Treatment of a Chronic, Nonhealing Neuropathic Ulcer in a Pediatric Patient With Spinal Dysraphism: A Case Report.
A neuropathic ulcer results from repetitive trauma to a hyposensitive distal extremity, usually on a weight-bearing bony prom-inence. In addition to neuropathy, deformities and adapted walking patterns increase the risk of these wounds in children with spinal dysraphism. Information about treatment strategies for these wounds is limited. The purpose of this case study was to describe the management of a chronic, nonhealing neuropathic ulcer on the dorsum of the left foot of an 11-year-old boy with spinal dysraphism. Autologous platelet-rich plasma (PRP), obtained using a double centri-fuge technique, was applied weekly underneath a nonadherent dressing and a below-knee plaster of paris cast. Complete non-weight-bearing was encouraged. The patient presented with a 9 cm2 wound and a Pressure Ulcer Scale for Healing (PUSH 3.0) score of 13, which was of 6 months' duration. For the first 3 weeks, the autologous PRP and plaster cast were applied weekly. After 3 weeks, the wound was 2.25 cm2 (PUSH score 7) and treatment was changed to moistened saline dress-ings underneath the cast. The wound was healed after 5 weeks. No adverse effects were observed. Studies are needed to evaluate the safety and effectiveness of autologous PRP in neuropathic ulcer management in pediatric populations and to obtain evidence for optimal management of these wounds in persons with spinal dysraphism.


Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.
Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides from the ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of this major epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies.


The circadian rhythm of "urgent" operative deliveries.
Even operative deliveries defined as "urgent" show marked diurnal variation with a significant increase during regular working hours. To investigate the diurnal variation of urgent operative deliveries and its potential implications on the outcome of newborns. We conducted a retrospective study of all deliveries in a public hospital from 1 January 1990 to 31 December 1998. Delivery mode variables analyzed were spontaneous vaginal delivery, urgent cesarean section and operative vaginal delivery. Deliveries were stratified hourly throughout the day. The rate of operative deliveries was calculated and the analysis was then performed according to the daily routine shifts of the medical staff. Birth weight and Apgar scores at 1 and 5 minutes were retrieved as outcome measures. The rate of urgent cesarean deliveries increased significantly between 8 a.m. and 2 p.m. (150%-230%) from that predicted. The lowest rate of urgent cesarean sections was found between 5 a.m. and 6 a.m. (5.3%). Mean birth weight in spontaneous deliveries was higher in the morning hours than during the night shift (3,293 +/- 520 g vs. 3,277 +/- 510 g, respectively, P < 0.005). Apgar scores of newborns delivered by urgent cesarean section during the morning were higher compared to those delivered during night shifts and the rate of low Apgar scores was lower in the morning than in evening and night shifts. Our results indicate a marked diurnal variation in urgent operative deliveries, caused perhaps by varying definition of "urgency" according to the time of day.


BRACNAC: A BRCA1 and BRCA2 Copy Number Alteration Caller from Next-Generation Sequencing Data.
Detecting copy number variations (CNVs) and alterations (CNAs) in the BRCA1 and BRCA2 genes is essential for testing patients for targeted therapy applicability. However, the available bioinformatics tools were initially designed for identifying CNVs/CNAs in whole-genome or -exome (WES) NGS data or targeted NGS data without adaptation to the BRCA1/2 genes. Most of these tools were tested on sample cohorts of limited size, with their use restricted to specific library preparation kits or sequencing platforms. We developed BRACNAC, a new tool for detecting CNVs and CNAs in the BRCA1 and BRCA2 genes in NGS data of different origin. The underlying mechanism of this tool involves various coverage normalization steps complemented by CNV probability evaluation. We estimated the sensitivity and specificity of our tool to be 100% and 94%, respectively, with an area under the curve (AUC) of 94%. The estimation was performed using the NGS data obtained from 213 ovarian and prostate cancer samples tested with in-house and commercially available library preparation kits and additionally using multiplex ligation-dependent probe amplification (MLPA) (12 CNV-positive samples). Using freely available WES and targeted NGS data from other research groups, we demonstrated that BRACNAC could also be used for these two types of data, with an AUC of up to 99.9%. In addition, we determined the limitations of the tool in terms of the minimum number of samples per NGS run (≥20 samples) and the minimum expected percentage of CNV-negative samples (≥80%). We expect that our findings will improve the efficacy of BRCA1/2 diagnostics. BRACNAC is freely available at the GitHub server.


An optical probe for noninvasive molecular imaging of orthotopic brain tumors overexpressing epidermal growth factor receptor.
We have developed a near-infrared (NIR) probe that targets cells overexpressing the EGF receptor (EGFR) for imaging glioblastoma brain tumors in live subjects. A peptide specific for the EGFR was modified with various lengths of monodiscrete polyethylene glycol (PEG) units and a NIR Cy5.5 fluorescence dye. The lead compound, compound 2, with one unit of PEG displayed good binding (8.9 μmol/L) and cellular uptake in glioblastoma cells overexpressing EGFR in vitro. The in vivo studies have shown that the probe was able to selectively label glioblastoma-derived orthotopic brain tumors. In vivo image analyses of peptide binding to the tumors using fluorescence-mediated molecular tomography revealed that the compound could distinguish between tumors expressing different levels of EGFR. The data presented here represent the first demonstration of differential quantitation of tumors expressing EGFR in live animals by a targeted NIR fluorescence probe using a molecular imaging device.


Uveitis in juvenile chronic arthritis.
About 20% of patients with juvenile chronic arthritis develop uveitis which is frequently bilateral. Risk factors for uveitis are: female gender, pauciarticular onset of arthritis, presence of circulating antinuclear antibodies, and the antigens HLA-DW5 and HLA-DPw2. The visual prognosis in patients with uveitis is good in 25% and fair in 50%. The remaining 25% develop cataract and/or glaucoma. The management of glaucoma is unsatisfactory, but the results of cataract surgery by lensectomy are good.


A questionnaire for determining prevalence of diabetes related foot disease (Q-DFD): construction and validation.
Community based prevalence for diabetes related foot disease (DRFD) has been poorly quantified in Australian populations. The aim of this study was to develop and validate a survey tool to facilitate collection of community based prevalence data for individuals with DRFD via telephone interview. Agreed components of DRFD were identified through an electronic literature search. Expert feedback and feedback from a population based construction sample were sought on the initial draft. Survey reliability was tested using a cohort recruited through a general practice, a hospital outpatient clinic and an outpatient podiatry clinic. Level of agreement between survey findings and either medical record or clinical assessment was evaluated. The Questionnaire for Diabetes Related Foot Disease (Q-DFD) comprised 12 questions aimed at determining presence of peripheral sensory neuropathy (PN) and peripheral vascular disease (PVD), based on self report of symptoms and/or clinical history, and self report of foot ulceration, amputation and foot deformity. Survey results for 38 from 46 participants demonstrated agreement with either clinical assessment or medical record (kappa 0.65, sensitivity 89.0%, and specificity 77.8%). Correlation for individual survey components was moderate to excellent. Inter and intrarater reliability and test re-test reliability was moderate to high for all survey domains. The development of the Q-DFD provides an opportunity for ongoing collection of prevalence estimates for DRFD across Australia.


The effectiveness of latanoprost for the treatment of pediatric glaucoma.
Latanoprost is a prostaglandin F2alpha analogue that substantially reduces intraocular pressure (IOP) in adults with open-angle glaucoma or ocular hypertension. The efficacy and safety of latanoprost in children is unknown. We wished to evaluate latanoprost therapy for children with glaucoma. This was a prospective study of all patients who were given latanoprost at our institution between September 1996 and January 1998. The baseline IOP was compared with the postlatanoprost IOP for each patient, and side effects and any iris color change were noted at each follow-up examination. Responders were defined as those who had at least a 15% IOP reduction on latanoprost, whereas nonresponders showed less than a 15% IOP reduction on latanoprost. Fifty-seven eyes of 48 pediatric patients with a variety of glaucoma diagnoses and an average age of 7.1 years were included in the study. Of these, 31 eyes of 31 patients had interpretable IOP data; the mean IOP reduction for this group after the addition of latanoprostwas 0.9% (0.2 mm Hg). Six patients (6 eyes) were responders, with an average IOP reduction of 8.5 mm Hg (34%), whereas the majority of patients (25) were nonresponders. In the responders, there was a good correlation (r = 0.9) between baseline IOP and the magnitude of IOP reduction. Responders were significantly more likely to have juvenile open-angle glaucoma and to be older than nonresponders. Systemic and ocular side effects were infrequent and mild, and no patient had noticeable iris color changes. When used in a group of pediatric patients with a variety of glaucoma diagnoses and on various therapies, latanoprost is effective in only a minority of cases. In selected patients, however, latanoprost shows an impressive ocular hypotensive effect, comparable with that obtained when this drug is used in adults with open-angle glaucoma. This drug appears to be well tolerated in this short-term study of pediatric patients with glaucoma.


Comparison of the IPAQ-Short Form and accelerometry predictions of physical activity in older adults.
Older adult physical activity (PA) levels obtained from the International Physical Activity Questionnaire-Short Form (IPAQ) and accelerometry (ACC) were compared. Mean difference scores between accumulated or bout ACC PA and the IPAQ were computed. Spearman rank-order correlations were used to assess relations between time spent in PA measured from ACC and self-reported form of the IPAQ, and percentage agreement across measures was used to classify meeting or not meeting PA recommendations. The IPAQ significantly underestimated sitting and overestimated time spent in almost all PA intensities. Group associations across measures revealed significant relations in walking, total PA, and sitting for the whole group (r = .29-.36, p < .05). Significant relationships between bout ACC and IPAQ walking (r = .28-.39, p < .05) were found. There was 40-46% agreement between measures for meeting PA recommendations. The IPAQ appears not to be a good indicator of individual older adult PA behavior but is better suited for larger population-based samples.


Accurate, Large-Scale Genotyping of 5HTTLPR and Flanking Single Nucleotide Polymorphisms in an Association Study of Depression, Anxiety, and Personality Measures.
The length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTTLPR) is one of the most studied polymorphisms for association with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling. We designed new assays for the 5HTTLPR suitable for large-scale genotyping projects and we genotyped 13 single nucleotide polymorphisms (SNPs) in a 38-kilobase region around the 5HTTLPR, including SNP rs25531, a polymorphism of the 5HTTLPR long allele. Association analysis was conducted for major depression and/or anxiety disorder in unrelated cases (n = 1161) and control subjects (n = 1051) identified through psychiatric interviews administered to a large population sample of Australian twin families. Participants had been scored for personality traits several years earlier (n > or = 2643 unrelated individuals). We identified a two-SNP haplotype proxy for 5HTTLPR; the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5HTTLPR (r(2) = .72). We found evidence for association (p = .0062, after accounting for multiple testing) for SLC6A4 SNPs rs6354 and rs2020936 (positioned in a different linkage disequilibrium [LD] block about 15.5 kb from 5HTTLPR) with anxiety and/or depression and neuroticism, with the strongest association for recurrent depression with onset in young adulthood (odds ratio = 1.55, 95% confidence interval = 1.16-2.06). The associated SNPs are in the same LD block as the variable number of tandem repeats serotonin transporter intron 2 marker, for which association has previously been reported.


A micro costing analysis of the development of a primary care intervention to improve the uptake of diabetic retinopathy screening.
The application of economic analysis within implementation science is still developing and the cost of intervention development, which differs markedly from the costs of initial implementation and maintenance, is often overlooked. Our aim was to retrospectively cost the development of a multifaceted intervention in primary care to improve attendance at diabetic retinopathy screening. A retrospective micro costing of developing the intervention from the research funder perspective was conducted. It was based on a systematic intervention development process involving analysis of existing audit data and interviews with patients and healthcare professionals (HCPs), conducting consensus meetings with patients and HCPs, and using these data together with a rapid review of the effectiveness of interventions, to inform the final intervention. Both direct (non-personnel, e.g. travel, stationary, room hire) and indirect (personnel) costs were included. Data sources included researcher time logs, payroll data, salary scales, an online financial management system, invoices and purchase orders. Personnel involved in the intervention development were consulted to determine the activities they conducted and the duration of their involvement. Sensitivity and scenario analyses were conducted to estimate uncertainty around parameters and scope. The total cost of intervention development (July 2014-January 2019) was €40,485 of which 78% were indirect (personnel) costs (€31,451). In total, personnel contributed 1368 h to intervention development. Highest cost activities were the patient interviews, and consensus process, contributing 23% and 34% of the total cost. Varying estimated time spent on intervention development activities by + 10% increased total intervention development cost by 6% to €42,982. Our results highlight that intervention development requires a significant amount of human capital input, combining research experience, patient and public experience, and expert knowledge in relevant fields. The time committed to intervention development is critical but has a significant opportunity cost. With limited resources for research on developing and implementing interventions, capturing intervention development costs and incorporating them as part of assessment of cost-effective interventions, could inform research priority and resource allocation decisions.


New consumers: The influence of affluence on the environment.
Growing consumption can cause major environmental damage. This is becoming specially significant through the emergence of over 1 billion new consumers, people in 17 developing and three transition countries with an aggregate spending capacity, in purchasing power parity terms, to match that of the U.S. Two of their consumption activities have sizeable environmental impacts. First is a diet based strongly on meat, which, because it is increasingly raised in part on grain, puts pressure on limited irrigation water and international grain supplies. Second, these new consumers possess over one-fifth of the world's cars, a proportion that is rising rapidly. Global CO(2) emissions from motor vehicles, of which cars make up 74%, increased during 1990-1997 by 26% and at a rate four times greater than the growth of CO(2) emissions overall. It is in the self-interest of new consumer countries, and of the global community, to restrict the environmental impacts of consumption; this restriction is achievable through a number of policy initiatives.


Nodular pulmonary sarcoidosis. Diagnosis with fine needle aspiration biopsy.
A case of sarcoidosis presenting as multiple pulmonary nodules and investigated by transthoracic fine needle aspiration biopsy is presented. Cohesive clusters of epithelial cells as well as multinucleated giant cells were observed. Special stains performed on the cell-block preparation were useful in ruling out an infectious etiology. The case demonstrates the value of fine needle aspiration biopsy in the investigation of pulmonary parenchymal disease and illustrates the cytologic findings in this unusual presentation of sarcoidosis.


Generation of pokeweed antiviral protein mutations in Saccharomyces cerevisiae: evidence that ribosome depurination is not sufficient for cytotoxicity.
Pokeweed antiviral protein (PAP) is a ribosome-inactivating protein that depurinates the highly conserved alpha-sarcin/ricin loop in the large rRNA. Here, using site-directed mutagenesis and systematic deletion analysis from the 5' and the 3' ends of the PAP cDNA, we identified the amino acids important for ribosome depurination and cytotoxicity of PAP. Truncating the first 16 amino acids of PAP eliminated its cytotoxicity and the ability to depurinate ribosomes. Ribosome depurination gradually decreased upon the sequential deletion of C-terminal amino acids and was abolished when a stop codon was introduced at Glu-244. Cytotoxicity of the C-terminal deletion mutants was lost before their ability to depurinate ribosomes. Mutations in Tyr-123 at the active site affected cytotoxicity without altering the ribosome depurination ability. Total translation was not inhibited in yeast expressing the non-toxic Tyr-123 mutants, although ribosomes were depurinated. These mutants depurinated ribosomes only during their translation and could not depurinate ribosomes in trans in a translation-independent manner. A mutation in Leu-71 in the central domain affected cytotoxicity without altering the ability to depurinate ribosomes in trans and inhibit translation. These results demonstrate that the ability to depurinate ribosomes in trans in a catalytic manner is required for the inhibition of translation, but is not sufficient for cytotoxicity.


Human cytochrome P450 enzymes bind drugs and other substrates mainly through conformational-selection modes.
Cytochrome P450 (P450) enzymes are major catalysts involved in the oxidations of most drugs, steroids, carcinogens, fat-soluble vitamins, and natural products. The binding of substrates to some of the 57 human P450s and other mammalian P450s is more complex than a two-state system and has been proposed to involve mechanisms such as multiple ligand occupancy, induced-fit, and conformational-selection. Here, we used kinetic analysis of binding with multiple concentrations of substrates and computational modeling of these data to discern possible binding modes of several human P450s. We observed that P450 2D6 binds its ligand rolapitant in a mechanism involving conformational-selection. P450 4A11 bound the substrate lauric acid via conformational-selection, as did P450 2C8 with palmitic acid. Binding of the steroid progesterone to P450 21A2 was also best described by a conformational-selection model. Hexyl isonicotinate binding to P450 2E1 could be described by either a conformational-selection or an induced-fit model. Simulation of the binding of the ligands midazolam, bromocriptine, testosterone, and ketoconazole to P450 3A4 was consistent with an induced-fit or a conformational-selection model, but the concentration dependence of binding rates for varying both P450 3A4 and midazolam concentrations revealed discordance in the parameters, indicative of conformational-selection. Binding of the P450s 2C8, 2D6, 3A4, 4A11, and 21A2 was best described by conformational-selection, and P450 2E1 appeared to fit either mode. These findings highlight the complexity of human P450-substrate interactions and that conformational-selection is a dominant feature of many of these interactions.


Individual differences in intrinsic ankle stiffness and their relationship to body sway and ankle torque.
When standing, intrinsic ankle stiffness is smaller when measured using large perturbations, when sway size is large, and when background torque is low. However, there is a large variation in individual intrinsic ankle stiffness. Here we determine if individual variation has consequences for postural control. We examined the relationship between ankle stiffness, ankle torque and body sway across different individuals. Ankle stiffness was estimated in 19 standing participants by measuring torque responses to small, brief perturbations. Perturbation sizes of 0.2 & 0.9 degrees (both lasting 140 ms) measured short- and long-range stiffness respectively, while participants either stood quietly on a fixed platform or were imperceptibly tilted to reduce stability (0.1 Hz sinusoid; 0.2 & 0.4 deg). The spontaneous body sway component (natural random relatively rapid postural adjustments) and background ankle torque were averaged from sections immediately before perturbations. The results show that, first, intrinsic ankle stiffness is positively associated with ankle torque, and that this relationship is stronger for long-range stiffness. Second, intrinsic ankle stiffness is negatively associated with body sway, but, in contrast to the relationship with torque, this relationship is stronger for short-range stiffness. We conclude that high short-range intrinsic ankle stiffness is associated with reduced spontaneous sway, although the causal relationship between these two parameters is unknown. These results suggest that, in normal quiet standing where sway is very small, the most important determinant of intrinsic ankle stiffness may be stillness. In less stable conditions, intrinsic ankle stiffness may be more dependent on ankle torque.


[Increased rate of sister chromatid exchange following therapy of acute lymphoblastic leukemias and non-Hodgkin lymphomas in childhood].
Sister chromatid exchanges rates (SCE) were studied in peripheral blood lymphocytes of 10 patients with acute lymphoblastic leukaemia (ALL) or leukaemic transformed non-Hodgkin-lymphomas (NHL) and in lymphocytes of 10 healthy juvenile donors (control). Following treatment the patient group has been in continuous complete remission for 11 months on the average. In the number of SCE's significant differences were found: 10,90/metaphases in the patients versus 7,56/metaphases in the controls. These results significantly show a long time influence of the treatment on the SCE rates, possibly inducing chromosome aberrations.


Routine ultrasound in pregnancy.
The interest in studying routine ultrasound in pregnancy has provided useful results that can be applied to practice. There is no consistent evidence of risk caused by ultrasound, neither biologic risk for the fetus nor increased use of health services as a result of ascertained conditions. There is also no consistent benefit to routine ultrasound in terms of important health outcomes. In the United States, this finding may be related to the excellent care provided to women in the usual-care arm of trials and possibly also to practice patterns. For example, with a high background induction rate in the United States, the prevalence of perinatal morbidity from post-term pregnancy may be so low that differences could not be ascertained between routine-ultrasound and usual care arms of the RADIUS study. The evidence from the use of ultrasound to screen for anomalies reveals substantial concern regarding interobserver variability, as might be expected when using a test for screening that requires considerable skill. The range of observed sensitivities underscores the disadvantages of performing basic ultrasound on a routine basis rather than on selected patients. Because routine ultrasound can reduce perinatal deaths in a population of women who would consider pregnancy termination, pretest counseling may identify a subset of women for whom screening may be effective in improving health outcomes. This remains to be demonstrated in the United States.


Hydrogen storage mechanism and diffusion in metal-organic frameworks.
Diffusion and storage of hydrogen molecules in metal-organic frameworks are crucial for the development of next-generation energy storage devices. By resorting to the first principles modeling, we compute the diffusion coefficient of molecular hydrogen in these systems in a range of temperatures where MOF-based devices are expected to operate. The explicit inclusion of the electronic structure shows that diffusivities are one order of magnitude smaller than those reported by classical simulations, evidencing the insufficiency of the empirical force fields used so far. We show that hydrogen is mainly rolled up around the metal oxide nodes both in MOF-5 and IRMOF-6, and partly around the carbon atoms in the case of IRMOF-6, where charged linkers are present. Metal ions embedded in the junction sites exert an electrostatic attraction toward hydrogen and the resulting distribution shows some ordering around these same sites at low temperature, whereas this tendency vanishes at room temperature. The induced polarization of hydrogen molecules generates an electrostatic interaction with charged atoms inside these nano-scaffolds and this is a key factor for the enhancement in hydrogen storage both in MOF-5 and IRMOF-6. The mechanism discussed hereby provides a novel understanding of metal-organic frameworks and acts as a guide to tune their efficiency for hydrogen storage. Moreover it paves the way to a computer-aided design of effective MOFs indicating that a fine control of the distribution of electrostatic charges inside the hydrogen hosting structure is crucial.


Comparing immobilized kinase inhibitors and covalent ATP probes for proteomic profiling of kinase expression and drug selectivity.
Kinases are involved in the regulation of many cellular processes and aberrant kinase signaling has been implicated in human disease. As a consequence, kinases are attractive drug targets. Assessing kinase function and drug selectivity in a more physiological context is challenging and often hampered by the generally low expression level of kinases and the extensive post-translation modification in vivo. Kinase drug selectivity screens by chemical proteomics have gained attention because they allow the profiling of hundreds of kinases against one drug at the same time. Here, we directly compared two such methods, notably, immobilized broad spectrum kinase inhibitors (kinobeads) and active site labeling using desthiobiotin-ATP and -ADP probes. Affinity purification of ∼ 100 kinases by either kinobeads or ATP/ADP probes was readily achieved using 1 mg of cellular protein. Bioinformatic analysis revealed a high degree of complementarity of the two techniques. Kinobeads covered the Tyrosine Kinase family particularly well and ATP probes enriched higher numbers of STE family kinases. A consecutive combination of both enrichment strategies therefore allowed for the coverage of a larger part of the kinome than any one technique alone. While kinobeads are very selective for kinases, the ATP/ADP probes also enriched a large number of other nucleotide binding proteins. Both methods were applied to the selectivity profiling of the small molecular Aurora kinase inhibitor tozasertib in K562 cells. Our data confirmed Aurora A, B, and BCR-ABL as the main targets of tozasertib and identified TNK1, STK2, RPS6KA1, and RPS6KA3 as submicromolar off targets.


Thalamocortical Connectivity Correlates with Phenotypic Variability in Dystonia.
Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.


Clinical Characteristics and Management of Patients with a Suspected COVID-19 Infection in Emergency Departments: A European Retrospective Multicenter Study.
Background: Our aim is to describe and compare the profile and outcome of patients attending the ED with a confirmed COVID-19 infection with patients with a suspected COVID-19 infection. Methods: We conducted a multicentric retrospective study including adults who were seen in 21 European emergency departments (ED) with suspected COVID-19 between 9 March and 8 April 2020. Patients with either a clinical suspicion of COVID-19 or confirmed COVID-19, detected using either a RT-PCR or a chest CT scan, formed the C+ group. Patients with non-confirmed COVID-19 (C− group) were defined as patients with a clinical presentation in the ED suggestive of COVID-19, but if tests were performed, they showed a negative RT-PCR and/or a negative chest CT scan. Results: A total of 7432 patients were included in the analysis: 1764 (23.7%) in the C+ group and 5668 (76.3%) in the C− group. The population was older (63.8 y.o. ±17.5 vs. 51.8 y.o. +/− 21.1, p < 0.01), with more males (54.6% vs. 46.1%, p < 0.01) in the C+ group. Patients in the C+ group had more chronic diseases. Half of the patients (n = 998, 56.6%) in the C+ group needed oxygen, compared to only 15% in the C− group (n = 877). Two-thirds of patients from the C+ group were hospitalized in ward (n = 1128, 63.9%), whereas two-thirds of patients in the C− group were discharged after their ED visit (n = 3883, 68.5%). Conclusion: Our study was the first in Europe to examine the emergency department's perspective on the management of patients with a suspected COVID-19 infection. We showed an overall more critical clinical situation group of patients with a confirmed COVID-19 infection.


Nonlinear behavior of human respiratory movement during different sleep stages.
To investigate the nonlinear properties of respiratory movement during different sleep stages, we applied an algorithm proposed by Grassberger and Procaccia to calculate the correlation dimension in rapid eye movement and non-rapid eye movement sleep. We also tested for nonlinearity in respiratory movement by comparing the correlation dimension for the original data with that for surrogate data. The study population included eight healthy volunteers. We recorded respiratory movement and the sleep electroencephalogram for 8 h. The correlation dimension for respiratory movement was 3.28+/-0.19 (mean +/- SD) during rapid eye movement sleep, 2.31+/-0.21 during light sleep (stage I) and 1.64+/-0.25 during deep slow-wave sleep (stage IV). Thus, the correlation dimension differed significantly by sleep stage (p < 0.001): it was least during stage IV sleep and greatest during REM. The correlation dimension for the original data also differed from that for surrogate data, confirming nonlinearity in original data. The results suggest that the nonlinear dynamics of respiratory movement in sleep changes with sleep stage, presumably due to the information processing by the cerebral cortex. The increased correlation dimension for respiratory movement in REM sleep may be related to increased cortical information processing associated with dreaming.


Role of Nerve and Muscle Biopsies in Pediatric Patients in the Era of Genetic Testing.
An operative biopsy is an important component in the diagnosis and treatment of neuromuscular disorders (NMDs). However, recent advances in molecular genetics suggest less invasive genetic testing should be the initial approach. The purpose of our study was to demonstrate the diagnostic value of muscle or nerve biopsy within the pediatric population at a pediatric academic center and offer recommendations for genetic testing in relation to biopsy to achieve the highest diagnostic yield. Following institutional review board approval, we retrospectively reviewed the electronic medical record of 221 pediatric patients who underwent muscle and/or nerve biopsy for suspicion of NMD from January 2007 to March 2018. Demographics, family history, clinical presentations, genetic testing results, pathology results, anesthesia complications, clinical diagnoses, and clinic follow-up data were collected. Chi-square analysis was done for statistical significance. A total of 220 underwent muscle biopsy, and 15 underwent nerve biopsy. Not all patients received genetic testing. The average age at biopsy was 7.7 y. Biopsy revealed significant histologic abnormalities in 62.9% (139), directly leading to a specific clinical diagnosis in 33.9% (75). When genetic testing was done before biopsy, definite pathogenic variants were found in 7.6% (9). When genetic testing was done after biopsy, definite pathogenic variants were found in 45.0% (27). Genetic testing yield for pathogenic variants was higher when done after biopsy (P value < 0.00001). Muscle and nerve biopsies may provide significant diagnostic value. Biopsy helped to rule in or out NMD and guide genetic testing. Our data suggest NMD genetic testing yield was higher when done after biopsy.


Peatland-fire interactions: A review of wildland fire feedbacks and interactions in Canadian boreal peatlands.
Boreal peatlands store a disproportionately large quantity of soil carbon (C) and play a critical role within the global C-climate system; however, with climatic warming, these C stores are at risk. Increased wildfire frequency and severity are expected to increase C loss from boreal peatlands, contributing to a shift from C sink to source. Here, we provide a comprehensive review of pre- and post-fire hydrological and ecological interactions that affect the likelihood of peatland burning, address the connections between peatland fires and the C-climate cycle, and provide a conceptual model of peatland processes as they relate to wildland fire, hydro-climate, and ecosystem change. Despite negative ecohydrological feedback mechanisms that may compensate for increased C loss initially, the cumulative effects of climatic warming, anthropogenic peatland fragmentation, and subsequent peatland drying will increase C loss to the atmosphere, driving a positive C feedback cycle. However, the extent to which negative and positive feedbacks will compensate for one another and the timelines for each remains unclear. We suggest that a multi-disciplinary approach of combining process knowledge with remotely sensed data and ecohydrological and wildland fire models is essential for better understanding the role of boreal peatlands and wildland fire in the global climate system.


The interplay between the cellular hypoxic response and Notch signaling.
The ability to sense and adapt to low oxygen levels (hypoxia) is central for most organisms and cell types. At the center of this process is a molecular mechanism, the cellular hypoxic response, in which the hypoxia inducible factors (HIFs) are stabilized by hypoxia, allowing the HIF proteins to act as master transcriptional regulators to adjust the cell to a low oxygen environment. In recent years, it has become increasingly appreciated that the cellular hypoxic response does not always operate in splendid isolation, but intersects with signaling mechanisms such as Notch signaling, a key regulatory signaling mechanism operating in most cell types controlling stem cell maintenance and differentiation. In this review, which is dedicated to the memory of Lorenz Poellinger,1 we discuss how the intersection between Notch and the cellular hypoxic response was discovered and our current understanding of the molecular basis for the cross-talk. We also provide examples of where Notch and hypoxia intersect in various physiological and disease contexts.


Impact of tongue biofilm removal on mechanically ventilated patients.
To evaluate the effectiveness of a tongue cleaner in the removal of tongue biofilm in mechanically ventilated patients. Tongue biofilm and tracheal secretion samples were collected from a total of 50 patients: 27 in the study group (SG) who were intubated or tracheostomized under assisted ventilation and treated with the tongue cleaner and 23 in the control group (CG) who did not undergo tongue cleaning. Oral and tracheal secretion cultures of the SG (initially and after 5 days) and the CG (at a single time-point) were performed to evaluate the changes in bacterial flora. The median age of the SG patients was 77 years (45-99 years), and that of the CG patients was 79 years (21-94 years). The length of hospital stay ranged from 17-1,370 days for the SG with a median stay of 425 days and from 4-240 days for the CG with a median stay of 120 days. No significant differences were found when the dental plaque indexes were compared between the SG and the CG. There was no correlation between the index and the length of hospital stay. The same bacterial flora was found in the dental plaque of 9 of the 27 SG patients before and after the tongue scraper was used for 5 days compared with the CG (p=0.683). Overall, 7 of the 27 SG patients had positive bacterial cultures for the same strains in both tongue biofilm and tracheal secretions compared with the CG (p=0.003). Significant similarities in strain resistance and susceptibility of the assessed microorganisms were observed between oral and tracheal microflora in 6/23 cases in the CG (p=0.006). The use of a tongue cleaner is effective at reducing tongue biofilm in patients on mechanical ventilation and facilitates oral hygiene interventions performed by caregivers.


Type Ia glycogenosis associated with hepatocellular carcinoma.
The predisposition of preexisting cirrhotic metabolic liver disease to the development of hepatocellular carcinoma is well established. However, the association between glycogenoses (a form of noncirrhotic metabolic liver disease) and the formation of benign and malignant liver tumors is less well known. The sixth case of simultaneous occurrence of glycogenosis type Ia and hepatocellular carcinoma, which occurred in a 34-year-old man referred for advice on therapy for his malignant neoplasm, is reported. Cases previously described in the literature are reviewed and management of this entity in light of the current knowledge in the diagnosis and treatment of hepatocellular carcinoma is discussed.


Asynchronous Brainstorming in an Industrial Setting: Exploratory Studies.
The goal of this study was to examine the effectiveness of brainwriting in an industrial setting. Research has demonstrated that group interaction can inhibit idea generation. Written exchanges of ideas in groups have been found to be an effective way to increase idea generation. To our knowledge, no study has examined the potential of brainwriting for group idea generation in work settings or the impact of different sequences of group and individual idea generation. Participants in a high-technology company participated in two brainwriting studies. In one study, participants generated ideas either first alone and then in a group or in the reverse order. In a second study, participants either generated as a group during the entire session or alternated individual ideation with a periodic review of the group's ideas. In the first study, participants who generated ideas first as a group and then as individuals performed best. In the first session, group writing also tended to lead to more ideas than did individual writing. In the second study, participants with periodic reviews performed best. The results suggest that alternation in individual and group brainwriting can enhance the number of ideas generated. The group-to-alone sequence is also beneficial since it allows group members to build on shared ideas. This research indicates that collaborative idea sessions can be beneficial in work sessions if the brainwriting paradigm is used with an appropriate alternation of group ideation or review sessions with individual idea generation sessions.


Characterization of background noise in MiSeq MPS data when sequencing human mitochondrial DNA from various sample sources and library preparation methods.
Improved resolution of massively parallel sequencing (MPS) allows for the characterization of mitochondrial (mt) DNA heteroplasmy to levels previously unattainable with traditional sequencing approaches. An essential criterion for the reporting of heteroplasmy is the ability of the MPS method to distinguish minor sequence variants (MSVs) from system noise, or error. Therefore, an assessment of the background noise in the MPS method is desirable to identify the point at which reliable data can be reported. Substitution and sequence specific error (SSE) was evaluated for a variety of sample types and two library preparations. Substitution error rates ranged from 0.18 to 0.49 per 100 nucleotides with C positions generally having the highest rate of misincorporation. Comparison of error rates across sample types indicated a significant increase for samples with damaged DNA. The positions of error were varied across datasets (pairwise concordance 0-68%), but had greater consistency within the damaged samples (80-96%). The most commonly observed motif preceding error in forward reads was CCG, while GGT was most common in reverse reads, both consistent with previous findings. The findings illustrate that for datasets containing samples with damaged DNA, reporting thresholds for heteroplasmy may have to be modified and individual sites with error levels exceeding thresholds should be scrutinized. Collectively, the shifting error profiles observed across the various sample types and library preparation methods demonstrates the need for an assessment of error under these varying circumstances. Characterization of the applicable background noise will help to ensure that thresholds are reliably set for detection of true MSVs.


Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-beta-D-arabinofuranosylcytosine.
Forty-five previously-untreated adult patients with acute myelogenous leukemia (AML) were treated with N4-behenoyl-1-beta-D-arabinofuranosyl-cytosine (BHAC) in a multi-institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea-anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti-leukemic drugs.


[Sequelae of diathermocoagulation of cerebellar arteries and veins in normal rabbits and rabbits sensitized to brain antigen].
Electrocauterization of an artery or a vein on the surface of the posterior lobe of the cerebellum may cause no focal changes in the bed of the occluded vessel, or result in varying severity and extension of lesion of the posterior cerebellar lobe. In occluding an artery a focus of complete necrosis or oedema is formed in its bed, while in occluding avein a focus of oedema is formed that may be accompanied by erythrocytic extravasation. In the group of animals sensitized with brain antigens a tendency towards oedema enhancement, and a vascular permeability increase is noted, neuronal changes are more frequent at a distance from the occluded vessel's basin. However, the importance of sensitization is, as a rule, masked by individual peculiarities of the collateral supply or venous return in the bed of the occluded vessel.


Molecular characterization and phylogenetic analysis of dengue viruses imported into Taiwan during 2011-2016.
A total of 1,596 laboratory-confirmed imported dengue cases were identified in Taiwan during 2011-2016. Most of the imported cases arrived from Southeast Asia as well as the Indian subcontinent, the Pacific region, Latin America, Australia and Africa. Phylogenetic analyses of the complete envelope protein gene sequences from 784 imported dengue virus (DENV) isolates were conducted, and the results suggest that the DENV-1 genotype I and DENV-2 Cosmopolitan genotype comprise the predominant serotype/genotype of DENV strains circulating in Southeast Asia. The DENV-1 genotype III, DENV-3 genotype III and DENV-4 genotype I and II strains were found to be newly emerging in several Southeast Asian countries. Our results also showed that geographical restrictions of DENV-1 genotype I, DENV-1 genotype III and DENV-2 Cosmopolitan genotype are becoming blurred, indicating the extensive introductions and continuous expansions of DENV strains between nations in Southeast Asia. In this study, we present the geographic distribution and dynamic transmission of DENV strains circulating in Southeast Asian countries. In addition, we demonstrated local dengue epidemics caused by several imported DENV strains in Taiwan during 2011-2016.


Adapting OSHA ergonomic guidelines to the rehabilitation setting.
Nursing aides and orderlies ranked second of all occupations in the number of occupational injuries and illness involving lost days at work. The majority of these injuries in nursing are associated with moving or assisting patients and residents in healthcare settings. OSHA has developed guidelines for nursing homes in order to provide information and step-by-step procedures for nursing home employers and employees about potential ergonomic hazards and ways to reduce those hazards. The purpose of this article is to adapt the OSHA guidelines for nursing homes to the inpatient rehabilitation facility so that evidence-based information can be utilized to establish programs and protocols to prevent employee injuries during patient lifting and movement in inpatient rehabilitation facilities. Rehabilitation facilities are uniquely positioned for innovative and successful ergonomic safety practices due to the rehabilitation philosophy and characteristics of the rehabilitation team.


Physical therapy for sleep apnea: a smartphone application for home-based physical therapy for patients with obstructive sleep apnea.
In this study, we described "PT for Sleep Apnea", a smartphone application for home-based physical therapy of patients with Obstructive Sleep Apnea (OSA). The application was created in a joint program between the University of Medicine and Pharmacy at Ho Chi Minh City (UMP), Vietnam, and National Cheng Kung University (NCKU), Taiwan. Exercises maneuvers were derived from the exercise program previously published by the partner group at National Cheng Kung University. They included exercises for upper airway and respiratory muscle training and general endurance training. The application provides video and in-text tutorials for users to follow at home and a schedule function to assist the user in organizing the training program, which may improve the efficacy of home-based physical therapy in patients with Obstructive Sleep Apnea. In the future, our group plans to conduct a user study and randomized-controlled trials to investigate whether our application can benefit patients with OSA.


Improved magnetic lateral flow assays with optimized nanotags for point-of-use inductive biosensing.
Lateral flow assays may be used by minimally trained personnel for fast and inexpensive bioanalyses in decentralized non-exigent environments. Their extension to a broader catalog of applications depends on improvements in their quantification and their sensitivity. We report a strategy that combines nanomagnetic tagging of the analyte of interest with radiofrequency inductive sensing, easy to achieve in friendly and portable format. To optimize nanotag performance, we investigated the influences of their magnetic core size and agglomeration. Iron oxide nanoparticles, with sizes from 5 to 23 nm, were synthesized by thermal decomposition and then coated with dimercaptosuccinic acid and functionalized with neutravidin protein. We tested the system by immobilizing biotin in lateral flow membrane strips. When a sample containing the particles flows along the membrane, the biotin captures the neutravidin together with the magnetic nanotags, which are detected by the inductive sensor. The optimal nanotag core size is the critical threshold for superparamagnetic behavior, which maximizes both the initial magnetic permeability and the saturation magnetization. Controlled agglomeration of the nanotags increases the magnetic mass captured in the test line and further amplifies the signal.


Hereditary angioedema in older adults: Understanding the patient perspective.
Hereditary angioedema (HAE) is a rare condition characterized by potentially fatal, recurrent episodes of painful swelling. Whereas there are limited studies evaluating the quality of life of individuals with HAE, none have evaluated the impact of HAE on older adults. To evaluate the effect of HAE on older adults through qualitative methodology. A group of 3 physicians with extensive research and clinical experience in HAE developed a focus group guidebook highlighting issues of importance to older adults. A total of 17 patients with HAE (type I or II) aged 60 years and older participated in focus groups. Three independent reviewers coded each focus group transcript using a thematic saturation approach. Reviewers identified 7 core themes from the focus groups. The themes identified encompassed the following: (1) challenges with securing medications and insurance concerns; (2) the experience of living with HAE before the advent of newer and more effective therapeutic options; (3) a worsening of HAE attack frequency and severity with aging; (4) the effects of comorbid conditions such as arthritis, memory loss, and irritable bowel syndrome; (5) changes in HAE with menopause; and (6) changing perspective on HAE with age, the effect of HAE on interpersonal relationships including the decision to have children, and goals for future care and research including support groups and a desire to be included in clinical trials. Older adults with HAE have specific challenges and concerns that may be unique compared with younger populations. Health care providers should address these to provide optimal care.


Block copolymer micelles with near infrared metal phthalocyanine dyes for laser induced writing.
A route has been developed to disperse metal-containing phthalocyanine dyes in a non-polar medium based on amphiphilic block copolymer micelles of poly[styrene-block-(4-vinylpyridine)] (PS-b-P4VP) and poly[styrene-block-(acrylic acid)] (PS-b-PAA) copolymers. Polar P4VP and PAA efficiently encapsulate cobalt(II), manganese(II), and nickel(II) phthalocyanine dyes by axial coordination of nitrogen and µ-oxo bridged dimerization with the transition metals, respectively. Good dispersion of the dyes is confirmed by the linear enhancement of Q-bands in UV-vis absorption spectra with dye concentration. A thin monolayered PS-b-P4VP micelle film that contained a nickel(II) phthalocyanine dye which efficiently adsorbs a laser beam on a localized area to generate a local heat higher than the glass transition temperatures of both blocks. One-dimensional laser writing on the dye-containing film allows the fabrication of a few submicrometer wide line patterns in which the self-assembled nanostructure of the block copolymer is modified by the directional heat arising from laser scanning.


Assessing the value of reflex fluorescence in situ hybridization testing in the diagnosis of bladder cancer when routine urine cytological examination is equivocal.
We evaluated the usefulness of fluorescence in situ hybridization in the treatment of patients with equivocal cytology. Fluorescence in situ hybridization was performed in residual urine from 124 patients with a cytological diagnosis of cell clusters (22), atypical findings (46) and suspicious findings (56) who had a same day cystoscopy result and bladder biopsy within 6 months of the cytology diagnosis. Urologists and fluorescence in situ hybridization technologists were blinded to the matching fluorescence in situ hybridization and cystoscopy results, respectively. In conjunction with cystoscopy fluorescence in situ hybridization was significantly more sensitive than cystoscopy alone for detecting cancer (87% vs 67%, p <0.001) and muscle invasive cancer (94% vs 56%, p = 0.031). Of the 124 equivocal cytology specimens 58 (47%) were positive by fluorescence in situ hybridization. Of these patients 53 (91%) had subsequent evidence of carcinoma, including Ta tumors in 17, Tis in 13, T1 in 8 and T2 or greater in 15, on the first followup biopsy. Three of the 5 remaining patients with a positive fluorescence in situ hybridization result and negative first followup biopsy had evidence of cancer at a later date, including TxN+ disease in 2 and Tis in 1. A total of 66 specimens were diagnosed as negative by fluorescence in situ hybridization. Of these patients 34 (52%) had negative biopsy results, whereas the remaining 32 (48%) demonstrated bladder cancer, including Ta disease in 20, Tis in 8, T1 in 2 and T2+ in 2. Cystoscopy detected 21 of the 32 tumors (66%) not detected by fluorescence in situ hybridization, while fluorescence in situ hybridization detected 17 of the 28 (61%) not detected by cystoscopy. Our data suggest that fluorescence in situ hybridization with cystoscopy can aid clinicians in the diagnosis of bladder cancer in patients with equivocal cytology.


Limit Theory for Panel Data Models with Cross Sectional Dependence and Sequential Exogeneity.
The paper derives a general Central Limit Theorem (CLT) and asymptotic distributions for sample moments related to panel data models with large n. The results allow for the data to be cross sectionally dependent, while at the same time allowing the regressors to be only sequentially rather than strictly exogenous. The setup is sufficiently general to accommodate situations where cross sectional dependence stems from spatial interactions and/or from the presence of common factors. The latter leads to the need for random norming. The limit theorem for sample moments is derived by showing that the moment conditions can be recast such that a martingale difference array central limit theorem can be applied. We prove such a central limit theorem by first extending results for stable convergence in Hall and Hedye (1980) to non-nested martingale arrays relevant for our applications. We illustrate our result by establishing a generalized estimation theory for GMM estimators of a fixed effect panel model without imposing i.i.d. or strict exogeneity conditions. We also discuss a class of Maximum Likelihood (ML) estimators that can be analyzed using our CLT.


An effective treatment for chronic periodontal abscesses.
In the past, chronic periodontal abscess was treated by conventional gingivectomy, flap access procedures, or by extraction of the affect tooth. A modified technique for the treatment of the chronic periodontal abscess is described. A surgical approach is combined with root conditioning with doxycycline. Application of this technique has resulted in rapid, uneventful healing in which neither further tissue breakdown or recurrence of the abscess has occurred.


Impact of tissue adhesives on the prevention of anastomotic leakage of colonic anastomoses: an in vivo study.
Tissue adhesives (TA) may be useful to strengthen colorectal anastomoses, thereby preventing anastomotic leakage (AL). Previous studies have identified cyanoacrylate (CA) TAs as the most promising colonic anastomotic sealants. This study investigates the protective effects of sealing colonic anastomoses with various CAs. Fifty-five Wistar rats underwent laparotomy and transection of the proximal colon. An anastomosis was created with 4 interrupted sutures followed by either application of Histoacryl Flexible, Omnex, Glubran 2, or no TA seal. An additional control group was included with a 12-suture anastomosis and no TA seal. After 7 days, the rats were sacrificed and scored for the presence of AL as the main outcome. Secondary outcomes were the occurrence of bowel obstruction, adhesions, and anastomotic bursting pressure. Histological evaluation was performed. The highest AL rate was found in the Glubran 2 group (7/11), followed by the 4-sutures group without TA (5/11), and the Omnex group (5/11). Histoacryl Flexible showed the lowest AL rate (2/11). In the control group, only one rat showed signs of AL. Histologically, the highest influx of inflammatory cells was found in the 4-suture group without TA and for Omnex and Glubran 2. Histoacryl Flexible caused more mature collagen deposition when compared to the other TA groups. Histoacryl Flexible showed the lowest leakage rate compared to the other TA groups and to the 4-suture control group. Glubran 2 showed the highest AL rate and a high inflammatory response. Histoacryl Flexible was associated with the presence of more mature collagen and seems to promote anastomotic healing.


Dark matter, structure, and strings.
In late July, about 150 astronomers gathered at the University of California, Santa Cruz, for a 2-week workshop on "Nearly Normal Galaxies." As the title suggests, the discussion was wide-ranging. Yet two issues stood out: dark matter and the large-scale structure. In itself this was hardly surprising, since these two issues have haunted extragalactic astronomy for nearly a decade. Indeed, they are central to an understanding of how galaxies formed. But some of the most dramatic findings have only been announced this year. Thus, the Santa Cruz workshop came at an especially opportune moment. In the following briefings, Research News draws on the workshop presentations to summarize astronomers' latest thinking on these subjects.


The brain in time: insights from neuromagnetic recordings.
The millisecond time resolution of magnetoencephalography (MEG) is instrumental for investigating the brain basis of sensory processing, motor planning, cognition, and social interaction. We review the basic principles, recent progress, and future potential of MEG in noninvasive tracking of human brain activity. Cortical activation sequences from tens to hundreds of milliseconds can be followed during, e.g., perception, motor action, imitation, and language processing by recording both spontaneous and evoked brain signals. Moreover, tagging of sensory input can be used to reveal neuronal mechanisms of binaural interaction and perception of ambiguous images. The results support the emerging ideas of multiple, hierarchically organized temporal scales in human brain function. Instrumentation and data analysis methods are rapidly progressing, enabling attempts to decode the four-dimensional spatiotemporal signal patterns to reveal correlates of behavior and mental contents.


In-flight sleep, pilot fatigue and Psychomotor Vigilance Task performance on ultra-long range versus long range flights.
This study evaluated whether pilot fatigue was greater on ultra-long range (ULR) trips (flights >16 h on 10% of trips in a 90-day period) than on long range (LR) trips. The within-subjects design controlled for crew complement, pattern of in-flight breaks, flight direction and departure time. Thirty male Captains (mean age = 54.5 years) and 40 male First officers (mean age = 48.0 years) were monitored on commercial passenger flights (Boeing 777 aircraft). Sleep was monitored (actigraphy, duty/sleep diaries) from 3 days before the first study trip to 3 days after the second study trip. Karolinska Sleepiness Scale, Samn-Perelli fatigue ratings and a 5-min Psychomotor Vigilance Task were completed before, during and after every flight. Total sleep in the 24 h before outbound flights and before inbound flights after 2-day layovers was comparable for ULR and LR flights. All pilots slept on all flights. For each additional hour of flight time, they obtained an estimated additional 12.3 min of sleep. Estimated mean total sleep was longer on ULR flights (3 h 53 min) than LR flights (3 h 15 min; P(F) = 0.0004). Sleepiness ratings were lower and mean reaction speed was faster at the end of ULR flights. Findings suggest that additional in-flight sleep mitigated fatigue effectively on longer flights. Further research is needed to clarify the contributions to fatigue of in-flight sleep versus time awake at top of descent. The study design was limited to eastward outbound flights with two Captains and two First Officers. Caution must be exercised when extrapolating to different operations.


Systematic review: outpatient management of acute uncomplicated diverticulitis.
Acute uncomplicated diverticulitis is traditionally managed by inpatient admission for bowel rest, intravenous fluids and intravenous antibiotics. In recent years, an increasing number of publications have sought to determine whether care might instead be conducted in the community, with earlier enteral feeding and oral antibiotics. This systematic review evaluates the safety and efficacy of such an ambulatory approach. Medline, Embase and Cochrane Library databases were searched. All peer-reviewed studies that investigated the role of ambulatory treatment protocols for acute uncomplicated diverticulitis, either directly or indirectly, were eligible for inclusion. Nine studies were identified as being suitable for inclusion, including one randomised controlled trial, seven prospective cohort studies and one retrospective cohort study. All, except one, employed imaging as part of their diagnostic criteria. There was inconsistency between studies with regards to whether patients with significant co-morbidities were eligible for ambulatory care and whether bowel rest therapy was employed. Neither of these variables influenced outcome. Across all studies, 403 out of a total of 415 (97 %) participants were successfully treated for an episode of acute uncomplicated diverticulitis using an outpatient-type approach. Cost savings ranged from 35.0 to 83.0 %. Current evidence suggests that a more progressive, ambulatory-based approach to the majority of cases of acute uncomplicated diverticulitis is justified. Based on this evidence, the authors present a possible outpatient-based treatment algorithm. An appropriately powered randomised controlled trial is now required to determine its safety and efficacy compared to traditional inpatient management.


Comparison of two preventive interventions on dental caries among children in Democratic People's Republic of Korea.
The aim was to compare the change in dental caries status in two different intervention groups of the Children's Oral Health Promotion Programme (COHPP). A longitudinal study among 500 children who had participated into the COHPP for 6 years was conducted in Pyongyang, Democratic People's Republic of Korea (DPRK). Children in Group I received intensified school-based intervention and were clinically examined at the age of 7 years in 2007 (n = 250), 10 years in 2010 (n = 250) and 13 years in 2013 (n = 242). Children in Group II (n = 250) joined the programme at the age of 4 years in kindergarten in 2007, were provided with early preschool-based intervention and were clinically examined at the age of 7 years in 2010 and 10 years in 2013. Both the prevalence and the mean number of dt + DT decreased significantly in both groups during the follow-up. This was due to decrease in the number of dt, whereas the number of DT remained relatively constant. Poisson regression showed that the association between the group status and the change in the number of dt + DT was statistically significant when adjusted for gender but disappeared when the school was included in the analysis. The decrease in dental caries may be partly due to the exfoliation of deciduous teeth and dental treatment received. However, the study gave some reference emphasizing the early starting of the prevention.


Hsp105α suppresses Adriamycin-induced cell death via nuclear localization signal-dependent nuclear accumulation.
Heat shock protein 105 (Hsp105) is a molecular chaperone, and the isoforms Hsp105α and Hsp105β exhibit distinct functions with different subcellular localizations. Hsp105β localizes in the nucleus and induces the expression of the major heat shock protein Hsp70, whereas cytoplasmic Hsp105α is less effective in inducing Hsp70 expression. Hsp105 shuttles between the cytoplasm and the nucleus; the subcellular localization is governed by the relative activities of the nuclear localization signal (NLS) and nuclear export signal (NES). Here, we show that nuclear accumulation of Hsp105α but not Hsp105β is involved in Adriamycin (ADR) sensitivity. Knockdown of Hsp105α induces cell death at low ADR concentration, at which ADR is less effective in inducing cell death in the presence of Hsp105α. Of note, Hsp105 is localized in the nucleus under these conditions, even though Hsp105β is not expressed, indicating that Hsp105α accumulates in the nucleus in response to ADR treatment. The exogenously expressed Hsp105α but not its NLS mutant localizes in the nucleus of ADR-treated cells. In addition, the expression level of the nuclear export protein chromosomal maintenance 1 (CRM1) was decreased by ADR treatment of cells, and CRM1 knockdown caused nuclear accumulation of Hsp105α both in the presence and absence of ADR. These results indicating that Hsp105α accumulates in the nucleus in a manner dependent on the NLS activity via the suppression of nuclear export. Our findings suggest a role of nuclear Hsp105α in the sensitivity against DNA-damaging agents in tumor cells.


The measurement of serum transferrin receptor.
The concentration of the soluble fragment of transferrin receptor in serum is an important new hematological parameter. Clinical and laboratory studies have shown that this serum form of the receptor reflects the total body mass of cellular transferrin receptor, 80% of which is contained in the erythroid marrow. The two disorders that result in an elevation in the serum transferrin receptor are anemias associated with enhanced erythropoiesis and tissue iron deficiency. The concentration of soluble transferrin receptor provides a useful quantitative measure of the erythroid marrow mass and thereby assists clinically in categorizing the type of anemia. The most important clinical use of the serum transferrin receptor is in determining the cause of iron deficient erythropoiesis (that is, identifying iron deficiency anemia whether it occurs alone or in the presence of the anemia of chronic disease). Present evidence supports the routine use of the serum transferrin receptor in the clinical evaluation of anemic patients.


Combined aerobic and resistance training, and incidence of diabetes: A retrospective cohort study in Japanese older women.
To investigate the relationship between combined aerobic and resistance training, and the incidence of type 2 diabetes mellitus. The present study included 10,680 Japanese women. Participants enrolled between 2005 and 2010, and were followed up until 2014. The frequency of combined training was counted for the first 3 months, the 6th month and the 9th month. In 2014, women reported whether or not they had diabetes, as well as the year of developing diabetes. Hazard ratios and 95% confidence intervals (CI) for the incidence of type 2 diabetes were obtained using Cox proportional hazard models. The median duration of follow up was 5 years, with 166 women developing type 2 diabetes. Using the lowest frequency of training group (1st quartile) as the reference, the hazard ratios for the second through fourth quartiles was as follows: 0.95 (95% CI 0.64-1.41), 0.73 (95% CI 0.48-1.13) and 0.69 (95% CI 0.44-1.07), respectively (P for trend = 0.116). After adjustment for age, body mass index and thigh circumference, the hazard ratios were: 0.84 (95% CI 0.56-1.26), 0.69 (95% CI 0.45-1.06) and 0.61 (95% CI 0.39-0.95), respectively (P for trend = 0.040). A higher frequency of combined aerobic and resistance training is associated with a lower risk of developing type 2 diabetes in Japanese women.


Quantitative morphology of physiologically identified and intracellularly labeled neurons from the guinea-pig laterodorsal tegmental nucleus in vitro.
Mesopontine cholinergic neurons have been implicated in the initiation and maintenance of rapid eye movement sleep via their efferent connections to the thalamus and the medial pontine reticular formation. As a first step toward understanding how these modulatory neurons integrate synaptic input, we have investigated the dendritic architecture of laterodorsal tegmental nucleus neurons. The principal cells of the guinea-pig laterodorsal tegmental nucleus were identified electrophysiologically in a brain slice preparation, then were intracellularly injected with biocytin and reconstructed using a computer-aided tracing system. The somata were large (27 +/- 3 microns; n = 11) and gave rise to an average of 4.8 primary dendrites which, in most cases, emerged from the soma in a pattern that was radially symmetric in the plane of the slice. Primary dendrites had an average of 3.7 endings. A single axon arose from either the soma or a proximal dendrite and exited the nucleus with a medial and/or lateral trajectory. Some axons also gave rise to a local terminal plexus composed of fine fibers bearing numerous punctate swellings that ramified profusely within the neuron's dendritic field. Total dendritic area averaged about 10(5) microns2, and therefore the average contribution of the soma to the total surface area (20%) was significantly larger than the values reported for many other cell types. Dendritic diameters were non-uniform in three respects. Some processes were sparsely spiny. Most processes were varicose, with the degree of varicosity increasing substantially in secondary and tertiary dendritic segments. There was also a large degree of taper in dendritic processes; those processes with a non-negative taper had an average diameter decrease of 40 +/- 25%. Dendritic processes deviated from the criteria necessary for a Rall equivalent cylinder approximation due to non-uniformity in morphotonic path length, failure to conform to the Rall 3/2 branching rule and non-uniformity of dendritic diameter. An analysis was done to assess the impact of dendritic varicosities on the extraction of cable parameters for these cells. Voltage traces were simulated by solving the cable equation for a varicose dendrite and then membrane parameters were recovered using an equivalent cylinder model. Errors in the extracted values of specific membrane conductance and specific membrane capacitance were quite small (< or = 5%), while larger errors were seen for electrotonic length (< or = 21%) and intracellular resistivity (< or = 5%). These data indicate that the principal cells of the laterodorsal tegmental nucleus, while possessing a relatively simple dendritic structure in terms of number and branchiness of dendrites, display a heterogeneity of dendritic process types. Processes range from smooth to markedly varicose, and can be aspiny or sparsely spiny. The possibility that the dendritic varicosities function as sites of either electrical or chemical compartmentalization is discussed. The degree of error resulting from a Rall equivalent cylinder approximation in light of these varicosities indicated that a generalized cable model approach may prove more effective in estimating their cable parameters.


Fatigue in immune-mediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group.
To determine the prevalence and severity of ongoing fatigue and to investigate the internal consistency, reliability, and validity of the Fatigue Severity Scale (FSS) in patients with immune-mediated polyneuropathies. The FSS was assessed in 113 patients who either experienced Guillain-Barré syndrome in the past or currently have a stable, chronic, inflammatory demyelinating polyradiculoneuropathy or a polyneuropathy associated with a monoclonal gammopathy of undetermined significance, and in 113 age- and sex-matched healthy controls. Data on four additional scales (Medical Research Council sumscore, functional grading scale [f-score], INCAT sensory sumscore, medical outcome study 36-items health survey [SF-36]) were obtained in all patients. SF-36 also was assessed in 59 controls. "Severe" fatigue (FSS scores > or =95th percentile values in controls) was present in 80% of the patients. Fatigue was not significantly related to general strength, sensory deficits, f-score, and duration of symptoms. Severe fatigue was reported in 81% to 86% of patients with normal strength or sensation. Eighty percent of the patients (controls, 12%) reported their fatigue being among the three most disabling symptoms. SF-36 health status scores in the patient group were significantly lower than the obtained values of the controls and partially related to the FSS scores. Good internal consistency, significant reliability, and validity were obtained for the FSS. Fatigue is a major symptom in patients with immune-mediated polyneuropathies and may persist for years after apparent recovery. The Fatigue Severity Scale seems appropriate for assessing fatigue in these patients because good internal consistency, reliability, and validity were demonstrated.


United States practice patterns in the use of transesophageal echocardiography during adult liver transplantation.
To characterize contemporary practice patterns in the use of transesophageal echocardiography during adult liver transplantation and to identify factors preventing more frequent use. Online questionnaire. Liver transplantation centers in the United States performing 12 or more adult liver transplants in 2011. One representative from each qualifying center: The transplant anesthesiology director, a transplant anesthesiologist personally known to the authors, or the department of anesthesiology chair. Three e-mail attempts were made to solicit participation in the study between June and August 2012. Of the 97 institutions identified, an anesthesiologist from each of 79 (81.4%) centers completed the questionnaire; 38.0% of centers reported routine use and 57.0% for special circumstances or rescue situations, yielding an overall use rate of 94.9%. This distribution was consistent regardless of operative volume, practice size, or academic affiliation. The sole factor predictive of routine transesophageal echocardiography use was an overlap between an institution's cardiac and transplant anesthesiology teams. In practices not routinely employing the technology, the most compelling reason was a sense that it was not necessary. Although 69.9% of transplant anesthesiologists reportedly were proficient in echocardiography, inadequate anesthesiologist training was also a strongly cited hindrance. Transesophageal echocardiography during adult liver transplantation in the United States has become widely prevalent, with notable growth in its use as a routine diagnostic and monitoring modality. Almost all institutions now use the technology at least occasionally, with the participation of cardiac anesthesiologists being predictive of a center's routine use.


Lacertus Fibrosus Versus Achilles Allograft Reconstruction for Distal Biceps Tears: A Biomechanical Study.
The bicipital aponeurosis, or lacertus fibrosus, can potentially be used as a reconstruction graft in chronic distal biceps tendon tears. To evaluate construct stiffness, load to failure, and failure mechanism with lacertus fibrosus versus Achilles allograft for distal biceps tendon reconstruction. Controlled laboratory study. Ten fresh-frozen matched cadaveric pairs of elbows were used. Three centimeters of the distal biceps tendon was resected. Specimens were randomized to the lacertus fibrosus or Achilles tendon group. In one group, the lacertus fibrosus was released from its distal attachment and then tubularized and repaired intraosseously to the radius. In the other group, an Achilles tendon graft was sutured to the biceps muscle and repaired to the ulna. The prepared radii were rigidly mounted at a 45° angle on a load frame. The proximal biceps muscle was secured in a custom-fabricated cryogenic grip. Displacement was measured using a differential variable reluctance transducer mounted at the radius-soft tissue junction and in the muscle- or muscle allograft-tissue junction proximal to the repair. Specimens were loaded at 20 mm/min until failure, defined as a 3-mm displacement at the radius-soft tissue junction. No significant difference was found in mean load to failure between the lacertus fibrosus and Achilles tendon group (mean ± SD, 20.2 ± 5.5 N vs 16.89 ± 4.54 N; P = .18). Stiffness also did not differ significantly between the lacertus fibrosus and Achilles tendon group (12.3 ± 7.1 kPa vs 10.5 ± 5.7 kPa; P = .34). The primary mode of failure in the lacertus fibrosus group was suture pullout from the tissue at the musculotendinous junction (7 of 10). In the Achilles group, failures were observed at the muscle-allograft interface (3) and the allograft-bone (radial tuberosity) interface (3), and 3 suture failures were observed. The button fixation did not fail in any specimens. The mean stiffness and load-to-failure values were not significantly different between a lacertus fibrosus construct and Achilles tendon allograft. Use of the lacertus fibrosus may be a potential alternative to Achilles tendon allograft reconstruction of chronic distal biceps tears when primary repair is not possible.


Predicting Fatigue 12 Months after Child Traumatic Brain Injury: Child Factors and Postinjury Symptoms.
Fatigue is a common and persisting symptom after childhood brain injury. This study examined whether child characteristics and symptomatology preinjury or 6 months postinjury (pain, sleep, and mood, inattention) predicted fatigue at 12months postinjury. Parents of 79 children (0-18 years) rated fatigue at 12 months after injury on a multidimensional scale (general, sleep/rest, and cognitive). Demographic and clinical data were collected at injury. Parents rated child sleep, pain, physical/motor function, mood, and inattention at injury (preinjury description), and 6 months postinjury. Children were divided into two traumatic brain injury severity groups: mild TBI (n=57) and moderate/severe TBI (n=27). Hierarchical regression models were used to examine (i) preinjury factors and (ii) symptoms 6 months postinjury predictive of fatigue (general, sleep/rest, and cognitive) at 12 months postinjury. Sleep/rest fatigue was predicted by preinjury fatigue (7% of variance) and psychological symptoms preinjury (10% of variance). General fatigue was predicted by physical/motor symptoms (27%), sleep (10%) and mood symptoms (9%) 6 months postinjury. Sleep/rest fatigue was predicted by physical/motor symptoms (10%), sleep symptoms (13%) and mood symptoms (9%) 6 months postinjury. Cognitive fatigue was predicted by physical/motor symptoms (17%) 6 months postinjury. Preinjury fatigue and psychological functioning identified those at greatest risk of fatigue 12 months post-TBI. Predictors of specific fatigue domains at 12 months differed across each of the domains, although consistently included physical/motor function as well as sleep and mood symptoms postinjury. (JINS, 2018, 24, 224-236).


Memory CD4 + T-Cells Expressing HLA-DR Contribute to HIV Persistence During Prolonged Antiretroviral Therapy.
To date, most assays for measuring the human immunodeficiency virus (HIV-1) reservoir do not include memory CD4+ T-cells expressing the activation marker, human leukocyte antigen-antigen D related (HLA-DR). However, little is known concerning the role these cells play in maintaining persistent HIV-1 during effective antiretroviral therapy (ART). To address this issue, we examined, cellular activation/exhaustion markers (Ki67, CCR5, PD-1, Lag-3 and Tim-3) and viral gag-pol DNA sequences within HLA-DR- and HLA-DR+ memory CD4+ T-cell subsets longitudinally from the peripheral blood of six participants over 3 to ≥15 years of effective therapy. HLA-DR expression was readily detected during the study period in all participants. The average expression levels of CCR5, PD-1 and Tim-3 were higher on the HLA-DR+ T-cell subset whereas the average of LAG-3 expression was higher on their HLA-DR- counterpart. The proportion of HIV-infected cells increased within the HLA-DR+ subset by an average of 18% per year of ART whereas the frequency of infected HLA-DR- T-cells slightly decreased over time (5% per year). We observed that 20-33% of HIV-DNA sequences from the early time points were genetically identical to viral sequences from the last time point within the same cell subset during ART. This indicates that a fraction of proviruses persists within HLA-DR+ and HLA-DR- T-cell subsets during prolonged ART. Our HIV-DNA sequence analyses also revealed that cells transitioned between the HLA-DR+ and HLA-DR- phenotypes. The Ki67 expression, a marker for cellular proliferation, and the combined markers of Ki67/PD-1 averaged 19-fold and 22-fold higher on the HLA-DR+ T-cell subset compared to their HLA-DR- counterpart. Moreover, cellular proliferation, as reflected by the proportion of genetically identical HIV-DNA sequences, increased within both T-cell subsets over the study period; however, this increase was greater within the HLA-DR+ T-cells. Our research revealed that cellular transition and proliferation contribute to the persistence of HIV in HLA-DR+ and HLA-DR- T-cell subsets during prolonged therapy. As such, the HIV reservoir expands during effective ART when both the HLA-DR+ and HLA-DR- cell subsets are included, and therapeutic interventions aimed at reducing the HIV-1 reservoir should target HLA-DR+ and HLA-DR- T-cells.


Influence of olfactory signals on the reproductive behaviour of social groups of rhesus monkeys (Macaca mulatta).
Olfactory influences are important in the control of reproductive function in many mammalian species including primates. Previous studies have shown that a mixture of volatile aliphatic acids (copulins), normally present in the vaginal secretions of rhesus monkeys, can exert a stimulatory effect on the sexual behaviour of males when pairs are tested in small cages. The present study deals with the role of these substances when tested in social groups of rhesus monkeys housed in a large testing arena, the purpose being to assess the effectiveness of olfactory signals under more nearly naturalistic conditions. Each group consisted of one male with four long-term ovariectomized females from which the male could choose. A counter-balanced experimental design was used in which each female of a testosterone-treated pair was given applications to the sexual skin of either copulins or control ether immediately before each 1-h behaviour test. After 16 tests, the procedure was repeated with the previously untreated pair in each group, and nine groups were separately studied. Testosterone was used here simply to enhance female proceptivity. The results showed that females received significantly more ejaculations (P less than 0.05), mounting attempts (P less than 0.01) and mounts (P less than 0.05) when bearing copulins than when bearing control ether. There were positive responses to copulins in 12 of the 36 males-females pairs, involving all males, and positive responses to ether in five of 36 pairs, involving four males. Copulins resulted in a change in the choice of sexual partner in five males, but there were no changes in the choice of partner with ether. Social factors, such as dominance, could override the responses to olfactory signals, and there was a significant treatment order effect, but this was eliminated by the counter-balanced design. These findings indicate a significant role for olfactory communication in mate selection in a socially living higher primate.


Trends in endoscopic sinus surgery rates in the Medicare population.
To examine the trends in rates of endoscopic sinus surgery, open sinus procedures (open sinus surgery), and the prevalence of diagnosis of chronic rhinosinusitis in the Medicare population from 1998 to 2006. Retrospective cohort analysis. Twenty-percent sample of Medicare beneficiaries aged 65 to 99 years for the years 1998 to 2006. Change in per capita annual rates of endoscopic sinus surgery, open sinus surgery, and chronic rhinosinusitis diagnosis among Medicare beneficiaries. From 1998 to 2006, the rate of patients undergoing endoscopic sinus surgery per 1000 Medicare beneficiaries increased by 20%, from 0.72 (95% confidence interval [CI], 0.70-0.74) to 0.92 (95% CI, 0.89-0.95). Over the same period, the rate of open sinus surgery declined 40%, from 0.20 (95% CI, 0.19-0.21) to 0.11 (95% CI, 0.10-0.12). However, the per capita rate of beneficiaries diagnosed as having chronic rhinosinusitis declined by 1.4% over the study period. Further analysis by age cohort revealed significantly higher rates of surgery and diagnosis rates in the 65- to 69-year-old beneficiaries relative to older age groups. Over the study period, the per capita rate of diagnosis of chronic rhinosinusitis declined or remained stable across age groups. Despite this, all age groups showed increases in endoscopic sinus surgery rates. Our findings indicate that endoscopic sinus surgery is increasingly becoming the mainstay of chronic rhinosinusitis management in the Medicare population. Because of the uncertainty regarding the outcomes of surgical vs medical management, the root causes of the observed increase in endoscopic sinus surgery rates need to be investigated. Given that sinusitis is a common diagnosis necessitating physician visits, comparative effectiveness studies examining medical vs surgical management would be warranted.


Clinical evaluation of Ortho Clinical Diagnostics high-sensitivity cardiac Troponin I assay in patients with symptoms suggestive of acute coronary syndrome.
As more companies obtain regulatory approval for high-sensitivity cardiac troponin (hs-cTn) assays there is an urgent need for independent analytical and clinical evaluations. To this end, we have evaluated Ortho Clinical Diagnostics' hs-cTnI assay and compared it to their contemporary cTnI-ES assay in emergency department (ED) patients with suspected acute coronary syndrome (ACS). The study cohort consisted of ED patients (n = 906) with symptoms suggestive of ACS who had Ortho hs-cTnI and cTnI-ES results at presentation and 3 h (with calculated delta (0-3 h) defined as the absolute concentration difference between paired results). The primary composite outcome was 7-day myocardial infarction (MI) or cardiovascular death, with secondary analyses performed for 7-day MI and index-MI. Analytical imprecision testing (i.e., coefficient of variation; CV), receiver-operating characteristic (ROC) curve analyses with area under the curve (AUC), and diagnostic parameters (sensitivity/specificity/predictive values) were calculated. The hs-cTnI assay had superior precision compared to the cTnI-ES assay below 5 ng/L in EDTA plasma (hs-cTnI CV ≤ 15% versus cTnI-ES CV ≥ 85%). The AUCs were higher for hs-cTnI as compared to cTnI-ES at 0 h (0.88 vs. 0.85), 3 h (0.94 vs. 0.92), and the delta (0-3 h) value (0.91 vs. 0.85) for the primary composite outcome (p < 0.05). At 3 h, the sensitivity/specificity for index-MI was ≥97%/≥82%, for 7-day MI was ≥89%/≥84%, and for the primary composite outcome was ≥90%/≥85% using the manufacturer's sex-specific 99th-percentile cutoffs. The Ortho hs-cTnI assay has superior analytical and clinical performance over their contemporary cTnI-ES assay in evaluating ED patients with symptoms suggestive of ACS.


Monitoring antiepileptic drugs: a level-headed approach.
Despite advances in epilepsy therapeutics, some physicians feel uncomfortable with newer antiepileptic drugs (AEDs) due to difficulty in promptly obtaining blood levels to guide medication adjustment, and even when levels for newer AEDs are obtained, many practitioners feel they are not very useful. Lacking confidence in AEDs whose levels that cannot readily or expeditiously be measured, many clinicians share uncertainty about proper use of the newer AEDs and monitoring AED administration. Similarly, some epilepsy patients inflate the importance of AED blood level monitoring, feeling that blood levels falling within traditionally therapeutic ranges are a fail-safe for seizure control, regardless of their compliance or personal behavior aggravating seizure burden, such as poor sleep or use of illicit substances. This review examines the elusive concept of therapeutic AED blood levels and potential uses and abuses of blood level monitoring, reinforcing appropriate uses for blood levels to ensure compliance and adjust for altered AED pharmacokinetics in the context of aging and disease states, pregnancy, or drug interactions.


Analysis of the behavior of a seizure neural mass model using describing functions.
Neural mass models are computational nonlinear models that simulate the activity of a population of neurons as an average neuron, in such a way that different inhibitory post-synaptic potential and excitatory post-synaptic potential signals could be reproduced. These models have been developed either to simulate the recognized neural mechanisms or to predict some physiological facts that are not easy to realize naturally. The role of the excitatory and inhibitory activity variation in seizure genesis has been proved, but it is not evident how these activities influence appearance of seizure like signals. In this paper a population model is considered in which the physiological inter-relation of the pyramidal and inter-neurons of the hippocampus has been appropriately modeled. The average neurons of this model have been assumed to act as a linear filter followed by a nonlinear function. By changing the gain of excitatory and inhibitory activities that are modeled by the gain of the filters, seizure-like signals could be generated. In this paper through the analysis of this nonlinear model by means of the describing function concepts, it is theoretically shown that not only the gains of the excitatory and inhibitory activities, but also the time constants may play an efficient role in seizure genesis.


Working Memory, Fluid Reasoning, and Complex Problem Solving: Different Results Explained by the Brunswik Symmetry.
In order to investigate the nature of complex problem solving (CPS) within the nomological network of cognitive abilities, few studies have simultantiously considered working memory and intelligence, and results are inconsistent. The Brunswik symmetry principle was recently discussed as a possible explanation for the inconsistent findings because the operationalizations differed greatly between the studies. Following this assumption, 16 different combinations of operationalizations of working memory and fluid reasoning were examined in the present study (N=152). Based on structural equation modeling with single-indicator latent variables (i.e., corrected for measurement error), it was found that working memory incrementally explained CPS variance above and beyond fluid reasoning in only 2 of 16 conditions. However, according to the Brunswik symmetry principle, both conditions can be interpreted as an asymmetrical (unfair) comparison, in which working memory was artificially favored over fluid reasoning. We conclude that there is little evidence that working memory plays a unique role in solving complex problems independent of fluid reasoning. Furthermore, the impact of the Brunswik symmetry principle was clearly demonstrated as the explained variance in CPS varied between 4 and 31%, depending on which operationalizations of working memory and fluid reasoning were considered. We argue that future studies investigating the interplay of cognitive abilities will benefit if the Brunswik principle is taken into account.


P2 growth restriction on an rpoC mutant is suppressed by alleles of the Rz1 homolog lysC.
Escherichia coli strain 397c carries a temperature-sensitive mutation, rpoC397, that removes the last 50 amino acids of the RNA polymerase beta' subunit and is nonpermissive for plating of bacteriophage P2. P2 gor mutants productively infect 397c and define a new gene, lysC, encoded by a reading frame that extensively overlaps the P2 lysis accessory gene, lysB. The unusual location of lysC with respect to lysB is reminiscent of the Rz/Rz1 lysis gene pair of phage lambda. Indeed, coexpression of lysB and lysC complemented the growth defect of lambda Rz/Rz1 null mutants, indicating that the LysB/C pair is similar to Rz/Rz1 in both gene arrangement and function. Cells carrying the rpoC397 mutation exhibited an early onset of P2-induced lysis, which was suppressed by the gor mutation in lysC. We propose that changes in host gene expression resulting from the rpoC397 mutation result in changes in the composition of the bacterial cell wall, making the cell more susceptible to P2-mediated lysis and preventing accumulation of progeny phage sufficient for plaque formation.


The signature of supernova ejecta in the X-ray afterglow of the gamma-ray burst 011211.
Now that gamma-ray bursts (GRBs) have been determined to lie at cosmological distances, their isotropic burst energies are estimated to be as high as 1054 erg (ref. 2), making them the most energetic phenomena in the Universe. The nature of the progenitors responsible for the bursts remains, however, elusive. The favoured models range from the merger of two neutron stars in a binary system to the collapse of a massive star. Spectroscopic studies of the afterglow emission could reveal details of the environment of the burst, by indicating the elements present, the speed of the outflow and an estimate of the temperature. Here we report an X-ray spectrum of the afterglow of GRB011211, which shows emission lines of magnesium, silicon, sulphur, argon, calcium and possibly nickel, arising in metal-enriched material with an outflow velocity of the order of one-tenth the speed of light. These observations strongly favour models where a supernova explosion from a massive stellar progenitor precedes the burst event and is responsible for the outflowing matter.