condylar tracings. Condylar tracings from patients with temporomandibular joint condyle-disk lacking coordination were inconsistent and unreproducible. Consistent, reproducible tracings for patients without condyle-disk disorders indicated that lateral retrusive guidance can cause a more posterior pathway of the lateral pole of the working condyle than lateral protrusive guidance. Future studies are necessary to establish the relationship between lateral tooth guidance and temporomandibular disorders.


Block of neurotensin receptor down-regulation by an aminosteroid in N1E-115 cells.
We have demonstrated that the aminosteroid, U-73122 (1-(6-([17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl)-1H-pyrrole- 2,5-dione) blocks agonist induced down-regulation of neurotensin receptors in murine neuroblastoma clone N1E-115 cells. U-73122 is known to inhibit polyphosphoinositide hydrolysis by affecting the coupling of GTP-binding proteins. Our results may indicate that GTP-binding proteins play a role in the mechanism of down-regulation of the neurotensin receptor.


Group-velocity control by quadratic nonlinear interactions.
We give direct experimental evidence that the group velocity of ultrashort pulses can be controlled through chi(2)-cascaded interactions, under the condition of large group-velocity mismatch. The group velocity can be finely tuned by acting on pulse intensity and phase mismatch. Group-delay shifts up to 50 fs are achieved by propagating 40 fs pulses around 1400 nm in a 25 mm long periodically poled stoichiometric lithium tantalate crystal.


Management of complex hernias with loss of domain using daily and fractioned preoperative progressive pneumoperitoneum: a retrospective single-center cohort study.
The incidence of complex hernias with loss of domain (CHLD) has been increasing and the treatment of these cases may require auxiliary techniques in addition to surgery. This study aims to refine the progressive preoperative pneumoperitonium (PPP) in patients with CHLD, to achieve an increased in wall dimensions. Patients presented with a CHLD undergoing PPP protocol were analyzed between May 2017 and May 2019. Our PPP protocol was to use two daily insufflations of 1000 ml of ambient air during a period of 14 days. We compared the abdominal cavity volume (ACV), the hernial sac volume (HSV) and the volume ratio (VR), before and after our refined PPP. During our evaluation period, the protocol was performed on 16 patients. The mean age was 55.73 (± 12.87), and the mean BMI was 31.35 (± 7.33). The median of HSV was 2104.53 ml; Mean ACV was 6722.36 ml, and median of VR was 29.97% (27.46-34.38 IIQ). The averages were: daily volume of gas ± 1526.66 ml, total volume ± 17,350 ml, and the PPP period of ± 10.7 days. The increase in post-PPP ACV was 52.13% (p < 0.0001), and the VR decreased to 26.9% (p < 0.609). All patients' symptoms and complications were mild (according Clavien-Dindo grades I and II), and there were no loop injuries, no catheter complications, or any surgical re-interventions. The study suggests that the use of this method results in a significant increase in ACV, and reduction of the herniated content in a safe and efficient manner, with mild complications.


The origin of life--a review of facts and speculations.
Three popular hypotheses attempt to explain the origin of prebiotic molecules: synthesis in a reducing atmosphere, input in meteorites and synthesis on metal sulfides in deep-sea vents. It is not possible to decide which is correct. It is also unclear whether the RNA world was the first biological world or whether some simpler world preceded it.


Diagnostic Performance of Ultrasound-Based International Ovarian Tumor Analysis Simple Rules and Assessment of Different NEoplasias in the adneXa Model for Predicting Malignancy in Women with Ovarian Tumors: A Prospective Cohort Study.
Comparative performance of various ultrasound models in diagnosing ovarian lesions has not been adequately studied. This study aimed to evaluate the diagnostic performance of the International Ovarian Tumor Analysis (IOTA) simple rules and Assessment of Different NEoplasias in the adneXa (ADNEX) models in women with ovarian lesions. Women 18-80 years, with an ovarian lesion planned for surgery were recruited in this prospective observational cohort study. Preoperative risk stratification was done by both IOTA simple rules and the ADNEX model. The diagnostic performance of both models was estimated using histopathology as the gold standard. A total of 90 women were recruited into the study. The IOTA simple rules were applicable to 77 (85.5%) participants and the ADNEX model on 100% women. Both the simple rules and the ADNEX model had good diagnostic performance. The sensitivity and specificity of the IOTA simple rules for predicting malignancy was 66.6% and 91%, while that of the ADNEXA model was 80% and 94%, respectively. The maximum diagnostic accuracy for prediction of both benign and malignant tumors was obtained when cancer antigen-125 (CA-125) was combined with the IOTA ADNEX model (91.0%), but for Stage I malignancy, the maximum diagnostic accuracy was for ADNEX without CA-125 (91.0%). Both the IOTA models have a good diagnostic accuracy and are of paramount importance in differentiating benign from malignant tumors and predicting the stage of the malignant disease.


Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody.
In this study we determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium 225 (225Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity. Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0 to 16.65 kBq of the alpha-particle emitter labeled antibody, 225Ac-DOTA-7.16.4, and euthanized at 1 to 9 days after treatment. Complete blood counts were performed. Femurs and tibias were collected, and bone marrow was isolated from 1 femur and tibia and counted for radioactivity. Contralateral intact femurs were fixed, decalcified, and assessed by histology. Marrow cellularity was the biologic endpoint selected for RBE2 determination. For the reference radiation, both femurs of the mice were photon irradiated with 0 to 5 Gy using a small animal radiation research platform. Response as measured by cellularity for the alpha-particle emitter RPT (αRPT) RPT and the external beam radiation therapy were linear and linear quadratic, respectively, as a function of absorbed dose. The resulting dose-independent RBE2 for bone marrow was 6. As αRPT gains prominence, preclinical studies evaluating RBE in vivo will be important in relating to human experience with beta-particle emitter RPT. Such normal tissue RBE evaluations will help mitigate unexpected toxicity in αRPT.


Sex differences in coronary catheterization and revascularization following acute myocardial infarction: time trends from 1994 to 2003 in British Columbia.
Studies before the turn of the century reported sex differences in procedure rates. It is unknown whether these differences persist. To examine time trends and sex differences in coronary catheterization and revascularization following acute myocardial infarction (AMI). A retrospective analysis was performed of all patients 20 years of age or older who were admitted to hospital in British Columbia with an AMI between April 1, 1994, and March 31, 2003. Segmented regression analysis was used to examine the inflection point of the time trend in 90-day catheterization rates post-AMI. Multivariable Cox regression modelling was used to evaluate sex differences in receiving catheterization and revascularization following AMI. Ninety-day coronary catheterization rates increased significantly over the study period for both men and women (P<0.0001 for trend), with a steeper increase beginning in September 2000. Women were less likely to undergo catheterization than men, even after adjustment for baseline differences; this sex effect was modified by age and care in the intensive care unit or cardiac care unit (ICU⁄CCU). Specifically, ICU⁄CCU admission eliminated the sex difference among patients who were younger than 65 years of age. Conditional on receiving cardiac catheterization post-AMI, female sex was not associated with a lower likelihood of receiving revascularization within one year (HR 0.96; 95% CI 0.91 to 1.02). Despite recent increases in catheterization rates post-AMI, women were less likely to undergo catheterization than men. Interestingly, access to ICU⁄CCU care removed the sex difference in catheterization access in patients younger than 65 years of age.


High-performance liquid chromatography fractionation using a silver-modified column followed by two-dimensional comprehensive gas chromatography for detailed group-type characterization of oils and oil pollutions.
Successful remediation of oil-contaminated soils relies on a sound preceding characterization of the oil chemical composition and physicochemical properties. Comprehensive two-dimensional gas chromatography with flame ionization detection (GCxGC/FID) is known to be very suitable for the analysis of complex samples such as petroleum hydrocarbons. However, in spite of the high-separation power offered by GCxGC, it fails to completely separate certain hydrocarbon groups in petroleum hydrocarbon mixtures. This hampers a detailed chemical composition assessment which can lead to wrong conclusions on the behaviour of the oil in soil systems, e.g. biological degradability and water solubility. This paper describes a high-performance liquid chromatography (HPLC) system with a silver-modified column as a prefractionation step to GCxGC to improve chemical identification. With HPLC, the petroleum hydrocarbons were baseline separated into a saturated fraction (including alkanes and cycloalkanes) and an unsaturated fraction (including alkenes, aromatic hydrocarbons and heterocyclic components). Each fraction eluted in a small time window limiting the dilution caused by HPLC. The two fractions were collected and quantitatively analyzed with GCxGC/FID. Cold splitless injection of 4 microl was adopted to compensate the dilution caused by the prefractionation step. With oil-spiked soil samples, a good reproducibility was obtained (RSD=3.5%; n=7) and the recovery was satisfactory (87.7%).


Cardiovascular Risk Factors and Heart Rate Variability: Impact of the Level of the Threshold-Based Artefact Correction Used to Process the Heart Rate Variability Signal.
The associations between cardiovascular disease (CVD) risk factors and heart rate variability (HRV) have shown some inconsistencies. To examine the impact of the different Kubios threshold-based artefact correction levels on the associations between different CVD risk factors and a heart rate variability (HRV) score in three independent human cohorts. A total of 107 children with overweight/obesity, 132 young adults, and 73 middle-aged adults were included in the present study. Waist circumference and the HRV score were negatively associated using the medium and the strong Kubios filters in children (β = -0.22 and - 0.24, P = 0.03 and 0.02 respectively) and the very strong Kubios filter in middle-aged adults (β = -0.39, P = 0.01). HDL-C was positively associated with the HRV score across Kubios filters (β ranged from 0.21 to 0.31, all P ≤ 0.04), while triglycerides were negatively associated with the HRV score using the very strong Kubios filter in young adults (β = -0.22, P = 0.02). Glucose metabolism markers (glucose, insulin, and HOMA index) were inversely associated with the HRV score across Kubios filters in young adults (β ranged from -0.29 to -0.22; all P ≤ 0.03). Importantly, most of these associations disappeared after including HR as a covariate, especially in children and young adults. It should be mandatory to report the Kubios filter used and to include the HR (as a confounder factor) to allow the comparability of the results across different studies.


The initial evaluation in ophthalmic injury.
The recognition and proper initial handling of the many types of ocular injury will result in increased preservation of eyesight and fewer complications. This presentation has attempted to provide some of the general principles of ocular examination as a guide to the physician in dealing with ocular trauma.


Synthesis and biological investigations of 5-substituted pyrimidine nucleosides coupled to a dihydropyridine/pyridinium salt redox chemical delivery system.
The syntheses, antiviral activities, and partition coefficients (P) of 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-coupled nucleosides are described. These novel compounds were designed in an effort to enhance the lipophilicity, and thereby the delivery to the CNS, without compromising the anti-HSV-1 activity of the parental nucleosides. We have previously reported the synthesis of 3'-O-(1-methyl-1,4-dihydropyridyl-3- carbonyl) analogs of 5-iodo-(5), 5-vinyl-(6), and (E)-5-(2-iodovinyl)-2'-deoxyuridines (7). We now report the synthesis of 5-iodo-3'-O-(1-methyl-1,4-dihydropyridyl-3- carbonyl)-5'-O-acetyl-2'-deoxyuridine (15) and 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2'-deoxyuridine (17). Quarternization of the 3'-O-(3-pyridylcarbonyl) compounds (10,12) using iodomethane afforded the corresponding 1-methyl pyridinium salts (13,14) which were reduced with sodium dithionite to yield the corresponding 3'-O-1-methyl-1,4-dihydropyridyl-3-carbonyl compounds (15,16). The deprotection of 3'-O-(1-methyl-1,4-dihydropyridyl- 3-carbonyl)-5'-O-t-butyldimethylsilyl-2'-deoxyuridine (16) with Bu4N+F- afforded 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2'-deoxyuridine (17). Compounds 5-7 and 15 were evaluated for their antiviral activity in vitro against HSV-1, HSV-2, HCMV, and VZV, and were found to retain anti-HSV-1, HSV-2 and VZV activity as compared to their parental nucleosides (1-3). In addition, the cellular toxicity of 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-coupled compounds (5-7 and 15) was found to be lower than the parent nucleosides. The lipophilicity of compounds (5-7,15,17) are enhanced substantially, compared to the parent nucleosides, as indicated by an increase in corresponding P values (1-octanol-water) upon replacement of the C-3' hydroxyl by 1-methyl-1,4-dihydropyridyl-3-carbonyl moiety.


Exploring the utility of robots in exposure studies.
Obtaining valid, reliable quantitative exposure data can be a significant challenge for industrial hygienists, exposure scientists, and other health science professionals. In this proof-of-concept study, a robotic platform was programmed to perform a simple task as a plausible alternative to human subjects in exposure studies for generating exposure data. The use of robots offers several advantages over the use of humans. Research can be completed more efficiently and there is no need to recruit, screen, or train volunteers. In addition, robots can perform tasks repeatedly without getting tired allowing for collection of an unlimited number of measurements using different chemicals to assess exposure impacts from formulation changes and new product development. The use of robots also eliminates concerns with intentional human exposures while removing health research ethics review requirements which are time consuming. In this study, a humanoid robot was programmed to paint drywall, while volatile organic compounds were measured in air for comparison to model estimates. The measured air concentrations generally agreed with more advanced exposure model estimates. These findings suggest that robots have potential as a methodology for generating exposure measurements relevant to human activities, but without using human subjects.


MiR171h restricts root symbioses and shows like its target NSP2 a complex transcriptional regulation in Medicago truncatula.
Legumes have the unique capability to undergo root nodule and arbuscular mycorrhizal symbiosis. Both types of root endosymbiosis are regulated by NSP2, which is a target of microRNA171h (miR171h). Although, recent data implies that miR171h specifically restricts arbuscular mycorrhizal symbiosis in the root elongation zone of Medicago truncatula roots, there is limited knowledge available about the spatio-temporal regulation of miR171h expression at different physiological and symbiotic conditions. We show that miR171h is functionally expressed from an unusual long primary transcript, previously predicted to encode two identical miR171h strands. Both miR171h and NSP2 transcripts display a complex regulation pattern, which involves the symbiotic status and the fertilization regime of the plant. Quantitative Real-time PCR revealed that miR171h and NSP2 transcript levels show a clear anti-correlation in all tested conditions except in mycorrhizal roots, where NSP2 transcript levels were induced despite of an increased miR171h expression. This was also supported by a clear correlation of transcript levels of NSP2 and MtPt4, a phosphate transporter specifically expressed in a functional AM symbiosis. MiR171h is strongly induced in plants growing in sufficient phosphate conditions, which we demonstrate to be independent of the CRE1 signaling pathway and which is also not required for transcriptional induction of NSP2 in mycorrhizal roots. In situ hybridization and promoter activity analysis of both genes confirmed the complex regulation involving the symbiotic status, P and N nutrition, where both genes show a mainly mutual exclusive expression pattern. Overexpression of miR171h in M. truncatula roots led to a reduction in mycorrhizal colonization and to a reduced nodulation by Sinorhizobium meliloti. The spatio-temporal expression of miR171h and NSP2 is tightly linked to the nutritional status of the plant and, together with the results from the overexpression analysis, points to an important function of miR171h to integrate the nutrient homeostasis in order to safeguard the expression domain of NSP2 during both, arbuscular mycorrhizal and root nodule symbiosis.


Mutation enhances cooperation in direct reciprocity.
Direct reciprocity is a powerful mechanism for the evolution of cooperation based on repeated interactions between the same individuals. But high levels of cooperation evolve only if the benefit-to-cost ratio exceeds a certain threshold that depends on memory length. For the best-explored case of one-round memory, that threshold is two. Here, we report that intermediate mutation rates lead to high levels of cooperation, even if the benefit-to-cost ratio is only marginally above one, and even if individuals only use a minimum of past information. This surprising observation is caused by two effects. First, mutation generates diversity which undermines the evolutionary stability of defectors. Second, mutation leads to diverse communities of cooperators that are more resilient than homogeneous ones. This finding is relevant because many real-world opportunities for cooperation have small benefit-to-cost ratios, which are between one and two, and we describe how direct reciprocity can attain cooperation in such settings. Our result can be interpreted as showing that diversity, rather than uniformity, promotes evolution of cooperation.


Systolic anterior motion of mitral valve-a savior in transposition of great arteries?
Arterial switch operation (ASO) is the procedure of choice for the management of d-transposition of the great arteries (TGA). However, the surgical management of infants older than 6 weeks with TGA and intact ventricular septum (IVS) remains contentious. We report a case of late-presenting TGA, IVS with systolic anterior motion (SAM) of the mitral valve with a preserved left ventricle (LV) and its management. The online version contains supplementary material available at 10.1007/s12055-023-01488-6.


[Coronary risk factors and social class. Screening in employees of a large industrial firm (author's transl)].
In Munich, 1477 employees (868 males and 609 females) of a large industrial firm were examined with regard to coronary heart disease risk factors. The known risk factors--overweight, disorders of the lipometabolism, diabetes, cigarette smoking, hypertension, pathologic ECG, physical inactivity--as well as certain somatic complaints and mental stress were checked for their distribution within the various social levels. With the exception of cigarette smoking among women and professional worries among men, in both sexes the members of the upper social group are less burdened with danger factors than the average. Aside from high blood pressure and disorders of the lipometabolism, which predominate in males in the middle layers, and cigarette smoking, which prevails among females in the upper social group, the risk factors pile up in the lowest social level. Our results will be discussed and compared with other studies.


Deterministic quantum teleportation of photonic quantum bits by a hybrid technique.
Quantum teleportation allows for the transfer of arbitrary unknown quantum states from a sender to a spatially distant receiver, provided that the two parties share an entangled state and can communicate classically. It is the essence of many sophisticated protocols for quantum communication and computation. Photons are an optimal choice for carrying information in the form of 'flying qubits', but the teleportation of photonic quantum bits (qubits) has been limited by experimental inefficiencies and restrictions. Main disadvantages include the fundamentally probabilistic nature of linear-optics Bell measurements, as well as the need either to destroy the teleported qubit or attenuate the input qubit when the detectors do not resolve photon numbers. Here we experimentally realize fully deterministic quantum teleportation of photonic qubits without post-selection. The key step is to make use of a hybrid technique involving continuous-variable teleportation of a discrete-variable, photonic qubit. When the receiver's feedforward gain is optimally tuned, the continuous-variable teleporter acts as a pure loss channel, and the input dual-rail-encoded qubit, based on a single photon, represents a quantum error detection code against photon loss and hence remains completely intact for most teleportation events. This allows for a faithful qubit transfer even with imperfect continuous-variable entangled states: for four qubits the overall transfer fidelities range from 0.79 to 0.82 and all of them exceed the classical limit of teleportation. Furthermore, even for a relatively low level of the entanglement, qubits are teleported much more efficiently than in previous experiments, albeit post-selectively (taking into account only the qubit subspaces), and with a fidelity comparable to the previously reported values.


Dye degradation, antimicrobial and larvicidal activity of silver nanoparticles biosynthesized from Cleistanthus collinus.
The present study aimed in green synthesis and characterization of silver nanoparticles (AgNPs) using the leaves of Cleistanthus collinus. The NPs showed various absorption peaks between 3402 cm-1 and 1063 cm-1. FTIR spectrum revealed the presence of OH group, alkene, aromatic hydrocarbon, aliphatic fluro compound and aliphatic chloro compounds. Scanning electron microscopic analysis revealed the particle size ranged from 30 to 50 nm. The biosynthesized NPs have potent activity against Shigella dysentriae, Staphylococcus aureus and Bacillus subtilis and the zone of inhibition was 21 ± 1, 20 ± 2, 16 ± 2 mm, respectively. Toxicity of the synthesized NPs was tested on green gram (Vigna radiata) seed at various concentrations (20-100%) and germination was induced by NPs treated seeds. Shoot length and root length was higher in NPs treated plant than control plant (p < 0.01). Elevated level of catalase (CAT) and superoxide dismutase (SOD) and about 13% CAT and 7% SOD activity registered than control. Superoxide dismutase activity of root and shoot varied based on the dosage of AgNPs (p < 0.01). Also, the NPs (1%) showed significant larvicidal activity on Aedes aegypti and 100% mortality was achieved after 24 h treatment. The green synthesized NPs reduced methylene blue and 4-nitrophenol significantly (p < 0.01). The colouration of methylene blue and 4-nitrophenol were considerably reduced after 60 min showed the potential of dye degrading ability.


Two-dimensional imaging in hyperbolic media-the role of field components and ordinary waves.
We study full vector imaging of two dimensional source fields through finite slabs of media with extreme anisotropy, such as hyperbolic media. For this, we adapt the exact transfer matrix method for uniaxial media to calculate the two dimensional transfer functions and point spread functions for arbitrary vector fields described in Cartesian coordinates. This is more convenient for imaging simulations than the use of the natural, propagation direction-dependent TE/TM basis, and clarifies which field components contribute to sub-diffraction imaging. We study the effect of ordinary waves on image quality, which previous one-dimensional approaches could not consider. Perfect sub-diffraction imaging can be achieved if longitudinal fields are measured, but in the more common case where field intensities or transverse fields are measured, ordinary waves cause artefacts. These become more prevalent when attempting to image large objects with high resolution. We discuss implications for curved hyperbolic imaging geometries such as hyperlenses.


Haptic information provided by the "anchor system" reduces trunk sway acceleration in the frontal plane during tandem walking in older adults.
This study assessed whether the use of an "anchor system" benefited older adults who performed a tandem walking task. Additionally, we tested the effects of practice with the anchor system during walking on trunk stability, in the frontal plane, of older adults. Forty-four older adults were randomly assigned to three groups: control group, 0g anchor group, and 125g anchor group. Individuals in each group performed a tandem walking task on the GaitRite system with an accelerometer placed on the cervical region. The participants in the 125g anchor group held, in each hand, a flexible cable with a light mass attached at the end of the cable, which rested on the ground. While the participants walked, they pulled on the cables just enough to keep them taut as the masses slid over the ground. The 0g anchor group held an anchor tool without any mass attached to the end portion. The results of this study demonstrated that the use of the anchor system contributed to the reduction of trunk acceleration in the frontal plane. However, this effect did not persist after removal of the anchors, which suggests that the amount of practice with this tool was insufficient to generate any lasting effect, or that the task was not sufficiently challenging, or both.


Drought monitoring based on TIGGE and distributed hydrological model in Huaihe River Basin, China.
Drought assessment is important for developing measures to reduce agricultural vulnerability and thereby secure the livelihoods of those who depend on agriculture. This study uses four global ensemble weather prediction systems: the China Meteorological Administration (CMA), the European Centre for Medium-Range Weather Forecasts (ECMWF), the UK Met Office (UKMO), and the US National Centres for Environmental Prediction (NCEP) in the THORPEX (The Observing System Research and Predictability Experiment) Interactive Grand Global Ensemble (TIGGE) archive from 2006 to 2010. Based on results from the XXT (the first X denotes Xinanjiang, the second X denotes hybrid, and the T denotes TOPMODEL) distributed hydrological model, as well as soil moisture observations and digital elevation model (DEM) data, synthesized drought grades were established in the Huaihe River Basin of China. To filter out the impact of short-term fluctuations on observed soil moisture, a 30-day moving average was calculated. Use of the moving average significantly improves the correlation between observed soil moisture and simulated soil water deficit depth. Finally, a linear regression model describing the relationship between observed soil moisture and simulated soil water deficit depth was constructed. The deterministic regression coefficient was 0.5872, the correlation coefficient was 0.77, and the regression coefficient was -154.23. The trends in drought grades calculated using soil moisture and soil water deficit depth were found to be the same, and the grades agreed to within one level. Our findings highlight the importance of synthesizing drought grading when assessing drought using different soil moisture indicators in order to obtain a more comprehensive forecast of drought conditions.


Delayed surgical strategy for type A aortic dissection associated with acute hepatitis C cryoglobulinaemia.
An aortic dissection is a condition resulting from a tunica intima tear of the aortic wall creating a 'false lumen'. An acute Stanford type A (involves the aortic arch and/or ascending aorta) aortic dissection requires emergency surgical repair. To our knowledge, we report the first case in the literature where the treatment for an acute type A aortic dissection was intentionally delayed. This was decided following a multidisciplinary team discussion where it was agreed that the patient's active hepatitis C infection should be treated prior to surgery. The patient re-presented to the hospital 4 months later with acute dyspnoea and orthopnoea where he was diagnosed with an acute-on-chronic type A aortic dissection with trachea compression. This was successfully treated with emergency surgery. However, the patient suffered residual dyspnoea, likely due to phrenic nerve injury demonstrating the impact of untreated aortic arch distension on the neighbouring trachea and phrenic nerve.


[Chronic Pseudomonas aeruginosa airway colonization in cystic fibrosis patients : Prevention concepts].
Pseudomonas aeruginosa (PsA) is a hallmark pathogen of the lung disease in cystic fibrosis (CF) patients. Chronic PsA colonization is a central factor in the course of CF lung disease. PsA contributes considerably to morbidity and mortality, and also has a significant impact on quality of life and the costs of CF treatment. Prevention of chronic colonization has therefore been a major goal in the treatment of CF patients for many years now. In the present article, studies are presented which suggest that prevention of chronic colonization can be achieved. Approaches to prevent chronic PsA colonization are critically evaluated and recommendations for preventative approaches are generated from this discussion.


Correction to: Active human herpesvirus infections in adults with systemic lupus erythematosus and correlation with the SLEDAI score.
An amendment to this paper has been published and can be accessed via the original article.


Gender-related factors associated with delayed diagnosis of tuberculosis in Eastern Europe and Central Asia.
Tuberculosis (TB), a preventable and treatable disease, yearly affects millions of people and takes more than a million lives. Recognizing the symptoms and obtaining the correct diagnosis are vital steps towards treatment and cure. How timely a person with TB gets diagnosed may be influenced by biological differences between the sexes, and factors that are linked to the person's gender, in the context of the prevailing gender norms. According to our hypothesis, gender-related factors contribute to delays in the diagnosis of TB. We investigated four countries (Georgia, Kazakhstan, Republic of Moldova, and Tajikistan) of Eastern Europe and Central Asia (EECA) - a region with a high burden of drug-resistant TB, scarcity of gender-related TB information, and varying gender equality. Retrospective information was collected directly from the people with a history of TB - through in-depth interviews and focus group discussions. We did not find differences between genders in the way participants recognized TB symptoms. In three countries women de-prioritized seeking diagnosis because of their lack of access to finances, and household-related obligations. In all four countries, men, traditionally carrying the weight of economically supporting the family, tended to postpone TB diagnosis. In two countries women experienced stigma more often than men, and it was a deterrent factor to seeking healthcare. The role of gender in obtaining the correct diagnosis came forth only among the respondents from Georgia and to some extent from Kazakhstan. We conclude that there are barriers to health care seeking and TB diagnosis that affect differently women, men and gender-diverse persons in EECA Region.


Legalisation of termination of pregnancy in Ireland and the development of a service between primary and secondary care.
Expanded termination of pregnancy (TOP) was regulated in Ireland in December 2018 and services began within the Irish healthcare system in January 2019. An audit was performed of all attendances at a newly established TOP clinic, for pregnancies <12 weeks, over a twelve month period. Sixty-six women were seen in the clinic; 13 underwent medical TOP, 22 underwent surgical TOP, 2 miscarriages, 20 retained products following termination in primary care and 3 were beyond the 12 week limit. In an age where TOP clinics are under threat, we have demonstrated the successful successfully introduction safe and effective person centred termination services within primary and secondary care. This requires a focus on women's health with timely care can provided by dedicated nurse specialists and clinicians.


Bariatric programs in nursing homes.
The increase in prevalence of obesity in older individuals and the association of obesity with increased morbidity, functional decline, hospitalization, and complications is expected to increase the number of individuals who have obesity requiring nursing home care, particularly subacute and short-term rehabilitation. Providing appropriate nursing home care to residents who have obesity requires environmental modifications, specialized equipment, and staff training. Effective nursing home care of residents who have obesity is interdisciplinary and requires special nursing, medical, nutritional, psychosocial, and rehabilitation considerations.


A proposal for a national program reporting beneficial drug responses, analogous to the existing program to detect adverse drug responses.
Many countries have regulatory agencies, such as the Food and Drug Administration in the United States, not only to determine approval of drugs into the marketplace, but also to monitor their safety following the approval process. The logic for the latter role of these agencies is that several important changes occur in the patient population after the approval to market. These changes include the tremendous expansion in the numbers of patients, the removal of many exclusion criteria of co-existing diseases that may have been included in the clinical trials, and the fact that the treatment time for agents used chronically will now exceed any previous exposure time. All of these factors may contribute to the development of adverse drug responses (ADRs) that were not predictable or observable during the clinical trial phases. While the programs to monitor ADRs have important limitations such as the absence of a control group, they are extremely useful at determining possible associations between a drug and an adverse response that can now be used to generate hypotheses to be tested in a more proper and controlled set of trials. A similar system could, in principle, be used to monitor non-predictable serendipitous beneficial drug responses (BDRs) that would otherwise not be seen due to the same limitations of clinical trials in detecting ADRs. The system would expand data collection beyond clinical trials - which often can pick up BDRs of drugs such as minoxidil and sildenafil. This system of monitoring for BDRs would have the tremendous advantages of generating hypotheses derived from data obtained in humans with the disease and a drug-able molecule. The data obtained from this system of monitoring for BDRs could lead to new uses for old drugs as well as provide starting molecules that could be modified to treat diseases unrelated to the original indicated disease for the parent drug. The cost of creating and maintaining a BDR database are in-line with budgets of some of the projects funded by agencies such as the NIH or MRC. One possible feature is that the patient, rather than the doctor, does the majority of BDR reporting. Although lay-reporting would lead to false positives; repeated observations of a beneficial association would be a reasonable basis for further study in formal, professional clinical investigations. It is time to create the largest stage ever for serendipity to appear in biomedical research. After all, her previous appearances have marked some of science's most amazing discoveries.


The effect of age and cell proliferation on the frequency of sister chromatid exchange in human lymphocytes cultured in vitro.
The impact of ageing on the frequencies of sister chromatid exchange of humans was determined in lymphocytes of 43 healthy male non-smokers. The frequencies of sister chromatid exchange in individuals under 70 years were the same, but were significantly lower than in men of 70 years and older. Since we did not see a difference in the frequencies of sister chromatid exchange between fast- and slow-cycling lymphocytes, this difference probably would still hold if the lymphocyte subpopulations of these people were all examined.


Joint reconstruction of cis-regulatory interaction networks across multiple tissues using single-cell chromatin accessibility data.
The rapid accumulation of single-cell chromatin accessibility data offers a unique opportunity to investigate common and specific regulatory mechanisms across different cell types. However, existing methods for cis-regulatory network reconstruction using single-cell chromatin accessibility data were only designed for cells belonging to one cell type, and resulting networks may be incomparable directly due to diverse cell numbers of different cell types. Here, we adopt a computational method to jointly reconstruct cis-regulatory interaction maps (JRIM) of multiple cell populations based on patterns of co-accessibility in single-cell data. We applied JRIM to explore common and specific regulatory interactions across multiple tissues from single-cell ATAC-seq dataset containing ~80 000 cells across 13 mouse tissues. Reconstructed common interactions among 13 tissues indeed relate to basic biological functions, and individual cis-regulatory networks show strong tissue specificity and functional relevance. More importantly, tissue-specific regulatory interactions are mediated by coordination of histone modifications and tissue-related TFs, and many of them may reveal novel regulatory mechanisms.


Raman spectroscopy in quality control of Chinese herbal medicine.
Chinese herbal medicine (CHM) is of noteworthy international interest due to its potential impact on healthcare and manifests numerous opportunities for new drug development. However, solid scientific evidence is still lacking regarding the safety, efficacy, and quality of CHM-derived medicines. Success in the modernization and globalization of CHM is heavily dependent on the achievements in advanced analytical techniques for in-line checks of CHM quality. Raman spectroscopy has become increasingly valued as an analytical technique in the pharmaceutical sector because it can provide a detailed chemical fingerprint. However, earlier research suggests that inadequate attention has been paid to the applications of Raman spectroscopy in CHM. Chinese and English literatures were reviewed via PubMed and Medicine databases, and through manual searches using keywords including traditional Chinese medicines, herbs, quality control, and Raman spectroscopy. Applications of Raman spectroscopy in various aspects of CHM, including the identification and analysis of raw materials, in-line checks of formulation, characterization of adulterants, and detection of counterfeits, were reviewed systematically. An updated systematic review of the published literature has been conducted to analyze the most important milestones and latest achievements in this topic. Raman spectroscopy is playing an increasingly important role in the quality control of CHM and effectively promotes the modernization of CHM.


Identification of the iroA gene product of Neisseria meningitidis as a lactoferrin receptor.
The iroA gene product is an iron limitation-inducible outer membrane protein of Neisseria meningitidis. A spontaneous mutant lacking the gene was unable to bind lactoferrin. Furthermore, Escherichia coli strains expressing the IroA protein were capable of binding lactoferrin. Apparently, the IroA protein functions as a lactoferrin receptor.


[The role of grief in palliative care--new models and approaches for accompaniment of grief].
On the basis of a case report, I want to discuss my experience with grief and its accompaniments in palliative care. Furthermore, issues will be addressed such as: accompanying a palliative patient whose daughter died of cancer three years earlier; establishing rapport with patients of different religious beliefs; the limits of psychotherapeutic aid: what it can offer and its acceptance. New models and approaches for accompaniment of grief.


Pre-operative screening for sleep disordered breathing: obstructive sleep apnoea and beyond.
Sleep disordered breathing describes an important group of conditions that causes abnormal nocturnal gas exchange, with important implications in the peri-operative management plan. An understanding of the pathophysiology behind obstructive sleep apnoea and other disorders that may lead to hypoventilation can help to prevent complications. Patients with these disorders may be minimally symptomatic and it requires careful screening in the pre-operative assessment process for a diagnosis to be made. Decisions regarding initiation of therapy, such as positive airway pressure, and delay of the operation need to be carefully weighed up against the urgency of the surgical intervention. Planning of the peri-operative care, including the use of positive airway pressure therapy and appropriate post-operative monitoring, can help to avoid respiratory and cardiovascular morbidities and improve clinical outcomes. To review different types of sleep disordered breathing and available screening methods in pre-operative assessment.To understand the pathophysiology behind sleep disordered breathing and how it can lead to complications in the peri-operative setting.To review the planning and treatment strategies that should be considered as part of peri-operative management.


Knowledge, perceptions, and readiness of telepharmacy among community pharmacists.
Telepharmacy is a practical part of telemedicine that refers to providing pharmaceutical services within the scope of the pharmacist's obligations while maintaining a temporal and spatial distance between patients, users of health services, and healthcare professionals. The present study was a cross-sectional study conducted among community pharmacists in Saudi Arabia between March and May 2022 to assess their knowledge, perceptions, and readiness for telepharmacy. The survey was filled out by 404 respondents. The majority of respondents were male (59.90%) and the age of more than half of them was between 30 and 39 years old (54.46%). Most participants worked in urban areas (83.66%), and 42.57% had less than five years of experience in a pharmacy. Most participants agreed that telepharmacy is available in Saudi Arabia (82.67%). Approximately 70% of pharmacists felt that telepharmacy promotes patient medication adherence, and 77.72% agreed that telepharmacy increases patient access to pharmaceuticals in rural areas. More than 72% of pharmacists said they would work on telepharmacy initiatives in rural areas for free, and 74.26% said they would work outside of usual working hours if necessary. In the future, this research could aid in adopting full-fledged telepharmacy pharmaceutical care services in Saudi Arabia. It could also help academic initiatives by allowing telepharmacy practice models to be included as a topic course in the curriculum to prepare future pharmacists to deliver telepharmacy services.


Infantile and juvenile cerebral aneurysms.
Primary cerebral aneurysms (i.e., of noninflammatory or nontraumatic etiology) are rare in the pediatric age group. Twelve cases of intracranial aneurysms occurring in infancy, childhood, and adolescence are presented and discussed. These aneurysms are different from the classic so-called berry aneurysms seen in adults. This group can be said to constitute a separate and novel entity.


Multiple benzodiazepine receptors: no reason for anxiety.
Since the introduction of the benzodiazepines into clinical practice in 1960, these drugs have been widely employed as anxiolytics, sedative/hypnotics and anticonvulsants. In recent years, concern has been expressed about their side-effects, and their use has declined. During this latter period many advances have been made in understanding the molecular mechanisms by which these drugs produce their effects. Adam Doble and Ian Martin review this progress and highlight the possibilities that these advances may hold for the development of more efficacious and specific medicines.


Regulation of Bombyx mori ferritin heavy-chain homolog on ROS induces multiple effects on BmNPV replication.
Ferritin is an iron-binding protein composed of light-chain and heavy-chain homologs with a molecular weight of about 500 kDa. Free iron ions significantly affect reactive oxygen species (ROS) accumulation. Previous research has shown that Bombyx mori nucleopolyhedrosis virus (BmNPV) can increase ROS accumulation, activate autophagy, induce apoptosis, and upregulate the expression of B. mori ferritin heavy-chain homolog (BmFerHCH). However, the mechanism of mutual regulation between BmFerHCH and ROS-mediated autophagy and apoptosis induced by BmNPV remains unclear. In this study, we found that BmNPV induced the time-dependent accumulation of ROS in BmN cells, thereby promoting BmFerHCH expression. Interestingly, in BmFerHCH-overexpressed cells, BmNPV replication was inhibited in the first 18 h after infection but stimulated after 24 h. Further research on H2O2 or antioxidant-treated cells indicated that ROS-induced autophagy slightly increased in the early infection stage and increased BmNPV replication, while in the late stage, a large accumulation of ROS induced apoptosis and inhibited BmNPV replication. In this process, BmFerHCH inhibits BmNPV-induced ROS accumulation by chelating Fe2+. Taken together, BmFerHCH regulates ROS-mediated autophagy and apoptosis to achieve its various effects on BmNPV replication. These findings will help elucidate BmNPV-induced autophagy and apoptosis mediated by ROS and BmFerHCH, as well as the mutually fighting relationship between viruses and hosts.


Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.
Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements. Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion. As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab. Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially. Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy.


Effect of incorporation of thermo-regulatory genes into exotic layers on egg production and quality under tropical environment.
A breed development strategy aimed at making exotic layers (Lohmann Brown) more productive under tropical environment using thermo-regulatory genes is underway at Akate Farms in Kumasi, Ghana. The present experiment was carried out to find out the effect of the genes on egg production in hot and humid environments. Three genetic groups comprising naked-neck, frizzle and their normally feathered sibs were obtained after successive generations of crossing between naked-neck and frizzle cocks and Lohmann brown hens. A total of 270 18-week-old pullets, 90 each of the 3 groups, were selected randomly and assigned to a completely randomized design experiment with 3 replicates, with 30 birds in each replicate group and kept up to a period of 72 weeks. The birds were kept in a partitioned open-sided deep-litter house constructed with sandcrete blocks with 30 pullets in each compartment. They were fed ad libitum with layer diets containing 18 % crude protein and 2,800 kcal ME/kg. Results obtained showed that the crossbred naked-neck and frizzle phenotypes produced eggs at a significantly (P < 0.05) higher rates than their normally feathered sibs and also out-performed their normally feathered sibs in other egg production parameters measured, even though they all segregated from similar parents. This is an indication of the favourable effect of the genes on egg production under hot and humid environments.


Sleep apnoea and heart failure.
Heart failure and sleep disordered breathing (SDB) are two common conditions that frequently overlap and have been studied extensively in the past three decades. Obstructive sleep apnoea (OSA) may result in myocardial damage due to intermittent hypoxia that leads to increased sympathetic activity and transmural pressures, low-grade vascular inflammation, and oxidative stress. On the other hand, central sleep apnoea and Cheyne-Stokes respiration (CSA-CSR) occurs in heart failure, irrespective of ejection fraction, either reduced (HFrEF), preserved (HFpEF) or mildly reduced (HFmrEF). The pathophysiology of CSA-CSR relies on several mechanisms leading to hyperventilation, breathing cessation and periodic breathing. Pharyngeal collapse may result at least in part from fluid accumulation in the neck, owing to daytime fluid retention and overnight rostral fluid shift from the legs. Although both OSA and CSA-CSR occur in heart failure, the symptoms are less suggestive than in typical (non-heart failure-related) OSA. Overnight monitoring is mandatory for a proper diagnosis, with accurate measurement and scoring of central and obstructive events, since the management will be different depending on whether the sleep apnoea in heart failure is predominantly OSA or CSA-CSR. SDB in heart failure is associated with worse prognosis, including higher mortality, than in patients with heart failure but without SDB. However, there is currently no evidence that treating SDB improves clinically important outcomes in patients with heart failure, such as cardiovascular morbidity and mortality.


Pharmacogenetics of glucose-lowering drug treatment: a systematic review.
Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.


Iatrogenic venous thrombosis secondary to supplemental medicine toxicity.
We described a case of cerebral venous sinus thrombosis in a patient taking multiple supplements as part of a naturopathic anti-aging regimen. Case report. The patient presented with a thalamic infarct associated with a thrombus in the vein of Galen. He reported no previous history of endocrinopathy and no known hypercoagulability risk factors. He was treated with therapeutic anticoagulation resulting in improvement. Diagnostic workup revealed hyperthyroidism and gonadotrophic deficiency attributed to significant supplement medicine usage. This case highlights a potential risk of dietary supplements. Use of these supplements may be a risk factor for idiopathic cerebral venous thrombosis.


Response characteristics of indigenous microbial community in polycyclic aromatic hydrocarbons (PAHs) contaminated aquifers under polyethylene microplastics stress: A microcosmic experimental study.
To understand the response characteristics of indigenous microbial community in PAH-contaminated aquifers to the coexistence of microplastics. In this paper, we constructed a groundwater microecosystem using lithologic media collected from the field and subjected it to the stress of a polyethylene microplastics (PE-MPs) concentration gradient. By conducting adsorption experiments and 16S rRNA sequencing, we revealed the growth, structure, metabolism, and resistance mechanisms of the indigenous microbial community in the aquifer lithologic media exposed to varying levels of co-stress from PE-MPs and phenanthrene. Our findings suggest that the adsorption capacity of aquifer lithologic media for phenanthrene is significantly weaker than that of PE-MPs. Additionally, our observations indicated that small particle lithologic media had a greater adsorption capacity for phenanthrene than large particle lithologic media. The presence of PE-MPs was found to increase both the abundance and diversity of microbial communities, although the relationship was not linear with the content of PE-MPs. When exposed to the combined stress of PE-MPs and phenanthrene, the relative abundance of Proteobacteria decreased while that of Bacteroidetes increased. Several genera belonging to Proteobacteria (Aeromonas, Desulfovibrio, Klebsiella, Pantoea, and Microvirgula) and Bacteroidetes (Macellibacteroides and Bacteroides) occupied a central position in the microbial community interaction network and showed significant correlations with other genera. Furthermore, an increase in the proportion of genera capable of degrading various refractory organics was observed. The presence of PE-MPs increased the phenanthrene content in the aquifer lithologic media, thereby intensifying the inhibitory effect on indigenous microbial community in this environment. Despite an increase in the phenanthrene content of aquifer lithologic media due to the presence of PE-MPs, indigenous microbial community in this environment exhibited resistance to the combined inhibition of PE-MPs and phenanthrene through a series of resistance mechanisms. These mechanisms included strengthening the N-cycle process, enhancing metabolic capacity for phenanthrene, improving perception, response, and adaptation to changes in the external environment or intracellular state, modifying the transmembrane transport of the cell membrane to the substrate, and regulating life processes.


Impact Of Dental Anxiety On The Decision To Have Implant Treatment.
Dental implants are increasingly used in modern dentistry as anchors for prosthetic restorations. Anxiety is a complex phenomenon which can become a risk factor for suppression of many functions of the body. The aim of this study was to investigate the effect dental anxiety exerts on the choice of method of treatment by patients wanting to have dental implants. The study included 174 patients that were referred to us for dental implants placement because of partial or total loss of teeth. Their dental anxiety was measured using the Dental Anxiety Scale (DAS) proposed by Norman Corah. The patients decided to have or refused to have treatment with dental implants either because they had dental anxiety or gave other reasons. Distribution of patients by level of anxiety was as follows: 33% were anxiety free, in 34% the dental anxiety was moderate, 25% had severe anxiety, and 8% experienced an extremely severe anxiety. Dental fear was given as a reason for refusal of treatment by 24.1% of the patients wanting to have dental implants. Of the patients wanting to have dental implants, 40.8% decided to proceed with the treatment; these patients exhibited low dental anxiety. The decision to have dental treatment with implants is affected by the patient's level of dental anxiety. Only those with low level of dental anxiety decide to proceed with such a treatment. The mild anxiety some patients experience is beneficial as it eliminates a risk factor that may hinder the process of osseointegration.


Regulation and spatial organization of PCNA in Trypanosoma brucei.
As in most eukaryotic cells, replication is regulated by a conserved group of proteins in the early-diverged parasite Trypanosoma brucei. Only a few components of the replication machinery have been described in this parasite and regulation, sub-nuclear localization and timing of replication are not well understood. We characterized the proliferating cell nuclear antigen in T. brucei (TbPCNA) to establish a spatial and temporal marker for replication. Interestingly, PCNA distribution and regulation is different compared to the closely related parasites Trypanosoma cruzi and Leishmania donovani. TbPCNA foci are clearly detectable during S phase of the cell cycle but in contrast to T. cruzi they are not preferentially located at the nuclear periphery. Furthermore, PCNA seems to be degraded when cells enter G2 phase in T. brucei suggesting different modes of replication regulation or functions of PCNA in these closely related eukaryotes.


Key issues surrounding the health impacts of electronic nicotine delivery systems (ENDS) and other sources of nicotine.
Answer questions and earn CME/CNE Over the last decade, the use of electronic nicotine delivery systems (ENDS), including the electronic cigarette or e-cigarette, has grown rapidly. More youth now use ENDS than any tobacco product. This extensive research review shows that there are scientifically sound, sometimes competing arguments about ENDS that are not immediately and/or completely resolvable. However, the preponderance of the scientific evidence to date suggests that current-generation ENDS products are demonstrably less harmful than combustible tobacco products such as conventional cigarettes in several key ways, including by generating far lower levels of carcinogens and other toxic compounds than combustible products or those that contain tobacco. To place ENDS in context, the authors begin by reviewing the trends in use of major nicotine-containing products. Because nicotine is the common core-and highly addictive-constituent across all tobacco products, its toxicology is examined. With its long history as the only nicotine product widely accepted as being relatively safe, nicotine-replacement therapy (NRT) is also examined. A section is also included that examines snus, the most debated potential harm-reduction product before ENDS. Between discussions of NRT and snus, ENDS are extensively examined: what they are, knowledge about their level of "harm," their relationship to smoking cessation, the so-called gateway effect, and dual use/poly-use. CA Cancer J Clin 2017;67:449-471. © 2017 American Cancer Society.


[Skewness and inequality of height distribution of young Pinus sylvestris var. mongolica stands introduced on sandy soil with lower limited precipitation for tree survival and normal growth].
Based on the investigation of a transect (20 m wide and 80 m long) along a gradient (bottom, middle, and top) of a dune, whose height was about 5-10 m, the population dynamics in young Pinus sylvestis var. mongolica stands was studied. The results showed that both skewness and height inequality declined before the self-thinning process occurred. Age, initial growth status, density of the population, and neighborhood competition were the main factors affected height inequality. The location at sand dune was also an important factor, and its effect was more obvious than that of density.


EEG coherence before and after giving birth.
During pregnancy and the postpartum period, changes in brain volume and in motivational, sensory, cognitive, and emotional processes have been described. However, to date, longitudinal modifications of brain function have been understudied. To explore regional cortical coupling, in pregnancy and at 3 months postpartum, we analyzed resting-state electroencephalographic (EEG) coherence in the delta, theta, alpha1, alpha2, beta1, and beta2 frequency bands across frontal and parietal regions of the maternal brain (Fp1, Fp2, F3, F4, P3, and P4). We found that from pregnancy to the postpartum period, mothers showed less intrahemispheric EEG coherence between the frontal and parietal regions in the alpha1 and alpha2 bands, as well as greater interhemispheric EEG coherence between frontopolar regions in the beta2 band. These changes suggest decreased inhibition of neural circuits. These neurophysiological changes may represent an adaptive process characteristic of motherhood.


A novel 3D-printed solid phase microextraction device equipped with silver-polyaniline coated pencil lead for the extraction of phthalate esters in cosmeceutical products.
A screw-based portable and simple solid phase microextraction device was fabricated by a 3D printer and used in combination with the developed silver-incorporated porous polyaniline film pencil lead solid-phase microextraction fiber (Ag/PANI SPME). Scanning electron microscopy revealed a porous structure of the electrodeposited Ag/PANI film. The spectrum from energy dispersive x-ray spectroscopy (EDS) and the elemental map confirmed the presence of silver in the porous polymer film. It was used under stirring for the extraction of five phthalate esters: dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and di-2-ethylhexyl phthalate (DEHP). The extracted solution was identified and quantified by gas chromatography using a flame ionization detector (GC-FID). Under the optimum conditions of the developed method, a good linearity was obtained in a concentration range of 5.0-1000 μg L-1 for all five phthalate esters with limits of detection (LODs) of 4.41 ± 0.91 μg L-1, 3.98 ± 0.92 μg L-1, 3.65 ± 0.74 μg L-1, 4.91 ± 0.52 μg L-1 and 4.25 ± 0.66 μg L-1 for DMP, DEP, DBP, BBP and DEHP, respectively. The developed method provided good precision when tested with standard solutions (RSD < 5.5%, n = 6) and real samples (RSD < 3.4%, n = 6). Good fiber-to-fiber reproducibility was also confirmed by extraction with six newly prepared fibers; recoveries ranged from 81.09 ± 0.54% to 92.92 ± 0.46% with RSD <6.6%. The developed method was used to determine phthalate esters in 14 cosmeceutical samples. In rubbing alcohol samples, DEP and DEHP were detected at 7.03 ± 0.76 μg L-1 and 5.89 ± 0.53 μg L-1, respectively, while in contact lens cleaners, DEHP was found in a concentration range from 5.3 ± 1.1 μg L-1 to 6.8 ± 1.2 μg L-1. No phthalate esters contamination was detectable in saline solutions, eye cleaners and antibacterial disinfectant liquids. Recoveries in the range of 81.92 ± 0.99% to 102.4 ± 1.1% indicated the good accuracy of the developed method.


Molecular epidemiology of Clostridium neonatale and its relationship with the occurrence of necrotizing enterocolitis in preterm neonates.
Clostridia-especially Clostridium butyricum-are among the taxa most frequently identified from stool samples of preterm neonates with necrotizing enterocolitis (NEC). Recently, Clostridium neonatale has also been detected from epidemic cases, but using a culture-based approach we were unable to confirm this discovery in a local cohort. In order to investigate this link by a molecular approach, a specific rpoB-based quantitative real-time PCR was developed to detect C. neonatale directly from patients' stool specimens. Design of this rpoB-based quantitative real-time PCR was based on the genomic analysis of seven clinical isolates of C. neonatale. It was tested on stool samples from 88 preterm neonates with necrotizing enterocolitis and 71 matched controls. C. neonatale was significantly more prevalent in stools from preterm neonates with necrotizing enterocolitis than in controls (respectively 30/88 (34%) versus 9/71 (13%); p 0.003). Whole-genome analysis also allowed the identification of three genomic clusters of C. neonatale. This clustering was associated with a geographical location regardless of isolation from the NEC or control, suggesting asymptomatic carriage. Although less prevalent than C. butyricum in our cohort, C. neonatale is significantly associated with the occurrence of necrotizing enterocolitis.


Multiply-charged negative clusters of adenosine-5'-monophosphate in the gas phase.
Multiply-charged noncovalent cluster anions of adenosine-5'-monophosphate (AMP) were formed by electrospray ionization (ESI). Ions in higher charge states were observed when the ions were accumulated in an ion trap with helium buffer gas before detection. We determined the smallest size (n(a)) or appearance size as a function of charge state (q), i.e., n(a) = 4 for q = 2, n(a) = 8 for q = 3, and n(a) = 13 for q = 4. The relation between n(a) and q can be described by a charged droplet model. When the size is larger than n(a) for a given q, the fragmentation pathway of an anion cluster is dominated by loss of neutral fragments. In contrast, when the size approaches the appearance size, only charged fragments are formed.


Does endoscopy of difficult to catheterize channels spare some patients from formal open revision?
Patients with continent catheterizable channels (CCC) may develop difficulty catheterizing postoperatively. In complex cases, endoscopic evaluation with indwelling catheter placement may be indicated, but the risk factors for subsequent formal channel revision are not well defined. The purpose of this study was to determine the risk factors for formal channel revision after attempted endoscopic management of difficulty catheterizing. We performed an IRB-approved retrospective review of pediatric (<21 years old) patients undergoing CCC construction at our institution from 1999 to 2014 to identify patients who underwent endoscopy for difficulty catheterizing. Fisher's Exact test was used for categorical data and Mann-Whitney U test for continuous variables to examine the association between endoscopic intervention and subsequent formal revision. Sixty-three of 434 patients (14.5%) underwent at least one endoscopy for reported difficulty catheterizing their CCC, with 77.8% of these requiring additional intervention during endoscopy (catheter placement, dilation, etc.). Of these, almost half with functioning channels (43.5%, 27/62) were managed successfully with endoscopy without formal revision; six (22.2%) of whom underwent more than one endoscopy. These 27 patients continued to catheterize well at a median follow-up of 3.2 years (interquartile range 2.0-6.0). Patients requiring revision had a median of 1.7 years between CCC creation and first endoscopy, versus 1.6 years in those who were not revised (p = 0.60). There was no statistically significant difference between revised and non-revised channels in terms of patient age at CCC creation, underlying patient diagnosis, status of bladder neck, stomal location, or channel type (p ≥ 0.05) (see Table). Approximately half of our patients did not require a formal channel revision after endoscopic management. We did not identify any specific risk factors for subsequent formal revision of a CCC. We recommend performing at least one endoscopic evaluation for those with difficulty catheterizing prior to proceeding with formal open revision.


Identification and subtyping of Francisella by pyrosequencing and signature matching of 16S rDNA fragments.
To analyse the V1 region of the 16S rDNA gene by a universal pyrosequencing protocol to identify and subtype Francisella in 31 strains from a repository collection and 96 patient isolates. Pyrosequencing was used to determine the nucleotide sequence of PCR amplification products of the variable region (V1) of the 16S rDNA from 31 repository strains and 96 isolates from Swedish patients with ulceroglandular tularaemia. Pyrosequencing resulted in a 37 nucleotide sequence, specific for Francisella sp., for all repository strains and patient samples analysed. In addition, the isolates could be divided into two groups based on the analysis of a single nucleotide polymorphism in the sequence: one group included Francisella tularensis ssp. tularensis, ssp. holarctica and ssp. mediasiatica, whereas the other group included Francisella tularensis ssp. novicida and other species of Francisella. The analysis of samples taken from patients suffering from ulceroglandular tularaemia revealed that all isolates belonged to the first group comprising subspecies of F. tularensis virulent for humans. The pyrosequencing analysis of the 16S rDNA V1 is a useful molecular tool for the rapid identification of suspected isolates of Francisella sp. in clinical or environmental samples. Virulent F. tularensis ssp. causing ulceroglandular tularaemia, or those with a potential to be used in a bioterrorism event, could rapidly be discriminated from subspecies less virulent for humans.


Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.
In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors.


A giant atrial thrombosis in a patient with fontan circulation.
We described a case of a quasi obstructive thrombus in the right atrium in a patient with a Fontan palliation. Different medical imaging techniques helped us for diagnosis and management strategy. We discussed the therapeutic choice between thrombolysis or surgery.


Trends in the incidence of cancer of the female breast and reproductive tract in Alberta, 1953 to 1977.
A log-linear model was used to separate age, secular, and cohort trends in the incidence of cancer of the breast, ovary, corpus uteri, cervix uteri, vagina, and vulva in female residents in Alberta over the period 1953 to 1977. The age trends are similar for each cancer site increasing sharply in the premenopausal period and then leveling off. In the case of breast cancer, a point of inflection at the menopause (Clemmesen's hook) persists. A gradually increasing secular trend in incidence was evident for all sites except cervix uteri, the incidence of which declined after 1960. Cyclical cohort trends were found for cancers of the breast, ovary, and corpus uteri, inversely correlated with early fertility. The cohort trends for cervix uteri, vagina, and vulva increased sharply for cohorts born after 1940.


Exploring Blastocystis genetic diversity in rural schoolchildren from Colombia using next-generation amplicon sequencing reveals significant associations between contact with animals and infection risk.
Blastocystis is a common intestinal protist with a global distribution in humans and many other animals. Yet, the status of Blastocystis as a pathogen, the risk factors associated with its transmission, and its zoonotic potential remain ill-defined. Here, we explored subtype (ST) diversity and potential risk factors for Blastocystis infection in 98 children from Apulo, Colombia. Samples were screened for Blastocystis via PCR, and ST identification was performed through next-generation amplicon sequencing (NGS). Associations between the presence of Blastocystis and individual STs and sociodemographic variables were assessed via logistic regression analyses. Seventy-one samples (72.4%) were Blastocystis-positive, and NGS revealed the presence of five STs (ST1-ST5). ST1, ST2, and ST3 were common and observed in nearly equal proportions (~ 40%), while samples with ST4 (1.4%) and ST5 (5.6%) were comparatively rare. The presence of mixed STs in the same sample was also common (28.2%). Comparisons among children within the same household identified that shared ST profiles were common, but diversity within family units was also observed. Logistic regression analyses returned significant associations between the presence of Blastocystis, individual subtypes, or mixed subtypes for several variables. Intriguingly, the presence of animals was one of the most common significant associations. Taken together, these data represent an important step forward in understanding both the potential routes and risk factors that may influence Blastocystis transmission and will be useful in shaping future studies which seek to clarify the relationships between STs, pathogenicity, and zoonotic transmission.