Low-dose broad-band UVA in morphea using a new method for evaluation.
Until recently, various therapies for localized scleroderma have been used with limited success. Recently, phototherapy, with or without psoralen, was proposed as a successful treatment modality. The aim of this study was to evaluate the effect of broad-band low-dose ultraviolet A (UVA) phototherapy in patients with localized scleroderma, using a new method for evaluation. Twelve patients complaining of morphea were exposed to UVA irradiation at a dose of 20 J/cm2 3 times per week for 20 sessions. Selected covered plaques served as internal controls. The efficacy of therapy was judged clinically by sequential inspection and palpation. In biopsy specimens from exposed and covered plaques stained with hematoxylin and eosin (H & E) and Masson trichrome stains, the concentration of collagen per dermal surface area was measured with the use of a computerized image analyzer. All patients reported remarkable softening of skin lesions, confirmed by sequential palpatory assessment. A significant reduction in the mean concentration of collagen per surface area was detected in the plaques exposed to UVA (the P value being 0.007, P<0.01), whereas in the covered plaques the difference was not statistically significant (the P value being 0.10, P>0.05). The conclusion is that low-dose broad-band UVA phototherapy is a very effective and safe treatment modality for localized scleroderma.


Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.
The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.


Does cranberry extract reduce antibiotic use for symptoms of acute uncomplicated urinary tract infections (CUTI)? Protocol for a feasibility study.
Consultations in primary care for symptoms of urinary tract infections (UTIs) are common and patients are frequently treated with antibiotics. Given increasing antimicrobial resistance, there has been interest in non-antibiotic treatment options for common infections. One such option is the use of cranberry extract to treat symptoms attributable to UTIs. A target of 45 women consulting in primary care, with symptoms suggestive of an uncomplicated UTI for whom the practitioner would normally prescribe antibiotics, will be randomised to receive one of three treatment approaches: (1) immediate prescription for antibiotics; (2) immediate prescription for antibiotics plus a 7-day course of cranberry capsules and (3) cranberry capsules plus a delayed prescription for antibiotics to be used in case their symptoms do not get better, or get worse. Follow-up will be by daily rating of symptoms and recording of treatments used for 2 weeks in an online symptom diary. Interviews will be conducted with around 10-15 study participants, as well as with around 10-15 women who have experienced a UTI but have not been approached to take part in the study. Both groups will be asked about their experience of having a UTI, their thoughts on non-antibiotic treatments for UTIs and their thoughts on, or experience of, the feasibility trial. The primary objective is to assess the feasibility of undertaking a full trial in primary care of the effectiveness of cranberry extract to reduce antibiotic use for symptoms of acute uncomplicated UTI. The secondary objective is to conduct a preliminary assessment of the extent to which cranberry might reduce antibiotic use and symptom burden. This feasibility study with embedded interviews will inform the planning and sample size calculation of an adequately powered trial to definitively determine whether cranberry helps to alleviate the symptoms of acute uncomplicated UTIs in women and whether it can safely reduce antibiotic use. ISRCTN registry, ID: 10399299. Registered on 24 January 2019.


Evidence for a pseudogap in underdoped Bi{2}Sr_{2}CaCu{2}O{8+delta} and YBa2Cu3O6.50 from in-plane optical conductivity measurements.
The real part of the in-plane optical self-energy data in underdoped Bi_{2}Sr_{2}CaCu_{2}O_{8+delta} (Bi-2212) and ortho II YBa2Cu3O6.5 contains new and important information on the pseudogap. Using a theoretical model approach, a major new finding is that states lost below the pseudogap Delta_{pg} are accompanied by a pileup of states just above this energy. The pileup along with a sharp mode in the bosonic spectral function leads to an unusually rapid increase in the optical scattering rate as a function of frequency and a characteristically sloped peak in the real part of the optical self-energy. These features are not found in optimally doped and overdoped samples and represent the clearest signature so far in the in-plane optical conductivity of the opening of a pseudogap.


M4T: a comparative protein structure modeling server.
Multiple Mapping Method with Multiple Templates (M4T) (http://www.fiserlab.org/servers/m4t) is a fully automated comparative protein structure modeling server. The novelty of M4T resides in two of its major modules, Multiple Templates (MT) and Multiple Mapping Method (MMM). The MT module of M4T selects and optimally combines the sequences of multiple template structures through an iterative clustering approach that takes into account the 'unique' contribution of each template, its sequence similarity to other template sequences and to the target sequences, and the quality of its experimental resolution. MMM module is a sequence-to-structure alignment method that is aimed at improving the alignment accuracy, especially at lower sequence identity levels. The current implementation of MMM takes inputs from three profile-to-profile-based alignment methods and iteratively compares and ranks alternatively aligned regions according to their fit in the structural environment of the template structure. The performance of M4T was benchmarked on CASP6 comparative modeling target sequences and on a larger independent test set and showed a favorable performance to current state-of-the-art methods.


O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents.
The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.


Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.
Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.


HaloTag is an effective expression and solubilisation fusion partner for a range of fibroblast growth factors.
The production of recombinant proteins such as the fibroblast growth factors (FGFs) is the key to establishing their function in cell communication. The production of recombinant FGFs in E. coli is limited, however, due to expression and solubility problems. HaloTag has been used as a fusion protein to introduce a genetically-encoded means for chemical conjugation of probes. We have expressed 11 FGF proteins with an N-terminal HaloTag, followed by a tobacco etch virus (TEV) protease cleavage site to allow release of the FGF protein. These were purified by heparin-affinity chromatography, and in some instances by further ion-exchange chromatography. It was found that HaloTag did not adversely affect the expression of FGF1 and FGF10, both of which expressed well as soluble proteins. The N-terminal HaloTag fusion was found to enhance the expression and yield of FGF2, FGF3 and FGF7. Moreover, whereas FGF6, FGF8, FGF16, FGF17, FGF20 and FGF22 were only expressed as insoluble proteins, their N-terminal HaloTag fusion counterparts (Halo-FGFs) were soluble, and could be successfully purified. However, cleavage of Halo-FGF6, -FGF8 and -FGF22 with TEV resulted in aggregation of the FGF protein. Measurement of phosphorylation of p42/44 mitogen-activated protein kinase and of cell growth demonstrated that the HaloTag fusion proteins were biologically active. Thus, HaloTag provides a means to enhance the expression of soluble recombinant proteins, in addition to providing a chemical genetics route for covalent tagging of proteins.


In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis.
In the adult mammalian brain, new neurons and glia are continuously generated but molecular factors regulating their differentiation and lineage relationships are largely unknown. We show that Ascl1, a bHLH (basic helix-loop-helix) transcription factor, transiently labels neuronal and oligodendrocyte precursors in the adult brain. Using in vivo lineage tracing with inducible Cre recombinase, we followed the maturation of these precursors in four distinct regions. In the hippocampus, Ascl1 mostly marks type-2a progenitor cells with some late stage type-1 stem cells. Thirty days after Ascl1 expression, although a majority of the cells matured to granule neurons, a few cells remained as immature progenitors. By 6 months, however, essentially all Ascl1 lineage cells were granule neurons. In contrast, in the olfactory bulb neuronal lineage, Ascl1 is restricted to transit amplifying cells, and by 30 d all cells matured into GABAergic interneurons. Ascl1 also broadly marks oligodendrocyte precursors in subcortical gray and white matter regions. In the corpus callosum, Ascl1 defines a ventral layer of early oligodendrocyte precursors that do not yet express other early markers of this lineage like PDGFRalpha and Olig2. By 30 d, most had transitioned to mature oligodendrocytes. In contrast, Ascl1 expressing oligodendrocyte precursors in gray matter already coexpressed the early oligodendrocyte markers, but by 30 d they mostly remained as precursors. Our results reveal that Ascl1 is a common molecular marker of early progenitors of both neurons and oligodendrocytes in the adult brain, and these Ascl1 defined progenitors mature with distinct dynamics in different brain regions.


On the importance of cognitive profiling: A graphical modelling analysis of domain-specific and domain-general deficits after stroke.
Cognitive problems following stroke are typically analysed using either short but relatively uninformative general tests or through detailed but time consuming tests of domain specific deficits (e.g., in language, memory, praxis). Here we present an analysis of neuropsychological deficits detected using a screen designed to fall between other screens by being 'broad' (testing multiple cognitive abilities) but 'shallow' (sampling the abilities briefly, to be time efficient) - the BCoS. Assessment using the Birmingham Cognitive Screen (BCoS) enables the relations between 'domain specific' and 'domain general' cognitive deficits to be evaluated as the test generates an overall cognitive profile for individual patients. We analysed data from 287 patients tested at a sub-acute stage of stroke (<3 months). Graphical modelling techniques were used to investigate the associative structure and conditional independence between deficits within and across the domains sampled by BCoS (attention and executive functions, language, memory, praxis and number processing). The patterns of deficit within each domain conformed to existing cognitive models. However, these within-domain patterns underwent substantial change when the whole dataset was modelled, indicating that domain-specific deficits can only be understood in relation to linked changes in domain-general processes. The data point to the importance of using over-arching cognitive screens, measuring domain-general as well as domain-specific processes, in order to account for neuropsychological deficits after stroke. The paper also highlights the utility of using graphical modelling to understand the relations between cognitive components in complex datasets.


Setting the pace: new insights into central pattern generator interactions in box jellyfish swimming.
Central Pattern Generators (CPGs) produce rhythmic behaviour across all animal phyla. Cnidarians, which have a radially symmetric nervous system and pacemaker centres in multiples of four, provide an interesting comparison to bilaterian animals for studying the coordination between CPGs. The box jellyfish Tripedalia cystophora is remarkable among cnidarians due to its most elaborate visual system. Together with their ability to actively swim and steer, they use their visual system for multiple types of behaviour. The four swim CPGs are directly regulated by visual input. In this study, we addressed the question of how the four pacemaker centres of this radial symmetric cnidarian interact. We based our investigation on high speed camera observations of the timing of swim pulses of tethered animals (Tripedalia cystophora) with one or four rhopalia, under different simple light regimes. Additionally, we developed a numerical model of pacemaker interactions based on the inter pulse interval distribution of animals with one rhopalium. We showed that the model with fully resetting coupling and hyperpolarization of the pacemaker potential below baseline fitted the experimental data best. Moreover, the model of four swim pacemakers alone underscored the proportion of long inter pulse intervals (IPIs) considerably. Both in terms of the long IPIs as well as the overall swim pulse distribution, the simulation of two CPGs provided a better fit than that of four. We therefore suggest additional sources of pacemaker control than just visual input. We provide guidelines for future research on the physiological linkage of the cubozoan CPGs and show the insight from bilaterian CPG research, which show that pacemakers have to be studied in their bodily and nervous environment to capture all their functional features, are also manifest in cnidarians.


Single Pathogen Challenge with Agents of the Bovine Respiratory Disease Complex.
Bovine respiratory disease complex (BRDC) is an important cause of mortality and morbidity in cattle; costing the dairy and beef industries millions of dollars annually, despite the use of vaccines and antibiotics. BRDC is caused by one or more of several viruses (bovine respiratory syncytial virus, bovine herpes type 1 also known as infectious bovine rhinotracheitis, and bovine viral diarrhea virus), which predispose animals to infection with one or more bacteria. These include: Pasteurella multocida, Mannheimia haemolytica, Mycoplasma bovis, and Histophilus somni. Some cattle appear to be more resistant to BRDC than others. We hypothesize that appropriate immune responses to these pathogens are subject to genetic control. To determine which genes are involved in the immune response to each of these pathogens it was first necessary to experimentally induce infection separately with each pathogen to document clinical and pathological responses in animals from which tissues were harvested for subsequent RNA sequencing. Herein these infections and animal responses are described.


Mesoporous semiconducting TiO2 with rich active sites as a remarkable substrate for surface-enhanced Raman scattering.
Recently, surface-enhanced Raman scattering (SERS) research based on semiconductor TiO2 has received increasing attention. However, the practical application of TiO2 SERS-active substrates has been hampered due to their lower surface performance and detection sensitivity. Here we report a new strategy to enhance the SERS activity of TiO2 nanoparticles (NPs) by means of formation of a mesoporous framework via reductive calcination of polymer coated nanocrystals. The 4-mercaptobenzoic acid (4-MBA) probe molecules on the mesoporous TiO2 substrate exhibit larger SERS enhancement compared with that on the ordinary TiO2 NP substrate; this considerable SERS enhancement mainly stems from the contributions of rich surface active sites of mesoporous TiO2, which can provide more effective adsorption sites for the molecules and promote the charge transfer between the substrate and the adsorbed molecule, and thus remarkably enhance SERS signals. On the mesoporous TiO2, a detection limit of 4-MBA as low as 1 × 10-8 mol L-1 can be achieved, which is the highest sensitivity among those reported for semiconducting substrates and even comparable with those of noble metal substrates. And, it is proved that the mesoporous TiO2 substrates are characterized by high stability and self-cleaning properties, and can be repeatedly used in SERS detection without losing their activity.


Deposition of radiocesium on the river flood plains around Fukushima.
The environment in the area around Fukushima Daiichi Nuclear Power Plant has been contaminated by widely deposited significant amount of radioactive materials, which were released to the atmosphere caused by the Fukushima Daiichi Nuclear Power Plant accident due to the Great East Japan Earthquake, which occurred on March 11, 2011. The radiocesium released in the accident mainly affects radiation dose in the environment. Decontamination work in the contaminated area except a mountain forests has been conducted to decrease the radiation dose. However, there are concerns that the redistribution of this radiation due to water discharge will occur due to the resulting transport of radiocesium. In particular, the deposition of soil particles containing radiocesium on the flood plains in the downstream areas of Fukushima's rivers can potentially increase the local radiation dose. Therefore, it is important to understand the influence of the deposition behavior of radiocesium on the radiation dose. Investigations of rivers have been performed to enhance the understanding of the mechanisms by which radiocesium is deposited on these flood plains. It was found that the spatial distribution of the radiocesium concentration on the flood plain along the river is heterogeneous with a dependence on the depositional condition and that the number of points with high air dose rates is limited. In detail, the radiocesium concentration and air dose rates in flood channels are higher than those at the edges of the river channels. Based on these heterogeneity and hydrological events, the deposition and transport mechanisms of the radiocesium due to water discharge at rivers were also interpreted, and a conceptual model was constructed.


Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation.
To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0-18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted.


Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion.
Neuropathic pain remains a pressing clinical problem. Here, we demonstrate that a local, intrathecal (i.t.) injection of bone marrow stromal cells (BMSCs) following lumbar puncture alleviates early- and late-phase neuropathic pain symptoms, such as allodynia and hyperalgesia, for several weeks in murine chronic constriction injury (CCI) and spared nerve injury models. Moreover, i.t. BMSCs reduced CCI-induced spontaneous pain and axonal injury of dorsal root ganglion (DRG) neurons and inhibited CCI-evoked neuroinflammation in DRGs and spinal cord tissues. BMSCs secreted TGF-β1 into the cerebrospinal fluid, and neutralization of TGF-β1, but not IL-10, reversed the analgesic effect of BMSCs. Conversely, i.t. administration of TGF-β1 potently inhibited neuropathic pain. TGF-β1 acted as a powerful neuromodulator and rapidly (within minutes) suppressed CCI-evoked spinal synaptic plasticity and DRG neuronal hyperexcitability via TGF-β receptor 1-mediated noncanonical signaling. Finally, nerve injury upregulated CXCL12 in lumbar L4-L6 DRGs, and this upregulation caused migration of i.t.-injected BMSCs to DRGs through the CXCL12 receptor CXCR4, which was expressed on BMSCs. BMSCs that migrated from the injection site survived at the border of DRGs for more than 2 months. Our findings support a paracrine mechanism by which i.t. BMSCs target CXCL12-producing DRGs to elicit neuroprotection and sustained neuropathic pain relief via TGF-β1 secretion.


An application of pain rating scales in geriatric patients.
This study examined the applicability of three different pain rating scales, the Visual Analogue Scale (VAS), the Graphic Rating Scale (GRS) and the Numeric Rating Scale (NRS), in geriatric patients. Data collection was performed in a geriatric clinic at a university hospital. A structured interview was conducted with 167 patients (mean age = 80.5 years). Patients rated their current experience of pain twice with a 5-minute pause in-between on the VAS, GRS and NRS, and were then asked if they experienced pain, ache or hurt (PAH) or other symptoms. The correlations were high and significant both between the ratings of the VAS, GRS and NRS (r = 0.78-0.92; p < 0.001) (alternative-forms reliability), and between the test and retesting (r = 0.75-r = 0.83; p < 0.001) (test-retest reliability). A logistic regression analysis showed that the probability to accomplish a rating on the pain scales decreased with advancing age of the patient, and this was especially marked for the VAS. The probability of agreement between the patients' ratings of pain and the verbal report of PAH tended to decrease with advancing age; this was especially so for the VAS. Patients who verbally denied PAH but reported pain on the scales rated it significant lower (p < 0.001) than those who verbally reported PAH and rated the pain as well. Eighteen percent of patients who denied pain but rated a pain experience verbally expressed suffering or distress. The study suggests that pain rating scales such as the VAS, GRS and NRS can be used to evaluate pain experience in geriatric patients. However, agreement between verbally expressed experience of PAH, and the rated experience of pain tended to decrease with advancing age. This indicates that the pain-evaluating process will be substantially improved by an additional penetration supported by a wide variety of expression of hurt, ache, pain, discomfort and distress.


Radiation exposure in endovascular surgery of the head and neck.
To evaluate the radiation risk to the operator and the patient during endovascular surgery of the head and neck. The dose was measured using thermoluminescence dosimeters attached at the body surface of the operator and the patient during 15 endovascular surgeries (3 for arteriovenous malformation, 8 for dural arteriovenous fistulas, and 4 for other disorders of the head and neck). The dose was measured at seven sites on the operator and at five sites on the patient. The mean number of digital subtraction angiography studies and fluoroscopy time were 21 +/- 10 and 73 +/- 24 minutes, respectively. The equivalent dose range at each site in the operator was 0.12 to 0.88 mSv (glabella), 0.06 to 1.1 and 0 to 0.09 mSv (neck, outside and inside the protector, respectively), 0 to 0.20 mSv (left should, inside the protector), 0.09 to 1.99 mSv (left arm), 0.05 to 3.55 mSv (left hand), and 0 to 0.49 mSv (pubis, inside the protector). Those in the patients were 3.1 to 136 mSv (glabella), 13 to 5441 mSv (right temporal area), 4 to 186 mSv (left temporal area), 0.1 to 51 mSv (neck), and 0 to 0.62 mSv (pubis). The total doses at the operator's eyes and left hand during the course of a year may exceed the dose limits recommended by the International Commission on Radiological Protection. Operators should wear not only body protectors, but also thyroid protectors and lead glass spectacles. The equivalent dose at the right temporal area of the patient may exceed the deterministic dose for transient erythema or alopecia of the skin even in one endovascular procedure.


Real-time imaging of methane gas leaks using a single-pixel camera.
We demonstrate a camera which can image methane gas at video rates, using only a single-pixel detector and structured illumination. The light source is an infrared laser diode operating at 1.651μm tuned to an absorption line of methane gas. The light is structured using an addressable micromirror array to pattern the laser output with a sequence of Hadamard masks. The resulting backscattered light is recorded using a single-pixel InGaAs detector which provides a measure of the correlation between the projected patterns and the gas distribution in the scene. Knowledge of this correlation and the patterns allows an image to be reconstructed of the gas in the scene. For the application of locating gas leaks the frame rate of the camera is of primary importance, which in this case is inversely proportional to the square of the linear resolution. Here we demonstrate gas imaging at ~25 fps while using 256 mask patterns (corresponding to an image resolution of 16×16). To aid the task of locating the source of the gas emission, we overlay an upsampled and smoothed image of the low-resolution gas image onto a high-resolution color image of the scene, recorded using a standard CMOS camera. We demonstrate for an illumination of only 5mW across the field-of-view imaging of a methane gas leak of ~0.2 litres/minute from a distance of ~1 metre.


Role of circulating tumor cell detection in differentiating tumor recurrence from treatment necrosis of brain gliomas.
Differentiating treatment necrosis from tumor recurrence poses a diagnostic conundrum for many clinicians in neuro-oncology. To investigate the potential role of circulating tumor cells (CTCs) detection in differentiating tumor recurrence and treatment necrosis in brain gliomas, we retrospectively analyzed the data of 22 consecutive patients with tumor totally removed and new enhancing mass lesion(s) showed on MRI after initial radiotherapy. The 22 patients were finally classified into tumor recurrence group (n = 10) and treatment necrosis group (n = 12), according to evidence from the clinical course (n = 11) and histological confirmation (n = 11). All 22 patients received CTCs detection, and DSC-MRP and 11C-MET-PET were performed on 20 patients (90.9%) and 17patients (77.3%) respectively. The data of the diagnosis efficacy to differentiate the two lesions by CTC detection, MPR and PET were analyzed by ROC analysis. The mean CTCs counts were significantly higher in the tumor recurrence group (6.10 ± 3.28) compared to the treatment necrosis group (1.08 ± 2.54, p < 0.001). The ROC curve showed that an optimized cell count threshold of 2 had 100% sensitivity and 91.2% specificity with AUC = 0.933 to declare tumor recurrence. The diagnostic efficacy of CTC detection was superior to rCBV of DSC-MRP and rSUVmax in MET-PET. Furthermore, we observed that CTCs detection could have a potential role in predicting tumor recurrence in one patient. Our research results preliminarily showed the potential value of CTC detection in differentiating treatment necrosis from tumor recurrence in brain gliomas, and is worthy of further confirmation with large samples involved.


Anemia in Critically Ill Patients With Acute Respiratory Distress Syndrome and Posthospitalization Physical Outcomes.
Anemia is common during critical illness and often persists after hospital discharge; however, its potential association with physical outcomes after critical illness is unclear. Our objective was to assess the associations between hemoglobin at intensive care unit (ICU) and hospital discharge with physical status at 3-month follow-up in acute respiratory distress syndrome (ARDS) survivors. This is a secondary analysis of a multisite prospective cohort study of 195 mechanically ventilated ARDS survivors from 13 ICUs at 4 teaching hospitals in Baltimore, Maryland. Multivariable regression was utilized to assess the relationships between ICU and hospital discharge hemoglobin concentrations with measures of physical status at 3 months, including muscle strength (Medical Research Council sumscore), exercise capacity (6-minute walk distance [6MWD]), and self-reported physical functioning (36-Item Short-Form Health Survey [SF-36v2] Physical Function score and Activities of Daily Living [ADL] dependencies). Median (interquartile range) hemoglobin concentrations at ICU and hospital discharge were 9.5 (8.5-10.7) and 10.0 (9.0-11.2) g/dL, respectively. In multivariable regression analyses, higher ICU discharge hemoglobin concentrations (per 1 g/dL) were associated with greater 3-month 6MWD mean percent of predicted (3.7% [95% confidence interval 0.8%-6.5%]; P = .01) and fewer ADL dependencies (-0.2 [-0.4 to -0.1]; P = .02), but not with percentage of maximal muscle strength (0.7% [-0.9 to 2.3]; P = .37) or SF-36v2 normalized Physical Function scores (0.8 [-0.3 to 1.9]; P = .15). The associations of physical outcomes and hospital discharge hemoglobin concentrations were qualitatively similar, but none were statistically significant. In ARDS survivors, higher hemoglobin concentrations at ICU discharge, but not hospital discharge, were significantly associated with improved exercise capacity and fewer ADL dependencies. Future studies are warranted to further assess these relationships.


Heart failure with preserved left ventricular systolic function: a hospital cohort study.
To investigate how patients with heart failure with preserved left ventricular systolic function (LVSF) compare with patients with reduced LVSF. Cohort study. Urban university hospital. 528 index emergency admissions with heart failure during the year 2000. Information on LVSF and follow up was available for 445 (84%) of these patients. 130 (29%) patients had preserved LVSF (defined as an ejection fraction > 40%). The median follow up was 814 days (range 632-978 days). The average (SD) age was 72 (13) years. Women accounted for 62% and 45% of patients with preserved and reduced LVSF, respectively (p = 0.001). Patients with preserved LVSF (compared with those with reduced LVSF) had a higher prevalence of left ventricular hypertrophy (56% v 29%) and aortic valve disease (mean gradient > 20 mm Hg; 31% v 9%). Fewer patients with preserved LVSF received an angiotensin converting enzyme inhibitor (65% v 78%, p = 0.008) or spironolactone (12% v 21%, p = 0.027). Anaemia tended to occur more often in patients with preserved LVSF than in those with reduced LVSF (43% v 33% for women, p = 0.12; 59% v 49% for men, p = 0.22). There was a similarly high prevalence of significant renal dysfunction in both groups (estimated glomerular filtration rate < 60 ml/min/1.73 m2 in 68% with preserved and 64% with reduced LVSF, p = 0.40). Mortality was similar in both groups (preserved versus reduced 51 (39%) v 132 (42%), p = 0.51). Compared with patients with reduced LVSF, patients with preserved LVSF tended to have a lower risk of death or hospital admission for heart failure (56 (42%) v 165 (53%), p = 0.072) but a similar rate of death or readmission for any reason. Patients with preserved LVSF had more co-morbid problems than those with reduced LVSF; however, prognosis was similar for both groups.


The small GTPase Rheb is required for spermatogenesis but not oogenesis.
The process of germ cell development is under the tight control of various signaling pathways, among which the PI3K-Akt-mTOR pathway is of critical importance. Previous studies have demonstrated sex-specific roles for several components of this pathway. In the current study, we aimed to evaluate the role of Rheb, a member of the small GTPase superfamily and a critical component for mTORC1 activation, in male and female gametogenesis. The function of Rheb in development and the nervous system has been extensively studied, but little is known about its role in the germ line. We have exploited genetic approaches in the mouse to study the role of Rheb in the germ line and have identified an essential role in spermatogenesis. Conditional knockout (cKO) of Rheb in the male germ line resulted in severe oligoasthenoteratozoospermia and male sterility. More detailed phenotypic analyses uncovered an age-dependent meiotic progression defect combined with subsequent abnormalities in spermiogenesis as evidenced by abnormal sperm morphology. In the female, however, germ-cell specific inactivation of Rheb was not associated with any discernible abnormality; these cKO mice were fertile with morphologically unremarkable ovaries, normal primordial follicle formation, and subsequent follicle maturation. The absence of an abnormal ovarian phenotype is striking given previous studies demonstrating a critical role for the mTORC1 pathway in the maintenance of primordial follicle pool. In conclusion, our findings demonstrate an essential role of Rheb in diverse aspects of spermatogenesis but suggest the existence of functionally redundant factors that can compensate for Rheb deficiency within oocytes.


Quantitative CT Analysis of Diffuse Lung Disease.
Quantitative analysis of thin-section CT of the chest has a growing role in the clinical evaluation and management of diffuse lung diseases. This heterogeneous group includes diseases with markedly different prognoses and treatment options. Quantitative tools can assist in both accurate diagnosis and longitudinal management by improving characterization and quantification of disease and increasing the reproducibility of disease severity assessment. Furthermore, a quantitative index of disease severity may serve as a useful tool or surrogate endpoint in evaluating treatment efficacy. The authors explore the role of quantitative imaging tools in the evaluation and management of diffuse lung diseases. Lung parenchymal features can be classified with threshold, histogram, morphologic, and texture-analysis-based methods. Quantitative CT analysis has been applied in obstructive, infiltrative, and restrictive pulmonary diseases including emphysema, cystic fibrosis, asthma, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, connective tissue-related interstitial lung disease, and combined pulmonary fibrosis and emphysema. Some challenges limiting the development and practical application of current quantitative analysis tools include the quality of training data, lack of standard criteria to validate the accuracy of the results, and lack of real-world assessments of the impact on outcomes. Artifacts such as patient motion or metallic beam hardening, variation in inspiratory effort, differences in image acquisition and reconstruction techniques, or inaccurate preprocessing steps such as segmentation of anatomic structures may lead to inaccurate classification. Despite these challenges, as new techniques emerge, quantitative analysis is developing into a viable tool to supplement the traditional visual assessment of diffuse lung diseases and to provide decision support regarding diagnosis, prognosis, and longitudinal evaluation of disease. ©RSNA, 2019.


Modulation of neural stereoscopic processing in primate area V1 by the viewing distance.
Accurate binocular depth perception requires information about both stereopsis (relative depth) and distance (absolute depth). It is unclear how these two types of information are integrated in the visual system. In alert, behaving monkeys the responsiveness of a large majority of neurons in the primary visual cortex (area V1) was modulated by the viewing distance. This phenomenon affected particularly disparity-related activity and background activity and was not dependent on the pattern of retinal stimulation. Therefore, extraretinal factors, probably related to ocular vergence or accommodation, or both, can affect processing early in the visual pathway. Such modulations could be useful for (i) judging true distance and (ii) scaling retinal disparity to give information about three-dimensional shape.


Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches.
Calcific uremic arteriolopathy (CUA)/calciphylaxis is an important cause of morbidity and mortality in patients with chronic kidney disease requiring renal replacement. Once thought to be rare, it is being increasingly recognized and reported on a global scale. The uremic milieu predisposes to multiple metabolic toxicities including increased levels of reactive oxygen species and inflammation. Increased oxidative stress and inflammation promote this arteriolopathy by adversely affecting endothelial function resulting in a prothrombotic milieu and significant remodeling effects on vascular smooth muscle cells. These arteriolar pathological effects include intimal hyperplasia, inflammation, endovascular fibrosis and vascular smooth muscle cell apoptosis and differentiation into bone forming osteoblast-like cells resulting in medial calcification. Systemic factors promoting this vascular condition include elevated calcium, parathyroid hormone, and hyperphosphatemia with consequent increases in the calcium x phosphate product. The uremic milieu contributes to a marked increased in upstream reactive oxygen species - oxidative stress and subsequent downstream increased inflammation, in part, via activation of the nuclear transcription factor NFkappaB and associated downstream cytokine pathways. Consitutive anti-calcification proteins such as Fetuin-A and matrix GLA proteins and their signaling pathways may be decreased, which further contributes to medial vascular calcification. The resulting clinical entity is painful, debilitating and contributes to the excess morbidity and mortality associated with chronic kidney disease and end stage renal disease. These same histopathologic conditions also occur in patients without uremia and therefore, the term calcific obliterative arteriolopathy could be utilized in these conditions.


Phase I trial of intraperitoneal docetaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity: dose-limiting toxicity and pharmacokinetics.
The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Tumor types included gastric adenocarcinoma (n=7), ovarian cancer (n=4), other gastrointestinal primaries (n=3), and other cancers (n=7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m2 i.p. docetaxel of 3.14 and 6.33 microM.h (ranges, 1.02-5.88 and 3.97-12.70 microM. h), respectively; the mean peritoneal AUCs were 315 and 1063 microM.h (ranges, 250-373 and 239-2222 microM.h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m2 i.p. docetaxel were 0.46 and 0.66 microM, and the mean peak peritoneal concentrations at those doses were 59 and 81 microM, respectively. The median and mean pharmacological advantage calculations (AUCperitoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 microM (range, 0.2-1.6 microM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 microM was 31.2 h (range, 27-36.5 h). i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.


Experience of therapeutic plasma exchange in rheumatic diseases: Albumin may be a suitable substitute for plasma.
In this study, we aimed to assess the value of therapeutic plasma exchange (TPE) in the treatment of rheumatic diseases and compare the safety of different replacement fluids used in TPE. A total of 727 TPE procedures in 285 patients (57 males, 228 females; mean age: 39.7±15.4 years; range, 13 to 79 years) with rheumatic diseases between January 2011 and February 2019 were retrospectively analyzed. Data including demographic and clinical characteristics of the patients were recorded. Treatment response to TPE and adverse events were evaluated in all patients. Indications for TPE included 13 different disorders, with the majority being systemic lupus erythematosus (up to 50%). The mean number of TPE sessions was 2.55±1.00 per patient and the mean exchange plasma volume was 2,270±256 mL per session. Combined plasma and albumin was the most frequently used replacement fluid (69.5%), followed by albumin and plasma in 20.5% and 10.0% of episodes, respectively. Up to 73.7% (210/285) patients achieved clinical improvement after TPE treatment. Adverse events occurred in 15.1% (110/727) of all the procedures, and allergic reaction (34.5%) was the most common event. The overall incidence rate of complication was similar among the three types of replacement fluids (p=0.214). Based on our study results, TPE is an invasive, but safe, useful and, sometimes, essential tool with an acceptable risk/benefit ratio for most rheumatic diseases. Albumin can be used as a feasible substitute for plasma in case of shortage of blood resources.


Archive film defect detection and removal: an automatic restoration framework.
In this paper, we present an automatic restoration system targeting on dirt and blotches in digitized archive films. The system is composed of mainly two modules: defect detection and defect removal. In defect detection, we locate the defects by combing temporal and spatial information across a number of frames. An HMM is trained for normal observation sequences and then applied within a framework to detect defective pixels. The resulting defect maps are refined in a two-stage false alarm elimination process and then passed over to the defect removal procedure. A labelled (degraded) pixels is restored in a multiscale framework by first searching the optimal replacement in its dynamically generated, random walk based region of candidate pixel-exemplars and then updating all its features (intensity, motion and texture). Finally, the proposed system is compared against state-of-the-art methods to demonstrate improved accuracy in both detection and restoration using synthetic and real degraded image sequences.


Alcohol consumption is associated with reduced creatine levels in the hippocampus of older adults.
Besides its well established susceptibility to ageing, the hippocampus has also been shown to be affected by alcohol consumption. Proton spectroscopy (1H-MRS) of the hippocampus, particularly at high-field 7T MRI, may further our understanding of these associations. Here, we aimed to examine how hippocampal metabolites varied with age and alcohol consumption. Hippocampal metabolite spectra were acquired in 37 older adults using 7T 1H-MRS, from which we determined the absolute concentration of N-acetylaspartate (NAA), creatine, choline, myo-inositol, glutamate and glutamine. Thirty participants (mean age = 70.4 ± 4.7 years) also had self-reported data on weekly alcohol consumption. Total choline inversely correlated with age, although this did not survive multiple comparisons correction. Crucially, adults with a higher weekly alcohol consumption had significantly lower levels of creatine, suggesting a deficit in their hippocampal metabolism. These findings add to an increasing body of evidence linking alcohol to hippocampal function.


Comparing Assay Performance of ELISA and Chemiluminescence Immunoassay in Detecting Antibodies to Hepatitis B Surface Antigen.
Antibodies to Hepatitis B surface Antigen (Anti-HBs) levels are measured as markers for immune response to vaccination and in decision making for post-exposure prophylaxis against Hepatitis-B. Several immunoassay formats are used to measure Anti-HBs, thus carrying the possibility of variation in measured levels between different assays. This study compares the performance of Chemiluminescence Immunoassay (CLIA) against Enzyme-linked Immunosorbent Assay (ELISA) in measuring Anti-HBs titer by looking into concordance between the two test reports. To compare the agreement between ELISA and CLIA in measurement of Anti-HBs antibody titers. This prospective comparative study conducted at Kasturba Medical College, Manipal measured consecutive serum samples (69) sent for anti-HBs levels during May-June 2016 using both CLIA (Abbott Architect) and ELISA (Bio-Rad). Anti-HBs values of ≤10mIU/ml was considered as non-protective and >10mIU/ml as protective. The agreement between the tests in classifying the antibody titers as non-protective or protective was computed using Kappa coefficient, and the difference in individual titer values between the tests compared using Bland-Altman plot on SPSS (v.15). Out of the 69 samples analysed, 18 samples (26.1%) were of health-care personnel and remaining of patients. Agreement between ELISA and CLIA in identifying the antibody titers as protective and non-protective were 96.5% and 90.9% respectively, resulting in an agreement of 0.84. The coefficient-of-variation of ELISA and CLIA were 74.5% and 113.1%, respectively. Three value based discordant results were noted; two samples deemed protective by ELISA were reported as non-protective by CLIA. One non-protective titer by ELISA was reported as protective by CLIA. Analytical agreement is good between the two immunoassays. However there are some discrepancies in quantitative measurement. This may have been due the variation in the standard calibrators used in each assay. Though CLIA showed more variation in the values, it has the advantage of being automated test with low turn around time. Therefore, both the test methodologies can be reliably used in place of each other for detection of Anti- HBs titer.


A functional link between RuBisCO-like protein of Bacillus and photosynthetic RuBisCO.
The genomes of several nonphotosynthetic bacteria, such as Bacillus subtilis, and some Archaea include genes for proteins with sequence homology to the large subunit of ribulose bisphosphate carboxylase/oxygenase (RuBisCO). We found that such a RuBisCO-like protein (RLP) from B. subtilis catalyzed the 2,3-diketo-5-methylthiopentyl-1-phosphate enolase reaction in the methionine salvage pathway. A growth-defective mutant, in which the gene for this RLP had been disrupted, was rescued by the gene for RuBisCOfrom the photosynthetic bacterium Rhodospirillum rubrum. Thus, the photosynthetic RuBisCO from R. rubrum retains the ability to function in the methionine salvage pathway in B. subtilis.


[Prevalence of hospital infections in adult intensive care units in Argentina].
To present consolidated results from two surveys of nosocomial infection incidence, within the framework of Argentina's National Surveillance of Hospital Infections Program. Two editions of the National Survey on the Incidence of Hospital Infections in Argentina were used, those of 2004 and 2005. Of the 68 hospitals, 53 reported data from adult intensive care units (in 2004, 26 units; in 2005, 27), for a total of 359 patients (in 2004, 158 patients; in 2005, 201). The survey was designed as a multicenter, observational, cross-sectional, and descriptive study. Data analysis was performed with several statistics programs, combining and standardizing variables and both time periods in order to include all the hospitals from the two surveys. The prevalence of hospital infection among patients was 24%. Of the 127 illnesses, the most frequently occurring was pneumonia (43.3%), which in 85% of the cases was associated with use of a respirator. Primary bloodstream infections took second place, at 20.5%, with 61% of these cases being associated with a central catheter. Patients given respiratory therapy were at greatest risk (P < 0.001) of developing pneumonia; this was not observed among patients with central or urinary catheters. The prevalence of hospital infections, the distribution of primary infection sites, and the associations with risk factors were similar to those observed by other authors in several countries. It is important to understand the local and national issues prior to initiating a surveillance program. Surveys such as these, with a national scope and administered by the State, are one way of motivating, raising awareness, and building capacity.


Multicenter Study of Long-Term Safety of Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.
Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety. Subjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter. Among 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538-924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan (i.e., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%-1.1%/0.0%-0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%-2.0%/0.0%-1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred. No new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations. Open Label Extension of TEMPO 3:4, NCT02251275.


Impact of Patient Navigation Interventions on Timely Diagnostic Follow Up for Abnormal Cervical Screening.
As part of the Patient Navigation Research Program, we examined the effect of patient navigation versus usual care on timely diagnostic follow-up, defined as clinical management for women with cervical abnormalities within accepted time frames. Participants from four Patient Navigation Research Program centers were divided into low- and high-risk abnormality groups and analyzed separately. Low-risk participants (n = 2088) were those who enrolled with an initial Pap test finding of atypical squamous cells of undetermined significance (ASCUS) with a positive high-risk human papillomavirus (HPV) serotype, atypical glandular cells, or low-grade squamous intraepithelial lesion (LGSIL). High-risk participants were those with an initial finding of high-grade squamous intraepithelial lesion (HGSIL) (n = 229). A dichotomous outcome of timely diagnostic follow-up within 180 days was used for the low-risk abnormality group and timely diagnostic follow-up within 60 days for the high-risk group, consistent with treatment guidelines. A logistic mixed-effects regression model was used to evaluate the intervention effect using a random effect for study arm within an institution. A backward selection process was used for multivariable model building, considering the impact of each predictor on the intervention effect. Low-risk women in the patient navigation arm showed an improvement in the odds of timely diagnostic follow-up across all racial groups, but statistically significant effects were only observed in non-English-speaking Hispanics (OR 5.88, 95% CI 2.81-12.29). No effect was observed among high-risk women. These results suggest that patient navigation can improve timely diagnostic follow-up among women with low-risk cervical abnormalities, particularly in non-English-speaking Hispanic women.


How perceptions of a successful physician-scientist varies with gender and academic rank: toward defining physician-scientist's success.
Physician-scientists (the physician-scientist workforce) are aging, and there are too few physician-scientists in the pipeline to replace those who retire. Moreover, the pipeline is leaky because some trainees and junior physician-scientists choose other career paths. Significant attention has been directed toward patching the leaking pipeline, thereby increasing the quantity of physician-scientists. Less attention has been devoted to identifying and training more successful physician-scientists, thereby increasing the quality of the pool and making up for the attrition. Though all training programs strive to develop more successful graduates, there is no clear understanding of what constitutes predictors of future success. Identifying characteristics of success would enable those who recruit trainees-and later hire and fund physician-scientists-to make more informed decisions. It also could impact on the training, as it would be possible to focus on competencies that foster success. Predictors of success are therefore important. Prior to taking on this task, however, we must first define success for physician-scientists. To identify likely characteristics of success, we undertook a qualitative case study where 21 physician-scientists were interviewed to determine their perceptions of what constitutes a successful physician-scientist. Sixteen interviewees were selected based on convenience sampling, while the remaining five were selected based on the snowball effect. Interviews were transcribed and coded in Dedoose® and a qualitative analysis was conducted using an inductive approach to content analysis. There was considerable variation in their perceptions based on seniority and gender. Junior physician-scientists focused on metrics on which their promotion is based, e.g., publications and grants; senior physician-scientists focused on their legacy, e.g., contribution to the field and mentoring. Women were more likely to emphasize objective measures of success, like publications, while concurrently concentrating on relational skills, like networking, collaboration and public recognition. Men emphasized the impact of science and subjective characteristics like boldness, confidence and critical thinking. Clearly, physician-scientists are not working off of a uniform metric of success, thereby making their evaluation and remuneration a convoluted process, especially if those evaluating the physician-scientists are not of the same mind as to the definition of success.


Yoga as a complementary therapy for children and adolescents: a guide for clinicians.
Yoga is being used by a growing number of youth and adults as a means of improving overall health and fitness. There is also a progressive trend toward use of yoga as a mind-body complementary and alternative medicine intervention to improve specific physical and mental health conditions. To provide clinicians with therapeutically useful information about yoga, the evidence evaluating yoga as an effective intervention for children and adolescents with health problems is reviewed and summarized. A brief overview of yoga and yoga therapy is presented along with yoga resources and practical strategies for clinical practitioners to use with their patients. The majority of available studies with children and adolescents suggest benefits to using yoga as a therapeutic intervention and show very few adverse effects. These results must be interpreted as preliminary findings because many of the studies have methodological limitations that prevent strong conclusions from being drawn. Yoga appears promising as a complementary therapy for children and adolescents. Further information about how to apply it most effectively and more coordinated research efforts are needed.


Dental Emergency Practice Characteristics Among North Carolina Pediatric and General Dentists.
The purpose of this study was to assess after-hours practice characteristics of pediatric dentists (PDs) and general dentists (GDs) and determine how patients-of-record obtain after-hours emergency dental care. A 29-item survey was electronically distributed to PDs and GDs in North Carolina in September 2014. Demographics and after-hours emergency practice characteristics were assessed. Survey respondents were subsequently called after-hours to validate reported after-hours emergency protocol. Descriptive and bivariate statistics compared responses from PDs and GDs. Concordance between survey and telephone responses was analyzed. Eighty-six (46 percent) PDs and 1,199 (36 percent) GDs completed the survey; 86 (100 percent) and 1,015 (85 percent) met inclusion criteria, respectively. Most dentists allowed patients to reach them via pager/cell phone after-hours (82.1 percent of PDs, 72.8 percent of GDs; P=0.04). More PDs than GDs had established after-hours emergency protocols (95.3 percent versus 56.7 percent, P<0.001), practiced in a group (71.1 percent versus 40.9 percent, P<0.001), and shared call (64.0 percent versus 30.1 percent, P<0.001). Telephone and survey responses significantly differed for GDs (P<0.001) but not PDs (P=0.14). After-hours emergency care is an important component of a comprehensive dental home. More pediatric dentists than general dentists provided after-hours emergency dental care. Survey and telephone responses were more consistent and favorable for PDs than GDs. This highlights gaps in emergency dental practice and breakdown of the dental home.


The coordination dynamics of social neuromarkers.
Social behavior is a complex integrative function that entails many aspects of the brain's sensory, cognitive, emotional and movement capacities. Its neural processes are seldom simultaneous but occur according to precise spatiotemporal choreographies, manifested by the coordination of their oscillations within and between brains. Methods with good temporal resolution can help to identify so-called "neuromarkers" of social function and aid in disentangling the dynamical architecture of social brains. In our ongoing research, we have used dual-electroencephalography (EEG) to study neuromarker dynamics during synchronic interactions in which pairs of subjects coordinate behavior spontaneously and intentionally (social coordination) and during diachronic transactions that require subjects to perceive or behave in turn (action observation, delayed imitation). In this paper, after outlining our dynamical approach to the neurophysiological basis of social behavior, we examine commonalities and differences in the neuromarkers that are recruited for both kinds of tasks. We find the neuromarker landscape to be task-specific: synchronic paradigms of social coordination reveal medial mu, alpha and the phi complex as contributing neuromarkers. Diachronic tasks recruit alpha as well, in addition to lateral mu rhythms and the newly discovered nu and kappa rhythms whose functional significance is still unclear. Social coordination, observation, and delayed imitation share commonality of context: in each of our experiments, subjects exchanged information through visual perception and moved in similar ways. Nonetheless, there was little overlap between their neuromarkers, a result that hints strongly of task-specific neural mechanisms for social behavior. The only neuromarker that transcended both synchronic and diachronic social behaviors was the ubiquitous alpha rhythm, which appears to be a key signature of visually-mediated social behaviors. The present paper is both an entry point and a challenge: much work remains to determine the nature and scope of recruitment of other neuromarkers, and to create theoretical models of their within- and between-brain dynamics during social interaction.


Brief topical sodium nitrite and its impact on the quality of life in patients with sickle leg ulcers.
Cutaneous ulceration from sickle cell disease negatively impacts quality of life. Topical sodium nitrite has previously been shown to reduce the size of sickle leg ulcers. This study examined how topical sodium nitrite impacted the quality of life scores in patients with sickle leg ulcers.We prospectively collected data in patients enrolled in a leg ulcer study (n = 17) or an allogeneic hematopoietic cell transplant study (nonulcer group, n = 15). Both groups completed a pretreatment Short Form-36 questionnaire; the ulcer group completed a second questionnaire after 4 weeks of topical sodium nitrite applications. Data were analyzed by age, sex, >50% area improvement postintervention, and sickle-related complications (vaso-occlusive crises, pulmonary hypertension, or avascular necrosis). Physical and mental component summary scores were analyzed with Student t test.Physical summary scores were lower than mental summary scores in all groups, indicating leg ulcers among other sickle related complications negatively impacted physical quality of life measures. After sodium nitrite use, physical summary scores improved in the leg ulcer group (34.5 ± 9.4 to 39 ± 10.3, P = .03), and mental summary scores improved more in ulcerated patients ≤35 years old (40.7 ± 6.9 to 51.7 ± 9.7, P = .01).Brief topical sodium nitrite has the potential to improve quality of life, especially in younger individuals. Longer treatment duration and randomized-controlled trials are needed to confirm the efficacy of this topical therapy.


Poststroke survival for black-Caribbean populations in barbados and South london.
There are variations in mortality rates for stroke in black communities, but the factors associated with survival remain unclear. The authors studied population-based stroke registers with follow up in South London (270 participants, 1995 to 2002) and Barbados (578 participants, 2001 to 2003). Differences in sociodemographic factors, stroke risk factors and their management, case severity, and acute management between London and Barbados were studied. Survival analysis used Kaplan-Meier curves, log-rank test, and Cox proportional hazards model with stratification. There were 1411 person-years of follow-up. Patients in Barbados had poorer survival (log-rank test P=0.037), particularly those with a prestroke Barthel index scores between 15 and 20 (1-year survival, 56.4% versus 74.3%; P<0.001). This disadvantage remained significant (hazard ratio [HR], 1.99; 95% CI, 1.23 to 3.21, P=0.005) after adjustment for age and year of stroke and stratification for stroke subtype and socioeconomic status (SES). After stratification by SES, clinical stroke subtype, and Glasgow Coma Score, and adjustment for other potential confounders, additional factors reducing survival were untreated atrial fibrillation (AF; HR, 8.54; 95% CI, 2.14 to 34.08, P=0.002), incontinence after stroke (HR, 2.64; 95% CI, 1.79 to 3.89), and dysphagia (HR, 2.25; 95% CI, 1.57 to 3.24). Patients not admitted to the hospital had improved survival (HR, 0.35; 95% CI, 0.21 to 0.58). Interaction terms between location and Barthel score, location and AF, and location and transient ischemic attack were included in the final model to reflect the greater difference in survival with a high Barthel score of 15 or more, absence of untreated AF, and having untreated transient ischemic attack. Black-Caribbean people with stroke living in Barbados have worse survival than similar patients in South London, particularly if they have good mobility before the stroke. Further exploration and refinement of measurement of confounding factors such as SES and poststroke management along with exploring the cultural/environmental differences between the communities is required to understand these stark differences.


Clinical and prognostic significance of coagulation assays in melanoma.
The activation of coagulation and fibrinolysis is frequently found among cancer patients. Such tumors are considered to be associated with a higher risk of invasion, metastases, and eventually worse outcome. The aim of this study is to explore the clinical and prognostic value of blood coagulation tests for melanoma patients. Pretreatment blood coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin activity (PTA), international normalized ratio (INR), D-dimer (DD), fibrinogen (F) levels, and platelet (PLT) counts were carried out. This prospective study included 61 melanoma patients [stage I-II (n=10), stage III (n=14), stage IV (n=37), M1c (n=26) disease], and 50 healthy controls. It included 34 (56%) men, median age 53 years, range 16-88 years. Over half of the patients (54%) were in the metastatic stage and most of them (70%) had M1c. The plasma level of pretreatment blood coagulation tests including DD, F, APTT, INR levels, and PLT counts showed a statistically significant difference between the patient and the control group (P<0.001 for all, but P=0.049 for INR). The levels of INR, DD, F, and PLT counts were higher and APTT was lower in the melanoma group, whereas the PT and PTA levels did not show any significant difference. There was a significant association between PT, PTA, INR, and PLT levels and the age of the patient. Patients with node metastasis in M0 disease had higher levels of PTA and PLT counts (P=0.002 and 0.048, respectively) and lower levels of PT and INR (P=0.056 and 0.046, respectively). The M1c patients tended to have higher plasma F levels (437 vs. 297 mg/dl, P=0.055) than M1a and M1b patients. The 1-year survival rate for all patients was 70%. In association with distant metastasis, advanced metastatic stage (M1c), elevated lactate dehydrogenase, and erythrocyte sedimentation rate, only elevated plasma F levels had a significantly adverse effect on survival among the coagulation parameters (P=0.031). The 1-year survival rates for patients with high and normal F levels were 58 and 88%, respectively. In conclusion, changes in the coagulation-fibrinolytic system are often present in melanoma and elevation in the plasma F level is associated with decreased survival.


Simulation in Occupational Therapy Curricula: A literature review.
Simulated learning experiences are increasingly being used in health-care education to enhance student engagement and provide experiences that reflect clinical practice; however, simulation has not been widely investigated in occupational therapy curricula. The aim of this paper was to: (i) describe the existing research about the use and evaluation of simulation over the last three decades in occupational therapy curricula and (ii) consider how simulation has been used to develop competence in students. A literature review was undertaken with searches of MEDLINE, CINAHL and ERIC to locate articles that described or evaluated the use of simulation in occupational therapy curricula. Fifty-seven papers were identified. Occupational therapy educators have used the full scope of simulation modalities, including written case studies (22), standardised patients (13), video case studies (15), computer-based and virtual reality cases (7), role-play (8) and mannequins and part-task trainers (4). Ten studies used combinations of these modalities and two papers compared modalities. Most papers described the use of simulation for foundational courses, as for preparation for fieldwork, and to address competencies necessary for newly graduating therapists. The majority of studies were descriptive, used pre-post design, or were student's perceptions of the value of simulation. Simulation-based education has been used for a wide range of purposes in occupational therapy curricula and appears to be well received. Randomised controlled trials are needed to more accurately understand the effects of simulation not just for occupational therapy students but for longer term outcomes in clinical practice.


Arrhythmia Detection based on Morphological and Time-frequency Features of T-wave in Electrocardiogram.
As the T-wave section in electrocardiogram (ECG) illustrates the repolarization phase of heart activity, the information which is accumulated in this section is so significant that it can explain the proper operation of electrical activities in heart. Long QT syndrome (LQT) and T-Wave Alternans (TWA) have imperceptible effects on time and amplitude of T-wave interval. Therefore, T-wave shapes of these diseases are similar to normal beats. Consequently, several T-wave features can be used to classify LQT and TWA diseases from normal ECGs. Totally, 22 features including 17 morphological and 5 wavelet features have been extracted from T-wave to show the ability of this section to recognize the normal and abnormal records. This recognition can be implemented by pre-processing, T-wave feature extraction and artificial neural network (ANN) classifier using Multi Layer Perceptron (MLP). The ECG signals obtained from 142 patients (40 normal, 47 LQT and 55 TWA) are processed and classified from MIT-BIH database. The specificity factor for normal, LQT, and TWA classifications are 99.89%, 99.90%, and 99.43%, respectively. T-wave features are one of the most important descriptors for LQT syndrome, Normal and TWA of ECG classification. The morphological features of T-wave have also more effect on the classification performance in LQT, TWA and normal samples compared with the wavelet features.


Do Age and Educational Stage Influence No-Mobile-Phone Phobia?
Technological progress not only brings with it resources that improve and facilitate the day-to-day life of the people who make up society but also entails health risks, with the emergence of terms, such as nomophobia, which is considered an anxiety disorder produced by the fear that not having a mobile phone generates in a person. This research aims to identify the relationship and influence between levels of nomophobia and the age or educational stage of students. The research method is based on a correlational and predictive design of quantitative methodology. The instrument used is the NMP-Q questionnaire. The study population is students from different educational stages (obligatory secondary education, baccalaureate, vocational training and university). The results show that students over 12 years old present an average level of "nomophobia" (no-mobile-phone phobia), namely, not being able to communicate with the family where the highest levels are presented. We conclude that students over 12 years of age and of any educational stage present an average level of nomophobia, and it cannot be determined that either the educational stage or the age are determining factors in the presentation of this problem. This can occur at any age and at any level of the different educational stages, although there are risk indicators that we should bear in mind to avoid the appearance of nomophobia.


Childhood adversity and behavioral health outcomes for youth: An investigation using state administrative data.
This study aimed to measure the relative contribution of adverse experiences to adolescent behavioral health problems using administrative data. Specifically, we sought to understand the predictive value of adverse experiences on the presence of mental health and substance abuse problems for youth receiving publicly funded social and health services. Medicaid claims and other service records were analyzed for 125,123 youth age 12-17 and their biological parents. Measures from administrative records reflected presence of parental domestic violence, mental illness, substance abuse, criminal justice involvement, child abuse and/or neglect, homelessness, and death of a biological parent. Mental health and substance abuse status of adolescents were analyzed as functions of adverse experiences and other youth characteristics using logistic regression. In multivariate analyses, all predictors except parental domestic violence were statistically significant for substance abuse; parental death, parental mental illness, child abuse or neglect and homelessness were statistically significant for mental illness. Odds ratios for child abuse/neglect were particularly high in both models. The ability to identify risks during childhood using administrative data suggests the potential to target prevention and early intervention efforts for children with specific family risk factors who are at increased risk for developing behavioral health problems during adolescence. This study illustrates the utility of administrative data in understanding adverse experiences on children and the advantages and disadvantages of this approach.


Brucella β 1,2 cyclic glucan is an activator of human and mouse dendritic cells.
Bacterial cyclic glucans are glucose polymers that concentrate within the periplasm of alpha-proteobacteria. These molecules are necessary to maintain the homeostasis of the cell envelope by contributing to the osmolarity of Gram negative bacteria. Here, we demonstrate that Brucella β 1,2 cyclic glucans are potent activators of human and mouse dendritic cells. Dendritic cells activation by Brucella β 1,2 cyclic glucans requires TLR4, MyD88 and TRIF, but not CD14. The Brucella cyclic glucans showed neither toxicity nor immunogenicity compared to LPS and triggered antigen-specific CD8(+) T cell responses in vivo. These cyclic glucans also enhanced antigen-specific CD4(+) and CD8(+) T cell responses including cross-presentation by different human DC subsets. Brucella β 1,2 cyclic glucans increased the memory CD4(+) T cell responses of blood mononuclear cells exposed to recombinant fusion proteins composed of anti-CD40 antibody and antigens from both hepatitis C virus and Mycobacterium tuberculosis. Thus cyclic glucans represent a new class of adjuvants, which might contribute to the development of effective antimicrobial therapies.


Effect of Corticosteroids on Pain Relief Following Root Canal Treatment: A Systematic Review.
Post-operative pain and flare-up may occur in up to 58% of patients following root canal treatment. The aim was to conduct a systematic review and a possible meta-analysis to determine the effect of glucocorticosteroid (GCS) on pain following root canal treatment. Scopus, MEDLINE and CENTRAL databases were searched up to 30th January 2017 with broad key words. In addition, the reference lists in eligible papers and text books were hand-searched. Assessment of the eligibility of papers and data extraction were performed by two independent reviewers. Of 9891 articles, 18 were recruited as eligible papers. Most of these papers showed pain reducing effect of GCS on post-endodontic pain. Because of wide heterogeneity among the recruited papers, it was not possible to perform meta-analysis. Based on the results of this systematic review, there is a vast heterogeneity amongst articles regarding the use of GCS and their effect on post-operative pain after endodontic treatment. Further investigations with similar methods and materials are needed before meta-analysis on the effect of GCS on post-operative pain following root canal treatment can be performed.


Diagnostic accuracy of Ber-EP4 for metastatic adenocarcinoma in serous effusions: a meta-analysis.
Numerous studies have investigated the utility of Ber-EP4 in differentiating metastatic adenocarcinoma (MAC) from malignant epithelial mesothelioma (MM) and/or reactive mesothelial cells (RM) in serous effusions. However, the results remain controversial. The aim of this study is to determine the overall accuracy of Ber-EP4 in serous effusions for MAC through a meta-analysis of published studies. Publications addressing the accuracy of Ber-EP4 in the diagnosis of MAC were selected from the Pubmed, Embase and Cochrane Library. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc 1.4 and STATA 12.0 softwares. 29 studies, based on 2646 patients, met the inclusion criteria and the summary estimating for Ber-EP4 in the diagnosis of MAC were: sensitivity 0.8 (95% CI: 0.78-0.82), specificity 0.94 (95% CI: 0.93-0.96), positive likelihood ratio (PLR) 12.72 (95% CI: 8.66-18.7), negative likelihood ratio (NLR) 0.18 (95% CI: 0.12-0.26) and diagnostic odds ratio 95.05 (95% CI: 57.26-157.77). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.91; the area under the curve was 0.96. Our findings suggest that BER-EP4 may be a useful diagnostic adjunctive tool for confirming MAC in serous effusions.


Postnatal changes in serotonin receptors following prenatal alterations in serotonin levels: further evidence for functional fetal serotonin receptors.
Recent work by ourselves and others has indicated that serotonin (5-HT) acts as a regulator of neuronal growth in fetal tissue, probably through an action on the high affinity 5-HT receptors known to be present. In order for our hypothesis to be correct, these receptors must be shown to be functional in fetal tissue. Furthermore, since 5-HT has a dual role in neuronal development, these receptors must be functional both in the region of the serotonergic cell body (brainstem) and in projection areas (forebrain). We have tested the functional status of fetal 5-HT receptors by testing their ability to adapt to changes in the level of 5-HT. Pregnant rats were treated with saline, p-chlorophenylalanine (a 5-HT depletor) or 5-methoxytryptamine (a 5-HT agonist) and the characteristics of the high affinity 5-HT receptors in the rat pups determined using a binding assay with [3H]5-HT. Our results show that both forebrain and brainstem receptors respond to alterations in transmitter level in a manner similar to adult brain. Thus, fetal 5-HT receptors are functional and capable of playing a role in neuronal development.


The S-layer protein from Campylobacter rectus: sequence determination and function of the recombinant protein.
The gene encoding the crystalline surface layer (S-layer) protein from Campylobacter rectus, designated slp, was sequenced and the recombinant gene product was expressed in Escherichia coli. The gene consisted of 4086 nucleotides encoding a protein with 1361 amino acids. The N-terminal amino acid sequence revealed that Slp did not contain a signal sequence, but that the initial methionine residue was processed. The deduced amino acid sequence displayed some common characteristic features of S-layer proteins previously reported. A homology search showed a high similarity to the Campylobacter fetus S-layer proteins, especially in their N-terminus. The C-terminal third of Slp exhibited homology with the RTX toxins from Gram-negative bacteria via the region including the glycine-rich repeats. The Slp protein had the same N-terminal sequence as a 104-kDa cytotoxin isolated from the culture supernatants of C. rectus. However, neither native nor recombinant Slp showed cytotoxicity against HL-60 cells or human peripheral white blood cells. These data support the idea that the N-terminus acts as an anchor to the cell surface components and that the C-terminus is involved in the assembly and/or transport of the protein.


Global electrosensory oscillations enhance directional responses of midbrain neurons in eigenmannia.
Eigenmannia, a genus of weakly electric fish, exhibits a specialized behavior known as the jamming avoidance response (JAR). The JAR results in a categorical difference between Eigenmannia that are in groups of conspecifics and those that are alone. Fish in groups exhibit the JAR behavior and thereby experience ongoing, global synchronous 20- to 50-Hz electrosensory oscillations, whereas solitary fish do not. Although previous work has shown that these ongoing signals do not significantly degrade electrosensory behavior, these oscillations nevertheless elicit short-term synaptic depression in midbrain circuits. Because short-term synaptic depression can have profound effects on the transmission of information through synapses, we examined the differences in intracellularly recorded responses of midbrain neurons in awake, behaving fish to moving electrosensory images under electrosensory conditions that mimic solitary fish and fish in groups. In solitary conditions, moving objects elicited Gaussian or sinusoidal postsynaptic potentials (PSPs) that commonly exhibited preferential responses to a direction of motion. Surprisingly, when the same stimulus was presented in the presence of the global oscillations, directional selectivity was increased in all neurons tested. The magnitudes of the differences in PSP amplitude for preferred and nonpreferred directions were correlated with a measure of short-term synaptic depression in both conditions. The electrosensory consequences of the JAR appear to result in an enhancement of the representation of direction of motion in midbrain neurons. The data also support a role for short-term synaptic depression in the generation and modulation of directional responses.


TopoLayout: multilevel graph layout by topological features.
We describe TopoLayout, a feature-based, multilevel algorithm that draws undirected graphs based on the topological features they contain. Topological features are detected recursively inside the graph, and their subgraphs are collapsed into single nodes, forming a graph hierarchy. Each feature is drawn with an algorithm tuned for its topology. As would be expected from a feature-based approach, the runtime and visual quality of TopoLayout depends on the number and types of topological features present in the graph. We show experimental results comparing speed and visual quality for TopoLayout against four other multilevel algorithms on a variety of data sets with a range of connectivities and sizes. TopoLayout frequently improves the results in terms of speed and visual quality on these data sets.


Cellular hypersensitivity to a synthetic dodecapeptide derived from human adenovirus 12 which resembles a sequence of A-gliadin in patients with coeliac disease.
The human intestinal adenovirus serotype 12 (Ad12) may be implicated in the pathogenesis of coeliac disease by virtue of immunological cross reactivity between epitopes shared by its early region E1b protein and A-gliadin. In the present study a synthetic dodecapeptide from the corresponding viral epitope (Ad12E1b, residues 384-395) was tested for its effect on peripheral blood mononuclear cells from 22 treated and eight untreated patients with coeliac disease, 22 healthy subjects, 11 patients with ulcerative colitis, and 11 patients with Crohn's disease by an indirect leucocyte migration inhibition assay. In addition, the effect of both the viral and the gliadin synthetic peptides was studied by proliferation and migration assays simultaneously performed in an unselected subgroup of 12 treated coeliac patients and 12 healthy subjects of the study. Coeliac patients with untreated disease showed no response to the viral peptide compared with treated patients (p greater than 0.1). Treated coeliac patients showed a significantly different response from healthy control subjects and control patients with disease (p less than 0.001) which was dependent on the concentration of the viral peptide. In the subgroup of the treated coeliac patients (n = 12) there was a significant correlation between the responses in the migration and the proliferation assay using either the viral (p less than 0.02) or the gliadin (p less than 0.005) peptide at the highest concentration (33.3 micrograms/ml). Furthermore, the responses obtained using viral peptide correlated significantly with the responses obtained with gliadin peptide in both the migration (p less than 0.001) and the proliferation (p less than 0.001) assays. These results show that in coeliac patients there is pronounced cross reactivity at the level of T cell recognition between synthetic peptides derived from the Ad12 and A-gliadin. This antigenic cross reactivity may be involved in the pathogenesis of coeliac disease.


Subsystem density-functional theory for interacting open-shell systems: spin densities and magnetic exchange couplings.
We investigate the possibility of describing interacting open-shell systems in high-spin and broken-symmetry (BS) states with subsystem density-functional theory (sDFT). This subsystem method typically starts from the electronic-structure results obtained for individual systems, for which the spin states can be individually defined. Through the confining effect of the embedding potential and/or the use of monomer basis sets, these individual spin states can be preserved in sDFT calculations. This offers the possibility of easy convergence to broken-symmetry states with arbitrary local spin patterns. We show that the resulting spin densities are in very good agreement with successfully converged broken-symmetry Kohn-Sham density-functional theory (KS-DFT) calculations. Yet sDFT can even cure those BS cases where KS-DFT suffers from convergence problems or convergence to undesired spin states. In contrast to KS-DFT, the sDFT-results only show a mild exchange-correlation functional dependence. We also show that magnetic coupling constants from sDFT are not satisfactory with standard approximations for the non-additive kinetic energy. When this component is evaluated "exactly", i.e. based on potential reconstruction, however, the magnetic coupling constants derived from spin-state energy differences are greatly improved. Hence, the interacting radicals studied here represent cases where even (semi-)local approximations for the non-additive kinetic-energy potential work well, while the parent energy functionals do not yield satisfactory results for spin-state energy differences.


Cellulose--model films and the fundamental approach.
This critical review describes the recent arrival of ultrathin films of cellulose. The methodology of preparation as well as the applications of the films for fundamental research is fully covered. The review places cellulose in a wider scientific context where cellulose research is no longer a field of interest for specialised scientists only. Cellulose and cellulosic materials should interest communities such as biochemists, physical chemists, surface chemists, organic chemists, polymer chemists and also physicists working close the disciplines mentioned. (149 references.).


Intramuscular stimulation vs sham needling for the treatment of chronic midportion Achilles tendinopathy: A randomized controlled clinical trial.
The insertion of filiform needles intramuscularly (a.k.a. intramuscular stimulation/dry needling) has been suggested as a possible treatment for various painful musculoskeletal conditions. Our aim was to answer the question, is intramuscular stimulation more effective than sham intramuscular stimulation/dry needling for the treatment of Achilles tendinopathy? 52 participants with persistent midportion Achilles tendinopathy began and 46 completed one of three treatment protocols which were randomly assigned: (G3) a 12-week rehabilitation program of progressive tendon loading plus intramuscular stimulation (n = 25), (G2) the same rehabilitation program but with sham intramuscular stimulation (n = 19), or (G1) a reference group of rehabilitation program alone (as an additional control) (n = 8). The a priori primary outcome measure was change in VISA-A score at 12 weeks-VISA-A was also measured at 6 weeks, and at 6 and 12 months. Secondary outcome measures include the proportion of patients who rated themselves as much or very much improved (%), dorsiflexion range of motion (degrees), and tendon thickness (mm). The study retention was 94% at 12 weeks and 88% at 1 year. VISA-A score improved in all three groups over time (p<0.0001), with no significant difference among the three groups in VISA-A score at the start of the study (mean ± SD: G3 59 ± 13, G2 57 ± 17, G1 56 ± 22), at 12 weeks (G3 76 ± 14, G2 76 ± 15, G1 82 ± 11) or at any other timepoint. The percentage of patients who rated themselves as much or very much improved (i.e. treatment success) was not different after 12 weeks (G3 70%, G2 89%, G1 86% p = 0.94), or at 26 (p = 0.62) or 52 weeks (p = 0.71). No clinically significant effects of intervention group were observed in any of the secondary outcome measures. The addition of intramuscular stimulation to standard rehabilitation for Achilles tendinopathy did not result in any improvement over the expected clinical benefit achieved with exercise-based rehabilitation alone.


Will access to COVID-19 vaccine in Aotearoa be equitable for priority populations?
This research examines the equity implications of the geographic distribution of COVID-19 vaccine delivery locations in Aotearoa New Zealand under five potential scenarios: (1) stadium mega-clinics; (2) Community Based Assessment Centres; (3) GP clinics; (4) community pharmacies; and (5) schools. We mapped the distribution of Aotearoa New Zealand's population and the location of potential vaccine delivery facilities under each scenario. Geostatistical techniques identified population clusters for Māori, Pacific peoples and people aged 65 years and over. We calculated travel times between all potential facilities and each Statistical Area 1 in the country. Descriptive statistics indicate the size and proportion of populations that could face significant travel barriers when accessing COVID-19 vaccinations. Several areas with significant travel times to potential vaccine delivery sites were also communities identified as having an elevated risk of COVID-19 disease and severity. All potential scenarios for vaccine delivery, with the exception of schools, resulted in travel barriers for a substantial proportion of the population. Overall, these travel time barriers disproportionately burden Māori, older communities and people living in areas of high socioeconomic deprivation. The equitable delivery of COVID-19 vaccines is key to an elimination strategy. However, if current health services and facilities are used without well-designed and supported outreach services, then access to vaccination is likely to be inequitable.