[Immunovac-VP-4 for prevention of acute respiratory diseases in children's communities].
Assessment of prophylactic effect of Immunovac-VP-4 against acute respiratory diseases (ARDs) in collectives of children. Immunovac-VP-4 was used for prophylaxis of ARDs in communities of children (daycare centers, boarding school). During 3 consecutive controlled studies performed during peak incidence of epidemic influenza and ARD (1st study) and during pre-epidemic period (2nd and 3rd studies) the incidence of ARDs was studied in groups of vaccinated and non-vaccinated children. Criteria for assessment of ARDs incidence and their severity were as follows: number of ARD episodes per child, number of children with recurrent episodes of ARD during period of follow-up, duration of ARDs, and number of children with bacterial complications (bronchitis, otitis, etc.). Effect of intervention on immunologic parameters was assessed on levels of sIgA, IgG, IgA, and antibody titers in saliva. Schedule of vaccine administration was 3 daily intranasal and 6 - 9 oral administration of the vaccine with 3 - 4 days interval. Results of all three studies were virtually the same: decrease of number of ARD episodes and their duration; 3.1-fold reduction of number of children with recurrent infections during 14 months of follow-up, and 10.9--12-fold reduction during first 7 months of follow-up; decrease of bacterial complications rate (1.9% in children in intervention group, 11.9%--in control group). Increase of total immunoglobulin level and antibody titers to antigenic components of the vaccine from low baseline level was observed in saliva of vaccinated children. Immunovac-VP-4 results in enhanced and prolonged prophylactic effect on ARDs incidence and recommended for building of optimal system of prevention of polyetiologic complex of ARDs.


Assessment of a new calendar pack--the 'C-Pak'.
Seventy-eight elderly patients in hospital were studied for up to four weeks to assess drug compliance. Forty patients received medication from individualized calendar packs ('C-Pak') and 38 received medication from standard bottles. There was no difference in compliance between the two groups, the percentage error for each group being 26%. This result suggests that C-Pak is unlikely to improve drug compliance in unselected elderly patients.


Parkinsonian signs in older people in a community-based study: risk of incident dementia.
Mild parkinsonian signs occur in 30% to 40% of community-dwelling older people. In a cross-sectional study, the severity of these signs was greater in people with dementia than in people without dementia. To determine whether baseline mild parkinsonian signs are a predictor of incident dementia. A prospective, longitudinal study of community-dwelling older people who did not have dementia or Parkinson disease at baseline. A neurological examination was performed on 1028 residents aged 65 years or older in the Washington Height-Inwood community in northern Manhattan, NY. Parkinsonian signs were rated with an abbreviated Unified Parkinson's Disease Rating Scale, resulting in a parkinsonian sign score (range, 0-40). The risk of incident dementia was assessed using Cox proportional hazards models. In some analyses, data from the modified Unified Parkinson's Disease Rating Scale were divided into 3 domains: rigidity, axial function, and tremor at rest. The mean duration of follow-up was 5.6 years, and 224 participants (21.8%) developed dementia. In a Cox model, the risk of incident dementia was 57% higher in participants with a baseline parkinsonian sign score of 2 vs 0 (relative risk, 1.56; 95% confidence interval, 1.04-2.33; P =.03). In a second Cox model, the baseline parkinsonian sign score was associated with incident dementia (relative risk, 1.08; 95% confidence interval, 1.01-1.16; P =.02) independent of associations with baseline age, education, ethnicity, diabetes mellitus, and stroke. Baseline mild parkinsonian signs are a predictor of incident dementia. Although these signs are mild, they are not prognostically benign. Brain imaging and postmortem examinations might further our insight into the anatomical and pathological basis for mild parkinsonian signs.


Functional analysis of problem behavior: a review.
Functional analysis methodology focuses on the identification of variables that influence the occurrence of problem behavior and has become a hallmark of contemporary approaches to behavioral assessment. In light of the widespread use of pretreatment functional analyses in articles published in this and other journals, we reviewed the literature in an attempt to identify best practices and directions for future research. Studies included in the present review were those in which (a) a pretreatment assessment based on (b) direct observation and measurement of (c) problem behavior was conducted under (d) at least two conditions involving manipulation of an environmental variable in an attempt (e) to demonstrate a relation between the environmental event and behavior. Studies that met the criteria for inclusion were quantified and critically evaluated along a number of dimensions related to subject and setting characteristics, parametric and qualitative characteristics of the methodology, types of assessment conditions, experimental designs, topographies of problem behaviors, and the manner in which data were displayed and analyzed.


Non-native fishes homogenize native fish communities and reduce ecosystem multifunctionality in tropical lakes over 16 years.
Non-native species are considered a major global threat to biodiversity, and their expansion to new ecosystems has recently increased. However, the effect of non-native species on ecosystem functioning is poorly understood, especially in hyperdiverse tropical ecosystems of which long-term studies are scarce. We analyzed the relationship between richness, biomass, and β-diversity of non-native and native fishes during 16 years in five hyperdiverse tropical shallow lakes. We further elucidated how an observed increase in the proportion of richness, biomass, and β-diversity of non-native over native fishes affect crucial multifunctional processes of lakes (decomposition, productivity). We found a general positive relationship between the richness and biomass of non-native and native fishes. However, the slope of this relationship decreased continuously with time, displaying an increase in non-native species richness and a decrease in native species richness over time. We also detected a negative relationship between the β-diversity of non-native and native fishes over time. Moreover, the increase in the non-native:native ratio of species richness, biomass, and β-diversity over time decreased ecosystem multifunctionality. Our results suggest that non-native fishes caused a homogenization of the native fish species over time, resulting in impoverishment of ecosystem multifunctionality; in part because non-native fishes are less productive than native ones. Therefore, focus on long-term effects and use of multiple biodiversity facets (α- and β-diversity) are crucial to make reliable predictions of the effects of non-native fish species on native fishes and ecosystem functioning.


Cadaveric biomechanical analysis of the distal radioulnar joint: influence of wrist isolation on accurate measurement and the effect of ulnar styloid fracture on stability.
Distal radioulnar joint (DRUJ) instability can be tested using biomechanical cadaveric models, but inadequate isolation of the DRUJ during instability testing may introduce measurement error. The first goal of this investigation was to develop an effective model for isolating the DRUJ during biomechanical cadaveric testing. The second goal was to use this model to measure the effect of ulnar styloid fracture and subsequent repair on DRUJ kinematics in cadaveric specimens. Five fresh cadaveric arms were tested using a Biodex System 3 device. The humerus was clamped firmly, the forearm rotated freely, and the hand/carpus was attached to the Biodex device. Three methods of DRUJ isolation were tested. In method 1, the specimen was firmly clamped at the midshaft humerus and the hand/carpus was clamped. In method 2, the distal radius was additionally fixed to the carpal clamp to reduce carpal motion. In method 3, proximal fixation of the olecranon to an elbow rest was added. Testing was done before ulnar styloid osteotomy (group 1), after osteotomy through dorsal capsulotomy (group 2), and after styloid fragment repair with a screw (group 3). Twelve pronation-supination cycles were performed while work of rotation, maximum pronation torque, and maximum supination torque for each method and group were recorded. Analysis of clamping methods showed work of rotation, maximum pronation torque, and maximum supination torque for method 3 were greater than those for methods 1 and 2. Analysis of groups showed the following statistically significant trends for work of rotation: group 1 >>> group 3 > group 2. Maximum supination torque similarly showed statistically significant differences: group 1 >>> group 3 > group 2. Maximum pronation torque showed a similar trend: group 1 >>> group 3 > group 2. However, in contrast with work of rotation and maximum supination torque, group 3 maximum pronation torque was not statistically different from that of group 2. Increased work of rotation represents decreased joint laxity. Maximum supination torque and maximum pronation torque assess soft tissue restraints at joint end points. Method 3 showed the greatest values in these variables, indicating reduced elbow and carpal motion and better DRUJ isolation. Work of rotation and maximum supination torque in group 3 were increased from those of group 2 but not restored to group 1 values. Styloid fixation restores some soft tissue tension but laxity persists. Maximum pronation torque in group 3 was not increased significantly from that of group 2, perhaps from dorsal capsulotomy causing soft tissue injury and laxity not corrected with fixation. The influence of ulnar styloid fracture on dynamic DRUJ kinematics can be demonstrated in this model.


Alexander's disease in an adult: clinicopathologic study of a case and review of the literature.
A case of Alexander's disease in a 39-year-old man is reported. The clinical course was characterized by headaches and cerebellar gait for 6 months. A state of acute unconsciousness followed, lasting 2 days. Subsequently, dysfunction of the lower cranial nerves on the left-side, left-sided motor incoordination, and a right-sided spastic hemiplegia were found. The patient died 49 days after an acute incident of lung embolism. Neuropathologically generalized and focally pronounced Rosenthal fibers in subpial, subependymal, and perivascular regions were found. They were especially predominant in the brain stem and cerebellum. Atypical fibrillary glia, moderate patchy demyelination, and circumscribed cystic necrosis in the brain stem were also observed.


Mercury concentrations in recent and ninety-year-old benthopelagic fish.
Several species of bottom-dwelling fish from 2500 meters with similar feeding habits had mercury concentrations that differed by an order of magnitude. Within one species there was a correlation between size and concentration, with the larger individuals having mercury concentrations as high as 0.8 part per million (wet weight). The mercury content of the water in the deep-ocean habitat of these fish appears not to determine the mercury content of a particular fish; species-specific factors and size do appear to determine this concentration. The species-specific variation between the recent fish also existed between the same two species in specimens collected 90 years ago from a depth of 2000 meters, and a 90-year-old specimen fit closely the size-concentration regression curve for nine recent individuals of the same species.


Practical Method for Salt Intake Follow-Up in Hypertensive Patients.
Background: Obese and hypertensive (HT) patients should restrict salt intake. In excessive salt intake, ouabain-like compounds inhibit Na/K-ATPase (Na+ pump), which increases intracellular Na+ and Ca2+. Ca2+ has a vasotonic effect on arteries and an inotropic effect on the heart and may cause cortical opacities in the lens. To our knowledge, there is still no practical method for salt intake follow-up. This study tested whether salt intake follow-up can be performed with the help of opacity tracking. Methods: In total, 400 HT patients (age 30-69 years) with cortical lens opacities were included in the study. Changes in opacities based on biomicroscopic examination at baseline and after 3 months were recorded digitally with the help of imaging software. Salt intake at 1 and 3 months was evaluated with a 24-hr urine Na assay. Changes in opacities were compared among group 1 (∼50% salt reduction), group 2 (∼10% salt reduction), and group 3 (∼15% salt increase). Results: Age and changes in small opacity diameter (SOD) and large opacity diameter (LOD) were the most important determinants of the 50% salt reduction in the third month. For changes in LOD, the sensitivity was 88.5% [confidence interval (95% CI) 85.2-91.7] and specificity was 95.5% (95% CI 93.1-98.7) for predicting a 50% salt restriction during the 3-month period. For SOD, the values were 85% (95% CI 82.5-87) and 95% (95% CI 92.3-97.5), respectively. Conclusions: Opacity changes are a practical method for predicting a 50% reduction in salt intake over a 3-month period in 30- to 59-year-old HT patients.


Are all low molecular weight heparins equivalent in the management of venous thromboembolism?
Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.


The role of gene fusions in melanocytic neoplasms.
Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are cost-effective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies.


Intrinsic noise induces critical behavior in leaky Markovian networks leading to avalanching.
The role intrinsic statistical fluctuations play in creating avalanches--patterns of complex bursting activity with scale-free properties--is examined in leaky Markovian networks. Using this broad class of models, we develop a probabilistic approach that employs a potential energy landscape perspective coupled with a macroscopic description based on statistical thermodynamics. We identify six important thermodynamic quantities essential for characterizing system behavior as a function of network size: the internal potential energy, entropy, free potential energy, internal pressure, pressure, and bulk modulus. In agreement with classical phase transitions, these quantities evolve smoothly as a function of the network size until a critical value is reached. At that value, a discontinuity in pressure is observed that leads to a spike in the bulk modulus demarcating loss of thermodynamic robustness. We attribute this novel result to a reallocation of the ground states (global minima) of the system's stationary potential energy landscape caused by a noise-induced deformation of its topographic surface. Further analysis demonstrates that appreciable levels of intrinsic noise can cause avalanching, a complex mode of operation that dominates system dynamics at near-critical or subcritical network sizes. Illustrative examples are provided using an epidemiological model of bacterial infection, where avalanching has not been characterized before, and a previously studied model of computational neuroscience, where avalanching was erroneously attributed to specific neural architectures. The general methods developed here can be used to study the emergence of avalanching (and other complex phenomena) in many biological, physical and man-made interaction networks.


Perforated vesicles composed of amphiphilic diblock copolymer: new artificial biomembrane model of nuclear envelope.
With the aim of creating a new artificial model of a biomembrane for the nuclear envelope, perforated vesicles were prepared employing an amphiphilic diblock copolymer of poly(methacrylic acid)-block-poly(methyl methacrylate-random-methacrylic acid-random-2,2,6,6-tetramethyl-4-piperidyl methacrylate), PMAA-b-P(MMA-r-MAA-r-TPMA), by polymerization-induced self-assembly through photo nitroxide-mediated controlled/living radical polymerization (photo NMP). The photo NMP in an aqueous methanol solution produced spherical vesicles perforated with various holes and pores in the surface. The perforation of the vesicles was prevented by trifluoroacetic acid based on the disturbance of the MAA-TPMA interaction in the hydrophobic block chain. The investigation of the morphology changes by the polymerization progress revealed that the perforated spherical vesicles were produced within the membrane of contorted huge vesicles that were formed during the early stage of the polymerization due to the extension of the hydrophobic block chain. The perforated vesicles were found to show a reversible thermo-responsive behavior in the range of 25-50 °C based on dynamic light scattering and transmittance measurements. The vesicles were fused and divided into much smaller vesicles at high temperature, but were restored by cooling. However, the restored vesicles only had a few holes and no pores in the surface. The rearrangement of the MAA-TPMA interaction at high temperature produced more morphologically stable non-perforated vesicles.


Application of Large Electronic Medical Database for Detecting Undiagnosed Patients in the General Population.
Clinical application of accumulated medical big data is a hot topic in medical informatics. Not only for suggesting possible diagnoses in each individual, large medical database can be possibly used for detecting undiagnosed patients in the general population. In this study, we tried to develop a computerized system of detecting overlooked undiagnosed patients with rare chronic diseases in the community population by utilizing the uniformed national medical insurance record database. A cumulative total of 489,823 hospital visits at one tertiary medical center were collected for this project. As the target disease, we selected esophagogastric junction outflow obstruction (EGJOO), including achalasia, which is known to be easily overlooked without performing a barium swallow test. Patient selection software automatically picked out 17,814 individuals with the given suspected diagnoses that could be misdiagnosed in patients with the target disease, from which the software further picked out 526 individuals who underwent upper endoscopy but did not undergo barium swallow test. Of them, the hospital medical records suggested that 39 people still suffered from prolonged symptoms lasting for more than 6 months after the first hospital visit. Among them, 16 individuals agreed to undergo the barium swallow test. One of them was confirmed to suffer from EGJOO, possibly based on some undiagnosed connective tissue diseases. An automated computerized detection system with uniform big medical data would realize more efficient and less expensive screening system for undiagnosed chronic diseases in the general population based on symptoms and previously performed examinations in each individual.


Epilepsy and everyday life risks. A case-referent study: rationale, study design, and preliminary results. Risk in Epilepsy Study Group.
Despite its favorable outcome in up to 90% of patients, epilepsy is still considered to carry a higher than normal risk of morbidity and accidents. Knowledge of the everyday life risks (illnesses, accidents) in patients with epilepsy is mostly anecdotal. For these reasons, a multinational cohort study has been started in 9 European countries to investigate the incidence and number of medical events and accidents in children and adults with unprovoked epilepsy (diagnosed in the recruiting centers in the previous 10 years) and in age- and sex-matched controls (relatives or friends). The 2 groups are being followed for at least 12 months. Using patients' diaries, data are being collected regarding the number and type of illnesses and accidents, the number of medical contacts and the actions taken, the number of hospital admissions, and the total number of days off work/school. In a preliminary report on 833 patients and 833 controls, the cases reported slightly less illnesses, medical contacts, and actions taken by doctors. Accidents and related events occurred in similar proportions in the 2 groups. Based on the results of the pilot study, idiopathic, cryptogenic and remote symptomatic epilepsy may be compatible with an at least fairly normal social life.


Genetic Variants in Cyclooxygenase-2 Contribute to Post-treatment Pain among Endodontic Patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established analgesic efficacy for inflammatory pain. These drugs exert their effect by inhibiting the enzyme cyclooxygenase (COX) and are commonly used for the management of pain after endodontic treatment. There are 2 distinct isoforms of COX: COX-1, which is constitutively expressed, and COX-2, which is primarily induced by inflammation. Previous studies have shown that functional human genetic variants of the COX-2 gene may explain individual variations in acute pain. The present study extends this work by examining the potential contribution of the 2 COX isoforms to pain after endodontic treatment. Ninety-four patients treated by endodontic residents at the University of North Carolina School of Dentistry were enrolled into a prospective cohort study. Data on potential predictors of post-treatment pain were collected, and all patients submitted saliva samples for genetic analysis. Nonsurgical root canal therapy was performed, and participants recorded pain levels for 5 days after. In this study, 63% of patients experienced at least mild pain after root canal therapy, and 24% experienced moderate to severe pain. The presence of pretreatment pain was correlated with higher post-treatment pain (P = .01). Elevated heart rate (P = .02) and higher diastolic blood pressure (P = .024) were also correlated with decreased post-treatment pain. Finally, we identified genetic variants in COX-2 (haplotype composed of rs2383515 G, rs5277 G, rs5275 T, and rs2206593 A) associated with post-treatment pain after endodontic treatment (P = .025). Understanding the genetic basis of pain after endodontic treatment will advance its prevention and management.


Metal wear in Lillehei-Kaster heart valve prostheses.
Ten Lillehei-Kaster heart valve prostheses, in situ for up to 10 years and recovered at surgery or necropsy, were examined by light and scanning electron microscopy. All showed metal wear on the luminal aspect of their struts. The volume of wear related to the duration a prosthesis had been in situ. The worn metal showed distinct, transverse surface corrugations, which became more obvious with time. Aortic prostheses wore more and faster than mitral ones. One strut usually showed more wear than the other, a change likely due to specific manufacturing methods. It is believed that the pattern of wear is caused by a velocity-controlled stick-slip abrasive wear process, resulting from an interaction between the edge of the moving pyrolytic carbon disc, the struts' titanium surface, and the protein coat covering that surface. None of the patients had prosthesis dysfunction attributable to metal wear. Disc escape seems unlikely considering the degree of wear observed after 10 years. Furthermore, the surface corrugations did not appear to cause disc sticking or other problems. However, clinicians might consider monitoring patients who have borne these prostheses for greater than 10 years.


Allogeneic stem cell transplantation as part of front line therapy for Mantle cell lymphoma.
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma that remains incurable for the majority of patients. Allogeneic stem cell transplantation (alloSCT) produces long-term disease-free remissions for around 30-40% patients, however it is reserved for the treatment of relapsed disease. This study examined the use of front line transplantation for young patients in an attempt to improve outcomes. Twenty-five patients received an alloSCT using BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan)-Campath conditioning following permissive induction therapy from both related and unrelated donors. This was a multi-centre prospective trial. Twenty-four of 25 patients engrafted with no non-relapse mortality events by day 100. With a median follow-up of 60·5 months, there have been six deaths (3 from MCL). The progression-free survival (PFS) and overall survival were 68% and 80% at 2 years and 56% and 76% at 5 years. PFS was very similar for both sibling and unrelated transplants and there was no difference in PFS between patients with respect to remission status prior to transplantation. Nine (38%) patients experienced acute graft-versus-host disease (GVHD) and 14 (58%) experienced chronic GVHD, of which 8 were extensive. Front line alloSCT is feasible but should only be considered for patients at high risk of early progression following conventional therapy.


Mapping of macular substructures with optical coherence tomography for glaucoma diagnosis.
To use optical coherence tomography (OCT) to identify the specific retinal layers and macular regions damaged in glaucoma. Observational cross-sectional study. One hundred forty-nine participants in the Advanced Imaging for Glaucoma Study, divided into 3 groups: normal (N) perimetric glaucoma (PG), and glaucoma suspect and preperimetric glaucoma (GSPPG) with 44, 73, and 29 persons, respectively. The Zeiss Stratus OCT system (Carl Zeiss Meditec, Inc., Dublin, CA) was used to map the macula over a 6-mm diameter and to scan the circumpapillary nerve fiber layer (cpNFL). The macular OCT images were exported for automatic segmentation using software developed by the authors. The thickness of the macular nerve fiber layer (mNFL), ganglion cell layer (mGCL), inner plexiform layer (mIPL), inner nuclear layer (mINL), outer retinal layer (mORL), and total retinal thickness were measured. Thickness measurements of GSPPG and PG eyes were compared with those of N eyes. The ability to differentiate between GSPPG and PG eyes against N eyes was assessed by fractional loss, standardized deviation, and the area under the receiver operating characteristic curve. Area-weighted average thicknesses of retinal sublayers in the macula. The mNFL, mGCL, mIPL, and mINL were significantly (P<0.001) thinner in both the GSPPG and PG eyes than in the N eyes. In PG eyes, mNFL, mGCL, and mIPL thinning was most severe (approximately 20%), mINL thinning was intermediate (7%), and mORL thinning was minimal (3%). The repeatability (coefficient of variation and intraclass correlation) of thickness measurements was improved by combining the mNFL, mGCL, and mIPL measurements as the inner retinal layer (mIRL). The mIRL was the best macular parameter for glaucoma diagnosis and had discriminant power comparable with that of the cpNFL. The fractional loss of mIRL thickness was most severe in the inferior perifoveal region for both the PG and GSPPG groups. Glaucoma leads to thinning of the mNFL, mGCL, mIPL, and mINL, even before detectable visual field changes occur. A combination of the 3 innermost layers seems to provide optimal glaucoma detection. Increasing the sampling of peripheral macula with a new OCT scan pattern may improve glaucoma diagnosis further.


Antibodies to HLA-E may account for the non-donor-specific anti-HLA class-Ia antibodies in renal and liver transplant recipients.
The non-donor-specific anti-HLA-Ia antibodies correlate significantly with lower graft survival in organ transplant patients. Based on our earlier findings that anti-HLA-E murine monoclonal antibodies (MEM-E/02 and 3D12) reacted with different HLA-Ia alleles and the peptides shared by HLA-E and HLA class, Ia alleles inhibited the HLA-Ia reactivity of the anti-HLA-E antibodies in normal non-alloimmunized males, the possibility of that anti-HLA-E IgG may account for the non-donor-specific anti-HLA-Ia antibodies in the allograft recipients was examined by multiplex-Luminex®-immunoassay. About 73% of renal and 53% of liver transplant patients' sera with high level of anti-HLA-E IgG showed reactivity to different non-donor HLA-Ia alleles. About 50% renal and 52% liver allograft recipients' sera with low level of anti-HLA-E IgG had no reactivity to any HLA-Ia alleles; however, the IgG isolated from the same sera with protein-G columns showed the presence of anti-HLA-E IgG with HLA-Ia reactivity. Furthermore, both recombinant HLA-E and the IgG-free serum containing soluble HLA-E (sHLA-E) inhibited HLA-Ia reactivity of anti-HLA-E murine monoclonal IgG significantly. The data suggest that the HLA-Ia reactivity of the anti-HLA-E antibody accounts for the non-donor-specific anti-HLA-Ia antibodies. It is proposed that the sHLA-E heavy chain, shed in circulation after organ transplantation, may expose cryptic epitopes of HLA-E to elicit anti-HLA-E IgG antibodies, which may cross react with HLA-Ia alleles due to the peptide sequences shared between them. This study provides a new explanation for the presence of non-donor-specific antibodies for non-existing HLA-Ia alleles, frequently observed and correlated with survival in organ transplant recipients.


Molecular association of Arabidopsis RTH with its homolog RTE1 in regulating ethylene signaling.
The plant hormone ethylene affects many biological processes during plant growth and development. Ethylene is perceived by ethylene receptors at the endoplasmic reticulum (ER) membrane. The ETR1 ethylene receptor is positively regulated by the transmembrane protein RTE1, which localizes to the ER and Golgi apparatus. The RTE1 gene family is conserved in animals, plants, and lower eukaryotes. In Arabidopsis, RTE1-HOMOLOG (RTH) is the only homolog of the Arabidopsis RTE1 gene family. The regulatory function of the Arabidopsis RTH in ethylene signaling and plant growth is largely unknown. The present study shows Arabidopsis RTH gene expression patterns, protein co-localization with the ER and Golgi apparatus, and the altered ethylene response phenotype when RTH is knocked out or overexpressed in Arabidopsis. Compared with rte1 mutants, rth mutants exhibit less sensitivity to exogenous ethylene, while RTH overexpression confers ethylene hypersensitivity. Genetic analyses indicate that Arabidopsis RTH might not directly regulate the ethylene receptors. RTH can physically interact with RTE1, and evidence supports that RTH might act via RTE1 in regulating ethylene responses and signaling. The present study advances our understanding of the regulatory function of the Arabidopsis RTE1 gene family members in ethylene signaling.


Increased metabolism of infused 1-methylxanthine by working muscle.
Exogenous substrates for capillary endothelial enzymes have potential as markers for changes in capillary recruitment (albeit nutritive flow). The metabolism of infused 1-methylxanthine (1-MX) to 1-methylurate (1-MU) by capillary endothelial xanthine oxidase of the constant-flow perfused rat hindlimb was shown previously to decrease with oxygen uptake (VO2) when nutritive flow was decreased. In the present study, the metabolism of 1-MX was investigated under conditions when VO2 and nutritive flow are known to increase during muscle contraction. The constant-flow red blood cell-perfused rat hindlimb at 37 degrees C was used with sciatic nerve stimulation, and perfusate samples from whole hindlimb and working muscles taken for analysis of oxygen, lactate, 1-MX and 1-MU. Flow to muscle was assessed separately using fluorescent microspheres and was found to increase 2.3-fold to the working muscles while flow to the non-working leg muscles decreased to compensate. The activity of xanthine oxidase of whole muscle extracts was not altered by contraction. Samples from the vein draining the working muscles, and microsphere measurements of flow, indicated increased VO2 (5.5-fold to 249.2 +/- 43.1 micromol h-1 g-1, P < 0.001), and 1-MX conversion (2.5-fold to 1.87 +/- 0.25 micromol h-1 g-1, P < 0.01) (SEM are shown). It is concluded that as 1-MX metabolism parallels VO2, this substrate may be a useful indicator of changes in capillary (nutritive) surface area in muscle.


[Advance directives in clinical practice : Living will, healthcare power of attorney and care directive].
In clinical practice, situations continuously occur in which medical professionals and family members are confronted with decisions on whether to extend or limit treatment for severely ill patients in end of life treatment decisions. In these situations, advance directives are helpful tools in decision making according to the wishes of the patient; however, not every patient has made an advance directive and in our experience medical staff as well as patients are often not familiar with these documents. The purpose of this article is therefore to explain the currently available documents (e.g. living will, healthcare power of attorney and care directive) and the possible (legal) applications and limitations in the routine clinical practice.


[Measuring pain is useful and every doctor can do it: 7 tips].
Pain is one of the main factors influencing quality of life; its incidence is higher than is generally assumed. Pain is not spontaneously reported in all cases; it should be asked about more often. Not measuring pain is one of the main reasons for inadequate pain treatment. Pain should be assessed and recorded more routinely in both primary and secondary healthcare. This can be done in simple and quick ways. Self-reporting using a visual-analogue scale or numeric rating scale is the preferred method. This can be done even by patients with a mild cognitive disorder. Several simple and reliable observational scales exist for patients who cannot report well, e.g. elderly patients with a cognitive disorder or young children. For chronic pain, the low-threshold use of a multi-dimensional scale will increase the likelihood of successful treatment.


Using typical daily flow patterns and dry-weather scenarios for screening flow rate measurements in sewers.
Monitoring systems for measuring rainfall, as well as flow rates and pollutant quantities conveyed by sewers and/or discharged by stormwater overflow devices, have become a common feature in many municipal sewer services, in part spurred by recent regulatory requirements. However, the state of measurement conditions in sewer facilities does not always ensure reliable results. For this reason, it is essential that measured values be carefully screened prior to their use, since many sources of disruption capable of skewing data can be encountered. The present article describes a method for validating dry-weather data a posteriori. This method relies upon flow rate forecasts, a combination of standard daily wastewater flow profiles and an estimation of infiltration flows. Measurement results are then compared with this forecast and an appropriate series of statistical tests are run to detect all major data anomalies. A number of diagnostic rules are then applied in order to derive an initial interpretation of these anomalies and, in particular, to identify the influence of rainfall events.


Musculoskeletal disorders in dentists.
Occupational injuries involving musculoskeletal tissues are often related to repetitive movements of upper limbs and prolonged postures such as sitting and standing--activities common in dentistry. Surveys of the incidence of musculoskeletal disorders among dentists are few, but in Nebraska, 29 percent of more than 1,000 dentists reported symptoms of peripheral neuropathy in the upper limbs or neck. The Nebraskan dentists reported that crown and bridge work was most likely to evoke altered sensations in their upper limbs. Furthermore, since 47 percent of carpal tunnel syndrome cases in the general population are work-related and are often associated with repetitive motions, it is reasonable to suspect that dentists may be at risk for this musculoskeletal disorder. And, since it is estimated that 60 percent to 80 percent of adults will experience low back pain at one time or another, resulting in it being the second leading cause of absences from work in the general population, dental practitioners are most likely to be among those susceptible to this problem. This article focuses on two ailments afflicting dentists: carpal tunnel syndrome and low back pain.


Preferential regulation of miRNA targets by environmental chemicals in the human genome.
microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent disease research showed the exposure to some environmental chemicals (ECs) can regulate the expression patterns of miRNAs, which raises the intriguing question of how miRNAs and their targets cope with the exposure to ECs throughout the genome. In this study, we comprehensively analyzed the properties of genes regulated by ECs (EC-genes) and found miRNA targets were significantly enriched among the EC-genes. Compared with the non-miRNA-targets, miRNA targets were roughly twice as likely to be EC-genes. By investigating the collection methods and other properties of the EC-genes, we demonstrated that the enrichment of miRNA targets was not attributed to either the potential collection bias of EC-genes, the presence of paralogs, longer 3'UTRs or more conserved 3'UTRs. Finally, we identified 1,842 significant concurrent interactions between 407 miRNAs and 497 ECs. This association network of miRNAs-ECs was highly modular and could be separated into 14 interconnected modules. In each module, miRNAs and ECs were closely connected, providing a good method to design accurate miRNA markers for ECs in toxicology research. Our analyses indicated that miRNAs and their targets played important roles in cellular responses to ECs. Association analyses of miRNAs and ECs will help to broaden the understanding of the pathogenesis of such chemical components.


[Changes in influenza vaccination coverage in Spain from 2001 to 2003. Analysis by autonomous communities].
To evaluate changes in influenza vaccination coverage in Spain by autonomous communities between 2001 and 2003 and to compare the influenza vaccination coverage obtained in Spanish National Health Surveys (NHS) with other official sources. A total of 42,722 cases from the NHS for 2001 (n = 21,072) and 2003 (n = 21,650) were analyzed. All the cases corresponded to adults aged more than 15 years old. Both surveys are representative of the autonomous communities. For the entire sample, vaccine coverages of 19.3% (95% CI, 18.8-19.8) and 22.1% (95% CI, 21.4-22.8) were estimated in 2001 and 2003 respectively. In the logit regression model adjusted by age, sex and associated chronic diseases, significant improvements were found in coverage in individuals aged more than 64 years (odds ratio = 1.26; 95% CI, 1.14-1.40) for Spain as a whole and for 6 autonomous communities between 2001 and 2003. For the group aged less than 65 years with associated chronic diseases, a significant improvement in coverage was found for Spain as a whole and for 3 autonomous communities. Between 2001 and 2003, influenza vaccination coverage in the risk groups studied significantly improved in Spain and in several autonomous communities. The information on influenza vaccination coverage obtained in the Spanish National Health Surveys was similar to that found in the Autonomous Communities Health Surveys and in the Ministry of Health and Consumer Affairs.


[Studies on HPLC method for determination of 4-methylaminoantipyrine and relative bioavailabilities of analgin nasal drops in human volunteers].
A new HPLC method for the determination of a metabolite of analgin, MAA (4-methylaminoantipyrine), in plasma and its application to determine the bioavailabilities of analgin nasal drops in human volunteers is reported in this paper. A Waters Model 481 instrument was used throughout the experiment. IAA (isopropylaminoantipyrine) was shown to be the most suitable internal standard at absorption wavelength of 254 nm. A mixture of phosphate buffer (pH 5.5) and methanol (68:32) was used as the mobile phase with a flow rate of 2 ml.min-1, and YWG-C18H37 as stationary phase. Calibration curve was linear (gamma = 0.9998) in the concentration range of 0.1-5 micrograms.ml-1. The within day and day-to-day precision (RSD) of this method were 2.35% and 2.61%, respectively, with average recoveries of 99.3%-103.9%. No interference was found in the body fluid. The plasma samples of healthy volunteers were treated with acid and extracted with ether. The system of mobile phase and the process of blood sample treatment were simpler than those reported in literature. So, the method is suitable for the study of pharmacokinetics and clinical determination of blood level of analgin. The studies on bioavailabilities of analgin nasal drops were carried out in 8 men relative to intramuscular injection and 6 men relative to oral tablets, respectively, at the dose of 250 mg analgin in different preparations administered by cross-over method. The main pharmacokinetic parameters were shown in Table 3. The results indicate that analgin nasal drops exhibited a higher bioavailability (relative to injection) and faster absorption (relative to tablet). So, analgin is suitable to be developed as a nasal preparation.


Impact of drug load and polymer molecular weight on the 3D microstructure of printed tablets.
This study investigates the influence of drug load and polymer molecular weight on the structure of tablets three-dimensionally (3D) printed from the binary mixture of prednisolone and hydroxypropyl methylcellulose (HPMC). Three different HPMC grades, (AFFINISOLTM HPMC HME 15LV, 90 Da (HPMC 15LV); 100LV, 180 Da (HPMC 100LV); 4M, 500 Da (HPMC 4M)), which are suitable for hot-melt extrusion (HME), were used in this study. HME was used to fabricate feedstock material, i.e., filaments, at the lowest possible extrusion temperature. Filaments of the three HPMC grades were prepared to contain 2.5, 5, 10 and 20 % (w/w) prednisolone. The thermal degradation of the filaments was studied with thermogravimetric analysis, while solid-state properties of the drug-loaded filaments were assessed with the use of X-ray powder diffraction. Prednisolone in the freshly extruded filaments was determined to be amorphous for drug loads up to 10%. It remained physically stable for at least 6 months of storage, except for the filament containing 10% drug with HPMC 15LV, where recrystallization of prednisolone was detected. Fused deposition modeling was utilized to print honeycomb-shaped tablets from the HME filaments of HPMC 15LV and 100LV. The structural characteristics of the tablets were evaluated using X-ray microcomputed tomography, specifically porosity and size of structural elements were investigated. The tablets printed from HPMC 15LV possessed in general lower total porosity and pores of smaller size than tablets printed from the HPMC 100LV. The studied drug loads were shown to have minor effect on the total porosity of the tablets, though the lower the drug load was, the higher the variance of porosity along the height of the tablet was observed. It was found that tablets printed with HPMC 15LV showed higher structural similarity with the virtually designed model than tablets printed from HPMC 100LV. These findings highlight the relevance of the drug load and polymer molecular weight on the microstructure and structural properties of 3D printed tablets.


A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer.
In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m2/day to 1.5 mg/m2/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m2/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/m2/day continuous i.v. infusion combined with tamoxifen 200 mg/kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer.


Online Effects of Beta-tACS Over the Left Prefrontal Cortex on Phonological Decisions.
The left posterior inferior frontal gyrus in the prefrontal cortex is a key region for phonological aspects of language processing. A previous study has shown that alpha-tACS over the prefrontal cortex applied before task processing facilitated phonological decision-making and increased task-related theta power. However, it is unclear how alpha-tACS affects phonological processing when applied directly during the task. Moreover, the frequency specificity of this effect is also unclear since the majority of neurostimulation studies tested a single frequency only. The present study addressed the question whether and how 10 Hz online tACS affects phonological decisions. To this end, 24 healthy participants received tACS at 10 Hz or 16.18 Hz (control frequency) or sham stimulation over the left prefrontal cortex during task processing in three sessions. As an unexpected finding, 16.18 Hz significantly impaired task accuracy relative to sham stimulation, without affecting response speed. There was no significant difference in phonological task performance between 10 Hz and 16.18 Hz tACS or between 10 Hz and sham stimulation. Our results support the functional relevance of the left prefrontal cortex for phonological decisions and suggest that online beta-tACS may modulate language comprehension.


Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes.
Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications. ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar. At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012). Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.


Congenital cerebrospinal fluid fistulae of the petrous temporal bone.
Spontaneous cerebrospinal fluid fistulae from the subarachnoid space into the middle ear cavity may be classified as perilabyrinthine or translabyrinthine. The very rare perilabyrinthine group, through bony defects close to but not involving the labyrinth, usually have normal hearing initially. The commoner translabyrinthine group are nearly always associated with anacusis, severe labyrinthine dysplasia and a route via the internal auditory meatus. The labyrinthine deformity is more severe than the type classically described by Mondini, and evidence of a dilated cochlear aqueduct in these cases is also unconvincing.


Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast.
We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h. CYP4Z1 is of interest because it is strongly overexpressed both in breast cancer cells and in breast cancer metastases; however, current knowledge about its catalytic properties is very limited. Screening of CYP4Z1-containing enzyme bags with 15 luminogenic substrates enabled us to identify two new hydroxylations and eleven ether cleavage reactions that are catalyzed by CYP4Z1. By far the best substrate found in this study was Luciferin benzyl ether (Luciferin-BE). On the basis of the recently published crystal structure of CYP4B1 we created a new homology model of CYP4Z1 and performed molecular docking experiments, which indicate that all active substrates show a highly similar binding geometry compared to the endogenous substrates. The model predicts that Ser113, Ser222, Asn381, and Ser383 are key hydrogen bonding residues. We also identified five new inhibitors of CYP4Z1: miconazole, econazole, aminobenzotriazole, tolazoline, and 1-benzylimidazole respectively, with the last compound being the most potent giving an IC50 value of 180nM in our test system.


Passive sensor technology interface to assess elder activity in independent living.
The effectiveness of clinical information systems to improve nursing and patient outcomes depends on human factors, including system usability, organizational workflow, and user satisfaction. The aim of this study was to examine to what extent residents, family members, and clinicians find a sensor data interface used to monitor elder activity levels usable and useful in an independent living setting. Three independent expert reviewers conducted an initial heuristic evaluation. Subsequently, 20 end users (5 residents, 5 family members, 5 registered nurses, and 5 physicians) participated in the evaluation. During the evaluation, each participant was asked to complete three scenarios taken from three residents. Morae recorder software was used to capture data during the user interactions. The heuristic evaluation resulted in 26 recommendations for interface improvement; these were classified under the headings content, aesthetic appeal, navigation, and architecture, which were derived from heuristic results. Total time for elderly residents to complete scenarios was much greater than for other users. Family members spent more time than clinicians but less time than residents did to complete scenarios. Elder residents and family members had difficulty interpreting clinical data and graphs, experienced information overload, and did not understand terminology. All users found the sensor data interface useful for identifying changing resident activities. Older adult users have special needs that should be addressed when designing clinical interfaces for them, especially information as important as health information. Evaluating human factors during user interactions with clinical information systems should be a requirement before implementation.


Increases in Spontaneous Activity in the Dorsal Cochlear Nucleus Following Exposure to High Intensity Sound: A Possible Neural Correlate of Tinnitus.
The purpose of this study was to test the effects of intense tone exposure on the spontaneous activity of multiunit clusters in the mammalian dorsal cochlear nucleus (DCN). Adult hamsters (60-101 days of age) were exposed to a 10 kHz tone at levels between 125 and 130 dB SPL for a period of 4 hours. The effects of tone exposure were studied following a recovery period of 30-58 days and were quantified by measuring the spontaneous rates, response thresholds and frequency tuning properties of neural clusters at the surface of the DCN. Measures were performed at each of 10-15 sites along the tonotopic axis of the DCN. The effects of the tone exposure were examined by comparison with identical measures obtained from normal unexposed animals. Results indicate that tone exposure induced major chronic increases in the spontaneous activity of the DCN. Such increases were broadly distributed across the tonotopic range of the DCN and were generally found in tonotopic map areas characterized by tone-induced elevations of neural thresholds. Mean spontaneous rate reached its maximum value at or close to the tonotopic locus which normally represents the frequency of the exposure tone. The increased activity induced by tone exposure resembled the heightened activity in normal animals during presentation of a moderate level continuous tone. These changes in spontaneous activity indicate that central auditory neurons are in a state of elevated activity for extended periods following intense sound exposure and suggest that the affected neurons may signal the presence of acoustic stimulation even though such stimulation is not present. Possible mechanisms of these changes and their relation to the clinical problem of tinnitus are discussed.


Electroacupuncture ameliorates abnormal defaecation and regulates corticotrophin-releasing factor in a rat model of stress.
To examine the effect of electroacupuncture (EA) treatment on abnormal defaecation in a rat model of chronic heterotypic stress (CHS) and investigate the underlying mechanisms. 20 male Sprague-Dawley rats were randomly divided into three groups: normal (n=6), CHS (n=7), and CHS+EA (n=7). Rats in the CHS group and CHS+EA groups received four different types of stressors for 7 days. For rats in the CHS+EA group, EA was applied at ST36 in the bilateral hind legs for 30 min before each stress-loading session. Rats in the normal group did not receive stressors or EA treatment. The faecal pellets of each rat were collected and weighed at a fixed time every day. Protein expression of corticotrophin-releasing factor (CRF) in the hypothalamus and colorectal tissues was measured by Western blotting at the end of the experiment on the 7th day. After 7 consecutive days of CHS, the number of faecal pellets, faecal wet weight, and faecal water content were significantly increased in the CHS group compared with the normal group (p=0.035, p=0.008 and p=0.008, respectively). All three parameters were significantly decreased in CHS+EA versus CHS groups (p=0.030, p=0.011 and p=0.006, respectively). Stress significantly increased CRF expression in both the hypothalamus and colorectal tissues. The excessive CRF responses seen following CHS were significantly suppressed by EA treatment. EA treatment can ameliorate stress loading induced abnormal defaecation in rats and decrease protein expression of CRF centrally (hypothalamus) and peripherally (colorectal tissues), suggesting a potentially therapeutic role for EA in stress-related responses.


Hidden Markov random field models for cell-type assignment of spatially resolved transcriptomics.
The recent development of spatially resolved transcriptomics (SRT) technologies has facilitated research on gene expression in the spatial context. Annotating cell types is one crucial step for downstream analysis. However, many existing algorithms use an unsupervised strategy to assign cell types for SRT data. They first conduct clustering analysis and then aggregate cluster-level expression based on the clustering results. This workflow fails to leverage the marker gene information efficiently. On the other hand, other cell annotation methods designed for single-cell RNA-seq data utilize the cell-type marker genes information but fail to use spatial information in SRT data. We introduce a statistical spatial transcriptomics cell assignment model, SPAN, to annotate clusters of cells or spots into known types in SRT data with prior knowledge of predefined marker genes and spatial information. The SPAN model annotates cells or spots from SRT data using predefined overexpressed marker genes and combines a mixture model with a hidden Markov random field to model the spatial dependency between neighboring spots. We demonstrate the effectiveness of SPAN against spatial and nonspatial clustering algorithms through extensive simulation and real data experiments. https://github.com/ChengZ352/SPAN.


Working life, health and well-being of parents: a joint effort to uncover hidden treasures in European birth cohorts.
Birth cohorts collect valuable and under-utilized information on employment and health of parents before and during pregnancy, at birth, and sometimes after birth. In this discussion paper, we examine how these data could be exploited to study the complex relationships and interactions between parenthood, work, and health among parents themselves. Using a web-based database of birth cohorts, we summarize information on maternal employment and health conditions and other potentially related variables in cohorts spread throughout Europe. This provided information on what data are available and could be used in future studies, and what was missing if specific questions are to be addressed, exploiting the opportunity to explore work-health associations across heterogenous geographical and social contexts. We highlight the many potentialities provided by birth cohorts and identify gaps that need to be addressed to adopt a life-course approach and investigate topics specific to the peri-pregnancy period, such as psychosocial aspects. We address the technical difficulties implied by data harmonization and the ethical challenges related to the repurposing of data, and provide scientific, ecological and economic arguments in favor of improving the value of data already available as a result of a serious investment in human and material resources. There is a hidden treasure in birth cohorts that deserves to be brought out to study the relationships between employment and health among working parents in a time when the boundaries between work and life are being stretched more than ever before.


[Effect of benzimidazole derivatives and levamisole (phenylimidothiazole) on cyclic 3':5'-AMP phosphodiesterase from pig brain].
The effects of phenylimidothiazole and some benzimidazole derivatives on phosphodiesterase of cyclic 3':5'-AMP (cAMP) from pig brain were studied. Depending on their concentrations the compounds tested activated or inhibited the enzyme activity. A correlation between the effects of benzimidazoles and phenylimidothiazole which is known to exert an immunomodulating action was observed.


Impact of the Hospital-Acquired Conditions Initiative on Falls and Physical Restraints: A Longitudinal Study.
The Centers for Medicare & Medicaid Services (CMS) implemented the Hospital-Acquired Conditions (HACs) Initiative in October 2008; the CMS no longer reimbursed hospitals for fall injury. The effects of this payment change on fall and fall injury rates are not well described, nor its effect on physical restraint use. The aim of this study was to examine the effects of the 2008 HACs Initiative on the rates of falls, injurious falls, and physical restraint use. This was a nine-year retrospective cohort study (July 2006-December 2015) involving 2,862 adult medical, medical-surgical, and surgical nursing units from 734 hospitals. Annual rates of change in falls, injurious falls, and physical restraint use during the two years before the payment rule went into effect were compared with one-, four-, and seven-year rates of annual change after implementation, adjusting for unit- and facility-level covariates. Stratified analyses were conducted according to bed size and teaching status. Compared with prior to the payment change, there was stable acceleration in the one-, four-, and seven-year annual rates of decline in falls as follows: -2.1% (-3.3%, -0.9%), -2.2% (-3.2%, -1.1%), and -2.2% (-3.4%, -1.0%) respectively. For injurious falls, there was an increasing acceleration in the annual declines, achieving statistical significance only at seven years post CMS change as follows: -3.2% (-5.5%, -1.0%). Physical restraint use prevalence decreased from 1.6% to 0.6%. Changes in the rates of falls, injurious falls, and restraint use varied according to hospital bed size and teaching status. Since the HACs Initiative, there was at best a modest decline in the rates of falls and injurious falls observed primarily in larger, major teaching hospitals. An increase in restraint use was not observed. Falls remain a difficult patient safety problem for hospitals, and further research is required to develop cost-effective, generalizable strategies for their prevention.


Local Adenoviral Delivery of Vascular Endothelial Growth Factor C Induces Lymphangiogenesis in the Conjunctiva in Rabbits.
The purpose of this study was to determine if conjunctival lymphangiogenesis can be induced using adenoviral delivery of vascular endothelial growth factor C (VEGF-C). Seventeen New Zealand white rabbits received a subconjunctival injection containing 3.5 × 107 plaque-forming units of an adenoviral vector containing the gene-encoding VEGF-C (Ad-VEGF-C). The contralateral eye was used for control experiment (the same volume of either saline or an empty vector). After 2 weeks, the animals were examined with trypan blue conjunctival lymphangiography, and the eyes were harvested for histology and immunohistochemistry (podoplanin and CD31). Trypan blue conjunctival lymphangiography revealed significantly more extensive conjunctival vessel network in the Ad-VEGF-C group compared with control: 1.35 ± 0.67 versus 0.28 ± 0.17 vessel length/analysed area (p = <0.0001). This finding was confirmed with immunohistochemistry, where a significant increase in the number of lymphatic vessels was found compared to control; 34 ± 9 per mm2 versus 13 ± 8 per mm2 (p = 0.0019). Furthermore, there was a significant increase in lymphatic cross-sectional area; 32,500 ± 7,900 µm2 per mm2 versus 17,600 ± 9,700 µm2 per mm2 (p = 0.0149). Quantification of blood vessels revealed no significant difference in blood vessel density between Ad-VEGF-C and control; 19 ± 9 per mm2 versus 14 ± 8 per mm2 (p = 0.1971). There was no significant difference in total blood vessel area; 13,200 ± 7,600 µm2 per mm2 versus 7,100 ± 3,000 µm2 per mm2 (p = 0.0715). Eyes treated with an adenoviral vector (VEGF-C or empty vector) responded with a reactive cellular response, predominantly lymphocytes, towards the vector. The study demonstrates the feasibility of inducing conjunctival lymphangiogenesis with a single subconjunctival injection of Ad-VEGF-C. Future studies will explore how this can be used with a therapeutic purpose.


Medical Complications After Adult Spinal Deformity Surgery: Incidence, Risk Factors, and Clinical Impact.
Retrospective review of a prospective multicenter database evaluating surgical adult spinal deformity (ASD) patients. This study aims to identify risk factors for medical complications in ASD patients undergoing surgery. ASD surgery is known for its high complication rate. This study examines baseline patient characteristics for predictors of medical complications in surgical ASD patients. Intra and perioperative medical complications were included. Medical complications were: infection, pneumonia, urinary tract infection, c-difficile, sepsis, stroke, delirium, deep venous thrombosis, pulmonary embolism, myocardial infarction, arrhythmia, congestive heart failure, pneumothorax, atelectasis, adult respiratory distress syndrome, bowel obstruction, ileus, and renal failure. Potential predictors were identified using univariate testing. Multivariate Poisson regression was used to determine independent predictors of medical complications. Health-related quality of life (HRQL) was measured using the Oswestry Disability Index and SF-36. Multivariate repeated measures mixed models were used to examine HRQL. Four hundred forty-eight patients were included. The incidence of patients with at least one medical complication was 26.8%. Potential predictors included: age, BMI, anemia, arthritis, depression, cardiac history, hypertension, lung disease, history of PVD, Charlson Comorbidity Index, ASA, smoking, sex, and the number of years with spine problems. Independent predictors identified on multivariate logistic regression modeling included hypertension (IRR 2.43 P = 0.0001), smoking (IRR 2.49 P = 0.0001), and number of years with spine problems (IRR 1.23 P = 0.03). Despite medical complications, patients experienced significant improvements in HRQL, as measured by the SF-36 (P = 0.0001) and oswestry disability index (P = 0.0001). The rate of improvement and overall improvement compared with baseline were not statistically different than that of patients who did not experience medical complications. Risk factors for the development of postoperative medical complications after correction of ASD include smoking, hypertension, and duration of symptoms. Patients who have one or more of these risk factors should be identified and informed during informed consent of their increased risks. They should be optimized preoperatively, and followed closely during the postoperative period. 3.


GsAPK, an ABA-activated and calcium-independent SnRK2-type kinase from G. soja, mediates the regulation of plant tolerance to salinity and ABA stress.
Plant Snf1 (sucrose non-fermenting-1) related protein kinase (SnRK), a subfamily of serine/threonine kinases, has been implicated as a crucial upstream regulator of ABA and osmotic signaling as in many other signaling cascades. In this paper, we have isolated a novel plant specific ABA activated calcium independent protein kinase (GsAPK) from a highly salt tolerant plant, Glycine soja (50109), which is a member of the SnRK2 family. Subcellular localization studies using GFP fusion protein indicated that GsAPK is localized in the plasma membrane. We found that autophosphorylation and Myelin Basis Protein phosphorylation activity of GsAPK is only activated by ABA and the kinase activity also was observed when calcium was replaced by EGTA, suggesting its independence of calcium in enzyme activity. We also found that cold, salinity, drought, and ABA stress alter GsAPK gene transcripts and heterogonous overexpression of GsAPK in Arabidopsis alters plant tolerance to high salinity and ABA stress. In summary, we demonstrated that GsAPK is a Glycine soja ABA activated calcium independent SnRK-type kinase presumably involved in ABA mediated stress signal transduction.


SAXS-guided Enhanced Unbiased Sampling for Structure Determination of Proteins and Complexes.
Molecular simulations can be utilized to predict protein structure ensembles and dynamics, though sufficient sampling of molecular ensembles and identification of key biologically relevant conformations remains challenging. Low-resolution experimental techniques provide valuable structural information on biomolecule at near-native conditions, which are often combined with molecular simulations to determine and refine protein structural ensembles. In this study, we demonstrate how small angle x-ray scattering (SAXS) information can be incorporated in Markov state model-based adaptive sampling strategy to enhance time efficiency of unbiased MD simulations and identify functionally relevant conformations of proteins and complexes. Our results show that using SAXS data combined with additional information, such as thermodynamics and distance restraints, we are able to distinguish otherwise degenerate structures due to the inherent ambiguity of SAXS pattern. We further demonstrate that adaptive sampling guided by SAXS and hybrid information can significantly reduce the computation time required to discover target structures. Overall, our findings demonstrate the potential of this hybrid approach in predicting near-native structures of proteins and complexes. Other low-resolution experimental information can be incorporated in a similar manner to collectively enhance unbiased sampling and improve the accuracy of structure prediction from simulation.


[Nursing participation in the National Conferences of Health].
The National Conferences of Health approached the question of Human Resources with emphasis, making prescriptions of interests for the Nursing, a huge class among the professionals of health. Aiming to identify, describe and analyze what the final reports of the last five conferences mentioned about this subject, it was done a documental study by means of analyses of the dissertation contained in those texts. The categories found are: job conditions; education; upbringing and qualification; formation of multi-professional teams and humanization. It was concluded that the aspects broached being in a punctual way or being in a more complex definition were driven to the human resources as a whole, with little specification for the nursing in contrast to the significance of this grouping for SUS.


Prevalence and correlates of Trichomonas vaginalis infection among female US federal prison inmates.
Previous studies have observed high prevalences of Trichomonas vaginalis infection among women entering US jails and state prisons (22%-47%). We sought to determine the prevalence among women incarcerated in 2 US female-only federal prisons. Female inmates were recruited at 2 prisons (n = 624). Participants completed a self-administered questionnaire and provided self-collected first-catch urine and vaginal swab specimens. Specimens were tested for T. vaginalis DNA. Approximately 8.5% of participants at the first prison, and 8.3% at the second prison had a positive urine result, vaginal swab result or both, for a combined prevalence of 8.5%. Using positivity in either specimen as the reference standard, urine polymerase chain reaction had a sensitivity of 66.7% and vaginal swab polymerase chain reaction had a sensitivity of 84.4%. The only significant positive correlate of T. vaginalis infection was lower household income before arrest. Other variables nonsignificantly positively correlated with T. vaginalis were being employed at the time of arrest, having experienced sexual, physical, or emotional abuse by a family member, having a parent who had not had a drug or alcohol addiction, never exchanging sex for money or drugs, ever being pregnant, having abnormal vaginal bleeding/spotting, and having concurrent chlamydia or gonorrhea. Although not as high as in other studies of women entering US jails and state prisons, our observed T. vaginalis prevalence of 8.5% was much higher than in the general US population. Therefore, screening for T. vaginalis infection may be warranted at federal prison entry, as well as sexual health education during prison stay.


Responses of multifunctional immune complement component 1q (C1q) and apoptosis-related genes in Macrophthalmus japonicus tissues and human cells following exposure to environmental pollutants.
Apoptosis is a key defense process for multiple immune system functions, playing a central role in maintaining homeostasis and cell development. The purpose of this study was to evaluate the effects of environmental pollutant exposure on immune-related apoptotic pathways in crab tissues and human cells. To do this, we characterized the multifunctional immune complement component 1q (C1q) gene and analyzed C1q expression in Macrophthalmus japonicus crabs after exposure to di(2-ethylhexyl) phthalate (DEHP) or hexabromocyclododecanes (HBCDs). Moreover, the responses of apoptotic signal-related genes were observed in M. japonicus tissues and human cell lines (HEK293T and HCT116). C1q gene expression was downregulated in the gills and hepatopancreas of M. japonicus after exposure to DEHP or HBCD. Pollutant exposure also increased antioxidant enzyme activities and altered transcription of 15 apoptotic signaling genes in M. japonicus. However, patterns in apoptotic signaling in response to these pollutants differed in human cells. HBCD exposure generated an apoptotic signal (cleaved caspase-3) and inhibited cell growth in both cell lines, whereas DEHP exposure did not produce such a response. These results suggest that exposure to environmental pollutants induced different levels of immune-related apoptosis depending on the cell or tissue type and that this induction of apoptotic signaling may trigger an initiation of carcinogenesis in M. japonicus and in humans as consumers.


Single instead of triplicate intraocular pressure measurements in dogs do not substantially lower accuracy and precision but do slightly reduce statistical power.
To compare single and triplicate applanation tonometry values across previous intraocular pressure (IOP) studies in dogs. 116 ophthalmologically normal dogs. Triplicate IOP readings (n = 1432) from studies evaluating effect of anesthetic protocols were analyzed to estimate a range of probable differences between averaged triplicate and first, averaged and lowest, and first and lowest IOPs. The decrease in variability with triplicate measurements and the magnitude of effects on statistical power were quantified. The 2.5th to 97.5th interpercentile range for differences of averaged triplicate values minus first IOP readings was -3 to 2.7 mm Hg; for averaged minus lowest: 0 to 3.7 mm Hg; for first minus lowest: 0 to 5 mm Hg. The 95% prediction interval for differences in study group means (n = 160 groups, n = 5 to 11 eyes per group) based on averaged minus first measurements was -1.0 to 0.9 mm Hg with associated SDs reduced by 4% on average. Analysis of previous studies using averaged instead of first IOP values resulted in minimal decreases in SEs of 3-9% (0.03 to 0.09 mm Hg). Of 11 comparisons found significant with averaged data, 2 (18%) were found nonsignificant with first measurements. Of 96 comparisons found nonsignificant with averaged data, 3 (3%) were found significant with first measurements. With applanation tonometry in ophthalmologically normal dogs, no clinically meaningful difference was found between the first, lowest, or averaged triplicate IOP measurements, but the first reading has a larger variance and hence will result in lower statistical power.


Paradoxical effects of iodine-125 decays in parent and daughter DNA: a new target model for radiation damage.
Chinese hamster ovary cells were synchronized at the G(1)/S-phase boundary of the cell cycle and were pulse-labeled with (125)I-iododeoxyuridine 30 min after they entered the S phase. Cell samples were harvested and frozen for accumulation of (125)I decays during the first and second G(2) phase after labeling. Cell aliquots that had accumulated the desired number of decays were thawed and plated for evaluation micronucleus formation and cell death. Cells subjected to (125)I decays during the first G(2) phase after labeling exhibited single-hit kinetics of cell killing (n = 1, D(0) 41 decays/cell). In contrast, decays accumulated during the second G(2) phase killed cells with dual-hit kinetics (n = 1.9, D(0) 81 decays/cell). A similar divergence in the action of (125)I was noted for micronucleus formation. These findings indicate that the effects of (125)I varied depending on whether the decays occurred in daughter DNA (first G(2) phase) or parent DNA (second G(2) phase). Control studies with external X rays showed no such divergence of the action of radiation. To account for this paradox, a model is proposed that invokes higher-order chromatin structures as radiation targets. This model implies differential spatial arrangements for parent and daughter DNA in the genome, with DNA strands organized such that a single (125)I decay originating in daughter DNA damages two targets during the first G(2) phase, but identical decays occurring during the second G(2) phase damage only one of the targets.


Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model.
We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 +/- 1.1, 3.28 +/- 0.4, and 3.34 +/- 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 +/- 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.


[Quantitative kinetic model of ATP hydrolysis-synthesis by membrane H+-ATPase].
A mathematical model of fermentative reactions of synthesis-hydrolysis of ATP by H+-ATPase, coupled to the charge transport across the membrane has been constructed. Quantitative calculations of the rate of hydrolysis--synthesis of ATP were performed. The nature of the membrane electrochemical gradient delta mu H+ is discussed.


Quantum correlations and energy currents across three dissipative oscillators.
We present a study that addresses both the stationary properties of the energy current and quantum correlations in a three-mode chain subjected to Ohmic and super-Ohmic dissipations. An extensive numerical analysis shows that the mean value and the fluctuations of the energy current remain insensitive to the emergence of a rich variety of quantum correlations, such as two-mode discord and entanglement and bipartite three-mode and genuine tripartite entanglement. The discussion of the numerical results is based on the derived expressions for the stationary properties in terms of the two-time correlation functions of the oscillator operators, which carry the quantum correlations. Interestingly, we show that quantum discord can be enhanced by considering both initially squeezed thermal bath states and imposing temperature gradients.


Validity and reliability of the Greek version of the Multisource Assessment of Social Competence Scale.
The aim of this study was to adapt the Multisource Assessment of Social Competence Scale to the Greek language. The validity and reliability of the scale were examined in three studies with 209, 192, and 147 sixth-grade students, respectively. The subscale structure of the Multisource Assessment of Social Competence Scale was supported through exploratory and confirmatory factor analysis. The hypothesized two main dimensions, Prosocial and Antisocial behavior, were divided into two factors, Cooperating skills and Empathy for Prosocial behavior and Quick-temperedness and Disruptiveness for Antisocial behavior. Internal consistency and test-retest reliability were high. Additionally, correlations between each factor and social desirability scores were nonsignificant. The resultant model of the present study is a behavior rating scale that should be considered a reliable choice for assessing Greek middle school students' social skills.


Infectivity in sheep of blood lymphocytes from bovine leukemia virus-infected cows with different nuclear pocket prevalences.
The infectivity for the bovine leukemia virus (BLV) of bovine blood lymphocytes, with varying lymphocyte nuclear pocket (LNP) prevalence, was studied by intradermal injection of buffy coat leukocytes from cows into sheep. Thirty-five sheep were assigned to 3 groups of 9, 11, and 15, respectively, as recipients of blood leukocytes from individual cows as follows: 9 leukocyte donor cows included 3 BLV-seropositive cows with high (greater than or equal to 2.0%) LNP prevalence (group 1); 3 BLV-seropositive cows with low (less than 0.5%) LNP prevalence (group 2); and 3 BLV-seronegative cows with increased (greater than or equal to 0.5%) LNP prevalence (group 3). The 9 sheep in group 1 became BLV-seropositive by postinoculation day (PID) 57 as determined by the agar-gel immunodiffusion test; 2 of 11 sheep in group 2 became agar-gel immunodiffusion seropositive by PID 40; none of the 15 sheep of group 3 became seropositive by PID 92. Seemingly, there is a real difference in infectivity among BLV-seropositive cattle which is related to LNP prevalence, and seronegative cattle with increased LNP prevalence may be noninfectious, ie, were not carrying covert BLV virogene.


Malleus and incus: correlates of size.
Wide ranges of dimensions of the malleus and incus have been reported for various human populations. Unaddressed are concordance of malleus and incus sizes, bilateral symmetry, whether ossicle size correlates with otitis media, and whether second-branchial arch derivatives have more variability than first-arch derivatives. We sought to quantitatively describe the malleus and incus in a population not heretofore reported, with the following hypotheses in mind: 1) an ear's malleus and incus sizes are concordant; 2) a cranium's malleus and incus sizes have bilateral symmetry; 3) the sizes of the malleus and incus are unrelated to the mastoid-size indicator of childhood otitis media; and 4) second-branchial arch derivatives have more variability than do first-arch derivatives. We performed a postmortem material analysis of 41 adult crania without clinical otitis. The sizes of clinically normal mallei (eg, 21.2 to 30.7 mg) and incudes (eg, 24.4 to 37.4 mg) were varied. Concordance of malleus mass and incus mass was found. However, no relation of malleus and incus sizes with mastoid size was found. The variability of first-arch derivatives was similar to that of second-arch derivatives. Clinically normal mallei and incudes had masses and dimensions that varied even more than previously reported. Nevertheless, bilateral symmetry was exhibited, as was concordance of masses.


Intention to use sport concussion guidelines among community-level coaches and sports trainers.
Sporting bodies have developed guidelines for managing community-level players with suspected concussion in response to international consensus statements on concussion in sport. The purpose of this study was to examine the factors that influence the intended use of concussion guidelines among community-level coaches and sports trainers from two popular football codes in Australia: Australian football and rugby league. Cross-sectional survey. The survey, based on an extended theory of planned behaviour model, was completed by 183 Australian football coaches, 121 Australian football sports trainers, 171 rugby league coaches, and 142 rugby league sports trainers. Personal norms and self-efficacy were significant predictors of intention to use concussion guidelines, although the relationship between self-efficacy and intention was stronger among Australian football coaches than rugby league coaches. Analysis of the salient beliefs that underpin self-efficacy found that coaches, irrespective of football code, felt less familiar (χ(2)=25.70, p<0.001) and less experienced (χ(2)=31.56, p<0.001) than sports trainers in using the concussion guidelines. At the same time, Australian football personnel, irrespective of their team role, felt that they had insufficient time (χ(2)=8.04, p<0.01) and resources (χ(2)=12.31, p<0.001) to implement the concussion guidelines relative to rugby league personnel. Programmes aimed at increasing the intended use of sport concussion guidelines should focus on enhancing self-efficacy and leveraging personal norms. Increasing coaches' familiarity and experience in using the concussion guidelines would also be warranted, as would finding ways to overcome the perceived time and resource constraints identified among Australian football personnel.


Lessons from movement ecology for the return to work: Modeling contacts and the spread of COVID-19.
Human behavior (movement, social contacts) plays a central role in the spread of pathogens like SARS-CoV-2. The rapid spread of SARS-CoV-2 was driven by global human movement, and initial lockdown measures aimed to localize movement and contact in order to slow spread. Thus, movement and contact patterns need to be explicitly considered when making reopening decisions, especially regarding return to work. Here, as a case study, we consider the initial stages of resuming research at a large research university, using approaches from movement ecology and contact network epidemiology. First, we develop a dynamical pathogen model describing movement between home and work; we show that limiting social contact, via reduced people or reduced time in the workplace are fairly equivalent strategies to slow pathogen spread. Second, we develop a model based on spatial contact patterns within a specific office and lab building on campus; we show that restricting on-campus activities to labs (rather than labs and offices) could dramatically alter (modularize) contact network structure and thus, potentially reduce pathogen spread by providing a workplace mechanism to reduce contact. Here we argue that explicitly accounting for human movement and contact behavior in the workplace can provide additional strategies to slow pathogen spread that can be used in conjunction with ongoing public health efforts.


Dynamics of levitated objects in acoustic vortex fields.
Acoustic levitation in gaseous media provides a tool to process solid and liquid materials without the presence of surfaces such as container walls and hence has been used widely in chemical analysis, high-temperature processing, drop dynamics and bioreactors. To date high-density objects can only be acoustically levitated in simple standing-wave fields. Here we demonstrate the ability of a small number of peripherally placed sources to generate acoustic vortex fields and stably levitate a wide range of liquid and solid objects. The forces exerted by these acoustic vortex fields on a levitated water droplet are observed to cause a controllable deformation of the droplet and/or oscillation along the vortex axis. Orbital angular momentum transfer is also shown to rotate a levitated object rapidly and the rate of rotation can be controlled by the source amplitude. We expect this research can increase the diversity of acoustic levitation and expand the application of acoustic vortices.


Covalent organic frameworks as multifunctional materials for chemical detection.
Sensitive and selective detection of chemical and biological analytes is critical in various scientific and technological fields. As an emerging class of multifunctional materials, covalent organic frameworks (COFs) with their unique properties of chemical modularity, large surface area, high stability, low density, and tunable pore sizes and functionalities, which together define their programmable properties, show promise in advancing chemical detection. This review demonstrates the recent progress in chemical detection where COFs constitute an integral component of the achieved function. This review highlights how the unique properties of COFs can be harnessed to develop different types of chemical detection systems based on the principles of chromism, luminescence, electrical transduction, chromatography, spectrometry, and others to achieve highly sensitive and selective detection of various analytes, ranging from gases, volatiles, ions, to biomolecules. The key parameters of detection performance for target analytes are summarized, compared, and analyzed from the perspective of the detection mechanism and structure-property-performance correlations of COFs. Conclusions summarize the current accomplishments and analyze the challenges and limitations that exist for chemical detection under different mechanisms. Perspectives on how future directions of research can advance the COF-based chemical detection through innovation in novel COF design and synthesis, progress in device fabrication, and exploration of novel modes of detection are also discussed.


Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions.
Does IVF/ICSI have an effect on the epigenetic regulation of the human placenta? We found a reduced DNA methylation level at the H19 and MEST differentially methylated regions (DMRs), and an increased RNA expression of H19 in placentas from pregnancies conceived by IVF/ICSI when compared with placentas from spontaneous conception. Changes in fetal environment are associated with adverse health outcomes. The placenta is pivotal for intrauterine environment. Animal studies show that epigenetic regulation plays an important role in these environment-induced phenotypic effects. Also, the preimplantation embryo environment affects birthweight as well as the risk of chronic adult diseases. Epigenetic processes are sensitive to the environment, especially during the period around conception. Placental tissue was collected from 35 spontaneously conceived pregnancies and 35 IVF/ICSI (5 IVF, 30 ICSI) derived pregnancies. We quantitatively analysed the DNA methylation patterns of a number of consecutive CpGs in the core regions of DMRs and other regulatory regions of imprinted genes, since these are involved in placental and fetal growth and development. By using pyrosequencing, the DNA methylation at seven germline-derived primary DMRs was analysed quantitatively. Five of these are maternally methylated (MEST isoform α and β, PEG3, KCNQ1OT1 and SNRPN) and two are paternally methylated [H19 DMR and the intergenic region between DLK1 and MEG3 (IG-DMR)]. The post-fertilization-derived secondary DMRs, IGF2 (DMR0 and 2) and IG-DMR (CG7, also called MEG3 DMR), and the MEG3 promoter region were examined as well. In case of differential methylation between the two groups, the effect on gene expression was assessed by quantitative real-time PCR. Both the promoter region of MEST isoform α and β and the 6th CTCF binding site within the H19 DMR were significantly hypomethylated in the IVF/ICSI group. The phenomenon was consistently observed over all CpG sites analysed and not restricted to single CpG sites. The other primary and secondary DMRs were not affected. Expression of H19 was increased in the IVF/ICSI group, while that of IGF2 and MEST remained similar. In the IVF/ICSI group, mostly ICSI pregnancies were investigated. The ICSI technique or male subfertility could be a confounding factor. Therefore, our results are less generalizable to IVF pregnancies. The clinical effects of the observed placental hypomethylations on the developmental programming of the IVF/ICSI progeny, if any, are as yet unknown. Whether the hypomethylation is an adaptation of the placenta to maintain fetal supply and ameliorate the effects of environmental cues, or whether it is a deregulation leading to deranged developmental programming with or without increased vulnerability for disease, consistent with the developmental origins of health and disease hypothesis, needs further investigation. Partly funded by an unrestricted research grant by Organon BV (now MSD BV) without any role in study design, data collection and analysis, or preparation of the manuscript. No conflict of interests to declare. Dutch Trial Registry (NTR) number 1298.


The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders.
Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.