[The predictive value of admission hyperglycemia in hospital and long-term mortality of diabetics versus non-diabetics with acute coronary syndrome].
To evaluate whether the predictive value of admission hyperglycemia for mortality differs between diabetics and non-diabetics with acute coronary syndrome (ACS). A total of 1534 consecutive patients admitted with ACS to Central Control Unit of Beijing Friendship Hospital were analyzed. Among these patients, 1332 patients who had a venous plasma glucose record at admission were retrospectively enrolled and were stratified according to admission glucose levels with or without diabetes. The primary end point was in-hospital and 2-year all-cause mortality. In patients without a history of diabetes, 649 patients had glucose level ≤ 7.8 mmol/L(group A), 204 patients with 7.8-11.0 mmol/L (group B) and 142 patients > 11.0 mmol/L (group C). Of those with diabetes, 124 patients were in group A, 142 in group B and 126 in group C. By Cox regression analysis, admission hyperglycemia (group B, HR 1.48, P = 0.05; group C, HR 2.78, P < 0.001) was an independent predictor of long-term all-cause mortality in patients without diabetes. In patients with diabetes, blood glucose > 11.0 mmol/L (group C, HR 2.68, P < 0.001) also independently predicted long-term all-cause mortality. Compared with the diabetic patients, elevation of blood glucose at admission is common in ACS patients without definite history of diabetes. Admission hyperglycemia should be considered as a risk factor strongly correlated with in-hospital and 2-year all-cause mortality in patients with ACS.


Ionoacoustic characterization of the proton Bragg peak with submillimeter accuracy.
Range verification in ion beam therapy relies to date on nuclear imaging techniques which require complex and costly detector systems. A different approach is the detection of thermoacoustic signals that are generated due to localized energy loss of ion beams in tissue (ionoacoustics). Aim of this work was to study experimentally the achievable position resolution of ionoacoustics under idealized conditions using high frequency ultrasonic transducers and a specifically selected probing beam. A water phantom was irradiated by a pulsed 20 MeV proton beam with varying pulse intensity and length. The acoustic signal of single proton pulses was measured by different PZT-based ultrasound detectors (3.5 and 10 MHz central frequencies). The proton dose distribution in water was calculated by Geant4 and used as input for simulation of the generated acoustic wave by the matlab toolbox k-WAVE. In measurements from this study, a clear signal of the Bragg peak was observed for an energy deposition as low as 10(12) eV. The signal amplitude showed a linear increase with particle number per pulse and thus, dose. Bragg peak position measurements were reproducible within ±30 μm and agreed with Geant4 simulations to better than 100 μm. The ionoacoustic signal pattern allowed for a detailed analysis of the Bragg peak and could be well reproduced by k-WAVE simulations. The authors have studied the ionoacoustic signal of the Bragg peak in experiments using a 20 MeV proton beam with its correspondingly localized energy deposition, demonstrating submillimeter position resolution and providing a deep insight in the correlation between the acoustic signal and Bragg peak shape. These results, together with earlier experiments and new simulations (including the results in this study) at higher energies, suggest ionoacoustics as a technique for range verification in particle therapy at locations, where the tumor can be localized by ultrasound imaging. This acoustic range verification approach could offer the possibility of combining anatomical ultrasound and Bragg peak imaging, but further studies are required for translation of these findings to clinical application.


Comparison of calculated and measured ion densities on the dayside of venus.
Datafrom the Pioneer Venus ion mass spectrometers are compared with model calculations of the ion density distributions appropriate for daytime conditions. The model assumes diffusive equilibrium upper boundary conditions for the major ions (O(2)(+), O(+), CO(2)(+), He(+), and H(+)); the agreement between the calculated and measured gross behavior of these ions is reasonably good except for H(+), which may be influenced strongly by convective transport processes. The distributions of five minor ions (C(+), N(+), NO(+), CO(+), and N(2)(+)) are also calculated for the chemically controlled region ( less, similar 200 kilometers); the agreements are, in general, poor, an indication that our present understanding of the Venus minor ion chemistry is still incomplete.


Inspiratory Muscle Training in the Severity of Obstructive Sleep Apnea, Sleep Quality and Excessive Daytime Sleepiness: A Placebo-Controlled, Randomized Trial.
Exercise programs have been considered as an adjuvant treatment in obstructive sleep apnea (OSA). However, few studies have focused on the effects of the inspiratory muscle training (IMT) in reducing the severity and the symptoms of OSA. A randomized controlled trial was conducted and approved by the local Ethics Committee. All subjects signed the informed consent form and were randomized into 2 groups: a) IMT group (n = 8), 8 weeks of IMT with 75% of maximal inspiratory pressure (MIP) and b) placebo group (n = 8): subjects performed IMT without load. IMT group showed reduction in the apnea-hypopnea index (AHI) (p = 0.01), in the Berlin questionnaire score (p = 0.001) and an increase in inspiratory muscle strength (p = 0.018). IMT group demonstrated a reduction in the AHI (31.7 ± 15.9 events/h vs 29.9 ± 15.8 events/h; p <0.001), in the Berlin questionnaire scores (2.6 ± 0.5 vs 1.2 ± 0.5; p = 0.016), Pittsburgh Sleep Quality Index (PSQI) score (7.2 ± 3.6 vs 3.7 ± 1.3; p = 0.008), in the Epworth Sleepiness Scale (ESS) (12.5 ± 4.0 vs 7.7 ± 3.0; p = 0.008) and increase in MIP (83.6 ± 26.5 cmH2O and 127.9 ± 32.5 cmH2O; p = 0.010). The IMT promotes discrete changes in the AHI and improves sleep quality and excessive daytime sleepiness in OSA. Moreover, IMT is a cheap, useful and simple home-based training program and can be considered as an adjunct therapy for OSA patients.


Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants.
Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.


Bisphosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation.
A library of bisphosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromophoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bisphosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bisphosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal.


Ion release from copper phosphate cement and influence on Streptococcus mutans growth in vitro: a comparative study.
The aim of this study was to compare the effects of a black copper cement (BCC), an established restorative material (a conventional glass ionomer cement) and two temporary restorative materials (a zinc phosphate and a zinc polycarboxylate cement) on the growth of Streptococcus mutans in vitro, and to correlate bacterial growth with ion release from each material. Test specimens were eluted in either 0.1 M lactic acid, pH 4, or 0.1 M sodium chloride, pH 7. At 2 days, 7 days, 28 days and 6 months, eluates were inoculated with S. mutans and bacterial growth was recorded. Metal ion (Cu(2+), Zn(2+ )and Mg(2+)) and fluoride release were measured. At most immersion times, the different materials had a statistically significant inhibitory effect on bacterial growth compared to the respective control, at both pH levels. The inhibitory effect decreased with time and in most cases was associated with high levels of ion release at the beginning of the experimental period, followed by significantly lower levels. For BCC, there were statistically significant relationships between the median rates of growth of S. mutans in the presence of BCC eluates and the median values for release of copper and zinc, although not magnesium. Of the different materials, BCC demonstrated greatest antibacterial activity.


Impulsivity, Sensation Seeking, and Decision-Making in Long-Term Abstinent Cannabis Dependent Patients.
In contrast to several studies that examined different domains of neurocognitive functions in long-term abstinent cannabis users, there are few studies examined impulsivity in cannabis users with prolonged abstinence. The aim of this study was to test whether impulsivity and sensation seeking traits and impulsive decision-making are transient or enduring in patients with cannabis dependence who were abstinent for at least 1 month. The study included 30 patients with cannabis dependence (CDP) who had been abstinent for at least 1 month and 30 healthy controls. All the participants were male and the two groups were matched for age and duration of education. As a result of Iowa Gambling Task (IGT) evaluation, there was no significant group (CDP vs. control) by block interaction in IGT performance (p=0.680). CDP showed significantly higher Barratt Impulsiveness Scale-11 (BIS-11) total (p=0.006), BIS-11 non-planning (p=0.006) and Zuckerman Sensation Seeking Scale experience seeking subscale (p=0.001) scores compared with controls. This is the first study to investigate decision-making, self-report impulsivity and sensation seeking in long-term abstinent CDP. Our findings suggest that both self-report impulsivity and experience seeking may reflect a stable trait in CDP but not deficits on decision-making. This suggestion is consistent with the hypothesis that elevated impulsivity and sensation seeking traits may lead to addiction when they occur together rather than alone.


Patient-Related Risk Factors Associated With Surgical Site Complications After Elective Hand Surgery.
The purpose of this study was to identify independent risk factors associated with an increased rate of surgical site complications after elective hand surgery. This study is a retrospective review of all patients who underwent elective hand, wrist, forearm, and elbow surgery over a 10-year period at a single institution. Electronic medical records were reviewed, and information regarding patient demographics, past medical and social history, perioperative laboratory values, procedures performed, and surgical complications was collected. Surgical site complications included surgical site infections, seromas or hematomas, and delayed wound healing or wound dehiscence. A univariate analysis was then performed to identify potential risk factors, which were then included in a multivariate regression analysis. A total of 3261 patients who underwent elective hand surgery and met the above inclusion and exclusion criteria were included in this study. The mean age was 57 years, with 65% female and 35% male patients. The overall surgical complication rate was 2.2%. Univariate analysis of patient factors identified male sex; number of procedures >1; history of drug, alcohol, or smoking use; American Society of Anesthesiologists (ASA) class III and IV; and serum albumin <3.5 mg/dL to be significantly associated with complications. However, multivariate regression analysis identified that only ASA class III and IV (odds ratio = 3.27) was significantly associated with surgical complications. Patients classified as ASA class III or IV were identified to be at a significantly increased risk of complications following elective hand surgery. Health factors which triage patients into these 2 groups may represent potentially modifiable factors to mitigate perioperative risk in the elective hand surgery population.


A novel method for discrimination of beef and horsemeat using Raman spectroscopy.
A new approach, based on the usage of Raman spectroscopy in combination with chemometrics, was developed for the rapid determination of beef adulteration with horsemeat. The data mining process of collected Raman spectra was performed with principal component analysis (PCA). Pure fat samples, extracted from forty-nine meat beef and horsemeat samples, were analysed using the Raman spectroscopy. All meat samples were classified successfully according to their origins. The presence of different concentrations (25%, 50%, 75%, w/w) of horsemeat in beef was also differentiated using the developed model system. This study offers a rapid assay for determination of meat adulteration by discriminating beef and horsemeat with high accuracy, a short analysis time (30s) and no requirement for time-consuming sample preparation procedures.


Meta-analysis of risk for relapse to substance use after transplantation of the liver or other solid organs.
For patients receiving liver or other organ transplants for diseases associated with substance use, risk for relapse posttransplantation is a prominent clinical concern. However, there is little consensus regarding either the prevalence or risk factors for relapse to alcohol or illicit drug use in these patients. Moreover, the evidence is inconsistent as to whether patients with pretransplantation substance use histories show poorer posttransplantation medical adherence. We conducted a meta-analysis of studies published between 1983 and 2005 to estimate relapse rates, rates of nonadherence to the medical regimen, and the association of potential risk factors with these rates. The analysis included 54 studies (50 liver, 3 kidney, and 1 heart). Average alcohol relapse rates (examined only in liver studies) were 5.6 cases per 100 patients per year (PPY) for relapse to any alcohol use and 2.5 cases per 100 PPY for relapse with heavy alcohol use. Illicit drug relapse averaged 3.7 cases per 100 PPY, with a significantly lower rate in liver vs. other recipients (1.9 vs. 6.1 cases). Average rates in other areas (tobacco use, immunosuppressant and clinic appointment nonadherence) were 2 to 10 cases per 100 PPY. Risk factors could be examined only for relapse to any alcohol use. Demographics and most pretransplantation characteristics showed little correlation with relapse. Poorer social support, family alcohol history, and pretransplantation abstinence of < or =6 months showed small but significant associations with relapse (r = 0.17-0.21). Future research should focus on improving the prediction of risk for substance use relapse, and on testing interventions to promote continued abstinence posttransplantation.


Method for more accurate transmittance measurements of low-angle scattering samples using an integrating sphere with an entry port beam diffuser.
For most integrating sphere measurements, the difference in light distribution between a specular reference beam and a diffused sample beam can result in significant errors. The problem becomes especially pronounced in integrating spheres that include a port for reflectance or diffuse transmittance measurements. The port is included in many standard spectrophotometers to facilitate a multipurpose instrument, however, absorption around the port edge can result in a detected signal that is too low. The absorption effect is especially apparent for low-angle scattering samples, because a significant portion of the light is scattered directly onto that edge. In this paper, a method for more accurate transmittance measurements of low-angle light-scattering samples is presented. The method uses a standard integrating sphere spectrophotometer, and the problem with increased absorption around the port edge is addressed by introducing a diffuser between the sample and the integrating sphere during both reference and sample scan. This reduces the discrepancy between the two scans and spreads the scattered light over a greater portion of the sphere wall. The problem with multiple reflections between the sample and diffuser is successfully addressed using a correction factor. The method is tested for two patterned glass samples with low-angle scattering and in both cases the transmittance accuracy is significantly improved.


A lipid-conjugated immunostimulating complex subunit vaccine against Salmonella infection in turkeys.
Immunostaining complexes (ISCOMs) are multimeric particles and have been used successfully for presentation of membrane proteins. In this study, outer-membrane proteins (OMPs) from Salmonella heidelberg were incorporated into lipid-conjugated ISCOM particles and evaluated for their use in a vaccine for turkeys against homologous and heterologous Salmonella challenge. Two types of lipid-conjugated ISCOMs were examined: ISCOM-phospholipid and ISCOM-sphingolipid preparations. The turkeys were challenged with one of the three Salmonella serotypes: S. heidelberg, S. reading, or S. enteritidis. The turkeys were monitored for clinical signs, shedding pattern post-challenge, and clearance of the challenge Salmonella from selected internal organs. Vaccines containing OMP with either lipid-conjugated ISCOM preparation produced significantly greater (P < 0.01) immune response than OMP alone. Cloacal swabs from turkeys given OMP along with ISCOM-phospholipid and challenged with a homologous serotype were completely negative for Salmonella. A certain degree of cross-protection against heterologous Salmonella was afforded by both OMP-ISCOM vaccines. The isolation rate of Salmonella from internal organs was significantly lower (P < 0.0001) in vaccinated turkeys than in unvaccinated controls.


Gibberellin is essentially required for carrot (Daucus carota L.) somatic embryogenesis: dynamic regulation of gibberellin 3-oxidase gene expressions.
A GA biosynthesis inhibitor, uniconazole, caused many shrunken embryos when it was supplied to cultured carrot (Daucus carota L.) cells at the induction of somatic embryos. The abnormality was prevented by exogenous GA(1) or GA(4). To analyze the status of GA biosynthesis during somatic embryogenesis, expression patterns of newly isolated genes encoding GA biosynthetic enzymes, two GA 20-oxidases, three GA 3-oxidases, and two GA 2-oxidases were observed by using a semi-quantitative reverse-transcription-polymerase chain reaction with gene-specific primers. Transcript levels of GA 20-oxidases and GA 2-oxidases did not change greatly during development of the somatic embryo. On the other hand, drastic changes were found in three GA 3-oxidase genes. Strikingly, expression of a GA 3-oxidase gene, DcGA3ox2, was elevated once in somatic embryogenesis, but not in the non-induced suspension cells. The enzymatic functions of these gene products were also confirmed using recombinant proteins expressed in Escherichia coli. Our results indicate that GA biosynthesis is required for carrot somatic embryogenesis.


Current knowledge on exosome biogenesis and release.
Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.


Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain.
The phosphorylated form of histone H2A.X (γ-H2AX) is a well documented early, sensitive, and selective marker of DNA double-strand breaks (DSBs). Previously, we found that excessive glutamatergic activity increased γ-H2AX in neurons in vitro. Here, we evaluated γ-H2AX formation in the adult rat brain following neuronal excitation evoked by seizure activity in vivo. We found that brief, repeated electroconvulsive shock (ECS)-induced seizures (three individual seizures within 60 min) did not trigger an increase γ-H2AX immunostaining. In contrast, a cluster of 5-7 individual seizures evoked by kainic acid (KA) rapidly (within 30 min) induced γ-H2AX in multiple neuronal populations in hippocampus and entorhinal cortex. This duration of seizure activity is well below threshold for induction of neuronal cell death, indicating that the γ-H2AX increase occurs in response to sublethal insults. Moreover, an increase in γ-H2AX was seen in dentate granule cells, which are resistant to cell death caused by KA-evoked seizures. With as little as a 5 min duration of status epilepticus (SE), γ-H2AX increased in CA1, CA3, and entorhinal cortex to a greater extent than that observed after the clusters of individual seizures, with still greater increases after 120 min of SE. Our findings provide the first direct demonstration that DNA DSB damage occurs in vivo in the brain following seizures. Furthermore, we found that the γ-H2AX increase caused by 120 min of SE was prevented by neuroprotective preconditioning with ECS-evoked seizures. This demonstrates that DNA DSB damage is an especially sensitive indicator of neuronal endangerment and that it is responsive to neuroprotective intervention.


Ethical concerns for anesthesiologists during an Ebola threat.
The World Health Organization has proclaimed the current Ebola outbreak as a public health emergency. If an outbreak of Ebola should occur in Canada, anesthesiologists and anesthesia departments may be called upon to respond. The purpose of this review is to highlight and discuss potential ethical concepts that may be relevant to anesthesiologists. A thorough literature search was conducted using a variety of MEDLINE® sources, and we used Stand on Guard for Thee. Ethical Considerations in Preparedness Planning for Pandemic Influenza, a report by The University of Toronto Joint Centre for Bioethics Pandemic Influenza Working Group, as the framework for our review. Two groups of ethical concerns were identified. The first group relates to public health ethics, which analyzes the morality of public health interventions, and the second group relates to medical ethics, particularly to "the duty to care". The Canadian Medical Association Code of Ethics is vague in the description of duties of physicians who may respond to high-risk contagious diseases. Government, public health authorities, and anesthesia departments need to be prepared to respond to an outbreak of Ebola. Anesthesiologists have a skill that is suited to treat the complications of Ebola virus disease, and in case they are called for duty, anesthesiologists should be aware of the ethical concerns of treating a highly contagious communicable disease.


Intracranial hemorrhage in a large cohort of patients supported with veno-venous ECMO. A retrospective single-center analysis.
Intracranial bleeding (ICB) is a serious complication during veno-venous extracorporeal membrane oxygenation (V-V ECMO), with potentially fatal consequences. This study aimed to evaluate the incidence, time of detection of ICB among patients treated with V-V ECMO and potential risk factors for developing ICB during V-V ECMO. Five hundred fifty six patients were included in this retrospective single center analysis. Median time on V-V ECMO was 9 (IQR 6-15) days. Intracranial bleeding during V-V ECMO was detected in 10.9% of all patients (61 patients with ICB). Only 17 patients with ICB presented obvious clinical symptoms. Intracranial bleeding was detected on cerebral imaging in median after 5 days (IQR 1-14) after starting V-V ECMO. Overall survival to hospital discharge was 63.7% (ICB: 29.5%). Risk factors of ICB before starting V-V ECMO in univariable analysis were platelets <100/nl (OR: 3.82), creatinine >1.5mg/dl (OR: 1.98), norepinephrine >2.5mg/h (OR: 2.5), ASAT >80U/L (OR: 1.86), blood-urea >100mg/dl (OR: 1.81) and LDH >550u/L (OR: 2.07). Factors associated with cannulation were rapid decrease in paCO2 >35mmHg (OR: 2.56) and rapid decrease in norepinephrine >1mg/h (OR: 2.53). Multivariable analysis revealed low platelets, high paCO2 before ECMO, and rapid drop in paCO2 after V-V ECMO initiation as significant risk factors for ICB. The results emphasize that ICB is a frequent complication during V-V ECMO. Many bleedings were incidental findings, therefore screening for ICB is advisable. The univariate risk factors reflect the underlying disease severity, coagulation disorders and peri-cannulation factors, and may help to identify patients at risk.


Echogenic bowel on second-trimester ultrasonography: evaluating the risk of adverse pregnancy outcome.
To estimate if echogenic bowel diagnosed on second-trimester ultrasonography has an independent risk association with intrauterine growth restriction (IUGR) and intrauterine fetal demise. This is a retrospective cohort study of all patients with singleton gestations who presented to our institution for second-trimester ultrasonography between 1990 and 2008. Study groups were defined by the presence or absence of echogenic bowel. Primary outcomes were IUGR, defined as birth weight less than the 10th percentile for gestational age and intrauterine fetal demise at 20 weeks or more of gestation. Univariable and multivariable logistic regression analyses were used to estimate the risk of intrauterine fetal demise and IUGR in fetuses with echogenic bowel. Analyses were repeated after excluding cases of aneuploidy, cytomegalovirus (CMV) infection, other major congenital anomalies, and abnormal second-trimester serum screening results. Of 64,048 patients, the incidence of echogenic bowel was 0.4%. Of these, echogenic bowel was an isolated finding in 188 (72.3%) cases. There were 579 (0.9%) cases of intrauterine fetal demise and 8,173 (12.8%) cases of IUGR in the entire cohort. After excluding cases of aneuploidy and CMV infection, the incidence of intrauterine fetal demise was 7.3% in the echogenic bowel group compared with 0.9% in the nonechogenic bowel group, translating to an absolute risk increase of 6.4%. The incidence of IUGR in the echogenic bowel group was 19.5% compared with 12.9% in the nonechogenic bowel group (absolute risk increase, 6.6%). After controlling for potential confounders, echogenic bowel was significantly associated with both intrauterine fetal demise (adjusted odds ratio [OR] 9.6, 95% confidence interval [CI] 5.8-15.9) and IUGR (adjusted OR 2.1, 95% CI 1.5-2.9). This risk association remained significant even when evaluating echogenic bowel as an isolated sonographic finding. The presence of echogenic bowel on ultrasonography is independently associated with an increased risk for both IUGR and intrauterine fetal demise. Serial growth assessment and antenatal testing may be warranted in these patients.


Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes.
2'-Bromo-4'-epi-daunorubicin (alpha-manno configuration, denoted WP401) is a new anthracycline drug that exhibits promising activity toward multidrug-resistant cancer cells. We carried out X-ray diffraction analyses of the complexes formed in the presence of formaldehyde between WP401 and two DNA hexamers, TGGCCG and CGG[br5C]CG. The two complexes crystallized in different crystal lattices with respective crystal data of space group P4322, a = b = 37.20 A, c = 70.53 A and space group P43212, a = b = 37.23 A, c = 61. 96 A. These new crystal forms are different from the P41212 form of other daunorubicin/doxorubicin complexes studied previously. The refined crystal structures at approximately 2.0 A resolution revealed that the entire 2:1 drug-DNA complex is in the asymmetrical unit. Two WP401 drug molecules bind to the duplex, with the aglycones intercalated between the CpG or TpG steps and their modified daunosamines in the minor groove. As observed earlier, in the presence of formaldehyde, WP401 more readily forms a covalent adduct with (C/T)GG*:CCG than with (C/T)GC:G*CG (G* is the crosslink site), the opposite of what is seen for daunorubicin and doxorubicin. Surprisingly, the two T-G mismatched base pairs in the WP401-TGGCCG complex adopt the reverse Watson-Crick conformation, instead of the wobble conformation. The unusual T-G reverse Watson-Crick conformation may be required in order to maintain favorable stacking interactions between the base pair and the aglycone of WP401. Our results show that chemical modifications like bromo or iodo substitution on anthracycline drugs have significant effects on their DNA binding properties.


In trials of physiotherapy for chronic low back pain, clinical relevance is rarely interpreted, with great heterogeneity in the frameworks and thresholds used: a meta-research study.
How do authors of randomised controlled trials (RCTs) interpret the clinical relevance of the effects of physiotherapy interventions compared with no intervention on pain intensity, physical function and time to recovery in people with chronic low back pain (CLBP)? How can the clinical relevance be re-interpreted based on the available smallest worthwhile effect (SWE) threshold for this comparison? Are the studies in this field adequately powered? Cross-sectional meta-research study. People with CLBP. Pain intensity, physical function and time to recovery. This review included 23 RCTs with 1,645 participants. Twenty-two and 18 studies were included in the analysis of pain intensity and physical function, respectively. No studies investigated time to recovery. Sixteen studies reported varying thresholds to interpret clinical relevance for physical function and pain intensity. Discrepancies between interpretation using the minimal important difference and SWE values were observed in five studies. Study power ranged from 9% to 98%, with only four studies having a power > 80%. Little attention is given to the interpretation of clinical relevance in RCTs comparing physiotherapy with no intervention in CLBP, with great heterogeneity in the frameworks and thresholds used. Future trials should inform patients and clinicians on whether the effect of an intervention is large enough to be worthwhile, using a reliable and comprehensive approach like available SWE estimates. medRxiv https://doi.org/10.1101/2022.12.14.22283454.


Changes in lung function and airway inflammation among asthmatic children residing in a woodsmoke-impacted urban area.
Fine particulate matter (PM(2.5)) is associated with respiratory effects, and asthmatic children are especially sensitive. Preliminary evidence suggests that combustion-derived particles play an important role. Our objective was to evaluate effect estimates from different PM(2.5) exposure metrics in relation to airway inflammation and lung function among children residing in woodsmoke-impacted areas of Seattle. Nineteen children (ages 6-13 yr) with asthma were monitored during the heating season. We measured 24-h outdoor and personal concentrations of PM(2.5) and light-absorbing carbon (LAC). Levoglucosan (LG), a marker of woodsmoke, was also measured outdoors. We partitioned PM(2.5) exposure into its ambient-generated (E(ag)) and nonambient (E(na)) components. These exposure metrics were evaluated in relation to daily changes in exhaled nitric oxide (FE(NO)), a marker of airway inflammation, and four lung function measures: midexpiratory flow (MEF), peak expiratory flow (PEF), forced expiratory volume in the first second (FEV(1)), and forced vital capacity (FVC). E(ag), but not E(na), was correlated with combustion markers. Significant associations with respiratory health were seen only among participants not using inhaled corticosteroids. Increases in FE(NO) were associated with personal PM(2.5), personal LAC, and E(ag) but not with ambient PM(2.5) or its combustion markers. In contrast, MEF and PEF decrements were associated with ambient PM(2.5), its combustion markers, and E(ag), but not with personal PM(2.5) or personal LAC. FEV(1) was associated only with ambient LG. Our results suggest that lung function may be especially sensitive to the combustion-generated component of ambient PM(2.5), whereas airway inflammation may be more closely related to some other constituent of the ambient PM(2.5) mixture.


A case-control study of autism and mumps-measles-rubella vaccination using the general practice research database: design and methodology.
An association between mumps-measles-rubella (MMR) vaccination and the onset of symptoms typical of autism has recently been suggested. This has led to considerable concern about the safety of the vaccine. A matched case-control study using data derived form the United Kingdom General Practice Research Database. Children with a possible diagnosis of autism will be identified from their electronic health records. All diagnoses will be validated by a detailed review of hospital letters and by using information derived from a parental questionnaire. Ten controls per case will be selected from the database. Conditional logistic regression will be used to assess the association between MMR vaccination and autism. In addition case series analyses will be undertaken to estimate the relative incidence of onset of autism in defined time intervals after vaccination. The study is funded by the United Kingdom Medical Research Council. Electronic health databases offer tremendous opportunities for evaluating the adverse effects of vaccines. However there is much scope for bias and confounding. The rigorous validation of all diagnoses and the collection of additional information by parental questionnaire in this study are essential to minimise the possibility of misleading results.


High Occurrence of Shiga Toxin-Producing Escherichia coli in Raw Meat-Based Diets for Companion Animals-A Public Health Issue.
Feeding pets raw meat-based diets (RMBDs) is becoming increasingly popular but comes with a risk of pathogenic bacteria, including Shiga toxin-producing Escherichia coli (STEC). In humans, STEC may cause gastrointestinal illnesses, including diarrhea, hemorrhagic colitis (HC), and the hemolytic uremic syndrome (HUS). The aim of this study was to evaluate commercially available RMBDs with regard to the occurrence of STEC. Of 59 RMBD samples, 59% tested positive by real-time PCR for the presence of Shiga toxin genes stx1 and/or stx2. STECs were recovered from 41% of the 59 samples, and strains were subjected to serotyping and virulence gene profiling, using whole genome sequencing (WGS)-based methods. Of 28 strains, 29% carried stx2a or stx2d, which are linked to STEC with high pathogenic potential. Twenty different serotypes were identified, including STEC O26:H11, O91:H10, O91:H14, O145:H28, O146:H21, and O146:H28, which are within the most common non-O157 serogroups associated with human STEC-related illnesses worldwide. Considering the low infectious dose and potential severity of disease manifestations, the high occurrence of STEC in RMBDs poses an important health risk for persons handling raw pet food and persons with close contact to pets fed on RMBDs, and is of concern in the field of public health.


Both mitochondrial KATP channel opening and sarcolemmal KATP channel blockage confer protection against ischemia/reperfusion-induced arrhythmia in anesthetized male rats.
this study was performed to assess the effect of selective sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) channel (K(ATP)) inhibition and the mitochondrial K(ATP) channel activation on ischemia and reperfusion (I/R)-induced arrhythmias in different gender of rats. We compared the effect of a selective sarcolemmal K(ATP) channel blocker HMR 1098, a selective mitochondrial K(ATP) channel opener diazoxide, a nonselective K(ATP) channel opener pinacidil, and the combination of pinacidil with HMR 1098 on the incidence and duration of ventricular arrhythmias in 2 groups: anesthetized males (n = 31) and females (n = 31). ischemia and reperfusion was produced by occluding the left main coronary artery of Sprague-Dowley rats for 6 minutes followed by re-opening of the artery for 6 minutes. the arrhythmia score and the duration of arrhythmias were significantly reduced by HMR 1098, diazoxide, and pinacidil in male rats. The combination of the pinacidil with HMR 1098 did not change the antiarrhythmic effect of pinacidil. The duration of arrhythmas was shorter in females than that in the corresponding males. Drug treatments were not effective in decreasing arrhythmias in female groups to the same extent as in the male group. However, the mitochondrial K( ATP) channel activation that is provided by the combination of pinacidil with HMR 1098 significantly decreased the total length of arrhythmias in females. results of the current study indicate that both mitochondrial K(ATP) channel activation and sarcolemmal K(ATP) channel inhibition exert antiarrhythmic action in male rats. The antiarrhythmic effect of pinacidil is not depend on the sarcolemmal K(ATP) channel opening. These results also indicate that K(ATP) channel modulators show no discernable effect in female rats due to the already low incidence of arrhythmias in females.


Does high C-reactive protein concentration increase atherosclerosis? The Whitehall II Study.
C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and sub-clinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis). We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50-74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and cross-sectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT. Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.


Computerized tomography and radionuclide scan in surgical patients -- a comparative prospective study in detecting liver metastases.
A prospective study was carried out in 100 patients with carcinoma of the digestive tract, in whom a CT-scan and a radionuclide scan were made prior to operation. The CT-scan and the radionuclide scan had the same degree of diagnostic relaibility (about 80% correct diagnoses). Routine pre-operative CT or isotope scans do not in our experience alter the surgical management. From the in vitro investigation in which the liver is cut into the same slices as the computerized tomography, it appears that liver metastases larger than 3.5 cm diameter are always seen, while smaller metastases may be missed. The alkaline phosphatase and the gamma CT are no reliable estimations in establishing the diagnosis of liver metastases.


Investigating somatic aneuploidy in the brain: why we need a new model.
The steady occurrence of DNA mutations is a key source for evolution, generating the genomic variation in the population upon which natural selection acts. Mutations driving evolution have to occur in the oocytes and sperm in order to be transmitted to the next generation. Through similar mechanisms, mutations also accumulate in somatic cells (e.g., skin cells, neurons, lymphocytes) during development and adult life. The concept that somatic cells can collect new mutations with time suggests that we are a mosaic of cells with different genomic compositions. Particular attention has been recently paid to somatic mutations in the brain, with a focus on the relationship between this phenomenon and the origin of human diseases. Given this progressive accumulation of mutations, it is likely that an increased load of somatic mutations is present later in life and that this could be associated with late-life diseases and aging. In this review, we focus on a particular type of mutation: the loss and/or gain of whole chromosomes (i.e., aneuploidy) caused by errors in chromosomes segregation in neurons and glia. Currently, it is hard to grasp the functional impact of somatic mutation in the brain because we lack reliable estimates of the proportion of aneuploid cells in the normal brain across different ages. Here, we revisit the key studies that attempted to quantify the proportion of aneuploid cells in both normal and diseased brains and highlight the deep inconsistencies among the different studies done in the last 15 years. Finally, our review highlights several limitations of studies performed in human and rodent models and explores a possible translational role for non-human primates.


Effect of duty hour standards on burnout among orthopaedic surgery residents.
We surveyed orthopaedic surgery residents and faculty from two university training programs to quantify quality of life measures including burnout, general health, and relationship issues. Residents exhibited high levels of burnout and emotional exhaustion but only average levels of personal achievement, while faculty showed lower levels of burnout and emotional exhaustion with above average scores for personal achievement. Resident burnout was positively correlated with number of hours worked while faculty hours worked was inversely related to burnout. The survey was readministered two years after implementing the Accreditation Council on Graduate Medical Education guidelines on residency duty hours. At this time resident scores for personal accomplishment had improved, while scores for emotional exhaustion showed a strong trend towards decreasing, and depersonalization scores also showed a possible trend towards decreasing. Resident duty hour limitation was associated with improvement in objective measures of burnout.


Familial focal epilepsy with variable foci mapped to chromosome 22q12: expansion of the phenotypic spectrum.
We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected individuals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.


The "DRIL" procedure--a neglected way to treat the "steal" syndrome of the hemodialysed patient.
The ischemic "steal" syndrome complicates angio-access in a growing number of hemodialysed patients. Until now, operative attempts (fistula ligation or banding) to treat this problem have met with only limited success. To assess the results of DRIL (distal revascularization-interval ligation) procedure in treating the "steal" syndrome. A retrospective review (1996-2002) was conducted of all 11 patients who underwent the DRIL procedure in two tertiary care hemodialysis units. Two patients were excluded because of inadequate medical documentation. All of the nine patients remaining suffered from overt atherosclerotic disease, six had diabetic nephropathy and four were smokers. The arteriovenous access, which led to the "steal" syndrome, was proximally located in all (antecubital in 8, thigh area in 1). "Steal" symptoms included hand pain, paraesthesia, neurologic deficits and gangrenous ulcers. DRIL was technically successful in all patients. There were no perioperative deaths. Immediate and complete relief of pain was achieved in eight of the nine patients. One patient with gangrene later required a transmetacarpal amputation. No patient required hand amputation. During follow-up (range 1-26 months) hemodialysis was continued uninterruptedly using the problematic AVA in all patients. Thrombosis occurred in the AVA in only two patients after the DRIL procedure at 9 and 24 months postoperatively, respectively. Three patient deaths were unrelated to the DRIL. In selected patients the DRIL procedure is a safe and effective way to treat the "steal" syndrome. AVA patency is not compromised by this operation. Preoperative angiography, before and after manual compression of the AVA, is crucial for the proper selection of patients who will benefit most from the DRIL procedure.


Conversion of the maltogenic alpha-amylase Novamyl into a CGTase.
Novamyl is a thermostable five-domain maltogenic alpha-amylase that shows sequence and structural homology with the cyclodextrin glycosyltransferases (CGTases). Comparing X-ray crystal structures of Novamyl and CGTases, two major differences in the active site cleft were observed: Novamyl contains a loop insertion consisting of five residues (residues 191-195) and the location of an aromatic residue known to be essential to obtain an efficient cyclization reaction. To convert Novamyl into a cyclodextrin (CD)-producing enzyme, the loop was deleted and two substitutions, F188L and T189Y, were introduced. Unlike the parent Novamyl, the obtained variant is able to produce beta-CD and showed an overall conversion of starch to CD of 9%, compared with CGTases which are able to convert up to 40%. The lower conversion compared with the CGTase is probably due to additional differences in the active site cleft and in the starch-binding E domain. A variant with only the five-residue loop deleted was not able to form beta-CD.


Murine and human myogenic cells identified by elevated aldehyde dehydrogenase activity: implications for muscle regeneration and repair.
Despite the initial promise of myoblast transfer therapy to restore dystrophin in Duchenne muscular dystrophy patients, clinical efficacy has been limited, primarily by poor cell survival post-transplantation. Murine muscle derived stem cells (MDSCs) isolated from slowly adhering cells (SACs) via the preplate technique, induce greater muscle regeneration than murine myoblasts, primarily due to improved post-transplantation survival, which is conferred by their increased stress resistance capacity. Aldehyde dehydrogenase (ALDH) represents a family of enzymes with important morphogenic as well as oxidative damage mitigating roles and has been found to be a marker of stem cells in both normal and malignant tissue. In this study, we hypothesized that elevated ALDH levels could identify murine and human muscle derived cell (hMDC) progenitors, endowed with enhanced stress resistance and muscle regeneration capacity. Skeletal muscle progenitors were isolated from murine and human skeletal muscle by a modified preplate technique and unfractionated enzymatic digestion, respectively. ALDH(hi) subpopulations isolated by fluorescence activate cell sorting demonstrated increased proliferation and myogenic differentiation capacities compared to their ALDH(lo) counterparts when cultivated in oxidative and inflammatory stress media conditions. This behavior correlated with increased intracellular levels of reduced glutathione and superoxide dismutase. ALDH(hi) murine myoblasts were observed to exhibit an increased muscle regenerative potential compared to ALDH(lo) myoblasts, undergo multipotent differentiation (osteogenic and chondrogenic), and were found predominately in the SAC fraction, characteristics that are also observed in murine MDSCs. Likewise, human ALDH(hi) hMDCs demonstrated superior muscle regenerative capacity compared to ALDH(lo) hMDCs. The methodology of isolating myogenic cells on the basis of elevated ALDH activity yielded cells with increased stress resistance, a behavior that conferred increased regenerative capacity of dystrophic murine skeletal muscle. This result demonstrates the critical role of stress resistance in myogenic cell therapy as well as confirms the role of ALDH as a marker for rapid isolation of murine and human myogenic progenitors for cell therapy.


Virtual reality simulation training for health professions trainees in gastrointestinal endoscopy.
Endoscopy has traditionally been taught with novices practicing on real patients under the supervision of experienced endoscopists. Recently, the growing awareness of the need for patient safety has brought simulation training to the forefront. Simulation training can provide trainees with the chance to practice their skills in a learner-centred, risk-free environment. It is important to ensure that skills gained through simulation positively transfer to the clinical environment. This updated review was performed to evaluate the effectiveness of virtual reality (VR) simulation training in gastrointestinal endoscopy. To determine whether virtual reality simulation training can supplement and/or replace early conventional endoscopy training (apprenticeship model) in diagnostic oesophagogastroduodenoscopy, colonoscopy, and/or sigmoidoscopy for health professions trainees with limited or no prior endoscopic experience. We searched the following health professions, educational, and computer databases until 12 July 2017: the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, BIOSIS Previews, CINAHL, AMED, ERIC, Education Full Text, CBCA Education, ACM Digital Library, IEEE Xplore, Abstracts in New Technology and Engineering, Computer and Information Systems Abstracts, and ProQuest Dissertations and Theses Global. We also searched the grey literature until November 2017. We included randomised and quasi-randomised clinical trials comparing VR endoscopy simulation training versus any other method of endoscopy training with outcomes measured on humans in the clinical setting, including conventional patient-based training, training using another form of endoscopy simulation, or no training. We also included trials comparing two different methods of VR training. Two review authors independently assessed the eligibility and methodological quality of trials, and extracted data on the trial characteristics and outcomes. We pooled data for meta-analysis where participant groups were similar, studies assessed the same intervention and comparator, and had similar definitions of outcome measures. We calculated risk ratio for dichotomous outcomes with 95% confidence intervals (CI). We calculated mean difference (MD) and standardised mean difference (SMD) with 95% CI for continuous outcomes when studies reported the same or different outcome measures, respectively. We used GRADE to rate the quality of the evidence. We included 18 trials (421 participants; 3817 endoscopic procedures). We judged three trials as at low risk of bias. Ten trials compared VR training with no training, five trials with conventional endoscopy training, one trial with another form of endoscopy simulation training, and two trials compared two different methods of VR training. Due to substantial clinical and methodological heterogeneity across our four comparisons, we did not perform a meta-analysis for several outcomes. We rated the quality of evidence as moderate, low, or very low due to risk of bias, imprecision, and heterogeneity.Virtual reality endoscopy simulation training versus no training: There was insufficient evidence to determine the effect on composite score of competency (MD 3.10, 95% CI -0.16 to 6.36; 1 trial, 24 procedures; low-quality evidence). Composite score of competency was based on 5-point Likert scales assessing seven domains: atraumatic technique, colonoscope advancement, use of instrument controls, flow of procedure, use of assistants, knowledge of specific procedure, and overall performance. Scoring range was from 7 to 35, a higher score representing a higher level of competence. Virtual reality training compared to no training likely provides participants with some benefit, as measured by independent procedure completion (RR 1.62, 95% CI 1.15 to 2.26; 6 trials, 815 procedures; moderate-quality evidence). We evaluated overall rating of performance (MD 0.45, 95% CI 0.15 to 0.75; 1 trial, 18 procedures), visualisation of mucosa (MD 0.60, 95% CI 0.20 to 1.00; 1 trial, 55 procedures), performance time (MD -0.20 minutes, 95% CI -0.71 to 0.30; 2 trials, 29 procedures), and patient discomfort (SMD -0.16, 95% CI -0.68 to 0.35; 2 trials, 145 procedures), all with very low-quality evidence. No trials reported procedure-related complications or critical flaws (e.g. bleeding, luminal perforation) (3 trials, 550 procedures; moderate-quality evidence).Virtual reality endoscopy simulation training versus conventional patient-based training: One trial reported composite score of competency but did not provide sufficient data for quantitative analysis. Virtual reality training compared to conventional patient-based training resulted in fewer independent procedure completions (RR 0.45, 95% CI 0.27 to 0.74; 2 trials, 174 procedures; low-quality evidence). We evaluated performance time (SMD 0.12, 95% CI -0.55 to 0.80; 2 trials, 34 procedures), overall rating of performance (MD -0.90, 95% CI -4.40 to 2.60; 1 trial, 16 procedures), and visualisation of mucosa (MD 0.0, 95% CI -6.02 to 6.02; 1 trial, 18 procedures), all with very low-quality evidence. Virtual reality training in combination with conventional training appears to be advantageous over VR training alone. No trials reported any procedure-related complications or critical flaws (3 trials, 72 procedures; very low-quality evidence).Virtual reality endoscopy simulation training versus another form of endoscopy simulation: Based on one study, there were no differences between groups with respect to composite score of competency, performance time, and visualisation of mucosa. Virtual reality training in combination with another form of endoscopy simulation training did not appear to confer any benefit compared to VR training alone.Two methods of virtual reality training: Based on one study, a structured VR simulation-based training curriculum compared to self regulated learning on a VR simulator appears to provide benefit with respect to a composite score evaluating competency. Based on another study, a progressive-learning curriculum that sequentially increases task difficulty provides benefit with respect to a composite score of competency over the structured VR training curriculum. VR simulation-based training can be used to supplement early conventional endoscopy training for health professions trainees with limited or no prior endoscopic experience. However, we found insufficient evidence to advise for or against the use of VR simulation-based training as a replacement for early conventional endoscopy training. The quality of the current evidence was low due to inadequate randomisation, allocation concealment, and/or blinding of outcome assessment in several trials. Further trials are needed that are at low risk of bias, utilise outcome measures with strong evidence of validity and reliability, and examine the optimal nature and duration of training.


A randomised controlled trial of ion-exchange water softeners for the treatment of eczema in children.
Epidemiological studies and anecdotal reports suggest a possible link between household use of hard water and atopic eczema. We sought to test whether installation of an ion-exchange water softener in the home can improve eczema in children. This was an observer-blind randomised trial involving 336 children (aged 6 months to 16 years) with moderate/severe atopic eczema. All lived in hard water areas (≥200 mg/l calcium carbonate). Participants were randomised to either installation of an ion-exchange water softener plus usual eczema care, or usual eczema care alone. The primary outcome was change in eczema severity (Six Area Six Sign Atopic Dermatitis Score, SASSAD) at 12 weeks, measured by research nurses who were blinded to treatment allocation. Analysis was based on the intent-to-treat population. Eczema severity improved for both groups during the trial. The mean change in SASSAD at 12 weeks was -5.0 (20% improvement) for the water softener group and -5.7 (22% improvement) for the usual care group (mean difference 0.66, 95% confidence interval -1.37 to 2.69, p = 0.53). No between-group differences were noted in the use of topical corticosteroids or calcineurin inhibitors. Water softeners provided no additional benefit to usual care in this study population. Small but statistically significant differences were found in some secondary outcomes as reported by parents, but it is likely that such improvements were the result of response bias, since participants were aware of their treatment allocation. A detailed report for this trial is also available at http://www.hta.ac.uk. Current Controlled Trials ISRCTN71423189 Please see later in the article for the Editors' Summary.


How to start a blog.
Blogs that address issues of health and medical education run by clinical and research teams can have a profound impact on how patients access and navigate health information. Regularly updated websites are useful tools to facilitate two-way communication with a range of different audiences from patients to the general public. They provide benefits of supporting patients to learn and self-manage their health, and to educate colleagues and disseminate research. This article describes how to set up a blog, pointing out some simple style and formatting considerations, usable methods and appropriate conduct for healthcare professionals to engage with patients online.


Parametric modeling in food package defect imaging.
A novel approach in food package defect detection is proposed based on system identification theory, in which the channel defect detection problem can be regarded as the conventional system identification problem, i.e., estimation of the system impulse response based on the input-output sequence using parametric and nonparametric models. The well-known parametric model ARX has been investigated in this paper. The data are collected with a focused ultrasound transducer (17.3 MHz, 6.35-mm diameter, f/2, 173 microm -6 dB pulse-echo lateral beam width at the focus) scanned over a rectangular grid, keeping the packages in the focus. Performance is measured in terms of detection rate, image contrast, and contrast-to-noise ratio. The results using the ARX model are compared with previous image formation techniques and also compared with the non-parametric method, i.e., spectral analysis. The results show that the ARX model has the comparable detection rate as RFCS and higher detection rate than BAI and RFS (except 6-microm air-filled channel in plastic trilaminate film) for channel in plastic trilaminate film. The ARX model has achieved the moderate contrast enhancement and ranks second in contrast-to-noise ratio enhancement among the compared techniques. The ARX model has a low detection rate for channel defects in aluminum trilaminate film, which shows that its performance is material-dependent. Finally, the parametric method, ARX model demonstrates better performance than the non-parametric method, spectral analysis for food package defect detection.


Netrin-1 controls sympathetic arterial innervation.
Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type-specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.


The role of trachelectomy in cervical cancer.
Cervical cancer is one of the most common cancers in women worldwide. Because it often affects women of childbearing age (19-45 years), fertility-sparing surgery is an important issue. The article reviews current viable fertility-sparing options with a special focus on trachelectomy, including vaginal radical trachelectomy, abdominal radical trachelectomy and simple trachelectomy. Neoadjuvant chemotherapy is also discussed. Finally, the decision to proceed with fertility-sparing treatment should be a patient-driven process.


BRCA1 and BRCA2 mutations in ovarian cancer: Covariation with specific cytogenetic features.
We analyzed 37 primary invasive carcinomas for BRCA1 and BRCA2 mutations by screening the entire coding regions of both genes. Seven predicted truncating mutations (four in BRCA1 and three in BRCA2) and one novel BRCA1 missense variant (S1542C) were identified (8/37, 22%). Two of the BRCA1 mutations were somatic changes, whereas the remaining three BRCA1 changes and all mutations of BRCA2 were found to be of germline origin. All eight BRCA-positive tumors were serous or seropapillary carcinomas (8/27 serous tumors, 30%), and all but one were poorly differentiated. The correlation between tumor karyotype and BRCA status showed that clonal chromosomal aberrations were present in all BRCA-positive tumors (8/8) compared with 20 of 29 BRCA-negative ones. The most consistently affected region in BRCA-positive tumors was the long arm of chromosome 6; alterations within this arm with a breakpoint in band 6q21 were seen in four of five BRCA1-positive and in two of three BRCA2-positive tumors, but only in four of 20 karyotypically abnormal tumors without BRCA mutations, suggesting that the genetic pathways of tumor progression differ in the two groups. The high frequency of germline BRCA mutations detected in this pilot study (16% of 37 invasive carcinomas) points to the need for more extended analyses of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population.


Assessment and management of patients with hypothyroidism.
This article explains how to assess, diagnose and treat patients with an underactive thyroid gland (hypothyroidism), including an outline of replacement therapy options. The need for regular monitoring and ongoing support is also highlighted.


Multiple and ancient origins of the domestic dog.
Mitochondrial DNA control region sequences were analyzed from 162 wolves at 27 localities worldwide and from 140 domestic dogs representing 67 breeds. Sequences from both dogs and wolves showed considerable diversity and supported the hypothesis that wolves were the ancestors of dogs. Most dog sequences belonged to a divergent monophyletic clade sharing no sequences with wolves. The sequence divergence within this clade suggested that dogs originated more than 100,000 years before the present. Associations of dog haplotypes with other wolf lineages indicated episodes of admixture between wolves and dogs. Repeated genetic exchange between dog and wolf populations may have been an important source of variation for artificial selection.


Porphyromonas gingivalis with collagen immunization induces ACPA-positive rheumatoid arthritis in C3H mice.
The pathogenic anti-citrullinated protein antibodies (ACPA) are thought to play a vital role in the initiation and immune maintenance of rheumatoid arthritis (RA). However, it is noteworthy that ACPA is not a salient characteristic of any conventional RA animal model. Porphyromonas gingivalis (Pg) was the first microorganism identified to induce citrullination and is a target of autoantibodies in early rheumatoid arthritis (RA). Thus, we employed C3H mice with specific MHC types and combined Pg infection with collagen immunity to develop an animal model of ACPA-positive RA. The resulting model exhibited citrullination characteristics, as well as pathological and immune cell changes. 1) Mice showed a significant increase in ACPA levels, and various organs and tissues exhibited elevated levels of citrullinated protein. 2) The mice experienced heightened pain, inflammation, and bone destruction. 3) The spleen and lymph nodes of the mice showed a significant increase in the proportion of Tfh-GCB cell subpopulations responsible for regulating autoantibody production. In conclusion, the C3H mouse model of Pg infection with collagen immunity demonstrated significant alterations in ACPA levels, citrullinated protein expression, and immune cell subpopulations, which could be a crucial factor leading to increased pain, inflammation, and bone destruction.


Necrotizing Soft Tissue Infections: A Focused Review of Pathophysiology, Diagnosis, Operative Management, Antimicrobial Therapy, and Pediatrics.
Background: Necrotizing fasciitis is a major health problem throughout the world. The purpose of this review is to assist providers with the care of these patients through a better understanding of the pathophysiology and management options. Methods: This is a collaborative review of the literature between members of the Surgical Infection Society of North America and World Society of Emergency Surgery. Results: Necrotizing fasciitis continues to be difficult to manage with the mainstay being early diagnosis and surgical intervention. Recognition of at-risk populations assists with the initiation of treatment, thereby impacting outcomes. Conclusions: Although there are some additional treatment strategies available, surgical debridement and antimicrobial therapy are central to the successful eradication of the disease process.


Genetics of alcoholism.
Great progress has been made by research on the contribution genetic factors make to a vulnerability toward alcoholism. Animal studies have demonstrated the importance of genetics in ethanol preference and levels of consumption, and human family, twin, and adoption research have revealed a 4-fold higher risk for offspring of alcoholics, even if they were adopted out at birth. The work presented in this symposium reviews the ongoing search for genetic trait markers of a vulnerability toward alcoholism. Dr. Li has used both animal and human research to demonstrate the possible importance of the genetic control of enzymes involved in ethanol metabolism and has worked to help develop an animal model of alcoholism. The possible importance of subgroups with different levels of predisposition toward alcoholism is emphasized by Dr. Cloninger. An overview of the studies of sons of alcoholics, given by Dr. Schuckit, reveals the potential importance of a decreased intensity of reaction to ethanol as part of a predisposition toward alcoholism and discusses the possible impact of some brain waves and ethanol metabolites to an alcoholism vulnerability. Dr. Deitrich reviews interrelationships between studies of animals and humans in the search for factors involved in a genetic vulnerability toward alcoholism. Taken together, these presentations underscore the importance of genetic factors in alcoholism, review animal and human research attempting to identify markers of a vulnerability, and reveal the high level of interaction between human and animal research.


Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis.
The p53 protein is a key tumor suppressor in mammals. In response to various forms of genotoxic stress p53 stimulates expression of genes whose products induce cell cycle arrest and/or apoptosis. An E3-ubiquitin ligase, Mdm2 (mouse-double-minute 2) and its human ortholog Hdm2, physically interact with the amino-terminus of p53 to mediate its ubiquitin-mediated degradation via the proteasome. Thus, pharmacological inhibition of the p53-Mdm2 interaction leads to overall stabilization of p53 and stimulation of its anti-tumorigenic activity. In this study we characterize the biological effects of a novel class of non-genotoxic isatin Schiff and Mannich base derivatives (ISMBDs) that stabilize p53 on the protein level. The likely mechanism behind their positive effect on p53 is mediated via the competitive interaction with Mdm2. Importantly, unlike Nutlin, these compounds selectively promoted p53-mediated cell death. These novel pharmacological activators of p53 can serve as valuable molecular tools for probing p53-positive tumors and set up the stage for development of new anti-cancer drugs.


Complete Genome Sequence of the Sesbania Symbiont and Rice Growth-Promoting Endophyte Rhizobium sp. Strain IRBG74.
Rhizobium sp. strain IRBG74 is the first known nitrogen-fixing symbiont in the Agrobacterium/Rhizobium clade that nodulates the aquatic legume Sesbania sp. and is also a growth-promoting endophyte of wetland rice. Here, we present the sequence of the IRBG74 genome, which is composed of a circular chromosome, a linear chromosome, and a symbiotic plasmid, pIRBG74a.


Interdisciplinary collaboration in the special care unit--Part II.
Collaborative interdisciplinary patient care is enhanced as healthcare professionals in special care units work to implement Joint Commission on Accreditation of Healthcare Organizations' standards for improving organizational performance. This second part of a two-part article provides a practical approach to developing a process action team to review the care of patients receiving mechanical ventilation. As a follow-up to the development of one special care unit committee, this was an important step in the transition from multidisciplinary, discipline-specific care to interdisciplinary, collaborative care.


Intrinsic dendritic filtering gives low-pass power spectra of local field potentials.
The local field potential (LFP) is among the most important experimental measures when probing neural population activity, but a proper understanding of the link between the underlying neural activity and the LFP signal is still missing. Here we investigate this link by mathematical modeling of contributions to the LFP from a single layer-5 pyramidal neuron and a single layer-4 stellate neuron receiving synaptic input. An intrinsic dendritic low-pass filtering effect of the LFP signal, previously demonstrated for extracellular signatures of action potentials, is seen to strongly affect the LFP power spectra, even for frequencies as low as 10 Hz for the example pyramidal neuron. Further, the LFP signal is found to depend sensitively on both the recording position and the position of the synaptic input: the LFP power spectra recorded close to the active synapse are typically found to be less low-pass filtered than spectra recorded further away. Some recording positions display striking band-pass characteristics of the LFP. The frequency dependence of the properties of the current dipole moment set up by the synaptic input current is found to qualitatively account for several salient features of the observed LFP. Two approximate schemes for calculating the LFP, the dipole approximation and the two-monopole approximation, are tested and found to be potentially useful for translating results from large-scale neural network models into predictions for results from electroencephalographic (EEG) or electrocorticographic (ECoG) recordings.


Human ERK1 induces filamentous growth and cell wall remodeling pathways in Saccharomyces cerevisiae.
Expression of an activated extracellular signal-regulated kinase 1 (ERK1) construct in yeast cells was used to examine the conservation of function among mitogen-activated protein (MAP) kinases. Sequence alignment of the human MAP kinase ERK1 with all Saccharomyces cerevisiae kinases reveals a particularly strong kinship with Kss1p (invasive growth promoting MAP kinase), Fus3p (pheromone response MAP/ERK kinase), and Mpk1p (cell wall remodeling MAP kinase). A fusion protein of constitutively active human MAP/ERK kinase 1 (MEK) and human ERK1 was introduced under regulated expression into yeast cells. The fusion protein (MEK/ERK) induced a filamentation response element promoter and led to a growth retardation effect concomitant with a morphological change resulting in elongated cells, bipolar budding, and multicell chains. Induction of filamentous growth was also observed for diploid cells following MEK/ERK expression in liquid culture. Neither haploids nor diploids, however, showed marked penetration of agar medium. These effects could be triggered by either moderate MEK/ERK expression at 37 degrees C or by high level MEK/ERK expression at 30 degrees C. The combination of high level MEK/ERK expression and 37 degrees C resulted in cell death. The deleterious effects of MEK/ERK expression and high temperature were significantly mitigated by 1 m sorbitol, which also enhanced the filamentous phenotype. MEK/ERK was able to constitutively activate a cell wall maintenance reporter gene, suggesting misregulation of this pathway. In contrast, MEK/ERK effectively blocked expression from a pheromone-responsive element promoter and inhibited mating. These results are consistent with MEK/ERK promoting filamentous growth and altering the cell wall through its ability to partially mimic Kss1p and stimulate a pathway normally controlled by Mpk1p, while appearing to inhibit the normal functioning of the structurally related yeast MAP kinase Fus3p.


Latest advancements in ureteral stent technology.
Urological diseases such as tumours, kidney stones, or strictures in the ureter can lead to a number of health consequences, including life-threatening complications. Ureteral stents have been widely used as a valid solution to restore compromised urological function. Despite their clinical success, stents are subject to failure due to encrustation and biofilm formation, potentially leading to urinary tract infection. The current review focuses on recent advancements in ureteral stent technology, which have been reported in recent scientific journals or patents. Web of Science and Google Scholar have been used as a search engine to perform this review, using the keywords "Ureteral + Stent + Design", "Ureteral + Stent + Material + Coating", "Ureteric + Stent" and "Ureteral + Stent". A significant proportion of technological developments has focused on innovating the stent design to overcome migration and urinary reflux, as well as investigating novel materials and coatings to prevent biofilm formation, such as poly(N,N-dimethylacrylamide) (PDMMA) and swellable polyethylene glycol diacrylate (PEGDA). Biodegradable ureteral stents (BUS) have also emerged as a new generation of endourological devices, overcoming the "forgotten stent syndrome" and reducing healthcare costs. Moreover, efforts have been made to develop pre-clinical test methods, both experimental and computational, which could be employed as a screening platform to inform the design of novel stent technologies.


Multichannel Dyson Equation: Coupling Many-Body Green's Functions.
We present the multichannel Dyson equation that combines two or more many-body Green's functions to describe the electronic structure of materials. In this work we use it to model photoemission spectra by coupling the one-body Green's function with the three-body Green's function. We demonstrate that, unlike methods using only the one-body Green's function, our approach puts the description of quasiparticles and satellites on an equal footing. We propose a multichannel self-energy that is static and only contains the bare Coulomb interaction, making frequency convolutions and self-consistency unnecessary. Despite its simplicity, we demonstrate with a diagrammatic analysis that the physics it describes is extremely rich. Finally, we present a framework based on an effective Hamiltonian that can be solved for any many-body system using standard numerical tools. We illustrate our approach by applying it to the Hubbard dimer and show that it is exact both at 1/4 and 1/2 filling.


Beneficial effects of bio-controlling agent Bacillus cereus IB311 on the agricultural crop production and its biomass optimization through response surface methodology.
Disease in agricultural field is a big problem that causes a massive loss in production. In this present investigation, we have reported a soil-borne bacterium Bacillus cereus IB311 which is antagonistic to plant pathogens (Pseudomonas syringae and Agrobacterium tumefaciens), and could make a substantial contribution to the prevention of plant diseases. To prove the practical application, the strain was directly applied in agricultural field. The results demonstrated that B. cereus IB311 has increased the production (20% and 26% in term of average pod number per plant, average seed number per pod, and seed yield per experimental plot) in ground nut (Arachis hypogaea var. Koushal, G201) and sesame (Sesamum indicum var. Kanak), respectively. To reduce the production cost, the biomass production was optimized through response surface methodology (RSM). Interactions of three variables (glucose, beef extract and inoculum) were studied using Central Composite Design. According to our analysis, optimum production of Bacillus cereus IB311 (5.383 µg/ mL) may be obtained at glucose 1.985%, beef extract 1.615% and inoculums size 0.757%. Therefore, we strongly believe that the application of this strain in agricultural field as bio-controlling agent will definitely enhance the production yield and will reduce the disease risk.


Women in hospital medicine: facts, figures and personal experiences.
Although females represent a high proportion of medical graduates, women are under represented at consultant level in many hospital specialties. Qualitative and quantitative analyses were undertaken which established female representation at all levels of the medical workforce in Ireland in 2011 and documented the personal experiences of a sample of female specialists. The proportions of female trainees at initial and higher specialist training levels are 765 (53%) and 656 (55%) respectively but falls to 1,685 (32%) at hospital specialist level (p < 0.0001). Significantly fewer women are found at specialist as compared to training levels in anaesthesia (p = 0.04), emergency medicine (p = 0.02), medicine (p < 0.0001), obstetrics/gynaecology (p = 0.0005), paediatrics (p = 0.006), pathology p = 0.03) and surgery (p < 0.0001). The lowest proportion of female doctors at specialist level exists in the combined surgical specialties 88 (10%); the highest is in psychiatry 380 (53%). Qualitative findings indicate that females who complete specialist training are wary of pursuing either flexible training or part time work options and experience discrimination at a number of levels. They appear to be resilient to this and tolerate it. Balancing motherhood and work commitments is the biggest challenge faced by female doctors with children and causes some to change career pathways.


Laboratory Based Surveillance of HIV-1 Acquired Drug Resistance in Cameroon: Implications for Use of Tenofovir-Lamivudine-Dolutegravir (TLD) as Second- or Third-Line Regimens.
Increased HIV drug resistance (HIVDR) with antiretroviral therapy (ART) rollout may jeopardize therapeutic options, especially in this era of transition to fixed-dose tenofovir-lamivudine-dolutegravir (TLD). We studied acquired HIVDR (ADR) patterns and describe potentially active drugs after first- and second-line failure in resource-limited settings (RLS) like Cameroon. A laboratory-based study with 759 patients (≥15 years) experiencing virological failure was carried out at the Chantal Biya International Reference Centre (CIRCB), Yaoundé, Cameroon. Socio-demographic, therapeutic and immunovirological data from patient records were analysed according to HIV-1 genotypic profiles. Median (IQR) ART-duration was 63 (50-308) months. Median CD4 and viremia were 153 (IQR:50-308) cells/mm3 and 138,666 (IQR:28,979-533,066) copies/mL, respectively. Overall ADR was high (93.4% first-line; 92.9%-second-line). TDF, potentially active in 35.7% of participants after first-line and 45.1% after second-line, suggested sub-optimal TLD-efficacy in second-line (64.3%) and third-line (54.9%). All PI/r preserved high efficacy after first-line failure while only DRV/r preserved high-level efficacy (87.9%) after second-line failure. In this resource-limited setting (RLS), ADR is high in ART-failing patients. PI/r strategies remain potent backbones for second-line ART, while only DRV/r remains very potent despite second-line failure. Though TLD use would be preferable, blind use for second- and third-line regimens may be sub-optimal (functional monotherapy with dolutegravir) with high risk of further failure, thus suggesting strategies for selective ART switch to TLD in failing patients in RLS.


Regeneration of douglas fir plantlets through tissue culture.
Douglas fir plantlets were produced in tissue culture under defined conditions from cotyledon explants obtained from 2- to 4-week-old seedlings. Tissue pieces were cultured on the surface of a fabric tissue support (100 percent polyester) saturated with liquid nutrient medium; this facilitated periodic changes of the medium to meet the requirements at successive developmental stages without transfer of cultured tissues. Plant growth regulators were needed to stimulate adventitious bud formation. Plantlets were regenerated by rooting excised shoots at 19 degrees C on agarsolidified medium containing sucrose and the auxin naphthalene-2-acetic acid. After root initiation, plant growth regulators were removed; this resulted in stimulation of root elongation and the subsequent development of plantlets, which were then established in soil.


[Effect of reduced extracellular level of sodium ions on the intracellular level of calcium ions in the cytoplasm of cultured rat cardiomyocytes].
Cytosolic free calcium [( Ca2+]in) was measured using fura-2 in isolated cultured ventricular myocytes of neonatal rat. Exposure of the cardiomyocyte to a solution in which all Na+ have been replaced by impermeable cations results in a 400-600 nmol/l increase of [Ca2+]in. This increase is followed by a slow decrease to the initial level. A decrease of the extracellular calcium concentration from 2.5 to 0.5 mmol./l or increase to 10 mmol/l produced, respectively, decrease and increase of the amplitude of [Ca2+]in rise in response to low-Na+ superfusion. Exposure of cardiomyocytes to low-Na+ solutions also led to a 2-3 fold increase of caffeine++-dependent Ca2+ release from intracellular stores. Changes in [Ca2+]in can be attributed to the operation of a sodium-calcium exchanger in heart cells.


Correspondence of self-reported fruit and vegetable intake with dietary intake data.
The association between greater fruit and vegetable intake and better health outcomes is now well established, and dietary guidelines and recommendations promote increased intake of fruit and vegetables. The correspondence of self-assessed change in, and adequacy of, fruit and vegetable intake with dietary intake data was investigated using data from a food frequency questionnaire administered in 1989 and again in 1992 to 453 randomly selected adults from Dalby, Queensland. There was some accuracy in self-reported increased intake of fruit for women, although the dietary data for 44 per cent of women who reported an increase in intake did not show such an increase. Self-reported increased intake did not correspond with dietary data for men or for vegetable intake for women. Self-assessed adequacy of fruit and vegetable intake was associated significantly with mean intake and intake frequency data. The association was stronger for men for fruit and for women for vegetables. Nonetheless, high percentages of people who consumed less than two servings of fruit or three servings of vegetables daily assessed their intake as 'about right'. There is a need for clear, consistent and widely promoted messages recommending intake of two fruit and five vegetable servings daily to increase awareness of the amounts of fruit and vegetables Australians should consume.


Expression and localisation of a senescence-associated KDEL-cysteine protease from Lilium longiflorum tepals.
Senescence is a tightly regulated process and both compartmentalisation and regulated activation of degradative enzymes is critical to avoid premature cellular destruction. Proteolysis is a key process in senescent tissues, linked to disassembly of cellular contents and nutrient remobilisation. Cysteine proteases are responsible for most proteolytic activity in senescent petals, encoded by a gene family comprising both senescence-specific and senescence up-regulated genes. KDEL cysteine proteases are present in senescent petals of several species. Isoforms from endosperm tissue localise to ricinosomes: cytosol acidification following vacuole rupture results in ricinosome rupture and activation of the KDEL proteases from an inactive proform. Here data show that a Lilium longiflorum KDEL protease gene (LlCYP) is transcriptionally up-regulated, and a KDEL cysteine protease antibody reveals post-translational processing in senescent petals. Plants over-expressing LlCYP lacking the KDEL sequence show reduced growth and early senescence. Immunogold staining and confocal analyses indicate that in young tissues the protein is retained in the ER, while during floral senescence it is localised to the vacuole. Our data therefore suggest that the vacuole may be the site of action for at least this KDEL cysteine protease during tepal senescence.


Extrarenal Wilm's tumour. A case report and review of literature.
An extrarenal Wilms' tumour exhibiting an unusual histology is reported in the inguinal region of a 3 year old girl. The tumour presents a tubulopapillary pattern associated with foci of nephroblastomatosis, a morphologic variant not previously described in any of the extrarenal Wilms' tumour. The unusual histologic picture enhances the difficulty in histogenetic based precise diagnosis. This case represents the 8th EWT of the inguinal region.


Computational Metabolomics: A Framework for the Million Metabolome.
"Sola dosis facit venenum." These words of Paracelsus, "the dose makes the poison", can lead to a cavalier attitude concerning potential toxicities of the vast array of low abundance environmental chemicals to which humans are exposed. Exposome research teaches that 80-85% of human disease is linked to environmental exposures. The human exposome is estimated to include >400,000 environmental chemicals, most of which are uncharacterized with regard to human health. In fact, mass spectrometry measures >200,000 m/z features (ions) in microliter volumes derived from human samples; most are unidentified. This crystallizes a grand challenge for chemical research in toxicology: to develop reliable and affordable analytical methods to understand health impacts of the extensive human chemical experience. To this end, there appears to be no choice but to abandon the limitations of measuring one chemical at a time. The present review looks at progress in computational metabolomics to provide probability-based annotation linking ions to known chemicals and serve as a foundation for unambiguous designation of unidentified ions for toxicologic study. We review methods to characterize ions in terms of accurate mass m/z, chromatographic retention time, correlation of adduct, isotopic and fragment forms, association with metabolic pathways and measurement of collision-induced dissociation products, collision cross section, and chirality. Such information can support a largely unambiguous system for documenting unidentified ions in environmental surveillance and human biomonitoring. Assembly of this data would provide a resource to characterize and understand health risks of the array of low-abundance chemicals to which humans are exposed.


[Evidence-based clinical practice guidelines in oral care 3. Support for the development of clinical practice guidelines].
Support is an important factor in the implementation of clinical practice guidelines. Data from 5 studies from 1998 through 2013 offer insight into the support for clinical practice guidelines among dentists, orthodontists, dental hygienists and denturists in the Netherlands. In these, attitudes, opinions, knowledge and behaviour were seen as indicators of support. Dentists have an increasingly positive attitude towards clinical practice guidelines. The majority is aware of and uses at least 1 of the guidelines available to them and are in favour of the development of clinical practice guidelines. Orthodontists and dental hygienists have available few such guidelines, but the majority of both groups favour their development. Among denturists, who also have little experience with clinical practice guidelines, there are fewer supporters for their development. All in all, among caregivers in oral healthcare in the Netherlands, support for the use and development of clinical practice guidelines is growing.


Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection.
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.


Knowledge and Awareness of Emergency Medical Physicians on the Management of Traumatic Dental Avulsion at Sultan Qaboos University Hospital.
This study aimed to assess the level of knowledge regarding traumatic dental avulsion management among emergency physicians at Sultan Qaboos University Hospital (SQUH), Muscat, Oman. This cross-sectional, survey-based observational study was conducted among emergency physicians at SQUH from August 2021 to October 2021. The data were collected through a standardised and validated questionnaire. Fisher's exact test and Mann-Whitney U tests were used to analyse the data. A total of 18 completed questionnaire forms were received (response rate: 72.0%). The data revealed that 66.7% of the participants had prior knowledge of avulsion management, and 50% had received education on dental trauma. However, 83.0% of the participants did not feel comfortable replanting an avulsed tooth themselves. Regarding their knowledge level, 45.0% of the participating physicians demonstrated low knowledge, 22.2% demonstrated moderate knowledge and 33.3% demonstrated high knowledge. Thus, 94.0% of the participants were interested in acquiring information about avulsion management. The level of knowledge was significantly associated with receiving dental education and a higher clinical grade. As a result, it is crucial to include information about avulsion and its management in both medical undergraduate and post-graduate curricula.


Fuzzy neural network quadratic stabilization output feedback control for biped robots via H/sub /spl infin// approach.
A novel fuzzy neural network (FNN) quadratic stabilization output feedback control scheme is proposed for the trajectory tracking problems of biped robots with an FNN nonlinear observer. First, a robust quadratic stabilization FNN nonlinear observer is presented to estimate the joint velocities of a biped robot, in which an H/sub /spl infin// approach and variable structure control (VSC) are embedded to attenuate the effect of external disturbances and parametric uncertainties. After the construction of the FNN nonlinear observer, a quadratic stabilization FNN controller is developed with a robust hybrid control scheme. As the employment of a quadratic stability approach, not only does it afford the possibility of trading off the design between FNN, H/sub /spl infin// optimal control, and VSC, but conservative estimation of the FNN reconstruction error bound is also avoided by considering the system matrix uncertainty separately. It is shown that all signals in the closed-loop control system are bounded.


Validation of an isotope dilution gas chromatography-mass spectrometry method for combined analysis of oxysterols and oxyphytosterols in serum samples.
We describe the validation of a method for the analysis of oxysterols, i.e. oxycholesterols and oxyphytosterols, in human serum using gas chromatography-mass spectrometry selected ion monitoring (GC-MS-SIM). Concentrations of 7α- and 7β-hydroxy-, and 7oxo-cholesterol, -campesterol, and -sitosterol as well as 4β-hydroxycholesterol and side-chain oxygenated 24S-, 25-, and 27-hydroxycholesterol were determined by isotope dilution methodology. After saponification at room temperature the oxysterols were extracted, separated from their substrates, cholesterol, campesterol, and sitosterol, by solid phase extraction, and subsequently derivatised to their corresponding trimethylsilyl-ethers prior to GC-MS-SIM. In order to prevent artificial autoxidation butylated hydroxytoluene and ethylenediaminetetraacetic acid were added. The validation of the method was performed according to the International Conference on Harmonisation guidance, including limits of detection and quantification, ranges, recovery and precision. Due to improved instrumental settings and work-up procedure, limits of detection and quantification ranged between 8.0-202.0pg/mL and 28.0-674pg/mL, respectively. Recovery data in five calibration points varied between 91.9% and 116.8% and in serum samples between 93.1% and 118.1%. The mean coefficient of variation (CV) for the recovery of all compounds was <10%. Well satisfying CVs for within-day precision (2.1-10.8%) and for between-day precision (2.3-12.1%) were obtained. More than 20 samples could be processed in a single routine day and test series of about 300 samples can be realised without impairment of the validation parameters during a sequence. Comparison of oxysterol and oxyphytosterol content in serum and plasma revealed no difference. A fully validated isotope dilution methodology for the quantification of oxycholesterols and oxyphytosterols from human serum or plasma is presented.