The impact of emergency department triage on the treatment outcomes of cancer patients with febrile neutropenia: A retrospective review.
The emergency department (ED) is an important entry point for patients with cancer requiring acute care due to oncological emergencies. Febrile neutropenia (FN) is one of the most common oncological emergencies and carries a significant risk of morbidity and mortality. There is evidence from previous studies that FN patients wait far longer in the ED than recommended by international guidelines. The aim was to examine whether individuals with cancer presenting at the ED with FN were triaged appropriately, and to explore if, and how, triage affected their treatment outcomes. A retrospective cohort design was employed to collect data over five years from all available ED records of adult cancer patients who presented with fever. Of the 431 eligible patients, 63% (n = 272) were assigned triage scores that were detrimental to their immediate health. Findings from the multiple linear regression analyses showed that inaccurate or under triage was significantly associated with delayed times for the initial physician assessment, administration of antibiotics, and decision on admission. The absence of fever at the time of triage assessment contributed significantly to the prediction of under triage. The allocation of patients with FN to a lower, inaccurate priority was partly responsible for the inability of those patients to meet the standard benchmarks for the initial physician assessment and the administration of antibiotics identified by the triage and febrile neutropenia guidelines. Ongoing strategies are needed to both enhance the application of the triage guidelines and institute organizational and system changes that promote timeliness and effectiveness throughout the entire ED episode of care.


Persistence of a continuous stochastic process with discrete-time sampling: non-Markov processes.
We consider the problem of "discrete-time persistence," which deals with the zero crossings of a continuous stochastic process X(T) measured at discrete times T=nDeltaT. For a Gaussian stationary process the persistence (no crossing) probability decays as exp(-theta(D)T)=[rho(a)](n) for large n, where a=exp(-DeltaT/2) and the discrete persistence exponent theta(D) is given by theta(D)=(ln rho)/(2 ln a). Using the "independent interval approximation," we show how theta(D) varies with DeltaT for small DeltaT and conclude that experimental measurements of persistence for smooth processes, such as diffusion, are less sensitive to the effects of discrete sampling than measurements of a randomly accelerated particle or random walker. We extend the matrix method developed by us previously [Phys. Rev. E 64, 015101(R) (2001)] to determine rho(a) for a two-dimensional random walk and the one-dimensional random-acceleration problem. We also consider "alternating persistence," which corresponds to a<0, and calculate rho(a) for this case.


Role of ryanodine receptor channels in Ca2+ oscillations of porcine tracheal smooth muscle.
Acetylcholine (ACh) induces repetitive, propagating intracellular Ca2+ concentration ([Ca2+]i) oscillations in porcine tracheal smooth muscle (TSM) cells. Using real-time confocal microscopy, we examined the role of sarcoplasmic reticulum (SR) Ca2+ release through inositol 1,4,5-trisphosphate (IP3) receptor and ryanodine receptor (RyR) channels in ACh-induced [Ca2+]i oscillations. In beta-escin permeabilized TSM cells, exposure to ACh in the presence of GTP also resulted in [Ca2+]i oscillations. [Ca2+]i oscillations could not be initiated by IP3 alone; however, an elevation of [Ca2+]i was observed. During ongoing [Ca2+]i oscillations, exposure to heparin, an IP3 receptor antagonist, caused a slowing of oscillation frequency but not complete inhibition. In contrast, ruthenium red, a RyR antagonist, completely abolished ACh-induced [Ca2+]i oscillations. Reverse transcriptase-polymerase chain reaction of TSM mRNA demonstrated the expression of RyR-2 and RyR-3 isoforms of the RyR. These results indicate that SR Ca2+ release through RyR channels is critical for ACh-induced [Ca2+]i oscillations in porcine TSM cells.


The analysis of endoscopic ultrasonographic finding for esophageal subepithelial lesion.
The number of endoscopic ultrasonography (EUS) for esophageal subepithelial lesion (SEL) is on the increase recently. We retrospectively investigated the 230 patients who underwent EUS for esophageal SEL from July 2010 to June 2013. We analyzed EUS finding and assumptive diagnosis. Among 230 enrolled patients, subepithelial tumor (SET) was observed in 189 (82.2%) patients. Mean size of SET was 8.5 ± 5.0 mm and mean distance from incisor tooth to lesion was 29.2 ± 6.7 cm. The most common origin wall layer of the SET was muscularis mucosa (59.4%), followed by submucosa (15.8%) and muscularis propria (21.1%). 3.7% of SET was indetermined. In the analysis of primary assumptive diagnosis, 70.5% was leiomyoma, 16.8% was granular cell tumor, 6.8% was gastrointestinal stromal tumor, 1.6% was cyst and 2.1% was vascular ectasia. The tissue sample by biopsy was checked in only 14.2% (27 cases) and the result was mostly (81.5%) non-specific inflammation. 21 cases (9.1%) of 230 patients revealed extrinsic compression, 61.9% was compressed by vessel, 33.3% was due to spine and one case (4.8%) was bronchus. 20 patients (8.7%) was normal without SEL. 107 patients (46.5%) of enrolled 230 patients repeatedly underwent EUS at least twice but, 79.4% (85/107) of SET was no change in size or shape. Esophageal SEL is mostly benign nature and misdiagnosed as extrinsic compression or normal variation easily. Thus, meticulous inspection is essential to distinguish SET and extrinsic compression. EUS is a good modality to examine esophageal SEL but, EUS is limited to accurate diagnosis of SET. The tissue acquisition for accurate diagnosis of SET is an important issue.


Attention Deficit Hyperactivity Disorder and Motor Impairment.
Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder during childhood, affecting approximately 3-6% of school-aged children; its cardinal symptoms of high activity, impulsivity, and behavioral distractibility might be assumed to have close relationships to interferences with motor skills. A separate body of literature attests to ways that motor problems can severely impact children's daily lives, as motor problems may occur in 30-50% of children with ADHD. This article critically reviews research on motor impairment in children with ADHD, notable differences in motor performance of individuals with ADHD compared with age-matched controls, and possible neural underpinnings of this impairment. We discuss the highly prevalent link between ADHD and developmental coordination disorder (DCD) and the lack of a clear research consensus about motor difficulties in ADHD. Despite increasing evidence and diagnostic classifications that define DCD by motor impairment, the role of ADHD symptoms in DCD has not been delineated. Similarly, while ADHD may predispose children to motor problems, it is unclear whether any such motor difficulties observed in this population are inherent to ADHD or are mediated by comorbid DCD. Future research should address the exact nature and long-term consequences of motor impairment in children with ADHD and elucidate effective treatment strategies for these disorders together and apart.


Large brachial artery diameter is associated with angiographic coronary artery disease in women.
Noninvasive methods are needed for the identification of women at highest risk for coronary artery disease (CAD) who might benefit most from aggressive preventive therapy. Identification of brachial artery atherosclerosis, which correlates with coronary artery atherosclerosis, may be useful to estimate or stratify CAD risk. Because atherosclerosis disrupts the arterial architecture that regulates vessel size, we hypothesized that noninvasively measured large brachial artery diameter is a manifestation of atherosclerosis that is associated with angiographic CAD in women with chest pain. We examined 376 women (mean age, 57.1 years) with chest pain in the National Heart, Lung, and Blood Institute's Women's Ischemia Syndrome Evaluation study who underwent B-mode ultrasound scan measurement of brachial artery diameter at rest and during hyperemic stress (to quantify flow-mediated dilation), quantitative coronary angiography, and risk factor assessment. Large resting brachial artery diameter was associated with significant angiographic CAD (3.90 +/- 0.79 mm vs 3.52 +/- 0.59 mm in women with CAD vs no CAD; P <.001). Impaired flow-mediated dilation, which correlated with resting diameter (r = -0.17; P =.001), was weakly associated with significant CAD (2.74% +/- 7.11% vs 4.48% +/- 9.52% in CAD vs no CAD; P =.046). After adjustment for age, body size, and CAD risk factors, women with large resting brachial artery diameters (>4.1 mm) had 3.6-fold increased odds (95% confidence interval, 1.8 to 7.1; P <.001) of significant angiographic CAD compared with those with small brachial arteries (</=3.6 mm). Large resting brachial artery diameter is an independent predictor of significant CAD in women with chest pain. Therefore, a simple ultrasonographic technique may be useful in the identification of women with chest pain who are at increased risk for CAD.


Sexual dysfunctions following low anterior resection of the rectum in rectal cancer patients.
Low anterior resection of the rectum (LAR) is a treatment of choice in patients with diagnosed low rectal cancer. Rectal cancer surgery has a close relationship with the urinary-sexual organs and also with related nerves and nerve plexus. Thus, the sympathetic and parasympathetic nerves of the pelvic area may be damaged. As a result of this, the important point is the sexual function loss following rectal surgeries. The aim of the study was to investigate the sexual disorders in patients with rectal cancer who underwent LAR. In this retrospective study the sexual activity, comfort of the experience, quality of sexual life (QoSL) during 3 periods were analyzed: before surgery, a month after and half a year after surgery. Analysis of demographic characteristics, comorbidities, previous surgeries, toumor characteristics and adjuvant therapy as was performed. Most patients (64/100, 64%) expressed that LAR operation has strongly affected their QoSL, 32 patients reported the mild decrease in QoSL, while only 4 patients stated that did not experience any changes in QoSL. QoSL was assessed in 3 different periods of time: before the operation, 1 month after and 6 months after the operation (22,6±3.7 vs. 11.3±7,9 vs. 17,0±6.3; p<0.0001 respectively). The decreased QoSL one and six months after the surgery were significantly lower in patients with diagnosed hypertension and higher BMI (p=0.0283). Sexual disorders after LAR for rectal cancer are often underestimated and it is very important to be aware of them. In our study, it was determined that male sex, higher BMI and hypertension are related to impair of sexual dysfunction after LAR. We observed that the most severe complaints related to sexual activity occur one month after the procedure, after 6 months in most of the patients' sexual disorders were decreased approaching the initial state.


Population targeting and durability of multimorbidity collaborative care management.
A patient-centered collaborative care program for depression and uncontrolled diabetes and/or coronary heart disease (CHD) demonstrated improved clinical outcomes relative to usual care. We report clinically stratified analyses of patient outcomes to inform the duration and targeting of care management services for complex patients with multimorbidity. A 12-month randomized controlled trial of a multimorbidity collaborative care program followed patients at 6, 12, 18, and 24 months for diabetes (glycated hemoglobin [A1C]), blood pressure (systolic; SBP), low-density lipoprotein (LDL) cholesterol, and depression (Symptoms Check List-20 score). Depressed patients with less favorable medical control (Patient Health Questionnaire-9 score > 10, A1C > 8.0 %, SBP > 140 mm Hg, and LDL cholesterol > 120 mg/dL) were compared with depressed patients with more favorable medical control to describe differential intervention benefits over time. In contrast to patients with more favorable baseline control, patients with depression and unfavorable control of A1C, SBP, and LDL at baseline showed improved outcomes as early as the 6-month follow-up assessment. Clinical benefits in the intervention group were largely sustained over the 24-month follow-up, except for some deterioration of glycemic control in intervention patients and trends toward improvement among controls over time. Among patients with depression and more favorable medical control at baseline, there were minimal between-group differences in medical disease outcomes. Clinical benefits of a multimorbidity collaborative care management program occurred early, and were only found among patients with poor control of baseline diabetes and CHD risk factors. Targeting may maximize reach and improve affordability of complex care management.


[Preparation of in situ gel systems for the oral delivery of ibuprofen and its pharmacokinetics study in beagle dogs].
The in situ gel systems can form gel in situ after administration to achieve sustained release, thus provides a promising strategy for drug delivery systems. The aim of this study was to design and prepare in situ gel systems for the oral delivery of ibuprofen (IBU-ISG) and study its pharmacokinetics in Beagle dogs. The characteristics of the basic material of gellan gum (Kelcogel, Kel) and sodium alginate (Manugel, M) were studied through investigating the complex viscosity of the Kel or M solution with or without different concentrations of calcium ion or sodium citrate to ascertain the amount range of the excipients. The measurement of complex viscosity of the solution (0. 5% Kel and 1% M) with different concentrations of sodium citrate and calcium ion was carried out to select the suitable proportion of calcium ion and sodium citrate. The formulation of binary IBU-ISG was optimized by monitoring the complex viscosity before gelling in vitro release property. The optimized formulation contains 1.0% sodium alginate, 0.5% gellan gum, 0. 21% sodium citrate and 0.056% calcium chloride. A single oral dose of IBU-ISG and reference formulation (IBU suspension) were given to each of the 6 healthy Beagle dogs, ibuprofen in plasma at different sampling times was determined by RP-HPLC. The pharmacokinetics parameters in 6 Beagle dogs were calculated. The Tmax of IBU-ISG and reference formulation were (1.8 +/- 0.6) and (0.4 +/- 0. 1) h. The Cmax values were (29.2 +/- 7.6) and (37.8 +/- 2.2) microg x mL(-1). The T(1/2) were (2.3 +/- 0.5) and (2.0 +/- 0.9) h, and the AUC(0-t) were (131.0 +/- 38.6) and (117.3 +/- 23.1) microg x mL(-1) x h, respectively. The binary IBU-ISG was successfully prepared.


Quantitative flow ratio‑derived index of microcirculatory resistance as a novel tool to identify microcirculatory function in patients with ischemia and no obstructive coronary artery disease (INOCA).
Coronary microvascular disease (CMVD) is associated with adverse cardiovascular outcomes. However, there is no reliable and noninvasive quantitative diagnostic method available for CMVD. The use of a pressure wire to measure the index of microcirculatory resistance (IMR) is possible, but it has inevitable practical restrictions. We hypothesized that computation of the quantitative flow ratio could be used to predict CMVD with symptoms of ischemia and no obstructive coronary artery disease (INOCA). We retrospectively assessed the diagnostic efficiency of the quantitative flow ratio‑derived index of microcirculatory resistance (QMR) in 103 vessels from 66 patients and compared it with invasive IMR using the thermodilution technique. Patients were divided into the CMVD group (41/66, 62.1%) and non-CMVD group (25/66, 37.9%). Pressure-wire IMR measurements were made in 103 coronary vessels, including 44 left descending arteries (LADs), 18 left circumflex arteries (LCXs) and 41 right coronary arteries (RCAs). ROC curve analysis showed a good diagnostic performance of QMR for all arteries (area under the curve=0.820, 95% confidence interval 0.736-0.904, p<0.001) in predicting microcirculatory function. The optimal cut-off for QMR to predict microcirculatory function was 266 (sensitivity: 82.9%, specificity: 72.6%, and diagnostic accuracy: 76.7%). QMR is a promising tool for the assessment of coronary microcirculation. The assessment of the IMR without the use of a pressure wire may enable more rapid, convenient, and cost-effective assessment of coronary microvascular function.


Vaginal disinfection for preventing mother-to-child transmission of HIV infection.
Mother-to-child transmission (MTCT) of HIV infection is one of the most tragic consequences of the HIV epidemic, especially in resource-limited countries, resulting in about 650 000 new paediatric HIV infections each year worldwide. The paediatric HIV epidemic threatens to seriously undermine decade-old child survival programmes. To estimate the effect of vaginal disinfection on the risk of MTCT of HIV and infant and maternal mortality and morbidity, as well as tolerability of vaginal disinfection in HIV-infected women. We searched the Cochrane Controlled Trials Register, Cochrane Pregnancy and Childbirth Register, PubMed, EMBASE, AIDSLINE, LILACS, AIDSTRIALS, and AIDSDRUGS, using standardised methodological filters for identifying trials. We also searched reference lists of identified articles, relevant editorials, expert opinions and letters to journal editors, and abstracts and proceedings of relevant conferences, and contacted subject experts and pharmaceutical companies. There were no language restrictions. Randomised trials or clinical trials comparing vaginal disinfection during labour with placebo or no treatment, in known HIV-infected pregnant women. Trials had to include an estimate of the effect of vaginal disinfection on MTCT of HIV and or infant and maternal mortality and morbidity. Three authors independently assessed trial eligibility and quality, and extracted data. Meta-analysis was performed using the Yusuf-Peto modification of Mantel-Haenszel's fixed effect method. Only two trials that included 708 patients met the inclusion criteria. The effect of vaginal disinfection on the risk of MTCT of HIV (OR 0.93, 95% CI 0.65 to 1.33), neonatal death (OR 1.38, 95% CI 0.30 to 6.33), and death after the neonatal period (OR 1.45, 95% CI 0.47 to 4.45) is uncertain. There was no evidence that vaginal disinfection increased adverse effects in mothers (OR 1.15, 95% CI 0.41 to 3.22), and evidence from one trial showed that adverse effects decreased in neonates (OR 0.14, 95% CI 0.07 to 0.31). Currently, there is no evidence of an effect of vaginal disinfection on the risk of MTCT of HIV. Given its simplicity and low cost, there is need for a large well-designed and well-conducted randomised controlled trial to assess the additive effect of vaginal disinfection on the risk of MTCT of HIV in antiretroviral treated women.


Improvement of xylanase production in solid state fermentation by alkali-tolerant Aspergillus fumigatus MKU1 using a fractional factorial design.
Optimization of media for the maximum production of xylanase by Aspergillus fumigatus MKUI was carried out using De Meo's fractional factorial design with seven components such as NaNO3, K2HPO4, MgSO4, FeSO4. KCl, peptone and yeast extract. A. fumigatus produced a maximum of 700 U/gds of enzyme after 48 hr of incubation (before optimization). After two steps of optimization, the medium designed favoured a 2.8 fold (1950 U/gds) increase in xylanase production by A. fumigatus. Optimized medium for Aspergillus fumigatus contained (g/l) NaNO3, 15; K2HPO4, 15; MgSO4, 5; FeSO4, 0.009; KCI, 0.5; peptone, 20; and yeast extract, 10.


Impact of night shifts on emergency medicine resident resuscitation performance.
Emergency medicine (EM) trainees often work nightshifts. We sought to measure how this circadian disruption affects EM resident performance during simulated resuscitations. This retrospective cohort study enrolled EM residents at a single Canadian academic centre over a six-year period. Residents completed twice-annual simulation-based resuscitation-focused objective structured clinical examinations (OSCEs) with assessment in four domains (primary assessment, diagnostic actions, therapeutic actions and communication), and a global assessment score (GAS). Primary and secondary exposures of interest were the presence of a nightshift (late-evening shifts ending between midnight and 03h00 or overnight shifts ending after 06h00) the day before or within three days before an OSCE. A random effects linear regression model was used to quantify the association between nightshifts and OSCE scores. From 57 residents, 136 OSCE scores were collected. Working a nightshift the day before an OSCE did not affect male trainee scores but was associated with a significant absolute decrease in mean total scores (-6% [95% CI -12% to 0%]), GAS (-7% [-13% to 0%]), and communication (-9% [-16% to -2%]) scores among women. Working any nightshift within three days before an OSCE lowered absolute mean total scores by 4% [-7% to 0%] and communication scores by 5% [-5% to 0%] irrespective of gender. Our results suggest that shift work may impact EM resident resuscitation performance, particularly in the communication domain. This impact may be more significant in women than men, suggesting a need for further investigation.


Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis.
Fistulas are debilitating complications of Crohn's disease (CD) that affect up to 50% of patients. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the efficacy of treatments for fistulizing CD. We searched publication databases from inception through December 13, 2016 for trials comparing the efficacy of a therapeutic agent (single or combination) with placebo or another active therapy in adult patients with any form of fistulizing CD. The Cochrane risk of bias tool was used to assess the methodological quality of trials; the overall quality of evidence was evaluated using GRADE. Primary outcomes included induction and maintenance of fistula response and remission. Pooled risk ratios (RRs) and 95% CIs were calculated for each outcome. We analyzed data from 27 trials; most studies (21/27) focused on patients with perianal fistulizing CD. We found moderate-quality evidence to support the efficacy of tumor necrosis factor (TNF) antagonists (RR, 2.01; 95% CI, 1.36-2.97), particularly infliximab, ustekinumab (RR, 1.77; 95% CI, 0.93-3.37), and mesenchymal stem cell therapy (RR, 1.31; 95% CI, 0.98-1.73) for induction of fistula remission. We found low-quality evidence for the efficacy of vedolizumab and immunosuppressives. There was also low-quality evidence to support the efficacy of combination therapy with TNF antagonists and antibiotics vs a TNF antagonist alone. In a systematic review and meta-analysis of 27 controlled trials, we found TNF antagonists to be effective for induction and maintenance of perianal fistula response and remission. There are few data on the effects on internal fistulae. Further studies are needed, particularly for ustekinumab, vedolizumab, and stem cell therapies, in patients with fistulizing CD.


Accuracy of a computer-aided surgical simulation protocol for orthognathic surgery: a prospective multicenter study.
The purpose of this prospective multicenter study was to assess the accuracy of a computer-aided surgical simulation (CASS) protocol for orthognathic surgery. The accuracy of the CASS protocol was assessed by comparing planned outcomes with postoperative outcomes of 65 consecutive patients enrolled from 3 centers. Computer-generated surgical splints were used for all patients. For the genioplasty, 1 center used computer-generated chin templates to reposition the chin segment only for patients with asymmetry. Standard intraoperative measurements were used without the chin templates for the remaining patients. The primary outcome measurements were the linear and angular differences for the maxilla, mandible, and chin when the planned and postoperative models were registered at the cranium. The secondary outcome measurements were the maxillary dental midline difference between the planned and postoperative positions and the linear and angular differences of the chin segment between the groups with and without the use of the template. The latter were measured when the planned and postoperative models were registered at the mandibular body. Statistical analyses were performed, and the accuracy was reported using root mean square deviation (RMSD) and the Bland-Altman method for assessing measurement agreement. In the primary outcome measurements, there was no statistically significant difference among the 3 centers for the maxilla and mandible. The largest RMSDs were 1.0 mm and 1.5° for the maxilla and 1.1 mm and 1.8° for the mandible. For the chin, there was a statistically significant difference between the groups with and without the use of the chin template. The chin template group showed excellent accuracy, with the largest positional RMSD of 1.0 mm and the largest orientation RMSD of 2.2°. However, larger variances were observed in the group not using the chin template. This was significant in the anteroposterior and superoinferior directions and the in pitch and yaw orientations. In the secondary outcome measurements, the RMSD of the maxillary dental midline positions was 0.9 mm. When registered at the body of the mandible, the linear and angular differences of the chin segment between the groups with and without the use of the chin template were consistent with the results found in the primary outcome measurements. Using this computer-aided surgical simulation protocol, the computerized plan can be transferred accurately and consistently to the patient to position the maxilla and mandible at the time of surgery. The computer-generated chin template provides greater accuracy in repositioning the chin segment than the intraoperative measurements.


Lateral lumbar interbody fusion at the lumbosacral junction.
Due to the obstruction of the iliac crest and the retroperitoneal vessels, lateral lumbar interbody fusion (LLIF) is generally considered contraindicated at the lumbosacral junction (LSJ). In particular the 'rise' of the psoas from the vertebral column in the lower lumbar segments has been associated with significant overlap of the lumbar plexus with the vertebral body and exclusion of a safe transpsoas entry. However in selected individuals anatomical variations may help circumvent the difficulties and the anatomical corridor posterior to the lumbar plexus may provide an alternative to the conventional anterior approach. Currently there is a dearth of information in informing the feasibility. We therefore reviewed the records of three patients in whom LLIF was successfully conducted at the LSJ. The patients' spinopelvic parameters and psoas anatomy were analysed by whole spine standing X-rays and MRI respectively. Intraoperative findings and postoperative outcome were examined. We found that in keeping with published morphometric data, low pelvic incidence (40-50°) appeared associated with 'low-lying' iliac crests which had facilitated lateral access to the LSJ in all cases. Patients with scoliosis provided added advantage when the concave side of the curve was utilised for the approach. A very high 'rising' psoas was found conducive to a novel posterior surgical corridor. No significant neurovascular sequelae were noted. In conclusion, LLIF can be safely performed at the LSJ in selected cases. To our knowledge this is the first report to describe the possibility of a safe LLIF working zone posterior to the lumbar plexus.


Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation.
Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure-activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.


Spinal and supraspinal contributions to central sensitization in peripheral neuropathy.
We will focus on spinal cord dorsal horn lamina I projection neurones, their supraspinal targets and involvement in pain processing. These spinal cord neurons respond to tonic peripheral inputs by wind-up and other intrinsic mechanisms that cause central hyper-excitability, which in turn can further enhance afferent inputs. We describe here another hierarchy of excitation - as inputs arrive in lamina I, neurones rapidly inform the parabrachial area (PBA) and periaqueductal grey (PAG), areas associated with the affective and autonomic responses to pain. In addition, PBA can connect to areas of the brainstem that send descending projections down to the spinal cord - establishing a loop. The serotonin receptor, 5HT3, in the spinal cord mediates excitatory descending inputs from the brainstem. These descending excitatory inputs are needed for the full coding of polymodal peripheral inputs from spinal neurons and are enhanced after nerve injury. Furthermore, activity in this serotonergic system can determine the actions of gabapentin (GBP) that is widely used in the treatment of neuropathic pain. Thus, a hierarchy of separate, but interacting excitatory systems exist at peripheral, spinal and supraspinal sites that all converge on spinal neurones. The reciprocal relations between pain, fear, anxiety and autonomic responses are likely to be subserved by these spinal-brainstem-spinal pathways we describe here. Understanding these pain pathways is a first step toward elucidating the complex links between pain and emotions.


Ergodicity, mixing, and recurrence in the three rotor problem.
In the classical three rotor problem, three equal point masses move on a circle subject to attractive cosine potentials of strength g. In the center of mass frame, energy E is the only known conserved quantity. In earlier works [Krishnaswami and Senapati, Indian Acad. Sci. Conf. Ser. 2(1), 139 (2019), and Chaos 29(12), 123121 (2019)], an order-chaos-order transition was discovered in this system along with a band of global chaos for 5.33g≤E≤5.6g. Here, we provide numerical evidence for ergodicity and mixing in this band. The distributions of relative angles and angular momenta along generic trajectories are shown to approach the corresponding distributions over constant energy hypersurfaces (weighted by the Liouville measure) as a power-law in time. Moreover, trajectories emanating from a small volume are shown to become uniformly distributed over constant energy hypersurfaces, indicating that the dynamics is mixing. Outside this band, ergodicity and mixing fail, though the distributions of angular momenta over constant energy hypersurfaces show interesting phase transitions from Wignerian to bimodal with increasing energy. Finally, in the band of global chaos, the distribution of recurrence times to finite size cells is found to follow an exponential law with the mean recurrence time satisfying a scaling law involving an exponent consistent with global chaos and ergodicity.


Saltbush-associated Asphondylia species (Diptera: Cecidomyiidae) in the Mediterranean Basin and their chalcidoid parasitoids (Hymenoptera: Chalcidoidea).
Numerous species of gall midges (Diptera: Cecidomyiidae) have been recorded from saltbush (Chenopodiaceae: Atriplex) around the world but only 11 of them belong to the large cecidomyiid genus Asphondylia. Of these, two species were described in the late 19th century from complex bud galls on Atriplex halimus in the Mediterranean Basin. In the present study Asphondylia punica is redescribed, A. conglomerata is synonymized with it, and Asphondylia scopuli is described from Atriplex lanfrancoi, an endemic plant to the Maltese Islands. Descriptions are accompanied by information about the galls and life history of the gall midges, and a review of the parasitic Hymenoptera associated with A. scopuli is provided. Four species of parasitoids were found and attributed to the families Eurytomidae, Pteromalidae, Eupelmidae and Eulophidae, of which the pteromalid Mesopolobus melitensis is described as new.


Antithrombotic strategies after interventional left atrial appendage closure: an update.
Interventional left atrial appendage occlusion (LAAO) has emerged as a valid alternative to oral anticoagulation (OAC) therapy for the prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). Areas covered: Antithrombotic therapy following interventional LAAO is critical in balancing the risk of thromboembolism and bleeding during the endothelialization of the implanted devices. In this article, the most recent clinical trials are reviewed and the current real-world antithrombotic strategies following LAAO device implantation are discussed. Expert commentary: For patients eligible for OAC and receiving a Watchman device, the most solid scientific evidence exists for warfarin plus aspirin for 45 days followed by dual antiplatelet therapy (DAPT) for 6 months and a lifelong aspirin therapy. In real-world most patients are being treated with DAPT for 3-6 months. Alternatively, the Watchman was approved for 3 months of novel OAC (NOAC) therapy in conjunction with aspirin. For all other devices, DAPT for 1-6 months has been used in the vast majority of cases. Considering major bleeding as the predominant complication following LAAO, evidence suggests that short-term DAPT (6 weeks) or single antiplatelet therapy using aspirin may be a viable option.


Expression of c-myc, epidermal growth factor receptor and c-erbB-2 in human endometrial carcinoma and cervical adenocarcinoma.
Thirty specimens of human endometrial carcinoma (n = 23) and cervical adenocarcinoma (n = 7) have been analyzed for c-myc, epidermal growth factor receptor (EGFR) and c-erbB-2 by immunohistochemistry. In endometrial carcinomas, expression of c-myc was observed in all cases, EGFR in 21 of 23 cases (91.3%) and c-erbB-2 in 7 of 23 cases (30.4%). In cervical adenocarcinomas, expression of c-myc was seen in 5 of 7 cases (71.6%), EGFR in all cases and c-erbB-2 in 2 of 7 cases (28.6%). c-myc immunoactivity was observed as nuclear or cytoplasmic stain or both, EGFR as membrane and cytoplasmic stain, c-erbB-2 as membrane stain. There was no relationship between expression of these three oncogenes and clinical prognostic factors in the present study.


Long-term results of malabsorptive distal Roux-en-Y gastric bypass in superobese patients.
The purpose of the present study was to evaluate the safety, efficacy, and nutritional outcomes of malabsorptive distal Roux-en-Y gastric bypass (D-RYGB) 20-25 years later at a university hospital. From 1985 to 1989, 49 mostly superobese (body mass index >50 kg/m(2)) patients had undergone D-RYGB. D-RYGB consisted of open laparotomy with a 50-mL proximal gastric pouch and gastroenterostomy performed 250 cm proximal to the ileocecal junction, with common channels of 50-150 cm. These 49 patients were compared with a similar group of 92 consecutive patients who had undergone long-limb RYGB, with a 75-cm biliopancreatic limb and 150-cm alimentary limb. The mean ± SD preoperative body mass index was 58.9 ± 9.3 kg/m(2). After 1 perioperative death secondary to pulmonary embolism, limb-lengthening revisions were required in 21 (43.7%) of the 48 remaining patients for protein-calorie malnutrition. Of the 23 with a 50-cm common channel, 13 required revision compared with 8 of 25 with ≥100-cm common channel (P <.05, chi-square). Of the 48 patients who had undergone D-RYGB, 8 had died 6-19 years after D-RYGB. Of the nonrevised patients, 19 (70.4%) of 27 had >5 years of follow-up. In these, the latest body mass index was 34.2 kg/m(2) at 10 ± 6.1 years. The percentage of excess weight loss was 66.8% ± 14%. The lowest late serum albumin level was 3.4 ± .5 g/dL (range 2.3-4.4). The mean 25-hydroxy vitamin D level was 14.6 ± 11.3 ng/mL. Compared with patients who had undergone long-limb RYGB, the D-RYGB patients had a significantly greater percentage of excess weight loss after 5 years but significantly lower albumin, hemoglobin, iron, and calcium levels. Although D-RYGB afforded superior long-term weight loss, it caused protein-calorie malnutrition requiring frequent revision. The nonrevised patients had frequent severe metabolic derangements. Thus, D-RYGB should not be the primary operation for morbid or superobese patients.


Pulse-resolved measurement of continuous-variable Einstein-Podolsky-Rosen entanglement with shaped local oscillators.
We report an experimental demonstration of the continuous-variable Einstein-Podolsky-Rosen (EPR) paradox and quantum steering using a pulsed light source and nonlinear optical waveguides. In this pulsed light source experiment, time-domain measurements were performed in which one measured value of the quadrature phase amplitude of the light field was independently obtained for each pulse. This independence is useful for application to quantum information processing and fundamental physics. To realize time-domain measurements, in-house built homodyne detectors were used to detect individual pulses. In addition, to improve the temporal-mode matching between the local oscillator (LO) and entangled pulse, the duration of the LO pulse was shortened by single-pass optical parametric amplification. The product of the conditional variances of the quadrature amplitudes was 0.82 ± 0.09 < 1, which satisfies the condition for realization of the EPR paradox and quantum steering.


Prediction of no-reflow phenomenon in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.
No-reflow is an important complication among patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).A retrospective study of 1658 STEMI patients undergoing direct PCI was performed. Patients were randomly assigned at a 7:3 ratio into development cohort and validation cohort and into no-reflow and normal blood flow groups. Clinical data and laboratory examinations were compared to identify independent risk factors and establish a no-reflow risk scoring system.In the development cohort (n = 1122), 331 (29.5%) had no-reflow. Multivariate analysis showed age ≥ 65 years (OR = 1.766, 95% confidence interval (CI): 1.313-2.376, P < .001), not using angiotonase inhibitor/angiotensin receptor antagonists (OR = 1.454, 95%CI: 1.084-1.951, P = .013), collateral circulation <grade 2 (OR = 3.056, 95%CI: 1.566-5.961, P = .001), thrombosis burden ≥4 points (OR = 2.033, 95%CI: 1.370-3.018, P < .001), diameter of target lesion ≥3.5 mm (OR = 1.511, 95%CI: 1.087-2.100, P = .014), thrombosis aspiration (OR = 1.422, 95%CI: 1.042-1.941, P = .026), and blood glucose >8 mmol/L (OR = 1.386, 95%CI: 1.007-1.908, P = .045) were related to no-reflow. Receiver operating characteristic (ROC) area under the curve was 0.648 (95%CI: 0.609-0.86). At 0.349 cutoff sensitivity was 42.0%, specificity was 79.3%, positive predictive value (PPV) was 44.7%, negative predictive value (NPV) was 77.4%, P < .001. The resulting risk scoring system was tested in the validation cohort (n = 536), with 30.1% incidence of no-reflow. The area under the ROC curve was 0.637 (95%CI: 0.582-0.692). At a cutoff of 0.349 sensitivity was 53.2% and specificity was 66.7%, PPV was 41.2%, NPV was 76.4%, P < .001.The no-reflow risk scoring system was effective in identifying high-risk patients.


Electro-optically tunable microring resonators on lithium niobate.
Electro-optical tuning of a microring resonator fabricated on lithium niobate (LiNbO3) is presented. The device structure, including microring resonator and couplers, is designed in detail and is produced by titanium diffusion on the wet-etched LiNbO3 ridge surface. The resonance wavelengths for TM and TE polarizations can be tuned by electro-optic effect. The output characteristics of through port and drop port in the microring resonators are measured, and the effect of applied voltage on the shift of resonant wavelength is discussed. The presented microring resonators have the features of fast tuning speed, high material stability, bidirection wavelength shift, and no heating interference. Realization of such a microring resonator on LiNbO3 makes the utilization of electro-optic tuning and nonlinear effects in the versatile photonic applications of microring resonators achievable.


[Is there an indication for general perioperative antibiotic prophylaxis in laparoscopic plastic hernia repair with implantation of alloplastic tissue?].
The implantation of alloplastic material in laparoscopically operated groin hernias is usually connected with perioperative prophylaxis by antibiotics. We doubted the usefulness of the general application in these operations. Therefore we made a prospective randomized study in 80 patients, beginning since April 1996. 40 of them received perioperatively antibiotics, other 40 ones remained without antibiotics. These 80 patients underwent an unilateral hernioplasty and were without major anaesthesiologic risk. Both the groups were statistically comparable. As a result, no patient of both the groups suffered from an infectious complication. Thus, we can recommend the laparoscopic implantation of alloplastic meshes in "simple hernias" without perioperative antibiotic prophylaxis. In risk patients, antibiotics should still given further.


Infectious disease morbidity and growth among young HIV-exposed uninfected children in Jamaica.
There is a growing body of data that demonstrates increased infectious disease outcomes for HIV-exposed uninfected (HIV-EU) infants as compared to their HIV-unexposed (HU) counterparts. We hypothesized that these HIV-EU infants are at greater risk for infectious morbidity and mortality when compared to the general childhood population. We therefore aimed to characterize infections and growth outcomes among HIV-EU infants in Jamaica during their first two years of life. By identifying these outcomes, specific interventions could be implemented to mitigate this risk of morbidity and mortality. HIV-EU infants born between 1 January 2004 and 31 December 2006 in Kingston, Jamaica, were enrolled and followed in multicenter health facilities, using standardized protocols. HIV status was determined by RNA/DNA polymerase chain reaction (PCR) and confirmatory HIV enzyme-linked immunoassay (ELISA). Data were collected on demographic and anthropometric characteristics, infectious morbidity and mortality, and hospitalizations. Outcomes (incidence of infections and hospitalizations; growth (z scores for weight)) were determined, using univariate analyses. Of 195 HIV-EU infants followed for 25.9 months (standard deviation, 10.9 months), 102 (52%) were male, 185 (95%) were non-breast-fed, 161 (83%) experienced at least one infection, and 58 (30%) were hospitalized at least once. Infectious disease incidence per 1 000 child-weeks included upper respiratory tract infection of 7.25 (95% confidence interval (CI): 5.92-8.90), otitis media of 4.12 (3.21-5.20), and acute gastroenteritis (AGE) of 1.92 (1.35-2.65). Hospitalization incidence per 1 000 child-weeks included lower respiratory tract infections (LRTIs) of 0.89 (0.53-1.40), sepsis of 0.48 (0.23-0.89), and AGE of 0.43 (0.20-0.81). These infection incidence rates among the HIV-EU infants were higher than those for published community controls. Among the HIV-EU infants, the low-birthweight ones and those born via cesarean section had significantly higher hospitalization rates from LRTI and sepsis than did published community controls. The mean z score for weight during the infants' first 6 months ranged from -0.06 to 0.78 in this predominantly non-breast-fed population. That score trended upwards to 24 months of age. Infectious disease morbidity was higher but growth was normal in this cohort of HIV-EU non-breast-fed infants, in comparison to published community controls. Specific interventions should be implemented to mitigate the risk in this setting.


Psychometric properties of the Tinnitus Functional Index (TFI): Assessment in a UK research volunteer population.
Questionnaires are essential for measuring tinnitus severity and intervention-related change but there is no standard instrument used routinely in research settings. Most tinnitus questionnaires are optimised for measuring severity but not change. However, the Tinnitus Functional Index (TFI) claims to be optimised for both. It has not however been fully validated for research purposes. Here we evaluate the relevant psychometric properties of the TFI, specifically the questionnaire factor structure, reproducibility, validity and responsiveness guided by quality criteria for the measurement properties of health-related questionnaires. The study involved a retrospective analysis of data collected for 294 members of the general public who participated in a randomised controlled trial of a novel tinnitus device (ClinicalTrials.gov Identifier: NCT01541969). Participants completed up to eight commonly used assessment questionnaires including the TFI, Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionnaire (THQ), a Visual Analogue Scale of loudness (VAS-Loudness), Percentage Annoyance question, the Beck's Depression Inventory (BDI), Beck's Anxiety Inventory (BAI), and the World Health Organisation Quality of Life-Bref (WHOQOL-BREF). A series of analyses assessed the study objectives. Forty four participants completed the TFI at a second visit (within 7-21 days and before receiving any intervention) providing data for reproducibility assessments. The 8-factor structure was not fully confirmed for this general (non-clinical) population. Whilst it was acceptable standalone subscale, the 'auditory' factor showed poor loading with the higher order factor 'functional impact of tinnitus'. Reproducibility assessments for the overall TFI indicate high internal consistency (α = 0.80) and extremely high reliability (ICC: 0.91), whilst agreement was borderline acceptable (93%). Construct validity was demonstrated by high correlations between scores on the TFI and THI (r = 0.82) and THQ (r = 0.82), moderate correlations with VAS-L (r = 0.46), PR-A (r = 0.58), BDI (r = 0.57), BAI (r = 0.39) and WHOQOL (r = -0.48). Floor effects were observed for more than 50% of the items. A smallest detectable change score of 22.4 is proposed for the TFI global score. Even though the proposed 8-factor structure was not fully confirmed for this population, the TFI appears to cover multiple symptom domains, and to measure the construct of tinnitus with an excellent reliability in distinguishing between patients. While the TFI may discriminate those whose tinnitus is not a problem, floor effects in many items means it is less appropriate as a measure of change in this subgroup. Further investigation is needed to determine whether these effects are relevant in other populations.


Exopolysaccharides from Lactobacillus plantarum NCU116 Facilitate Intestinal Homeostasis by Modulating Intestinal Epithelial Regeneration and Microbiota.
Regeneration of epithelia is crucial for maintaining the intestinal barrier and homeostasis. Our previous work showed that exopolysaccharides from Lactobacillus plantarum NCU116 (EPS116) regulated the barrier function and homeostasis of the intestine; however, the relevant mechanisms remain obscure. Therefore, we sought to explore the role of EPS116 in promoting intestinal epithelial regeneration. Our data showed that the administration of EPS116 markedly ameliorated inflammatory bowel disease-related phenotypes and promoted the regeneration of crypts in the colon of colitis mice. The results of immunofluorescence and reverse transcription-quantitative polymerase chain reaction experiments indicated that EPS116 strikingly increased the number of intestinal stem cells (ISCs) and the expression of differentiation markers for goblet cells, enterocytes, and enteroendocrine cells in the mouse colon. Intestinal microbiota analysis showed that EPS116 increased microbial populations associated with intestinal regeneration and glycan metabolism. Therefore, the present study revealed a novel model that EPS116 promoted the intestinal homeostasis through modulating the proliferation and differentiation of ISCs and altering the gut microbiota profile.


Template-assisted filament growth by parallel stacking of tau.
Tau filaments are found in >20 neurodegenerative diseases. Yet, because of their enormous molecular weights and poor tendency to form highly ordered 3D crystal lattices, they have evaded high-resolution structure determination. Here, we studied 25 derivatized tau mutants by using electron paramagnetic resonance and fluorescence spectroscopy to report structural details of tau filaments. Based on strong spin exchange and pyrene excimer formation of core residues, we find that individual tau proteins form single molecule layers along the fiber axis that perfectly stack on top of each other by in-register, parallel alignment of beta-strands. We suggest a model of filament growth wherein the existing filament serves as a template for the incoming, unfolded tau molecule, resulting in a new structured layer with maximized hydrogen-bonded contact surface and side-chain stacking.


Initial dose of oncolytic myxoma virus programs durable antitumor immunity independent of in vivo viral replication.
Oncolytic therapy uses live-replicating viruses to improve the immunological status of treated tumors. Critically, while these viruses are known to self-amplify in vivo, clinical oncolytic therapies still appear to display a strong dose dependence and the mechanisms mediating this dose dependence are not well understood. To explore this apparent contradiction, we investigated how the initial dose of oncolytic myxoma virus affected the subsequent ability of treatment to alter the immunological status of tumors as well as synergize with programmed cell death protein 1 (PD1) blockade. Our results indicate that, due to viral self-amplification in vivo, the overall load of myxoma virus rapidly normalizes within treated tumors despite up to 3-log differences in inoculating dose. Because of this, therapeutic efficacy in the absence of checkpoint blockade is largely dose independent. Despite this rapid normalization, however, treatment with high or low doses of myxoma virus induces distinct immunological changes within treated tumors. Critically, these changes appear to be durably programmed based on the initial oncolytic dose with low-dose treatment failing to induce immunological improvements despite rapidly achieving equivalent viral burdens. Finally, due to the distinct immunological profiles induced by high and low myxoma virus doses, oncolytic efficacy resulting from combination with PD1 blockade therapy displays a strong dose dependence. Taken together, these data suggest that the ability of oncolytic myxoma virus to immunologically reprogram treated tumors is dependent on initial viral dose. Additionally, this work could provide a possible mechanistic explanation for clinical results observed with other oncolytic viruses.


Reconstruction of knee ligaments with a free tensor fascia lata myocutaneous flap transfer.
A 26-year-old woman suffered a grinding injury of the thigh and knee, resulting in the loss of a large amount of soft tissue and some of the femur. A contralateral tensor fascia lata myocutaneous free flap was used to reconstruct the soft tissues and the lateral ligament compartment around the knee. Later, a ceramic artificial bone was implanted. The patient was able to walk, and a stress radiograph showed that the implanted artificial bone and the knee joint were stable. There was no donor-site morbidity. The functional and cosmetic results were satisfactory.


Automation of plasma protein binding assay using rapid equilibrium dialysis device and Tecan workstation.
Binding of drug molecules to plasma proteins is an important parameter in assessing drug ADME properties. Plasma protein binding (PPB) assays are routinely performed during drug discovery and development. A fully automated PPB assay was developed using rapid equilibrium dialysis (RED) device and Tecan workstation coupled to an automated incubator. The PPB assay was carried out in unsealed RED plates which allowed the assay to be fully automated. The plasma pH was maintained at 7.4 during the 6-h dialysis under 2% CO2 condition. The samples were extracted with acetonitrile and analyzed by liquid chromatography tandem mass spectrometry. The percent bound results of 10 commercial drugs in plasma protein binding were very similar between the automated and manual assays, and were comparable to literature values. The automated assay increases laboratory productivity and is applicable to high-throughput screening of drug protein binding in drug discovery.


Use of H2(15)O-PET and DCE-MRI to measure tumor blood flow.
Positron emission tomography (PET) with H2(15)O and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide noninvasive measurements of tumor blood flow. Both tools offer the ability to monitor the direct target of antiangiogenic treatment, and their use is increasingly being studied in trials evaluating such drugs. Antiangiogenic therapy offers great potential and, to an increasing extent, benefit for oncological patients in a variety of palliative and curative settings. Because this type of targeted therapy frequently results in consolidation of the tumor mass instead of regression, monitoring treatment response with the standard volumetric approach (Response Evaluation Criteria in Solid Tumors) leads to underestimation of the response rate. Monitoring direct targets of anticancer therapy might be superior to indirect size changes. In addition, measures of tumor blood flow contribute to a better understanding of tumor biology. This review shows that DCE-MRI and H2(15)O-PET provide reliable measures of tumor perfusion, provided that a certain level of standardization is applied. Heterogeneity in scan acquisition and data analysis complicates the interpretation of study results. Also, limitations inherent to both techniques must be considered when interpreting DCE-MRI and H2(15)O-PET results. This review focuses on the technical and physiological aspects of both techniques and aims to provide the essential information necessary to critically evaluate the use of DCE-MRI and H2(15)O-PET in an oncological setting.


A Note on Calibration of Clinical Prediction Models with Copas Statistics.
Calibration of clinical prediction models often entails assessing goodness of fit with independent, non-identically distributed Bernoulli random variables. We here investigate two statistics studied by Copas in this setting. We present distribution theory and a simulation study to compare the operating characteristics of the Copas statistics. In our simulation study with relatively small sample sizes, we found a simple Cornish-Fisher approximation tail quantiles of the distributions of the Copas statistics to perform adequately. Upon illustrating their use in a calibration study relating to prediction of atherosclerotic cardiovascular disease risk, power properties appear to reflect differential weighting accorded to observations, as evinced with other goodness-of-fit statistics. The Copas statistics are easily implemented, have proven value in other contexts, and appear to be underutilized in calibration studies. They ought to be part of the armamentarium of calibration tools for all researchers.


Observation of runaway electron beams by visible color camera in the Experimental Advanced Superconducting Tokamak.
The synchrotron radiation originated from the energetic runaway electrons has been measured by a visible complementary metal oxide semiconductor camera working in the wavelength ranges of 380-750 nm in the Experimental Advanced Superconducting Tokamak [H. Q. Liu et al., Plasma Phys. Contr. Fusion 49, 995 (2007)]. With a tangential viewing into the plasma in the direction of electron approach on the equatorial plane, the synchrotron radiation from the energetic runaway electrons was measured in full poloidal cross section. The synchrotron radiation diagnostics provides a direct pattern of the runaway beam inside the plasma. The energy and pitch angle of runaway electrons have been obtained according to the synchrotron radiation pattern. A stable shell shape of synchrotron radiation has been observed in a few runaway discharges.


Bronchogenic carcinoma treated by concomitant resection of lung and chest wall.
Chest wall invasion by bronchogenic carcinoma is found in 5% of all cases of pulmonary carcinoma. During the last 3 years, 11 cases of lung cancer with chest wall involvement have been encountered at the Jackson Veterans Administration Medical Center. We reviewed these cases to reassess the role of concomitant resection of the lung and chest wall. From this experience, we have concluded that (1) chest wall involvement is potentially curable; (2) chest wall resection adds little if any morbidity to the procedure; (3) resections of fewer than four ribs usually require only soft tissue coverage, without a prosthesis; (4) patients with squamous cell cancer have longer survival; (5) chest wall resection is highly effective in the relief of pain due to invasion of the chest wall; and (6) survival is greater than in other stage III lung carcinomas and is more closely related to nodal involvement than to chest wall invasion.


Modelling of atrazine transport in the presence of surfactants.
Laboratory experiments were conducted to examine the effect of detergents on transport of atrazine [2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine] through loam and sandy loam soils under saturation conditions. The Convection Dispersion Equation (CDE) was used to model and quantify the effects of detergents on atrazine model parameters: the retardation factor (R), pore velocity (v) and dispersion coefficient (D). The transport parameters were estimated using moment technique and partition coefficient obtained from batch experiments and compared with best-fitted parameters, R and D, keeping pore velocity constant. Results indicated the CDE model was not successful in predicting atrazine transport in the presence of surfactants at high concentrations. In the case of anionic surfactant with Elora loam, the average predicted R and D from moment technique of 3.4 and 11.1 cm2/h, respectively were significantly different than fitted parameters (R = 39 and D = 227 cm2/h). The poor performance of CDE in the presence of surfactants results from physiochemical changes in herbicide solubility and retention to the soil matrix rather than changes in soil hydraulic properties since the predicted pore water velocities from moment technique were similar to those measured during leaching experiments. Nevertheless, BTC analysis with CDE showed that land application of anionic surfactant (sulphonic) significantly increased R and D and decrease v for both soils. Addition of sulphonic increased R of atrazine by 12 and 26 folds for loam and sandy loam soils, respectively. On the other hand non-ionic surfactants seemed to decrease R, especially in sandy loam soil, thus facilitating atrazine leaching through soil. Non-equilibrium conditions seemed to govern atrazine transport in the presence of surfactants; double peaks in breakthrough curves were observed, indicating a need for mathematical models to account for such phenomena. Atrazine dispersion and tailing seemed to be higher through Elora loam compared to Caledon sandy loam due to higher aggregation of the Elora soil.


Antimicrobial susceptibility/resistance and molecular epidemiological characteristics of Neisseria gonorrhoeae in 2009 in Belarus.
Increased antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global concern, and ultimately gonorrhoea may become untreatable. Nonetheless, AMR data from East-Europe are scarce beyond Russia, and no AMR data or other characteristics of gonococci have been reported from Belarus for more than 20 years. The aim was to describe the prevalence of AMR, and report molecular epidemiological characteristics of gonococci circulating in 2009 in Belarus. In a sample of 80 isolates, resistance prevalences to antimicrobials used for gonorrhoea treatment in Belarus were: Ceftriaxone 0%, spectinomycin 0%, azithromycin 17.3%, tetracycline 25.9%, ciprofloxacin 34.6% and erythromycin 59.2%. The isolates displayed no penA mosaic alleles, 38 porB gene sequences and 35 N. gonorrhoeae multiantigen sequence types, of which 20 have not been described before worldwide. Due to the high levels of antimicrobial resistance, only ceftriaxone and spectinomycin can be recommended for empirical treatment of gonorrhoea in Belarus according to WHO recommendations. Continuous gonococcal AMR surveillance in Eastern Europe is crucial. This is now initiated in Belarus using WHO protocols.


Esophageal cyst--a case report.
Mediastinal cysts are rare and classified into thymic cysts, bronchogenic cysts, enteric cysts, pericardial cysts, lymphatic cysts and other rare types. We describe a case of foregut cyst of esophageal type in a 22 day old male infant. The CT scan showed a cystic lesion. Excised cyst was bilocular and was filled with clear fluid. Microscopically, the cyst was lined by columnar epithelium with well formed lamina propria and double layered muscularis. In view of presence of double layer of muscularis and absence of gastric glands, intestinal epithelium or cartilage, it was classified as esophageal cyst. We report this case of esophageal cyst because of its rarity.


MYB30 Is a Key Negative Regulator of Arabidopsis Photomorphogenic Development That Promotes PIF4 and PIF5 Protein Accumulation in the Light.
Phytochromes are red (R) and far-red (FR) light photoreceptors in plants, and PHYTOCHROME-INTERACTING FACTORS (PIFs) are a group of basic helix-loop-helix family transcription factors that play central roles in repressing photomorphogenesis. Here, we report that MYB30, an R2R3-MYB family transcription factor, acts as a negative regulator of photomorphogenesis in Arabidopsis (Arabidopsis thaliana). We show that MYB30 preferentially interacts with the Pfr (active) forms of the phytochrome A (phyA) and phytochrome B (phyB) holoproteins and that MYB30 levels are induced by phyA and phyB in the light. It was previously shown that phytochromes induce rapid phosphorylation and degradation of PIFs upon R light exposure. Our current data indicate that MYB30 promotes PIF4 and PIF5 protein reaccumulation under prolonged R light irradiation by directly binding to their promoters to induce their expression and by inhibiting the interaction of PIF4 and PIF5 with the Pfr form of phyB. In addition, our data indicate that MYB30 interacts with PIFs and that they act additively to repress photomorphogenesis. In summary, our study demonstrates that MYB30 negatively regulates Arabidopsis photomorphogenic development by acting to promote PIF4 and PIF5 protein accumulation under prolonged R light irradiation, thus providing new insights into the complicated but delicate control of PIFs in the responses of plants to their dynamic light environment.


Building an empowerment program to improve the health of patients with severe mental disorders
Risk factors and cardiovascular diseases are overrepresented in people with severe and persistent mental disorders. A person diagnosed with schizophrenia or bipolar disorder is two to three times more likely to die of cardiovascular disease than the general population. An empowerment program has been co-created to reduce these health inequalities. It is one part of the COPsyCAT project. The people-centered approach has been used. The participation of the patients, caregivers, and health professionals was decisive. Stakeholders redefined the objectives of the program. The aim is to improve quality of life, rather than reducing cardiovascular risk. Existing tools -that have been evaluated for their usability - were selected to allow for self-directed patient orientation, so that the constraints between psychiatry and primary care could be circumvented. The program is based on the pooling of existing resources in a territory. The individual power of action and the organization of healthy offers are thus designed to reinforce each other. This article concretely describes the steps through to which the COPsyCAT empowerment program was designed, in co-construction by the researchers of the study, the users and user associations and healthcare professionals at based on their experiential knowledge. The feasibility of the program and the appropriation of tools in real situations will soon be evaluated. The measure of the program's effectiveness on cardiovascular risk will come in second time.


Detection of circulating toxocaral antigens in dogs by sandwich enzyme-immunoassay.
This study describes the presence of circulating toxocaral antigens (CTA) in the sera of dogs infected with Toxocara canis (T. canis) by using a sandwich enzyme-immunoassay (SEIA). A specificity of this assay with different antigens was observed, i.e. the EIA values, which express the antigen concentration, of excretory-secretory antigen from T. canis larvae were higher than those of other antigens (Ascaris lumbricoides, Dirofilaria immitis and Fasciola hepatica). The variability in intra-assay was below 10%. In age distribution of CTA levels, the highest level was observed at 1 month of age. Thereafter, the levels decreased gradually until 6 months of age and then the same levels were maintained until adult age. Also, slightly elevated levels were found in the sera of foetuses. A significant correlation was obtained between age and CTA levels. The positive correlation between the number of worms and CTA levels was significant. As for the IgG, IgM and IgA antibodies, a significant correlation was observed between the IgM antibody activities and CTA levels, but this was not observed with IgG and IgA antibodies. From these results, it was indicated that the immunological response to T. canis infection in dogs may not be reached until 1 or 2 months after birth, although detectable CTA levels were observed in foetal and early life. It was also suggested that the immunological stimulation for canine toxocariasis may be maintained by the excretory-secretory materials from the larvae through life and as a result, IgM antibody production may be observed even in chronically infected adult dogs. The SEIA technique reported in this study may be useful as a diagnostic tool of human toxocariasis, since the CTA can be directly demonstrated by the technique.


Adjuvanted recombinant zoster vaccine in adult autologous stem cell transplant recipients: polyfunctional immune responses and lessons for clinical practice.
Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.


Osteoactivin attenuates skeletal muscle fibrosis after distraction osteogenesis by promoting extracellular matrix degradation/remodeling.
The aim of this study was to determine whether osteoactivin attenuated skeletal muscle fibrosis caused by distraction osteogenesis. Tibial osteotomies were performed on wild-type and osteoactivin-transgenic (OA-Tg) mice, and tibiae were distracted for 2 weeks. Ankle plantar flexion torque and the gastrocnemius muscles were analyzed. The amount and area of collagenous tissue and the passive torque were reduced in the OA-Tg group at 8 weeks after osteotomy. Transcript levels of matrix metalloprotease (mmp)-3 and MMP-9 were upregulated, and MMP-3 and MMP-9 proteins were increased in the OA-Tg group. Osteoactivin-mediated increase in MMPs may attenuate skeletal muscle fibrosis.


Relativistic Electron Vortices.
The desire to push recent experiments on electron vortices to higher energies leads to some theoretical difficulties. In particular the simple and very successful picture of phase vortices of vortex charge ℓ associated with ℓℏ units of orbital angular momentum per electron is challenged by the facts that (i) the spin and orbital angular momentum are not separately conserved for a Dirac electron, which suggests that the existence of a spin-orbit coupling will complicate matters, and (ii) that the velocity of a Dirac electron is not simply the gradient of a phase as it is in the Schrödinger theory suggesting that, perhaps, electron vortices might not exist at a fundamental level. We resolve these difficulties by showing that electron vortices do indeed exist in the relativistic theory and show that the charge of such a vortex is simply related to a conserved orbital part of the total angular momentum, closely related to the familiar situation for the orbital angular momentum of a photon.


Results of wrist extension reconstruction in C5-8 brachial plexus palsy by transferring the pronator quadratus motor branch to the extensor carpi radialis brevis muscle.
OBJECT The objective of this study was to report the results of pronator quadratus (PQ) motor branch transfers to the extensor carpi radialis brevis (ECRB) motor branch to reconstruct wrist extension in C5-8 root lesions of the brachial plexus. METHODS Twenty-eight patients, averaging 24 years of age, with C5-8 root injuries underwent operations an average of 7 months after their accident. In 19 patients, wrist extension was impossible at baseline, whereas in 9 patients wrist extension was managed by activating thumb and wrist extensors. When these 9 patients grasped an object, their wrist dropped and grasp strength was lost. Wrist extension was reconstructed by transferring the PQ motor to the ECRB motor branch. After surgery, patients were followed for at least 12 months, with final follow-up an average of 22 months after surgery. RESULTS Successful reinnervation of the ECRB was demonstrated in 27 of the 28 patients. In 25 of the patients, wrist extension scored M4, and in 2 it scored M3. CONCLUSIONS In C5-8 root injuries, wrist extension can be predictably reconstructed by transferring the PQ motor branch to reinnervate the ECRB.


Artificial intelligence and machine learning for clinical pharmacology.
Artificial intelligence (AI) will impact many aspects of clinical pharmacology, including drug discovery and development, clinical trials, personalized medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation in clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner. This review serves as an introduction to AI for the clinical pharmacologist, highlighting current applications, aspects of model development and issues surrounding evaluation and deployment. The aim of this article is to empower clinical pharmacologists to embrace and lead on the safe and effective use of AI within healthcare.


Correlation between cell killing effect and cell membrane potential after heat treatment: analysis using fluorescent dye and flow cytometry.
Exposure of mammalian cells to a temperature between 42 and 44 degrees C produces multiple effects on cellular metabolism. However, none of these effects have been demonstrated to be casually related to cell death. The plasma membrane has also been suggested to be one of the targets for hyperthermia. Hyperthermia influences the membrane fluidity and membrane fluidity affects both passive diffusion and active transport process. Here, we examined the effect of hyperthermia on the transmembrane potential V-79 cells using a lopophilic probe and flow cytometry. The underlying principle on which this method is based is that a freely diffusible cation distributes itself across the membrane according with the transmembrane potential and with the concentration gradient. By these methods, we tried to find the relation between the change of surviving fraction and membrane potential. We revealed that the membrane potential becomes to be depolarized by heat treatment between 41 and 44 degrees C immediately after heat treatment. In the relationship between the change in membrane potential and cell surviving fraction, the difference between 43 and 44 degrees C was not statistically significant but between 42 and 43 degrees C was statistically significant. These results imply that the cell membrane (potassium ion channel) is one of the targets of heat treatment and that duration of depolarized condition leads to cell death.


NanI Sialidase Contributes to the Growth and Adherence of Clostridium perfringens Type F Strain F4969 in the Presence of Adherent Mucus.
Clostridium perfringens type F strains causing nonfoodborne human gastrointestinal diseases (NFD) typically produce NanI sialidase as their major secreted sialidase. Type F NFDs can persist for several weeks, indicating their pathogenesis involves intestinal colonization, including vegetative cell growth and adherence, with subsequent sporulation that fosters enterotoxin production and release. We previously reported that NanI contributes to type F NFD strain adherence and growth using Caco-2 cells. However, Caco-2 cells make minimal amounts of mucus, which is significant because the intestines are coated with adherent mucus. Therefore, it was important to assess if NanI contributes to the growth and adherence of type F NFD strains in the presence of adherent mucus. Consequently, the current study first demonstrated greater growth of nanI-carrying versus non-nanI-carrying type F strains in the presence of HT29-MTX-E12 cells, which produce an adherent mucus layer, versus their parental HT29 cells, which make minimal mucus. Demonstrating the specific importance of NanI for this effect, type F NFD strain F4969 or a complementing strain grew and adhered better than an isogenic nanI null mutant in the presence of HT29-MTX-E12 cells versus HT29 cells. Those effects involved mucus production by HT29-MTX-E12 cells since mucus reduction using N-acetyl cysteine reduced F4969 growth and adherence. Consistent with those in vitro results, NanI contributed to growth of F4969 in the mouse small intestine. By demonstrating a growth and adherence role for NanI in the presence of adherent mucus, these results further support NanI as a potential virulence factor during type F NFDs.


Assessment of long-range corrected functionals performance for n-->pi* transitions in organic dyes.
The first n-->pi* transitions of 18 nitroso and 16 thiocarbonyl dyes have been computed by time-dependent density functional theory (TD-DFT) using pure as well as global and range-separated hybrid functionals. It turns out that the accuracy of all hybrids is relatively similar, i.e., the inclusion of a growing fraction of exact exchange does neither worsen nor improve significantly the raw TD-DFT estimations. However, after a simple linear regression, it appears that the range-separated hybrids provide a better accuracy than global hybrids.


Changes in aspects of social functioning depend upon prior changes in neurodisability in people with acquired brain injury undergoing post-acute neurorehabilitation.
Post-acute community-based rehabilitation is effective in reducing disability. However, while social participation and quality of life are valued as distal outcomes of neurorehabilitation, it is often not possible to observe improvements on these outcomes within the limited time-frames used in most investigations of rehabilitation. The aim of the current study was to examine differences in the sequence of attainments for people with acquired brain injury (ABI) undergoing longer term post-acute neurorehabilitation. Participants with ABI who were referred to comprehensive home and community-based neurorehabilitation were assessed at induction to service, at 6 months and again at 1.5 years while still in service on the Mayo-Portland Adaptability Index (MPAI-4), Community Integration Questionnaire, Hospital Anxiety and Depression Scale, and World Health Organisation Quality of Life measure. At 6 months post-induction to service, significant differences were evident in MPAI abilities, adjustment, and total neurodisability; and in anxiety and depression. By contrast, there was no significant effect at 6 months on more socially oriented features of experience namely quality of life (QoL), Community Integration and Participation. Eighteen month follow-up showed continuation of the significant positive effects with the addition of QoL-related to physical health, Psychological health, Social aspects of QoL and Participation at this later time point. Regression analyses demonstrated that change in QoL and Participation were dependent upon prior changes in aspects of neurodisability. Age, severity or type of brain injury did not significantly affect outcome. Results suggest that different constructs may respond to neurorehabilitation at different time points in a dose effect manner, and that change in social aspects of experience may be dependent upon the specific nature of prior neurorehabilitation attainments.


Characterization of the Fluorescent Spectra and Intensity of Dabigatran and Dabigatran Etexilate: Application to HPLC Analysis with Fluorescent Detection†.
There is considerable interest in dabigatran etexilate (Pradaxa) and its major metabolite, dabigatran, which has been shown to be an important inhibitor of thrombin and clotting. In this study, the fluorescent excitation and emission spectra of dabigatran and dabigatran etexilate were characterized. In addition, a ultra performance liquid chromatography (UPLC) and high performance liquid chromatography (HPLC) method using fluorescent detection was developed for the analysis of dabigatran. Dabigatran and dabigatran etexilate were found to have excitation and emission maxima of 310 and 375 nm and 335 and 400 nm, respectively. UPLC analysis of dabigatran standards and plasma dabigatran samples were analyzed on a reversed phase C-18 column with methanol-water (70:30, v/v) as the mobile phase. The lower limit of quantitation for dabigatran was 10.0 ng/mL for both the standards and plasma samples. Standard curves were linear from 10.0 to 1000.0 ng/mL (R2 = 0.995). Within-day coefficient of variations of the fluorometric method at 50.0, 100.0 and 500.0 ng/mL were 1.38%, 4.83% and 2.31%, respectively. The intense fluorescent properties of dabigatran permit the sensitive and specific UPLC or HPLC fluorescent analysis of dabigatran.


Late duodenal metastasis from renal cell carcinoma with newly developed malignant lymphoma: A case report.
Duodenal metastasis from renal cell carcinoma (RCC) is rare. The current case report presents a very rare case of late duodenal metastasis from RCC with newly developed malignant lymphoma (diffuse large B-cell lymphoma: DLBCL) at the same time. A 64-year-old man with systemic lymph nodes swelling who had undergone left nephrectomy for RCC 25 years previously, was admitted to the present hospital. Inguinal lymph node biopsy was performed, leading to a diagnosis of DLBCL. fluorine-18-fluorodeoxy-glucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) revealed multiple lymph nodes, spleen, and ileocecal lesions. CT revealed an obvious hypervascular tumor involving the duodenum/pancreatic head. The tumor was false-negative on 18F-FDG-PET/CT. On esophagogastroduodenoscopy, the tumor was detected in the descending portion of the duodenum and was observed to be consistent with the submucosal tumor with a central ulcer, resembling those of ulcer-forming DLBCL. A biopsy was then performed carefully, and a clear cell RCC-derived metastatic cancer was diagnosed. Ileocolonoscopy revealed mucosal thickening of the terminal ileum, and led to a diagnosis of DLBCL infiltration with biopsy. To the best of the author's knowledge, this is the first case report of the coexistence of metastatic cancer from RCC and malignant lymphoma in the small intestine simultaneously. It was necessary to make a careful differential diagnosis in the imaging studies.


Tissue-engineered edible bird's nests (TeeBN).
Edible bird's nests (EBN)-the nests of swiftlet birds harvested from the wild- are high-end healthcare food in East Asia, while their excessive harvesting poses increasing ecological, environmental, and food safety concerns. Here, we report for the first time a tissue-engineering (TE) approach for fabricating EBNs substitutes by integrating the technologies of three-dimensional (3D) printing and live cell culture. The engineered products, tissue-engineered edible bird's nests (TeeBN), comprise two layers. The first is a feeding layer that encapsulates epithelial cells in 3D-printed biocompatible gelation scaffolds. These cells secrete bioactive ingredients, e.g., sialic acid and epidermal growth factors (EGF), recapitulating the natural production of these substances by birds. The second is a receiving layer, consisting of foodgrade natural polymers, e.g., polysaccharides, which mimics the building blocks of natural EBNs while biologically stabilizing the factors released from the feeding layer. In vitro characterizations demonstrate that the feeding layer facilitates 3D cell growth and functions, and the receiving layer (as the end product) contains the necessary nutrients expected from natural EBNs-while without harmful substances commonly detected in natural EBNs. Further, in vivo metabolomics studies in mice indicate that TeeBN showed a similar profile of serum metabolites as natural EBN, reflecting comparable nutritional effects. In summary, we innovatively developed a tissue engineering-based substitute for EBNs with comparable metabolic functions and minimized safety risks, opening a new avenue for producing delicacy food from laboratorial cell culture with 3D printing technology.


[Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research].
We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3. and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3. A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease. This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well. This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.


Metabolomics approach for multibiomarkers determination to investigate dengue virus infection in human patients.
Dengue is one of the major public health problems in the world, affecting more than fifty million cases in tropical and subtropical region every year. The metabolome, as pathophysiological end-points, provide significant understanding of the mechanism and progression of dengue pathogenesis via changes in the metabolite profile of infected patients. Recent developments in diagnostic technologies provide metabolomics for the early detection of infectious diseases. The mid-stream urine was collected from 96 patients diagnosed with dengue fever at Penang General Hospital (PGH) and 50 healthy volunteers. Urine samples were analyzed with proton nuclear magnetic resonance (1H NMR) spectroscopy, followed by chemometric multivariate analysis. NMR signals highlighted in the orthogonal partial least square-discriminant analysis (OPLS-DA) S-plots were selected and identified using Human Metabolome Database (HMDB) and Chenomx Profiler. A highly predictive model was constructed from urine profile of dengue infected patients versus healthy individuals with the total R2Y (cum) value 0.935, and the total Q2Y (cum) value 0.832. Data showed that dengue infection is related to amino acid metabolism, tricarboxylic acid intermediates cycle and β-oxidation of fatty acids. Distinct variations in certain metabolites were recorded in infected patients including amino acids, various organic acids, betaine, valerylglycine, myo-inositol and glycine. Metabolomics approach provides essential insight into host metabolic disturbances following dengue infection.


A reversal learning task detects cognitive deficits in a Dachshund model of late-infantile neuronal ceroid lipofuscinosis.
The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive lysosomal storage diseases characterized by progressive neurodegeneration and by accumulation of autofluorescent storage material in the central nervous system and other tissues. One of the most prominent clinical signs of NCL is progressive decline in cognitive function. We previously described a frame shift mutation of TPP1 in miniature long-haired Dachshunds which causes an early-onset form of NCL analogous to classical late-infantile onset NCL (CLN2) in children. Dogs homozygous for the TPP1 mutation exhibit progressive neurological signs similar to those exhibited by human patients. In order to establish biomarkers for evaluating the efficacy of ongoing therapeutic studies in this canine model, we characterized phenotypic changes in 13 dogs through 9 months of age. Cognitive function was assessed using a T-maze reversal learning (RL) task. Cognitive dysfunction was detected in affected dogs as early as 6 months of age and worsened as the disease progressed. Physical and neurological examination, funduscopy and electroretinography (ERG) were performed at regular intervals. Only the changes in ERG responses showed signs of disease progression earlier than the RL task. In the later stages of the disease clinical signs of visual and motor deficits became evident. The visual and motor deficits were not severe enough to affect the performance of dogs in the T-maze. Declining performance on the RL task is a sensitive measure of higher-order cognitive dysfunction which can serve as a useful biomarker of disease progression.


Demand-Driven Clustering in Relational Domains for Predicting Adverse Drug Events.
Learning from electronic medical records (EMR) is challenging due to their relational nature and the uncertain dependence between a patient's past and future health status. Statistical relational learning is a natural fit for analyzing EMRs but is less adept at handling their inherent latent structure, such as connections between related medications or diseases. One way to capture the latent structure is via a relational clustering of objects. We propose a novel approach that, instead of pre-clustering the objects, performs a demand-driven clustering during learning. We evaluate our algorithm on three real-world tasks where the goal is to use EMRs to predict whether a patient will have an adverse reaction to a medication. We find that our approach is more accurate than performing no clustering, pre-clustering, and using expert-constructed medical heterarchies.


[Myocardial infarction--symptoms and procedures. Longitudinal observation of a population of 280,000 women and men--Project POL-MONICA in Krakow. VI: Enzymatic diagnosis and myocardial infarction].
Different combinations of serum enzymes activity determinations are used in the diagnostics of myocardial infarction. The goal of the present paper was: 1) to assess the frequency of determinations of asparagine aminotransferase (AspAT) and to compare it with the frequency of determinations of creatinine phosphokinase (CPK) in patients hospitalized due to ischaemic heart disease in district hospitals, and 2) to assess to what extent the parallel determination of both enzymes effected to diagnostic classification of events according to The WHO MONICA Project. The analysis was done in 7406 hospitalized events registered with the clinical diagnosis of ischaemic heart disease (1810 myocardial infarctions, 402 acute coronary heart disease and 5194 other forms of ischaemic heart disease), registered in POL-MONICA Kraków Project in 1988-1993. Serum activity of AspAT was determined in over 90% events with either myocardial infarction or acute coronary heart disease. Number of determinations of CPK increased since 1990 and then, fluctuated from 15% to 36%. In 718 hospitalized events with clinical diagnosis of ischaemic heart disease, for whom both CPK and AspAT were determined, there was 96% observed agreement between diagnostic classification of events based on complains, ecg and alternatively: 1) both AspAT and CPK and 2) CPK only. Potential agreement beyond chance-kappa was 0.94 (almost perfect agreement). The parameters of the agreement were worse when AspAT only was used in the second option. The results indicate that efforts to increase the number of determinations of CPK in myocardial infarction diagnostics should be undertaken. At least for a part of events with myocardial infarction diagnosis confirmed by ecg and CPK tests, determination of AspAT is not necessary.


Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels.
The slow delayed rectifier K(+) current (I(Ks)) is a major determinant of action potential repolarization in the heart. I(Ks) channels are formed by coassembly of pore-forming KCNQ1 alpha-subunits and ancillary KCNE1 beta-subunits. Two gain of function mutations in KCNQ1 subunits (S140G and V141M) have been associated with atrial fibrillation (AF). Previous heterologous expression studies found that both mutations caused I(Ks) to be instantaneously activated, presumably by preventing channel closure. The purpose of this study was to refine our understanding of the channel gating defects caused by these two mutations located in the S1 domain of KCNQ1. Site-directed mutagenesis was used to replace S140 or V141 with several other natural amino acids. Wild-type and mutant channels were heterologously expressed in Xenopus oocytes and channel function was assessed with the two-microelectrode voltage clamp technique. Long intervals between voltage clamp pulses revealed that S140G and V141M KCNQ1-KCNE1 channels are not constitutively active as previously reported, but instead exhibit extremely slow deactivation. The slow component of I(Ks) deactivation was decreased 62-fold by S140G and 140-fold by the V141M mutation. In addition, the half-point for activation of these mutant I(Ks) channels was approximately 50 mV more negative than wild-type channels. Other substitutions of S140 or V141 in KCNQ1 caused variable shifts in the voltage dependence of activation, but slowed I(Ks) deactivation to a much lesser extent than the AF-associated mutations. Based on a published structural model of KCNQ1, S140 and V141 are located near E160 in S2 and R237 in S4, two charged residues that could form a salt bridge when the channel is in the open state. In support of this model, mutational exchange of E160 and R237 residues produced a constitutively open channel. Together our findings suggest that altered charge-pair interactions within the voltage sensor module of KCNQ1 subunits may account for slowed I(Ks) deactivation induced by S140 or V141.


Giant cell arteritis.
Giant cell arteritis (GCA) is a granulomatous arteritis and it occurs older (more than 50 years) individuals. As GCA frequently involves temporal artery, this disease had been called as temporal arteritis. However, except for the temporal artery, GCA affects branches of the carotid arteries, as well as aorta and its major branches preferentially. Thus, this arteritis is collectively called as GCA from the characteristic histological findings. We systematically introduce the clinical pictures of GCA in the first half of this article. Because affected arteries of GCA are different in each patient, some patients do not present with classical clinical features, such as headache and tenderness of temporal artery. Recently, there are several variant forms of GCA have been recognized. Certain subtypes demonstrate organ dysfunction, such as visual loss or peripheral neuropathy with minimal or absent classical and systemic manifestations. This form of GCA is referred to as occult GCA. On the other hand, other form of GCA presents with a systemic inflammatory syndrome in the absence of focal ischemic symptoms. This is referred to as silent or masked GCA. In the latter half of this article, we introduce two patients presenting with such atypical presentations. One could be diagnosed as occult GCA, and the other was diagnosed as silent GCA with large vessel type. GCA is a heterogenous disease with more than a single clinical picture. This article can provide considerations of the wide spectrum of presentation of this characteristic systemic arteritis.


Embracing informal stakeholder conversations for evidence-based crisis response: Two work processes based on crisis intelligence.
This paper shares best practices for crisis managers and advisers, with a focus on crisis communication. These approaches are based on collecting, generating and analysing relevant real-time data. After introducing the concept of data-driven crisis strategies, the paper describes how continuous sentiment analysis can be used to tap into informal conversations on social media and other sources. The paper demonstrates how this can stimulate and improve strategic thinking, resulting in a far more effective response to a crisis situation. Using real-life examples, the paper demonstrates how such analysis techniques can deliver high-impact crisis communication that truly addresses stakeholder needs, especially compared with traditional public relations approaches. The paper describes several common methodologies that are built upon these techniques, with particular focus on crisis communication. Finally, the authors explain Stijn Pieters how enriching situational information based on data collected in the informal sphere is invaluable in a crisis. Indeed, accurate information can also significantly improve decision-making related to other crisis management disciplines. A new approach to data-driven and evidencebased crisis management is introduced, known as 'crisis intelligence'. The authors propose a model - the crisis intelligence work process - as a framework for the further development of work in this area.