Solution processed polydimethylsiloxane/gold nanostar flexible substrates for plasmonic sensing.
Gold nanostars can display tunable optical properties in the visible and near IR, which lead to strong electromagnetic field enhancement at their tips. We report generalized application of gold nanostars for ultrasensitive identification of molecules, based on both localized surface plasmon resonance (LSPR) and surface enhanced Raman scattering (SERS). We address the requirements of plasmonic sensors, related to sufficiently large areas where nanoparticles are uniformly immobilized with high density, as well as mechanical flexibility, which offers additional advantages for real-world applications. Gold nanostar monolayers were thus immobilized on transparent, flexible polydimethylsiloxane substrates, and their refractive index sensitivity and SERS performance were studied. The application of such substrates for LSPR based molecular sensing is demonstrated via detection of a model analyte, mercaptoundecanoic acid. We further demonstrate SERS-based pesticide detection on fruit skin, by simply covering the fruit surface with the flexible plasmonic substrate, at the area where the target molecule is to be detected. The transparency of the substrate allows SERS detection through backside excitation, thereby facilitating practical implementation.


An observational multi-center study on type 2 diabetes treatment prescribing pattern and patient adherence to treatment.
In 2021, the International Diabetes Federation (IDF) reported that the prevalence of diabetes in Pakistan was 9.6%, higher than the global average. However, adherence to treatment guidelines, e.g., American Diabetes Association and Pakistan Endocrine Society and prescription patterns for Oral anti-diabetes (OAD), is poorly understood in Pakistan. Therefore, this study aimed to examine the prescribing practices of anti-diabetic medications, an association of lifestyle modification with drugs prescribed, and their effectiveness in preserving ideal glycemic levels in diabetic patients undergoing treatment in tertiary care teaching hospitals in rural and urban Pakistan. In this cross-sectional study, data were collected from prescriptions of outpatient diabetic patients from different rural and urban tertiary care hospitals between October 2021 and February 2022. 388 participants were enrolled in the study for a detailed interview on prescription evaluation and glycemic control. The coinvestigators conducted an interview with the patient and used a pre-validated questionnaire to collect the data. The relationship between following treatment guidelines and clinical and demographic factors was found using chi-square tests for bivariate analyses. The study reported that out of 388, the mean ages of the patients were 48 ± 12.4, and the majority were female. It was observed that 60.1% and 66.5% have uncontrolled fasting and random blood glucose, respectively. The education level of the study participants was also below par to have a complete understanding of the medical condition and self-management therapy. Even though they were taking the right medications-an average prescription regimen included 5.08 medications-52.1% of the studied people had glycated haemoglobin (HbA1c) levels higher than the therapeutic threshold set by the International Diabetes Federation. In this modern era, it was observed that the prescribing trend was still focused on traditional therapeutic options Biguanides, sulfonylureas, and dipeptidyl peptidase-4 inhibitors were prescribed in 64.6% of the patients. A significant association was found between glycemic control and body mass index, adherence to lifestyle modifications, and the number of medications prescribed (p-value < 0.05). The study reveals that Pakistan's prescribing practices do not align with international and national guidelines, leading to a high prevalence of uncontrolled diabetes and widespread use of polypharmacy among patients. To address this issue, policymakers should prioritize establishing a comprehensive national diabetes action plan. Additionally, there is a pressing need to develop diabetes education and awareness programs emphasizing the importance of lifestyle modifications for effective diabetes management.


Antihypertensive therapy and the progression of renal disease.
Systemic hypertension accelerates the progression of glomerular injury. Studies in experimental animals indicate that the beneficial effects of antihypertensive agents may relate to their intrarenal haemodynamic consequences, and specifically to their effects on the arteriolar resistances. Relative afferent arteriolar vasodilation allows transmission of systemic pressure into the glomerular capillary network; the resultant glomerular capillary hypertension is associated with progressive structural injury. Antihypertensive agents, such as angiotensin converting enzyme (ACE) inhibitors, relax the efferent arteriole, alleviate glomerular hypertension and protect the kidney from progressive injury. These agents are effective in numerous animal models, and preliminary clinical observations suggest that they may also be effective in humans. In contrast, vasodilator/diuretic regimens are effective in some animal models, but fail to reduce glomerular pressure or injury in others. Less is known about the potential renal protective effects of calcium channel blockers, with reported observations offering conflicting findings. Further experimental and clinical studies are needed to define the optimal antihypertensive therapy for patients at risk of glomerular injury.


The use of infrared thermography for detecting digital dermatitis in dairy cattle: What is the best measure of temperature and foot location to use?
Lameness in dairy cattle is a persistent problem, indicating pain caused by underlying disease states and is associated with reduced milk yields. Digital dermatitis is a common cause of lameness. Thermal imaging is a technique that may facilitate early detection of this disease and has the potential for use in automated detection systems. Previous studies with thermal imaging have imaged either the heels or the coronary band of the foot and typically only used the maximum temperature (Max) value as the outcome measure. This study investigated the utility of other statistical descriptors: 90th percentile (90PCT), 95th percentile (95PCT), standard deviation (SD) and coefficient of variation (CoV) and compared the utility of imaging the heel or coronary band. Images were collected from lame and healthy cows using a high-resolution thermal camera. Analyses were done at the cow and foot level. There were significant differences between lame and healthy feet detectable at the heels (95th percentile: P<0.05; SD: P<0.05) and coronary band (SD: P<0.05). Within lame cows, 95PCT values were higher at the heel (P<0.05) and Max values were higher at the coronary band (P<0.05) in the lame foot compared to the healthy foot. ROC analysis showed an AUC value of 0.72 for Max temperature and 0.68 for 95PCT at the heels. It was concluded that maximum temperature is the most accurate measure, but other statistical descriptors of temperature can be used to detect lameness. These may be useful in certain contexts, such as where there is contamination. Differentiation of lame from healthy feet was most apparent when imaging the heels.


Reduction of nilutamide by NO synthases: implications for the adverse effects of this nitroaromatic antiandrogen drug.
Nitric oxide synthases (NOSs) are flavohemeproteins that catalyze the oxidation of l-arginine to l-citrulline with formation of the widespread signal molecule NO. Beside their fundamental role in NO biosynthesis, these enzymes are also involved in the formation of reactive oxygen species and in the interactions with some xenobiotic compounds. Nilutamide is a nonsteroidal antiandrogen that behaves as a competitive antagonist of the androgen receptors and is proposed in the treatment of metastatic prostatic carcinoma. However, therapeutic effects of nilutamide are overshadowed by the occurrence of several adverse reactions mediated by toxic mechanism(s), which remain(s) poorly investigated. Here, we studied the interaction of NOSs with nilutamide. Our results show that the purified recombinant neuronal NOS reduced the nitroaromatic nilutamide to the corresponding hydroxylamine. The reduction of nilutamide catalyzed by neuronal NOS proceeded with intermediate formation of a nitro anion free radical easily observed by EPR, was insensitive to the addition of the usual heme ligands and l-arginine analogues, but strongly inhibited by O(2) and a flavin/NADPH binding inhibitor. Involvement of the reductase domain of nNOS in the reduction of nilutamide was confirmed by (i) the ability of the isolated reductase domain of nNOS to catalyze the reaction and (ii) the stimulating effect of Ca(2+)/calmodulin on the accumulation of hydroxylamine and nitro anion radical. In a similar manner, the recombinant inducible and endothelial NOS isoforms also displayed nitroreductase activity, albeit with lower yields. The selective reduction of nilutamide to its hydroxylamino derivative by the NOSs could explain some of the toxic effects of this drug.


Towards functional de novo designed proteins.
Our ability to design completely de novo proteins is improving rapidly. This is true of all three main approaches to de novo protein design, which we define as: minimal, rational and computational design. Together, these have delivered a variety of protein scaffolds characterised to high resolution. This is truly impressive and a major advance from where the field was a decade or so ago. That all said, significant challenges in the field remain. Chief amongst these is the need to deliver functional de novo proteins. Such designs might include selective and/or tight binding of specified small molecules, or the catalysis of entirely new chemical transformations. We argue that, whilst progress is being made, solving such problems will require more than simply adding functional side chains to extant de novo structures. New approaches will be needed to target and build structure, stability and function simultaneously. Moreover, if we are to match the exquisite control and subtlety of natural proteins, design methods will have to incorporate multi-state modelling and dynamics. This will require more than black-box methodology, specifically increased understanding of protein conformational changes and dynamics will be needed.


Utility of diffusion tensor imaging studies linked to neuronavigation and other modalities in repeat hemispherotomy for intractable epilepsy.
OBJECT Hemispherectomy for unilateral, medically refractory epilepsy is associated with excellent long-term seizure control. However, for patients with recurrent seizures following disconnection, workup and investigation can be challenging, and surgical options may be limited. Few studies have examined the role of repeat hemispherotomy in these patients. The authors hypothesized that residual fiber connections between the hemispheres could be the underlying cause of recurrent epilepsy in these patients. Diffusion tensor imaging (DTI) was used to test this hypothesis, and to target residual connections at reoperation using neuronavigation. METHODS The authors identified 8 patients with recurrent seizures following hemispherectomy who underwent surgery between 1995 and 2012. Prolonged video electroencephalography recordings documented persistent seizures arising from the affected hemisphere. In all patients, DTI demonstrated residual white matter association fibers connecting the hemispheres. A repeat craniotomy and neuronavigation-guided targeted disconnection of these residual fibers was performed. Engel class was used to determine outcome after surgery at a minimum of 2 years of follow-up. RESULTS Two patients underwent initial hemidecortication and 6 had periinsular hemispherotomy as their first procedures at a median age of 9.7 months. Initial pathologies included hemimegalencephaly (n = 4), multilobar cortical dysplasia (n = 3), and Rasmussen's encephalitis (n = 1). The mean duration of seizure freedom for the group after the initial procedure was 32.5 months (range 6-77 months). In all patients, DTI showed limited but definite residual connections between the 2 hemispheres, primarily across the rostrum/genu of the corpus callosum. The median age at reoperation was 6.8 years (range 1.3-14 years). The average time taken for reoperation was 3 hours (range 1.8-4.3 hours), with a mean blood loss of 150 ml (range 50-250 ml). One patient required a blood transfusion. Five patients are seizure free, and the remaining 3 patients are Engel Class II, with a minimum follow-up of 24 months for the group. CONCLUSIONS Repeat hemispherotomy is an option for consideration in patients with recurrent intractable epilepsy following failed surgery for catastrophic epilepsy. In conjunction with other modalities to establish seizure onset zones, advanced MRI and DTI sequences may be of value in identifying patients with residual connectivity between the affected and unaffected hemispheres. Targeted disconnection of these residual areas of connectivity using neuronavigation may result in improved seizure outcomes, with minimal and acceptable morbidity.


Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250).
Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.


Evaluation design of New York City's regulations on nutrition, physical activity, and screen time in early child care centers.
This article describes the multi-method cross-sectional design used to evaluate New York City Department of Health and Mental Hygiene's regulations of nutrition, physical activity, and screen time for children aged 3 years or older in licensed group child care centers. The Center Evaluation Component collected data from a stratified random sample of 176 licensed group child care centers in New York City. Compliance with the regulations was measured through a review of center records, a facility inventory, and interviews of center directors, lead teachers, and food service staff. The Classroom Evaluation Component included an observational and biometric study of a sample of approximately 1,400 children aged 3 or 4 years attending 110 child care centers and was designed to complement the center component at the classroom and child level. The study methodology detailed in this paper may aid researchers in designing policy evaluation studies that can inform other jurisdictions considering similar policies.


Imaging of Extracellular Vesicles by Atomic Force Microscopy.
Exosomes and other extracellular vesicles (EVs) are molecular complexes consisting of a lipid membrane vesicle, its surface decoration by membrane proteins and other molecules, and diverse luminal content inherited from a parent cell, which includes RNAs, proteins, and DNAs. The characterization of the hydrodynamic sizes of EVs, which depends on the size of the vesicle and its coronal layer formed by surface decorations, has become routine. For exosomes, the smallest of EVs, the relative difference between the hydrodynamic and vesicles sizes is significant. The characterization of vesicles sizes by the cryogenic transmission electron microscopy (cryo-TEM) imaging, a gold standard technique, remains a challenge due to the cost of the instrument, the expertise required to perform the sample preparation, imaging and data analysis, and a small number of particles often observed in images. A widely available and accessible alternative is the atomic force microscopy (AFM), which can produce versatile data on three-dimensional geometry, size, and other biophysical properties of extracellular vesicles. The developed protocol guides the users in utilizing this analytical tool and outlines the workflow for the analysis of EVs by the AFM, which includes the sample preparation for imaging EVs in hydrated or desiccated form, the electrostatic immobilization of vesicles on a substrate, data acquisition, its analysis, and interpretation. The representative results demonstrate that the fixation of EVs on the modified mica surface is predictable, customizable, and allows the user to obtain sizing results for a large number of vesicles. The vesicle sizing based on the AFM data was found to be consistent with the cryo-TEM imaging.


A numerical study on distributions during cryoprotectant loading caused by laminar flow in a microchannel.
In this work, we conduct a computational study on the loading of cryoprotective agents into cells in preparation for cryopreservation. The advantages of microfluidics in cryopreserving cells include control of fluid flow parameters for reliable cryoprotectant loading and reproducible streamlined processing of samples. A 0.25 m long, three inlet T-junction microchannel serves as an idealized environment for this process. The flow field and concentration distribution are determined from a computational fluid dynamics study and cells are tracked as inert particles in a Lagrangian frame. These particles are not confined to streamlines but can migrate laterally due to the Segre-Sildeberg effect for particles in a shear flow. During this tracking, the local concentration field surrounding the cell is monitored. This data are used as input into the Kedem-Katchalsky equations to numerically study passive solute transport across the cell membrane. As a result of the laminar flow, each cell has a unique pathline in the flow field resulting in different residence times and a unique external concentration field along its path. However, in most previous studies, the effect of a spatially varying concentration field on the transport across the cell membrane is ignored. The dynamics of this process are investigated for a population of cells released from the inlet. Using dimensional analysis, we find a governing parameter α, which is the ratio of the time scale for membrane transport to the average residence time in the channel. For [Formula: see text], cryoprotectant loading is completed to within 5% of the target concentration for all of the cells. However, for [Formula: see text], we find the population of cells does not achieve complete loading and there is a distribution of intracellular cryoprotective agent concentration amongst the population. Further increasing α beyond a value of 2 leads to negligible cryoprotectant loading. These simulations on populations of cells may lead to improved microfluidic cryopreservation protocols where more consistent cryoprotective agent loading and freezing can be achieved, thus increasing cell survival.


Effect of topical administration of 2% dorzlamide hydrochloride or 2% dorzlamide hydrochloride-0.5% timolol maleate on intraocular pressure in clinically normal horses.
To evaluate the effect of topical administration of 2% dorzolamide hydrochloride or 2% dorzolamide hydrochloride-0.5% timolol maleate on intraocular pressure (IOP) in clinically normal horses. 18 healthy adult horses without ocular abnormalities. The IOP was measured at 5 time points (7 AM, 9 AM, 11 AM, 3 PM, 7 PM) over 11 days. On days 1 and 2, baseline values were established. On days 3 through 5, horses received 2% dorzolamide HCI (group D, n = 9) or 2% dorzolamide HCl-0.5% timolol maleate (group DT, 9) in 1 randomly assigned eye every 24 hours immediately following each daily 7 AM IOP measurement. On days 6 through 9, each drug was given every 12 hours (7 AM and 7 PM) in the treated eye. Measurements on days 10 and 11 assessed return to baseline. Mixed linear regression models compared mean IOP difference for each drug at each time period. Mean IOP decreased significantly in all eyes during the 2 dose/d period, compared with the baseline, 1 dose/d, and follow-up periods. Administration of either drug every 24 hours for short-term treatment does not reduce IOP significantly. Administering either drug every 12 hours induced a significant reduction of IOP; however, controlling for all variables, the reduction was less than 2 mm Hg.


The acoustic environment of intensive care wards based on long period nocturnal measurements.
The patients in the Intensive Care Units are often exposed to excessive levels of noise and activities. They can suffer from sleep disturbance, especially at night, but they are often too ill to cope with the poor environment. This article investigates the acoustic environment of typical intensive care wards in the UK, based on long period nocturnal measurements, and examines the differences between singlebed and multibed wards, using statistical analysis. It has been shown that the acoustic environment differs significantly every night. There are also significant differences between the noise levels in the singlebed and multibed wards, where acoustic ceilings are present. Despite the similar background noises in both ward types, more intrusive noises tend to originate from the multibed wards, while more extreme sounds are likely to occur in the single wards. The sound levels in the measured wards for each night are in excess of the World Health Organization's (WHO) guide levels by at least 20 dBA, dominantly at the middle frequencies. Although the sound level at night varies less than that in the daytime, the nocturnal acoustic environment is not dependant on any specific time, thus neither the noisiest nor quietest period can be determined. It is expected that the statistical analysis of the collected data will provide essential information for the development of relevant guidelines and noise reduction strategies.


Insulin signaling in skeletal muscle of HIV-infected patients in response to endurance and strength training.
Human immunodeficiency virus (HIV)-infected patients with lipodystrophy have decreased insulin-stimulated glucose uptake. Both endurance and resistance training improve insulin-stimulated glucose uptake in skeletal muscle of HIV-infected patients, but the mechanisms are unknown. This study aims to identify the molecular pathways involved in the beneficial effects of training on insulin-stimulated glucose uptake in skeletal muscle of HIV-infected patients. Eighteen sedentary male HIV-infected patients underwent a 16 week supervised training intervention, either resistance or strength training. Euglycemic-hyperinsulinemic clamps with muscle biopsies were performed before and after the training interventions. Fifteen age- and body mass index (BMI)-matched HIV-negative men served as a sedentary baseline group. Phosphorylation and total protein expression of insulin signaling molecules as well as glycogen synthase (GS) activity were analyzed in skeletal muscle biopsies in relation to insulin stimulation before and after training. HIV-infected patients had reduced basal and insulin-stimulated GS activity (%fractional velocity, [FV]) as well as impaired insulin-stimulated Akt(thr308) phosphorylation. Despite improving insulin-stimulated glucose uptake, neither endurance nor strength training changed the phosphorylation status of insulin signaling proteins or affected GS activity. However; endurance training markedly increased the total Akt protein expression, and both training modalities increased hexokinase II (HKII) protein. HIV-infected patients with lipodystrophy have decreased insulin-stimulated glucose uptake in skeletal muscle and defects in insulin-stimulated phosphorylation of Akt(thr308). Endurance and strength training increase insulin-stimulated glucose uptake in these patients, and the muscular training adaptation is associated with improved capacity for phosphorylation of glucose by HKII, rather than changes in markers of insulin signaling to glucose uptake or glycogen synthesis.


Targeted protein delivery: carbodiimide crosslinking influences protein release from microparticles incorporated within collagen scaffolds.
Tissue engineering response may be tailored via controlled, sustained release of active agents from protein-loaded degradable microparticles incorporated directly within three-dimensional (3D) ice-templated collagen scaffolds. However, the effects of covalent crosslinking during scaffold preparation on the availability and release of protein from the incorporated microparticles have not been explored. Here, we load 3D ice-templated collagen scaffolds with controlled additions of poly-(DL-lactide-co-glycolide) microparticles. We probe the effects of subsequent N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride crosslinking on protein release, using microparticles with different internal protein distributions. Fluorescein isothiocyanate labelled bovine serum albumin is used as a model protein drug. The scaffolds display a homogeneous microparticle distribution, and a reduction in pore size and percolation diameter with increased microparticle addition, although these values did not fall below those reported as necessary for cell invasion. The protein distribution within the microparticles, near the surface or more deeply located within the microparticles, was important in determining the release profile and effect of crosslinking, as the surface was affected by the carbodiimide crosslinking reaction applied to the scaffold. Crosslinking of microparticles with a high proportion of protein at the surface caused both a reduction and delay in protein release. Protein located within the bulk of the microparticles, was protected from the crosslinking reaction and no delay in the overall release profile was seen.


Tracing phylogenomic events leading to diversity of Haemophilus influenzae and the emergence of Brazilian Purpuric Fever (BPF)-associated clones.
Here we report the use of a multi-genome DNA microarray to elucidate the genomic events associated with the emergence of the clonal variants of Haemophilus influenzae biogroup aegyptius causing Brazilian Purpuric Fever (BPF), an important pediatric disease with a high mortality rate. We performed directed genome sequencing of strain HK1212 unique loci to construct a species DNA microarray. Comparative genome hybridization using this microarray enabled us to determine and compare gene complements, and infer reliable phylogenomic relationships among members of the species. The higher genomic variability observed in the genomes of BPF-related strains (clones) and their close relatives may be characterized by significant gene flux related to a subset of functional role categories. We found that the acquisition of a large number of virulence determinants featuring numerous cell membrane proteins coupled to the loss of genes involved in transport, central biosynthetic pathways and in particular, energy production pathways to be characteristics of the BPF genomic variants.


On the way to Hepatitis C elimination in the Republic of Georgia-Barriers and facilitators for people who inject drugs for engaging in the treatment program: A formative qualitative study.
Hepatitis C virus (HCV) infection is a significant public health concern worldwide. Georgia is among the countries with a high burden of HCV infection. People who inject drugs (PWID) have the highest burden of infection in Georgia. In 2015, the Government of Georgia, with partners' support, initiated one of the world's first Hepatitis C Elimination Programs. Despite notable progress, challenges to achieving targets persist. This qualitative study is aimed to better understand some of the barriers and facilitators to HCV testing and treatment services for PWID to inform HCV treatment policies and practices. The study instrument examined social, structural, and individual factors influencing HCV testing and treatment practices. We started with key informant interviews to guide the study instrument development and compare the study findings against health care planners' and health care providers' views. Forty PWID with various HCV testing and treatment experiences were recruited through the snowball method. The study found that along with structural factors such as political commitment, co-financing of diagnostic and monitoring tests, and friendly clinic environments, knowledge about HCV infection and elimination program benefits, and support from family and peers also play facilitating roles in accessing testing and treatment services. On the other hand, inability to co-pay for diagnostic tests, fear of side effects associated with treatment, poor knowledge about HCV infection, and lack of social support hampered testing and treatment practices among PWID. Findings from this study are important for increasing the effectiveness of this unique program that targets a population at high risk of HCV infection.


Understanding iridium oxide nanoparticle surface sites by their interaction with catechol.
Iridium oxide (IrOx) is one of the best water splitting electrocatalysts, but its active site details are not well known. As with all heterogeneous catalysts, a strategy for counting the number of active sites is not clear, and understanding their nature and structure is remarkably difficult. In this work, we performed a combined study using optical spectroscopy, magnetic resonance and electrochemistry to characterize the interaction of IrOx nanoparticles (NPs) with a probe molecule, catechol. The catalyst is heterogeneous given that the substrate is in a different phase, but behaves as a homogeneous catalyst from the point of view of electrochemistry since it remains in colloidal suspension. We find two types of binding sites: centers A which bind catechol irreversibly making up 21% of the surface, and centers B which bind catechol reversibly making up 79% of the surface. UV-vis absorption spectroscopy shows that the A sites are responsible for the characteristic blue color of the NPs. Electrochemical experiments indicate that the B sites are catalytically active and we give the number of active sites per nanoparticle. We conclude by performing a survey of ligands used in solar cell architectures and show which ones bind well to the surface and which ones inhibit the catalytic activity when doing so, presenting quantitative guidelines for the correct handling of IrOx nanoparticles during their incorporation into multifunctional solar energy harvesting architectures. We suggest ligands binding on the surface oxygen atoms allow for large bound ligand densities with no detrimental effect on the catalytic activity.


Lineage-specific transcription factors and the evolution of gene regulatory networks.
Nature is replete with examples of diverse cell types, tissues and body plans, forming very different creatures from genomes with similar gene complements. However, while the genes and the structures of proteins they encode can be highly conserved, the production of those proteins in specific cell types and at specific developmental time points might differ considerably between species. A full understanding of the factors that orchestrate gene expression will be essential to fully understand evolutionary variety. Transcription factor (TF) proteins, which form gene regulatory networks (GRNs) to act in cooperative or competitive partnerships to regulate gene expression, are key components of these unique regulatory programs. Although many TFs are conserved in structure and function, certain classes of TFs display extensive levels of species diversity. In this review, we highlight families of TFs that have expanded through gene duplication events to create species-unique repertoires in different evolutionary lineages. We discuss how the hierarchical structures of GRNs allow for flexible small to large-scale phenotypic changes. We survey evidence that explains how newly evolved TFs may be integrated into an existing GRN and how molecular changes in TFs might impact the GRNs. Finally, we review examples of traits that evolved due to lineage-specific TFs and species differences in GRNs.


Comanagement of coral reef social-ecological systems.
In an effort to deliver better outcomes for people and the ecosystems they depend on, many governments and civil society groups are engaging natural resource users in collaborative management arrangements (frequently called comanagement). However, there are few empirical studies demonstrating the social and institutional conditions conducive to successful comanagement outcomes, especially in small-scale fisheries. Here, we evaluate 42 comanagement arrangements across five countries and show that: (i) comanagement is largely successful at meeting social and ecological goals; (ii) comanagement tends to benefit wealthier resource users; (iii) resource overexploitation is most strongly influenced by market access and users' dependence on resources; and (iv) institutional characteristics strongly influence livelihood and compliance outcomes, yet have little effect on ecological conditions.


Interaction of antibodies with human glomerular epithelial cells.
We tested the hypothesis that the pathogenesis of human idiopathic membranous glomerulonephritis is similar to that of Heymann glomerulonephritis, a model of membranous glomerulonephritis induced in rats by immunization with renal brush border preparations; the characteristic subepithelial deposits result from interaction of antibodies with a brush border antigen (gp330) expressed on the plasma membrane of glomerular visceral epithelial cells (GEC), followed by redistribution and shedding of gp330 immune complexes. The experiments were performed in cultured glomerular visceral epithelial cells, in living monkeys and rats, and in isolated perfused human, monkey, and rat kidneys. Antigens from plasma membranes of human renal brush border vesicles (HBBV) and GEC vesicles (HGECV) and their corresponding polyclonal and monoclonal antibodies reactive with human and monkey GEC were prepared. First, polyclonal antibodies to HGECV bound diffusely to cultured GEC; monoclonal antibody 8G5, recognizing a 60-kDa protein, mainly bound to the coated pits and apical invaginations; both polyclonal HGECV and 8G5 monoclonal antibodies induced antigen redistribution (capping) at 37 degrees C. Second, monkeys were actively or passively immunized, and isolated human and monkey kidneys were perfused with the antibodies. Active immunization with HBBV induced tubular immune deposits, whereas active immunization with HGECV did not provoke renal lesions. After passive immunization HBBV and HGECV antibodies bound diffusely to glomerular cells, and subepithelial deposits were observed during the autologous phase; in contrast, 8G5 induced early (day 3) granular deposits. Third, fine granular deposits developed in glomeruli of human and monkey kidneys perfused for 4 hours at 37 degrees C with 8G5; these deposits were more difficult to detect by electron microscopy than those occurring in kidneys of Lewis rats perfused with sheep antiHBBV. The results show that some antibodies redistribute antigens at the surface of human and monkey GEC in vitro, in vivo, and ex vivo and induce formation of granular deposits in human glomerular capillary walls. Failure to induce more severe lesions in human and monkey kidneys may be ascribed to lack of GEC antigens comparable to rat gp330, insufficient cross linking by monoclonal antibody, lack or insufficient concentration of epitope-specific antibodies, insufficient time of kidney perfusion, or a combination of these factors.


Childhood trauma and health outcomes in HIV-infected patients: an exploration of causal pathways.
Traumatic life histories are highly prevalent in people living with HIV/AIDS and predict sexual risk behaviors, medication adherence, and all-cause mortality. Yet the causal pathways explaining these relationships remain poorly understood. We sought to quantify the association of trauma with negative behavioral and health outcomes and to assess whether those associations were explained by mediation through psychosocial characteristics. In 611 outpatient people living with HIV/AIDS, we tested whether trauma's influence on later health and behaviors was mediated by coping styles, self-efficacy, social support, trust in the medical system, recent stressful life events, mental health, and substance abuse. In models adjusting only for sociodemographic and transmission category confounders (estimating total effects), pasttrauma exposure was associated with 7 behavioral and health outcomes including increased odds or hazard of recent unprotected sex [odds ratio (OR) = 1.17 per each additional type of trauma, 95% confidence interval = 1.07 to 1.29], medication nonadherence (OR = 1.13, 1.02 to 1.25), hospitalizations (hazard ratio = 1.12, 1.04 to 1.22), and HIV disease progression (hazard ratio = 1.10, 0.98 to 1.23). When all hypothesized mediators were included, the associations of trauma with health care utilization outcomes were reduced by about 50%, suggesting partial mediation (eg, OR for hospitalization changed from 1.12 to 1.07), whereas point estimates for behavioral and incident health outcomes remained largely unchanged, suggesting no mediation (eg, OR for unprotected sex changed from 1.17 to 1.18). Trauma remained associated with most outcomes even after adjusting for all hypothesized psychosocial mediators. These data suggest that past trauma influences adult health and behaviors through pathways other than the psychosocial mediators considered in this model.


Analysis of Intravesical Recurrence After Bladder-preserving Therapy for Muscle-invasive Bladder Cancer.
The aim of the present study was to analyze the pattern of recurrences after bladder-preserving therapy for muscle-invasive bladder cancer. The subjects were 77 patients with T2-3N0M0 bladder cancer whose bladder was preserved by intra-arterial chemotherapy and radiation. The patterns of the first recurrences were retrospectively analyzed. With a median follow-up of 38.5 months, 17 patients (22.1%) experienced intravesical recurrence without metastasis, 14 (82.4%) of which were cases of non-muscle-invasive bladder cancer recurrence and 3 (17.6%) of which were muscle-invasive bladder cancer recurrences. Muscle-invasive bladder cancer recurred at the same site as the initial tumor site in all three cases, whereas non-muscle-invasive bladder cancer recurred at different sites in 64% of the patients in that group. The peak hazard of the non-muscle-invasive bladder cancer recurrence was observed at around a year after treatment. Recurrent non-muscle-invasive bladder cancer was of a significantly lower histological grade with lower Ki-67-labeling indices than the initial muscle-invasive bladder cancer. Twelve (85.7%) of 14 patients with non-muscle-invasive bladder cancer recurrence achieved disease-free status. The multivariate analysis revealed that multiplicity, grade and tumor size were significantly correlated with the recurrence (P= 0.0001, 0.0442 and 0.0412, respectively). Most of the recurrences after bladder-preserving therapy were cases of non-muscle-invasive bladder cancer. The recurrence pattern and characteristics of the tumors did not differ from those of primary non-muscle-invasive bladder cancer. Patients with high-risk factors would be candidates for prophylactic intravesical therapy for non-muscle-invasive bladder cancer recurrence.


Cardiac Physiology of Pregnancy.
Although the physiology of the heart and vascular system has not changed, there are many things we have learned and are still learning today. Research related to heart adaptations during pregnancy has been performed since the 1930s. Since the mid-1950s, researchers began to look at changes in the maternal cardiovascular system during exercise while pregnant. Research related to exercise during pregnancy and offspring heart development began and has continued since the 1970s. We will review the normal female cardiovascular system adaptations to pregnancy in general. Additionally, topics related to maternal cardiac adaptations to pregnancy during acute exercise, as well as the chronic conditioning response from exercise training will be explored. Since physical activity during pregnancy influences fetal development, the fetal cardiac development will be discussed in regards to acute and chronic maternal exercise. Similarly, the influence of various types of maternal exercise on acute and chronic fetal heart responses will be described. Briefly, the topics related to how and if there is maternal-fetal synchrony will be explained. Lastly, the developmental changes of the fetal cardiovascular system that persist after birth will be explored. Overall, the article will discuss maternal cardiac physiology related to changes with normal pregnancy, and exercise during pregnancy, as well as fetal cardiac physiology related to changes with normal development, and exercise during pregnancy as well as developmental changes in offspring after birth.


Symmetry theorems on the forward and backward scattering Mueller matrices for light scattering from a nonspherical dielectric scatterer.
The symmetry theorems on the complete forward and backward scattering Mueller matrices for light scattering from a single dielectric scatterer (as opposed to an ensemble of scatterers) are systematically and thoroughly analyzed. Symmetry operations considered include discrete rotations about the incident direction and mirror planes not coinciding with the scattering plane. For forward scattering we find sixteen different symmetry shapes (not including the totally asymmetric one), which may be classified into five symmetry classes, with identical reductions in the forward scattering matrices for all symmetry shapes that fall into the same symmetry class. For backward scattering we find only four different symmetry shapes, which may be classified into only two symmetry classes. The forward scattering symmetry theorems also lead to a symmetry theorem on the total extinction cross section. Based on the conclusions of this work it should be possible to design quick and nondestructive methods for the identification of certain small objects, when suitable partial information about the objects to be identified is already available. A promising practical example is given.


Computer-assisted surgery prevents complications during peri-acetabular osteotomy.
The aim of study is to evaluate the accuracy of a navigation system during curved peri-acetabular osteotomy (CPO). Forty-seven patients (53 hips) with hip dysplasia were enrolled and underwent CPO with or without navigation during surgery. Clinical and radiographical evaluations were performed and compared between the navigation group and non-navigation group, post-operatively. The clinical outcomes were not significantly different between the navigation and non-navigation groups. Furthermore, post-operative reorientation of the acetabular fragment was similar between the navigation and non-navigation groups. However, the discrepancy between the pre-operative planning line and post-operative osteotomy line was significantly improved in the navigation group compared with that in the non-navigation group (p < 0.05). Further, the complication rate was significantly improved in the navigation group (p < 0.001). The accuracy of the osteotomy's position was significantly improved by using the navigation. Therefore, the use of navigation during peri-acetabular osteotomy can avoid complications.


Lineage commitment and maturation of epithelial cells in the gut.
The dynamic concepts of gut epithelial cell populations which heralded the era of modern gut cell biology have been generally substantiated by recent studies and are still being correlated with functional properties. Multipotent stem cells are anchored in specific locations along the gut epithelium where decisions concerning proliferation and differentiation/migration pathways are made. Stem cells give rise to lineage precursors which transform into transit cells and sequentially express lineage specific features during their differentiation program. Morphologically and functionally mature cells along the gut epithelium are dynamically heterogeneous. 1) The squamous lineage of the esophagus forms a stratified epithelium which has an average turnover time of about 7. 5 days. 2) In the stomach, the oxyntic pit-gland unit includes pit, zymogenic and parietal cells which respectively migrate outwards, inwards, and in both directions; their turnover times average 3, 194 and 54 days, respectively. 3) The mucous units of the pyloric antrum are populated by pit cells which migrate outwards and gland cells which migrate inwards; their turnover times are about 3 and 1-60 days, respectively. 4) In the crypt-villus units of the small intestine, while both absorptive and goblet cells migrate outwards and for each the turnover time is about 3 days, Paneth cells migrate inwards and their turnover time is about 15 days. 5) In the crypts of the descending colon, both vacuolated-columnar and goblet cells migrate outwards and for each the turnover time is about 5 days. The ascending colon has an additional cell type called deep crypt secretory cells which migrate inwards and their turnover time is about 14-21 days. Finally, while the factors maintaining the gut epithelium in a steady state remain to be elucidated, this epithelium represents a remarkable system for studying the biological features of stem cells and their hierarchies.


Generation of nondiffracting Bessel beam using digital micromirror device.
We experimentally demonstrated Bessel-like beams utilizing digital micromirror device (DMD). DMD with images imitating the equivalent axicon can shape the collimated Gaussian beam into Bessel beam. We reconstructed the 3D spatial field of the generated beam through a stack of measured cross-sectional images. The output beams have the profile of Bessel function after intensity modulation, and the beams extend at least 50 mm while the lateral dimension of the spot remains nearly invariant. Furthermore, the self-healing property has also been investigated, and all the experimental results agree well with simulated results numerically calculated through beam propagation method. Our observations demonstrate that the DMD offers a simple and efficient method to generate Bessel beams with distinct nondiffracting and self-reconstruction behaviors. The generated Bessel beams will potentially expand the applications to the optical manipulation and high-resolution fluorescence imaging owing to the unique nondiffracting property.


Temperature-dependent solvation modulates the dimensions of disordered proteins.
For disordered proteins, the dimensions of the chain are an important property that is sensitive to environmental conditions. We have used single-molecule Förster resonance energy transfer to probe the temperature-induced chain collapse of five unfolded or intrinsically disordered proteins. Because this behavior is sensitive to the details of intrachain and chain-solvent interactions, the collapse allows us to probe the physical interactions governing the dimensions of disordered proteins. We find that each of the proteins undergoes a collapse with increasing temperature, with the most hydrophobic one, λ-repressor, undergoing a reexpansion at the highest temperatures. Although such a collapse might be expected due to the temperature dependence of the classical "hydrophobic effect," remarkably we find that the largest collapse occurs for the most hydrophilic, charged sequences. Using a combination of theory and simulation, we show that this result can be rationalized in terms of the temperature-dependent solvation free energies of the constituent amino acids, with the solvation properties of the most hydrophilic residues playing a large part in determining the collapse.


De-implementation strategy to Reduce the Inappropriate use of urinary and intravenous CATheters: study protocol for the RICAT-study.
Urinary and (peripheral and central) intravenous catheters are widely used in hospitalized patients. However, up to 56% of the catheters do not have an appropriate indication and some serious complications with the use of these catheters can occur. The main objective of our quality improvement project is to reduce the use of catheters without an appropriate indication by 25-50%, and to evaluate the affecting factors of our de-implementation strategy. In a multicenter, prospective interrupted time series analysis, several interventions to avoid inappropriate use of catheters will be conducted in seven hospitals in the Netherlands. Firstly, we will define a list of appropriate indications for urinary and (peripheral and central) intravenous catheters, which will restrict the use of catheters and urge catheter removal when the indication is no longer appropriate. Secondly, after the baseline measurements, the intervention will take place, which consists of a kick-off meeting, including a competitive feedback report of the baseline measurements, and education of healthcare workers and patients. Additional strategies based on the baseline data and local conditions are optional. The primary endpoint is the percentage of catheters with an inappropriate indication on the day of data collection before and after the de-implementation strategy. Secondary endpoints are catheter-related infections or other complications, catheter re-insertion rate, length of hospital (and ICU) stay and mortality. In addition, the cost-effectiveness of the de-implementation strategy will be calculated. This study aims to reduce the use of urinary and intravenous catheters with an inappropriate indication, and as a result reduce the catheter-related complications. If (cost-) effective it provides a tool for a nationwide approach to reduce catheter-related infections and other complications. Dutch trial registry: NTR6015 . Registered 9 August 2016.


Highly enhanced liquid flows via thermoosmotic effects in soft and charged nanochannels.
Enhancing nanoscale liquid flows remains an existing challenge in nanofluidics. Here we propose the generation of highly augmented thermoosmotic (TOS) liquid flows in soft nanochannels (or nanochannels functionalized by grafting with end-charged polyelectrolyte or PE brushes) by employing an axial temperature gradient. The TOS transport is a combination of the induced-electric-field electroosmotic (EOS) transport and a thermo-chemioosmotic (TCOS) transport with the latter resulting from an induced pressure gradient on account of the changes associated with the imposition of the axial temperature gradient. The end-charged brushes develop an electric double layer (EDL) localized at the charged, non-grafted brush end. Depending on the system parameters, this EDL localization massively augments the influence of the EOS body force and the induced pressure-gradient resulting in a TOS transport in soft nanochannels that can be more than one order of magnitude larger than that in brush-free nanochannels. Given the existing notion that the presence of the brushes invariably reduces the flow strength, this result of massive flow augmentation is extremely significant and non-trivial serving as a paradigm shift in the study of liquid transport in brush-grafted nanochannels.


Altered rectal perception in irritable bowel syndrome is associated with symptom severity.
Diverging results exist regarding the connection between altered visceral perception and gastrointestinal (GI) symptoms, as well as the effects of psychological status on visceral sensitivity. We sought to investigate different aspects of rectal perception in irritable bowel syndrome (IBS) and the association with GI and psychological symptoms. We included 109 patients with IBS meeting Rome II criteria (77 women; age range, 20-71 years) and 29 healthy controls (21 women; age range, 20-68 years). They underwent rectal balloon distentions determining sensory thresholds for discomfort and pain, the perceived intensity of unpleasantness, and the viscerosomatic referral area. The fifth percentile (thresholds) and 95th percentile (unpleasantness and referral area) in controls were used to define altered perception. Questionnaires were used to assess severity of IBS-related GI symptoms and psychological symptoms. When combining the 3 aspects of perception, 67 patients (61%) had altered rectal perception. These patients, compared with normosensitive patients, more frequently reported moderate or severe pain (73% vs 44%; P < .01), bloating (73% vs 36%; P < .0001), diarrhea (47% vs 21%; P < .01), satiety (39% vs 13%; P < .01), and clinically significant anxiety (31% vs 12%; P < .05). In a multivariate analysis, only pain and bloating remained associated with altered rectal perception. Altered rectal perception is common in IBS and seems to be one important pathophysiologic factor associated with GI symptom severity in general and pain and bloating in particular. It is not just a reflection of the psychological state of the patient.


Epidemiological evaluation of colonic diverticulosis and dietary fiber in Japan.
The incidence of colonic diverticulosis was examined in 5 hospitals geographically isolated from each other in Japan during the period between mid '70s and 1986. The incidence rapidly increased in all hospitals from 3.5-9.0% in mid '70s and 8.4-23.2% in 1986. The ratio of right-sided type colonic diverticulosis was approximately 70-80% in each hospital and the ratio did not fluctuate significantly during the period. Birth cohort analysis revealed that although the incidence of right-sided diverticula had increased with aging, in groups born in more recent decades right-sided diverticula appeared in younger age than other groups. It was suggested that environmental factors rather than congenital factors may cause the increase of the incidence of right-sided colon diverticula.


Impact of obesity, overweight and underweight on life expectancy and lifetime medical expenditures: the Ohsaki Cohort Study.
People who are obese have higher demands for medical care than those of the normal weight people. However, in view of their shorter life expectancy, it is unclear whether obese people have higher lifetime medical expenditure. We examined the association between body mass index, life expectancy and lifetime medical expenditure. Prospective cohort study using individual data from the Ohsaki Cohort Study. Miyagi Prefecture, northeastern Japan. The 41 965 participants aged 40-79 years. The life expectancy and lifetime medical expenditure aged from 40 years. In spite of their shorter life expectancy, obese participants might require higher medical expenditure than normal weight participants. In men aged 40 years, multiadjusted life expectancy for those who were obese participants was 41.4 years (95% CI 38.28 to 44.70), which was 1.7 years non-significantly shorter than that for normal weight participants (p=0.3184). Multiadjusted lifetime medical expenditure for obese participants was £112 858.9 (94 954.1-131 840.9), being 14.7% non-significantly higher than that for normal weight participants (p=0.1141). In women aged 40 years, multiadjusted life expectancy for those who were obese participants was 49.2 years (46.14-52.59), which was 3.1 years non-significantly shorter than for normal weight participants (p=0.0724), and multiadjusted lifetime medical expenditure was £137 765.9 (123 672.9-152 970.2), being 21.6% significantly higher (p=0.0005). According to the point estimate, lifetime medical expenditure might appear to be higher for obese participants, despite their short life expectancy. With weight control, more people would enjoy their longevity with lower demands for medical care.


Nanomedicinal products: a survey on specific toxicity and side effects.
Due to their specific properties and pharmacokinetics, nanomedicinal products (NMPs) may present different toxicity and side effects compared to non-nanoformulated, conventional medicines. To facilitate the safety assessment of NMPs, we aimed to gain insight into toxic effects specific for NMPs by systematically analyzing the available toxicity data on approved NMPs in the European Union. In addition, by comparing five sets of products with the same active pharmaceutical ingredient (API) in a conventional formulation versus a nanoformulation, we aimed to identify any side effects specific for the nano aspect of NMPs. The objective was to investigate whether specific toxicity could be related to certain structural types of NMPs and whether a nanoformulation of an API altered the nature of side effects of the product in humans compared to a conventional formulation. The survey of toxicity data did not reveal nanospecific toxicity that could be related to certain types of structures of NMPs, other than those reported previously in relation to accumulation of iron nanoparticles (NPs). However, given the limited data for some of the product groups or toxicological end points in the analysis, conclusions with regard to (a lack of) potential nanomedicine-specific effects need to be considered carefully. Results from the comparison of side effects of five sets of drugs (mainly liposomes and/or cytostatics) confirmed the induction of pseudo-allergic responses associated with specific NMPs in the literature, in addition to the side effects common to both nanoformulations and regular formulations, eg, with liposomal doxorubicin, and possibly liposomal daunorubicin. Based on the available data, immunotoxicological effects of certain NMPs cannot be excluded, and we conclude that this end point requires further attention.


Species distribution and susceptibility profile of yeasts isolated from blood cultures: results of a multicenter active laboratory-based surveillance study in Argentina.
The Mycology Department of the Instituto Nacional de Enfermedades Infecciosas "Dr. C. Malbrán", conducted the Second National Multicenter Survey on Fungemia due to Yeasts in Argentina. The aim was to obtain updated data of the frequency of the causative species encountered and their in vitro susceptibility to seven antifungal agents. Yeast species were identified by micromorphological and biochemical studies. Antifungal susceptibility testing was performed by the reference microdilution method E.Def 7.1 of the European Committee on Antibiotic Susceptibility Testing (EUCAST). A total of 461 viable yeasts were identified. The most frequent species were: Candida albicans (38.4 %), Candida parapsilosis (26 %), Candida tropicalis (15.4 %) and Candida glabrata (4.3 %). Other uncommon species, such as Candida viswanathii (0.6 %), Candida haemulonii (0.4 %), Candida inconspicua (0.2 %) and Candida fermentati (0.2 %) were also isolated. Among the Candida spp., 5.4 % and 1.6 % were resistant to fluconazole and voriconazole, respectively. Itraconazole and caspofungin were the most efficient agents against all Candida spp. tested (MIC < 1 mg/l). For anidulafungin, 21.6 % of C. parapsilosis showed a MIC value of 4 mg/l. Fluconazole was less active against 53.1 % of Cryptococcus neoformans (MIC > 8 mg/l), 75 % of Trichosporon spp., and 100 % of Rhodotorula spp., Geotrichum candidum, Saccharomyces cerevisiae. The global percentage of mortality was 20 %. The presence of uncommon species reinforces the need for performing continuous laboratory surveillance in order to monitor possible changes, not only in the epidemiological distribution of species, but also in the resistance to antifungal drugs.


Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study.
People with Huntington's disease (HD) have been observed to have lower rates of cancers. To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis.


Gait and foot clearance parameters obtained using shoe-worn inertial sensors in a large-population sample of older adults.
In order to distinguish dysfunctional gait, clinicians require a measure of reference gait parameters for each population. This study provided normative values for widely used parameters in more than 1,400 able-bodied adults over the age of 65. We also measured the foot clearance parameters (i.e., height of the foot above ground during swing phase) that are crucial to understand the complex relationship between gait and falls as well as obstacle negotiation strategies. We used a shoe-worn inertial sensor on each foot and previously validated algorithms to extract the gait parameters during 20 m walking trials in a corridor at a self-selected pace. We investigated the difference of the gait parameters between male and female participants by considering the effect of age and height factors. Besides; we examined the inter-relation of the clearance parameters with the gait speed. The sample size and breadth of gait parameters provided in this study offer a unique reference resource for the researchers.


Titling indigenous communities protects forests in the Peruvian Amazon.
Developing countries are increasingly decentralizing forest governance by granting indigenous groups and other local communities formal legal title to land. However, the effects of titling on forest cover are unclear. Rigorous analyses of titling campaigns are rare, and related theoretical and empirical research suggests that they could either stem or spur forest damage. We analyze such a campaign in the Peruvian Amazon, where more than 1,200 indigenous communities comprising some 11 million ha have been titled since the mid-1970s. We use community-level longitudinal data derived from high-resolution satellite images to estimate the effect of titling between 2002 and 2005 on contemporaneous forest clearing and disturbance. Our results indicate that titling reduces clearing by more than three-quarters and forest disturbance by roughly two-thirds in a 2-y window spanning the year title is awarded and the year afterward. These results suggest that awarding formal land titles to local communities can advance forest conservation.


The Barrel stent: new treatment option for stent-assisted coiling of wide-necked bifurcation aneurysms-results of a single-center study.
The Barrel stent is a laser cut stent designed for stent-assisted coil embolization of wide-necked bifurcation or branch aneurysms with a single device, with the purpose of lowering the metal-to-artery ratio and its inherent risk of thromboembolic complications of multiple stents. We report our early experiences with this device in 17 patients in this retrospective single-center analysis. 17 consecutive patients who underwent stent-assisted coil embolization of wide-necked bifurcation aneurysms with the Barrel stent were retrospectively identified. We analyzed the feasibility of successful deployment and post-treatment angiographic results. Adverse events, clinical outcome, and angiographic follow-up results were also analyzed. Aneurysms were located in the internal carotid artery (n=3), the middle cerebral artery (n=9), the anterior communicating artery (n=3), and the basilar artery (n=2). In the immediate post-treatment angiography, adequate occlusion (neck remnant or total occlusion) was observed in 16/17 (94.1%) of aneurysms. One patient experienced a transient ischemic attack. No permanent neurologic deficits were observed. 13/17 (76.5%) patients underwent short-term follow-up angiography after 3 months, all of which showed adequate occlusion of the aneurysm. In this small retrospective single-center analysis we show that stent-assisted coiling with the Barrel stent is a safe and effective option for the endovascular treatment of intracranial wide-necked bifurcation aneurysms.


Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations.
Hypokalemic periodic paralysis and normokalemic periodic paralysis are caused by mutations of the gating charge-carrying arginine residues in skeletal muscle Na(V)1.4 channels, which induce gating pore current through the mutant voltage sensor domains. Inward sodium currents through the gating pore of mutant R666G are only approximately 1% of central pore current, but substitution of guanidine for sodium in the extracellular solution increases their size by 13- +/- 2-fold. Ethylguanidine is permeant through the R666G gating pore at physiological membrane potentials but blocks the gating pore at hyperpolarized potentials. Guanidine is also highly permeant through the proton-selective gating pore formed by the mutant R666H. Gating pore current conducted by the R666G mutant is blocked by divalent cations such as Ba(2+) and Zn(2+) in a voltage-dependent manner. The affinity for voltage-dependent block of gating pore current by Ba(2+) and Zn(2+) is increased at more negative holding potentials. The apparent dissociation constant (K(d)) values for Zn(2+) block for test pulses to -160 mV are 650 +/- 150 microM, 360 +/- 70 microM, and 95.6 +/- 11 microM at holding potentials of 0 mV, -80 mV, and -120 mV, respectively. Gating pore current is blocked by trivalent cations, but in a nearly voltage-independent manner, with an apparent K(d) for Gd(3+) of 238 +/- 14 microM at -80 mV. To test whether these periodic paralyses might be treated by blocking gating pore current, we screened several aromatic and aliphatic guanidine derivatives and found that 1-(2,4-xylyl)guanidinium can block gating pore current in the millimolar concentration range without affecting normal Na(V)1.4 channel function. Together, our results demonstrate unique permeability of guanidine through Na(V)1.4 gating pores, define voltage-dependent and voltage-independent block by divalent and trivalent cations, respectively, and provide initial support for the concept that guanidine-based gating pore blockers could be therapeutically useful.


Approaching the adiabatic timescale with machine learning.
The control and manipulation of quantum systems without excitation are challenging, due to the complexities in fully modeling such systems accurately and the difficulties in controlling these inherently fragile systems experimentally. For example, while protocols to decompress Bose-Einstein condensates (BECs) faster than the adiabatic timescale (without excitation or loss) have been well developed theoretically, experimental implementations of these protocols have yet to reach speeds faster than the adiabatic timescale. In this work, we experimentally demonstrate an alternative approach based on a machine-learning algorithm which makes progress toward this goal. The algorithm is given control of the coupled decompression and transport of a metastable helium condensate, with its performance determined after each experimental iteration by measuring the excitations of the resultant BEC. After each iteration the algorithm adjusts its internal model of the system to create an improved control output for the next iteration. Given sufficient control over the decompression, the algorithm converges to a solution that sets the current speed record in relation to the adiabatic timescale, beating out other experimental realizations based on theoretical approaches. This method presents a feasible approach for implementing fast-state preparations or transformations in other quantum systems, without requiring a solution to a theoretical model of the system. Implications for fundamental physics and cooling are discussed.


French ccAFU guidelines – Update 2018–2020: Bladder cancer
To propose updated French guidelines for non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers. A Medline search was achieved between 2015 and 2018, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence. Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS < 1) and renal function (creatinine clearance > 60 mL/min) allow it (only in 50 % of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival. These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC.


Chopping and Changing: the Evolution of the Flavin-dependent Monooxygenases.
Flavin-dependent monooxygenases play a variety of key physiological roles and are also very powerful biotechnological tools. These enzymes have been classified into eight different classes (A-H) based on their sequences and biochemical features. By combining structural and sequence analysis, and phylogenetic inference, we have explored the evolutionary history of classes A, B, E, F, and G and demonstrate that their multidomain architectures reflect their phylogenetic relationships, suggesting that the main evolutionary steps in their divergence are likely to have arisen from the recruitment of different domains. Additionally, the functional divergence within in each class appears to have been the result of other mechanisms such as a complex set of single-point mutations. Our results reinforce the idea that a main constraint on the evolution of cofactor-dependent enzymes is the functional binding of the cofactor. Additionally, a remarkable feature of this family is that the sequence of the key flavin adenine dinucleotide-binding domain is split into at least two parts in all classes studied here. We propose a complex set of evolutionary events that gave rise to the origin of the different classes within this family.


Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response.
Gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, safe in clinical trials for inflammatory bowel disease (PL 10, PLD 116, PLD 14736, Pliva, Croatia)) has a particular cytoprotective/adaptive cytoprotective activity. The cytoprotective/adaptive cytoprotection researches largely neglect that stomach distension could per se jeopardize the mucosal integrity, with constantly stretched mucosa and blood vessels, and sphincters more prone for reflux induction. After absolute alcohol instillation in fully distended rat stomach, gastric, esophageal and duodenal lesions occur. Throughout next 3 min, left gastric artery blood vessels clearly disappear at the serosal site, indicative for loss of vessels both integrity and function. Contrary, constant vessels presentation could predict the beneficial effect of applied agent. After pentadecapeptide BPC 157 instillation into the stomach the vessels presentation remains constant, and lesions of stomach, esophagus, and duodenum are inhibited. Standards (atropine, ranitidine, omeprazole) could only slightly improve the vessels presentation compared to control values, and they have only a partial effect on the lesions. In this review we emphasize BPC 157 unusual stability, and some of its important effects: effectiveness against various lesions in gastrointestinal tract, on nitric oxide (NO)-system, and NO-agents effects, on somatosensory neurons, salivary glands function, recovery of AMP-ADP-ATP system, endothelium protection, effect on endothelin, and on angiogenesis promotion. It also antagonizes other alcohol effects, including acute and chronic intoxication. Given peripherally, it counteracts the consequence of central dopamine system disturbances (receptor blockade), and induces serotonin release in substantia nigra. Therapeutic potential of BPC 157 as a cytoprotective agent is also seen in its capability to heal various wounds. Given directly into the stomach, BPC 157 instantly recovers disturbed lower esophageal and pyloric sphincter pressure in rats after 12-20 months of untreated esophagitis. All these could be suggestive for its role as a natural protectant in gastric juice with particular function throughout stomach distension.


Retrospective investigation of automated hematology analyzer-determined indicators of neutrophil activation in blood samples from horses with asthma.
To investigate indicators of neutrophil activation in the blood of healthy and asthma-affected horses and assess associations between corticosteroid treatment and these variables. 48 horses (14 with severe equine asthma [SEA], 21 with mild to moderate equine asthma [MEA], and 13 healthy controls). In a 3-part retrospective study, hematology analyzer data for horses included in previous studies were reviewed. Neutrophil size, neutrophil light absorbance (NLA), and myeloperoxidase (MPO) index were recorded. Data for each variable were compared among groups for the entire study sample (part 1). Changes in each variable were assessed for one subset of horses (5 SEA-affected and 6 controls) after treatment for 2 weeks with dexamethasone (0.06 mg/kg, PO, q 24 h; part 2) and for another subset (8 SEA-affected horses) after the same treatment and after a 1-week posttreatment washout period (part 3). All 3 variables were significantly greater for the SEA group, compared with the MEA and control groups in part 1. Following dexamethasone treatment, the control- and SEA-group NLA and MPO index significantly decreased and SEA-group neutrophil size significantly decreased in part 2; immediate posttreatment results for SEA-affected horses were similar in part 3, with significantly increased neutrophil size and nonsignificant increases in NLA and MPO index following washout. Results suggested horses with exacerbated SEA have larger neutrophils that contain more MPO, compared with neutrophils of MEA-affected and healthy control horses. The clinical value of these variables for the diagnosis of equine asthma was deemed limited owing to data overlap among groups.


Traditional Chinese medicine practices used in COVID-19 (Sars-cov 2/Coronavirus-19) treatment in clinic and their effects on the cardiovascular system.
The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.


Analysis of 23 364 patient-generated, physician-reviewed malpractice claims from a non-tort, blame-free, national patient insurance system: lessons learned from Sweden.
In Sweden, patient malpractice claims are handled administratively and compensated if an independent physician review confirms patient injury resulting from medical error. Full access to all malpractice claims and hospital discharge data for the country provided a unique opportunity to assess the validity of patient claims as indicators of medical error and patient injury. To determine: (1) the percentage of patient malpractice claims validated by independent physician review, (2) actual malpractice claims rates (claims frequency / clinical volume) and (3) differences between Swedish and other national malpractice claims rates. Design, setting and material: Swedish national malpractice claims and hospital discharge data were combined, and malpractice claims rates were determined by county, hospital, hospital department, surgical procedure, patient age and sex and compared with published studies on medical error and malpractice. From 1997 to 2004, there were 23 364 inpatient malpractice claims filed by Swedish patients treated at hospitals reporting 11 514 798 discharges. The overall claims rate, 0.20%, was stable over the period of study and was similar to that found in other tort and administrative compensation systems. Over this 8-year period, 49.5% (range 47.0-52.6%) of filed claims were judged valid and eligible for compensation. Claims rates varied significantly across hospitals; surgical specialties accounted for 46% of discharges, but 88% of claims. There were also large differences in claims rates for procedures. Patient-generated malpractice claims, as collected in the Swedish malpractice insurance system and adjusted for clinical volumes, have a high validity, as assessed by standardised physician review, and provide unique new information on malpractice risks, preventable medical errors and patient injuries. Systematic collection and analysis of patient-generated quality of care complaints should be encouraged, regardless of the malpractice compensation system in use.


Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53.
Etiology of aberrant social behavior consistently points to a strong polygenetic component involved in fundamental developmental pathways, with the potential of being enhanced by defects in bioenergetics. To this end, the occurrence of social deficits and mitochondrial outcomes were evaluated in conditional Pten (Phosphatase and tensin homolog) haplo-insufficient mice, in which only one allele was selectively knocked-out in neural tissues. Pten mutations have been linked to Alzheimer's disease and syndromic autism spectrum disorders, among others. By 4-6 weeks of age, Pten insufficiency resulted in the increase of several mitochondrial Complex activities (II-III, IV and V) not accompanied by increases in mitochondrial mass, consistent with an activation of the PI3K/Akt pathway, of which Pten is a negative modulator. At 8-13 weeks of age, Pten haplo-insufficient mice did not show significant behavioral abnormalities or changes in mitochondrial outcomes, but by 20-29 weeks, they displayed aberrant social behavior (social avoidance, failure to recognize familiar mouse, and repetitive self-grooming), macrocephaly, increased oxidative stress, decreased cytochrome c oxidase (CCO) activity (50%) and increased mtDNA deletions in cerebellum and hippocampus. Mitochondrial dysfunction was the result of a downregulation of p53-signaling pathway evaluated by lower protein expression of p21 (65% of controls) and the CCO chaperone SCO2 (47% of controls), two p53-downstream targets. This mechanism was confirmed in Pten-deficient striatal neurons and, HCT 116 cells with different p53 gene dosage. These results suggest a unique pathogenic mechanism of the Pten-p53 axis in mice with aberrant social behavior: loss of Pten (via p53) impairs mitochondrial function elicited by an early defective assembly of CCO and later enhanced by the accumulation of mtDNA deletions. Consistent with our results, (i) SCO2 deficiency and/or CCO activity defects have been reported in patients with learning disabilities including autism and (ii) mutated proteins in ASD have been found associated with p53-signaling pathways.


The primary transcriptome, small RNAs and regulation of antimicrobial resistance in Acinetobacter baumannii ATCC 17978.
We present the first high-resolution determination of transcriptome architecture in the priority pathogen Acinetobacter baumannii. Pooled RNA from 16 laboratory conditions was used for differential RNA-seq (dRNA-seq) to identify 3731 transcriptional start sites (TSS) and 110 small RNAs, including the first identification in A. baumannii of sRNAs encoded at the 3' end of coding genes. Most sRNAs were conserved among sequenced A. baumannii genomes, but were only weakly conserved or absent in other Acinetobacter species. Single nucleotide mapping of TSS enabled prediction of -10 and -35 RNA polymerase binding sites and revealed an unprecedented base preference at position +2 that hints at an unrecognized transcriptional regulatory mechanism. To apply functional genomics to the problem of antimicrobial resistance, we dissected the transcriptional regulation of the drug efflux pump responsible for chloramphenicol resistance, craA. The two craA promoters were both down-regulated >1000-fold when cells were shifted to nutrient limited medium. This conditional down-regulation of craA expression renders cells sensitive to chloramphenicol, a highly effective antibiotic for the treatment of multidrug resistant infections. An online interface that facilitates open data access and visualization is provided as 'AcinetoCom' (http://bioinf.gen.tcd.ie/acinetocom/).


Influenza vaccine efficacy induced by orally administered recombinant baculoviruses.
Although vaccine delivery through the oral route remains the most convenient and safest way for mass immunization purposes, this method is limited by the requirement for large antigen doses and low vaccine efficacy. In this study, we generated recombinant baculoviruses (rBVs) expressing influenza hemagglutinin (A/PR/8/34) and orally delivered a low dose of rBVs to evaluate its vaccine efficacy in mice. Intranasal rBV vaccination was included in the whole experiment for comparison. We found that oral vaccination elicited high levels of virus-specific IgG and IgA antibody responses in both serum and mucosal samples (lung, tracheal, intestinal, fecal and vaginal). Surprisingly, complete protection from the lethal influenza challenge was observed, as indicated by reductions in the virus titer, inflammatory cytokine production, body weight change, and enhanced survival. These results suggest that oral delivery of the influenza rBV vaccine induces mucosal and systemic immunity, which protect mice from the lethal influenza virus challenge. Oral delivery of baculovirus vaccines can be developed as an effective vaccination route.


Comparison of cellular response to anorganic bone matrix/cell binding peptide and allogenic cranial bone after sinus augmentation in rhesus monkeys.
This study compared cellular responses of maxillary sinuses after augmentation with anorganic bovine-derived hydroxyapatite matrix linked to the cell binding polypeptide P-15 (ABM/P-15) or PepGen P-15 and allogenic freeze-dried cranial bone slabs. Five adult Macaque fascicularis monkeys were used. On one side, the floor of the sinus was augmented with ABM/P-15, while the other side was augmented with 2 cranial bone slabs. Trephine bone biopsies were obtained 6, 12, and 24 weeks postgrafting. Animals were sacrificed 8 months after grafting. Soft X-ray microradiography was used to determine bone density. The volume fraction (Vv) of regenerated bone, the number of mesenchymal cells, and the numbers of proliferating cell nuclear antigen (PCNA)- and alkaline phosphatase-positive cells at different augmentation sites were measured and compared. Basal bone heights were calculated at surgery and compared with total heights of the augmented sinus floors 8 months postgrafting. Bone formation, number of mesenchymal cells, PCNA index, and alkaline phosphatase index were significantly higher for the ABM/P-15 side than for the allogenic bone-augmented side. Both sides ended with a significant increase in bone height. The PCNA index decreased significantly over time (P < .05), while the alkaline phosphatase index increased significantly (P < .05) over time on both sides. Both graft materials have led to significant augmentation of the floor of the maxillary sinus with new bone; however, new bone formation and maturation were faster on the ABM/P-15 sites.


Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.
Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.


Circadian and multiday seizure periodicities, and seizure clusters in canine epilepsy.
Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.


Reliability and validity of the KIPPPI: an early detection tool for psychosocial problems in toddlers.
The KIPPPI (Brief Instrument Psychological and Pedagogical Problem Inventory) is a Dutch questionnaire that measures psychosocial and pedagogical problems in 2-year olds and consists of a KIPPPI Total score, Wellbeing scale, Competence scale, and Autonomy scale. This study examined the reliability, validity, screening accuracy and clinical application of the KIPPPI. Parents of 5959 2-year-old children in the Rotterdam area, the Netherlands, were invited to participate in the study. Parents of 3164 children (53.1% of all invited parents) completed the questionnaire. The internal consistency was evaluated and in subsamples the test-retest reliability and concurrent validity with regard to the Child Behavioral Checklist (CBCL). Discriminative validity was evaluated by comparing scores of parents who worried about their child's upbringing and parent's that did not. Screening accuracy of the KIPPPI was evaluated against the CBCL by calculating the Receiver Operating Characteristic (ROC) curves. The clinical application was evaluated by the relation between KIPPPI scores and the clinical decision made by the child health professionals. Psychometric properties of the KIPPPI Total score, Wellbeing scale, Competence scale and Autonomy scale were respectively: Cronbach's alphas: 0.88, 0.86, 0.83, 0.58. Test-retest correlations: 0.80, 0.76, 0.73, 0.60. Concurrent validity was as hypothesised. The KIPPPI was able to discriminate between parents that worried about their child and parents that did not. Screening accuracy was high (>0.90) for the KIPPPI Total score and for the Wellbeing scale. The KIPPPI scale scores and clinical decision of the child health professional were related (p<0.05), indicating a good clinical application. The results in this large-scale study of a diverse general population sample support the reliability, validity and clinical application of the KIPPPI Total score, Wellbeing scale and Competence scale. Also, the screening accuracy of the KIPPPI Total score and Wellbeing scale were supported. The Autonomy scale needs further study.


Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study.
Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly "snapshots"; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few "lessons learned." The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.