An Open Platform for Seamless Sensor Support in Healthcare for the Internet of Things.
Population aging and increasing pressure on health systems are two issues that demand solutions. Involving and empowering citizens as active managers of their health represents a desirable shift from the current culture mainly focused on treatment of disease, to one also focused on continuous health management and well-being. Current developments in technological areas such as the Internet of Things (IoT), lead to new technological solutions that can aid this shift in the healthcare sector. This study presents the design, development, implementation and evaluation of a platform called Common Recognition and Identification Platform (CRIP), a part of the CareStore project, which aims at supporting caregivers and citizens to manage health routines in a seamless way. Specifically, the CRIP offers sensor-based support for seamless identification of users and health devices. A set of initial requirements was defined with a focus on usability limitations and current sensor technologies. The CRIP was designed and implemented using several technologies that enable seamless integration and interaction of sensors and people, namely Near Field Communication and fingerprint biometrics for identification and authentication, Bluetooth for communication with health devices and web services for wider integration with other platforms. Two CRIP prototypes were implemented and evaluated in laboratory during a period of eight months. The evaluations consisted of identifying users and devices, as well as seamlessly configure and acquire vital data from the last. Also, the entire Carestore platform was deployed in a nursing home where its usability was evaluated with caregivers. The evaluations helped assess that seamless identification of users and seamless configuration and communication with health devices is feasible and can help enable the IoT on healthcare applications. Therefore, the CRIP and similar platforms could be transformed into a valuable enabling technology for secure and reliable IoT deployments on the healthcare sector.


Differentiation between glucose-induced desensitization of insulin secretion and beta-cell exhaustion in the HIT-T15 cell line.
Refractoriness of the pancreatic beta-cell to glucose stimulation plays a role in the secretory defect of NIDDM, but the mechanisms underlying this refractoriness are not clear. The purpose of this study was to determine whether the HIT-T15 pancreatic beta-cell line can be used as an investigative model for refractoriness of glucose-induced insulin secretion and, if so, whether the mechanism for this refractoriness involves alteration in stimulus-secretion coupling (desensitization) or results from exhaustion of insulin stores. In perifusion experiments, acute insulin responses (AIRs) in HIT-T15 cells progressively diminished during consecutive 5-min glucose (11.1 mmol/l) pulses (G) given every 20 min (G1=9.2+/-1.3, G2=4.1+/-1.0, G3=2.7+/-0.7, G4=2.5+/-1.1 microU/ml). To determine whether this refractoriness for glucose extended to the potentiating effects of glucose on nonglucose secretagogues, cells were challenged with arginine after desensitization with glucose. In HIT-T15 cells, the response to the arginine pulse (16.7+/-5.2 microU/ml) after three glucose pulses was significantly less (P < 0.01) than the response to a control arginine pulse (29.6+/-12.1 microU/ml) preceded by an infusion of buffer in the absence of glucose pulses. Variable rest periods after desensitization allowed recovery of the AIR in HIT-T15 cells; responses 30, 60, 90, and 120 min after the desensitization procedure increased in a stepwise fashion (3.8+/-2.7, 4.5+/-2.7, 7.8+/-5.2, and 9.7+/-5.3 microU/ml, respectively). To differentiate desensitization from exhaustion of insulin stores, studies were performed in the presence of epinephrine, a potent inhibitor of insulin secretion. In HIT-T15 cells, after three pulses of glucose during the epinephrine infusion, epinephrine was discontinued and the insulin response to a fourth pulse was assessed. The G4 AIR (1.9+/-0.6 microU/ml) was markedly less than a control G4 AIR (5.4+/-1.2 microU/ml) that followed an epinephrine infusion alone with no concurrent glucose pulses. Beta-cell refractoriness was also induced in the HIT-T15 cell using 45-min steady-state infusions of glucose. Cells were exposed to a 45-min infusion of either 3.7 or 11.1 mmol/l glucose, rested for 20 min in the absence of glucose, and then challenged with a 5-min, 11.1 mmol/l glucose pulse. In both cases, the AIR to the 5-min pulse (10.2+/-5.1 and 2.9+/-1.4 microU/ml after the 3.7 and 11.1 mmol/l infusion, respectively) was lower than the AIR to a control pulse (27.4+/-5.9 microU/ml) not preceded by glucose infusion. These studies demonstrated that the HIT-T15 cell line is an appropriate model for studying mechanisms of beta-cell refractoriness to glucose signaling. The short-term intensive glucose stimulation paradigms used in our studies induced an abnormality in insulin secretion that is consistent with desensitization but not beta-cell exhaustion.


Geological and hydrochemical prerequisites of unexpectedly high biodiversity in spring ecosystems at the landscape level.
This study explores the factors affecting the biodiversity of diatoms, vegetation with focus on bryophytes, and invertebrates with focus on water mites, in a series of 16 spring-habitats. The springs are located primarily from the mountainous part of the Emilia-Romagna Region (Northern Apennines, Italy), and two pool-springs from agricultural and industrial lowland locations. Overall, data indicate that biological diversity (Shannon-Wiener, α-diversity) within individual springs was relatively low, e.g.: Sdiatoms = 0-46, Swater-mites = 0-11. However, when examined at the regional scale, they hosted a very high total number of taxa (γ-diversity; Sdiatoms = 285, Swater-mites = 40), including several new or putatively-new species, and many Red-List taxa. This pattern suggested there is high species turnover among springs, as well as high distinctiveness of individual spring systems. A key goal was to assess the hydrogeological and hydrochemical conditions associated with this high regional-pool species richness, and to provide a guide to future conservation strategies. There was a striking variety of geological conditions (geodiversity, captured mainly with lithotype and aquifer structure) across the study region, which led to wide variation in the hydrosphere, especially in conductivity and pH. Agriculture and industrial activities (anthroposphere) in the lowlands resulted in nutrient enrichment and other forms of pollution. Across all 16 spring-systems, several hydrogeological conditions most strongly influenced the presence or absence of particular biota and were determinants of species importance: spring-head morphology, hydroperiod, discharge, current velocity, and elemental concentration. These findings have important practical consequences for conservation strategies. Our data show that it is imperative to protect entire regional groups of springs, including representatives of the different ecomorphological spring types, lithologies, and degrees of human influence. These findings suggest that springs, when studied from an ecohydrogeological perspective, are excellent systems in which to further investigate and understand geo-biodiversity relationships.


Separation of small metabolites and lipids in spectra from biopsies by diffusion-weighted HR-MAS NMR: a feasibility study.
High Resolution Magic Angle Spinning (HR-MAS) NMR allows metabolic characterization of biopsies. HR-MAS spectra from tissues of most organs show strong lipid contributions that are overlapping metabolite regions, which hamper metabolite estimation. Metabolite quantification and analysis would benefit from a separation of lipids and small metabolites. Generally, a relaxation filter is used to reduce lipid contributions. However, the strong relaxation filter required to eliminate most of the lipids also reduces the signals for small metabolites. The aim of our study was therefore to investigate different diffusion editing techniques in order to employ diffusion differences for separating lipid and small metabolite contributions in the spectra from different organs for unbiased metabonomic analysis. Thus, 1D and 2D diffusion measurements were performed, and pure lipid spectra that were obtained at strong diffusion weighting (DW) were subtracted from those obtained at low DW, which include both small metabolites and lipids. This subtraction yielded almost lipid free small metabolite spectra from muscle tissue. Further improved separation was obtained by combining a 1D diffusion sequence with a T2-filter, with the subtraction method eliminating residual lipids from the spectra. Similar results obtained for biopsies of different organs suggest that this method is applicable in various tissue types. The elimination of lipids from HR-MAS spectra and the resulting less biased assessment of small metabolites have potential to remove ambiguities in the interpretation of metabonomic results. This is demonstrated in a reproducibility study on biopsies from human muscle.


Procedural justice as autonomy regulation.
The present research investigated the relation between autonomy (i.e., freedom of choice) and procedural justice. Three studies tested the hypothesis that people would be particularly sensitive to the fairness of decision-making procedures when they experience deprivation of autonomy needs. Study 1 indicated that procedural justice judgments indeed were influenced more strongly by variations in decision-making procedures among participants who experienced little autonomy in their life. In Study 2, these findings were conceptually replicated by manipulating whether participants were provided with choice on an issue that was unrelated to the outcomes of the subsequent decision-making process. Study 3 revealed evidence for the hypothesis in a field setting. It is concluded that procedural justice is functional to regulate basic autonomy needs.


Surfer's Myelopathy: A Rare Form of Spinal Cord Infarction in Novice Surfers: A Systematic Review.
Surfer's myelopathy is a rare, acute, atraumatic myelopathy that occurs in novice surfers. To review the literature and to present an illustrative case. Medical literature was queried for all reports of this condition, systematically abstracted, and analyzed. An illustrative case that provides the most definitive support for a vascular cause is presented. Treatment considerations based on prior cases and expert opinions are provided. Sixty-four cases of surfer's myelopathy have been reported to date. This atraumatic thoracic/conus medullaris myelopathy with only a 42% neurological recovery rate almost uniformly affects young, healthy, novice surfers who have no pre-existent spinal disease. Symptoms usually start with back pain and rapidly progress to complete or incomplete myelopathy. T2 magnetic resonance images show increased signal in the central spinal cord within 24 to 72 hours. Gadolinium enhancement and diffusion-weighted imaging are not helpful. Angiography has been underused. Angiogram in our case showed the absence of a right T12 radicular artery and no artery of Adamkiewicz, which, along with clinical findings, support the vascular origin theory. Incomplete cases often improve within 24 hours of onset, whereas no improvement has been reported for American Spinal Injury Association class A cases. Several acute interventions have been tried. Steroids are most common, and patients receiving steroids improved 55% of the time with no reported adverse effects. Surfer's myelopathy is a clinical entity associated with complete deficit in >50% of cases. Its prognosis is almost exclusively dictated by severity at presentation/nadir. Thus, publicizing this rare but serious condition (within and outside the medical literature) may be an effective intervention.


Measures of frailty in population-based studies: an overview.
Although research productivity in the field of frailty has risen exponentially in recent years, there remains a lack of consensus regarding the measurement of this syndrome. This overview offers three services: first, we provide a comprehensive catalogue of current frailty measures; second, we evaluate their reliability and validity; third, we report on their popularity of use. In order to identify relevant publications, we searched MEDLINE (from its inception in 1948 to May 2011); scrutinized the reference sections of the retrieved articles; and consulted our own files. An indicator of the frequency of use of each frailty instrument was based on the number of times it had been utilized by investigators other than the originators. Of the initially retrieved 2,166 papers, 27 original articles described separate frailty scales. The number (range: 1 to 38) and type of items (range of domains: physical functioning, disability, disease, sensory impairment, cognition, nutrition, mood, and social support) included in the frailty instruments varied widely. Reliability and validity had been examined in only 26% (7/27) of the instruments. The predictive validity of these scales for mortality varied: for instance, hazard ratios/odds ratios (95% confidence interval) for mortality risk for frail relative to non-frail people ranged from 1.21 (0.78; 1.87) to 6.03 (3.00; 12.08) for the Phenotype of Frailty and 1.57 (1.41; 1.74) to 10.53 (7.06; 15.70) for the Frailty Index. Among the 150 papers which we found to have used at least one of the 27 frailty instruments, 69% (n = 104) reported on the Phenotype of Frailty, 12% (n = 18) on the Frailty Index, and 19% (n = 28) on one of the remaining 25 instruments. Although there are numerous frailty scales currently in use, reliability and validity have rarely been examined. The most evaluated and frequently used measure is the Phenotype of Frailty.


Suggested guidelines for pharmacotherapy curricula in family medicine residency training: recommendations from the Society of Teachers of Family Medicine Group on Pharmacotherapy.
Rational drug use has increasingly received public policy attention in efforts to maintain quality health care at lower costs. Prescribing habits are developed during residency training, and education regarding rational drug use should be an integral part of the residency curricula. Considering that many medical errors in family medicine are related to incorrect medication management, there is need for a focused education in pharmacotherapy. This paper outlines suggested guidelines for pharmacotherapy curricula in family medicine residency training, as recommended by the Society of Teachers of Family Medicine Group on Pharmacotherapy. A pharmacotherapy curriculum should include common conditions managed in family medicine, as well as general principles of pharmacotherapy. This should allow for repeated exposure to core topics over a 3-year cycle and be delivered in various settings (didactic teaching, longitudinal active learning, point-of-care education, and rotations). The curriculum should apply and evaluate pharmacotherapy education according to the six core competencies of the Accreditation Council for Graduate Medical Education (ACGME). Although physician faculty can be responsible for pharmacotherapy education, a clinical pharmacist is uniquely qualified to provide this service. Overall, family medicine residents need comprehensive instruction in pharmacotherapy to develop rational prescribing habits. A structured pharmacotherapy curriculum may assist in achieving this goal and in meeting the ACGME core competencies for residency training.


Factors Associated with HIV Testing History among Pregnant Women and Their Partners in Georgia: The ANRS 12127 Prenahtest Trial.
Despite the benefits of timely diagnosis of HIV infection and the wide availability of VCT services, the acceptance of HIV testing and counseling still remains a challenge in Georgia. The goal of our study was to assess the history of HIV testing and associated factors among pregnant women. The recruitment of study participants took place during routine antenatal care visits at one of the large Maternity Hospitals in Tbilisi, capital of Georgia. A total of 491 pregnant women were included in the sample. More than a third of women (38.5%) reported that they were tested for HIV before the current pregnancy and almost all of them (91.5%) were tested during previous pregnancies. Bivariate analysis revealed statistically significant association of women's history of HIV testing with age, education level, remunerated activity, history of STI, and multiparity. In multivariate analysis, the only independent predictor of being HIV tested was ever being pregnant. In conclusion, HIV testing history among women at reproductive age was poor in Georgia. Women mostly received HIV testing at prenatal centers. Efforts should be made to promote HIV testing in primary care settings, which would increase its acceptability and overall testing rate in the population.


Design of a biochemical circuit motif for learning linear functions.
Learning and adaptive behaviour are fundamental biological processes. A key goal in the field of bioengineering is to develop biochemical circuit architectures with the ability to adapt to dynamic chemical environments. Here, we present a novel design for a biomolecular circuit capable of supervised learning of linear functions, using a model based on chemical reactions catalysed by DNAzymes. To achieve this, we propose a novel mechanism of maintaining and modifying internal state in biochemical systems, thereby advancing the state of the art in biomolecular circuit architecture. We use simulations to demonstrate that the circuit is capable of learning behaviour and assess its asymptotic learning performance, scalability and robustness to noise. Such circuits show great potential for building autonomous in vivo nanomedical devices. While such a biochemical system can tell us a great deal about the fundamentals of learning in living systems and may have broad applications in biomedicine (e.g. autonomous and adaptive drugs), it also offers some intriguing challenges and surprising behaviours from a machine learning perspective.


[Cancer patients adherence and symptom management: the influence of the patient-physician relationship].
Appropriate management of cancer symptoms positively influences quality of life. Inappropriate symptom management, disease recurrence, co-morbidity and death result from lack of medication adherence. Factors influencing adherence are multidimensional and include personal attributes, knowledge and beliefs regarding the disease and medication, self-efficacy and social support. The patient-physician relationship is a significant factor of influence in patient medication adherence and ultimate positive outcomes. If patients are satisfied with the relationship, they are highly likely to comply with health provider advice. Improving patient-physician relationships can effectively promote patient medication adherence. In cancer pain management and adjuvant hormone therapy for breast cancer, regular follow-up examinations have a positive impact. The physician-patient relationship with regard to cancer patient satisfaction is a relatively new topic of discussion, and many implications are scarcely understood. However, the physician-patient relationship should not be ignored as a factor in cancer symptoms management, especially with regard to promoting compliance behavior.


Capacitive Field-Effect Biosensor Studying Adsorption of Tobacco Mosaic Virus Particles.
Plant virus-like particles, and in particular, tobacco mosaic virus (TMV) particles, are increasingly being used in nano- and biotechnology as well as for biochemical sensing purposes as nanoscaffolds for the high-density immobilization of receptor molecules. The sensitive parameters of TMV-assisted biosensors depend, among others, on the density of adsorbed TMV particles on the sensor surface, which is affected by both the adsorption conditions and surface properties of the sensor. In this work, Ta2O5-gate field-effect capacitive sensors have been applied for the label-free electrical detection of TMV adsorption. The impact of the TMV concentration on both the sensor signal and the density of TMV particles adsorbed onto the Ta2O5-gate surface has been studied systematically by means of field-effect and scanning electron microscopy methods. In addition, the surface density of TMV particles loaded under different incubation times has been investigated. Finally, the field-effect sensor also demonstrates the label-free detection of penicillinase immobilization as model bioreceptor on TMV particles.


The development and evaluation of a PDA-based method for public health surveillance data collection in developing countries.
EpiData and Epi Info are often used together by public health agencies around the world, particularly in developing countries, to meet their needs of low-cost public health data management; however, the current open source data management technology lacks a mobile component to meet the needs of mobile public health data collectors. The goal of this project is to explore the opportunity of filling this gap through developing and trial of a personal digital assistant (PDA) based data collection/entry system. It evaluated whether such a system could increase efficiency and reduce data transcription errors for public surveillance data collection in developing countries represented by Fiji. A generic PDA-based data collection software eSTEPS was developed. The software and the data collected using it directly interfaces with EpiData. A field trial was conducted to test the viability of public health surveillance data collection using eSTEPS. The design was a randomised, controlled trial with cross-over design. 120 participants recruited from the Fiji School of Medicine were randomly assigned to be interviewed by one of six interviewers in one of the two ways: (1) paper-based survey followed by PDA survey and (2) PDA survey followed by paper-based survey. Data quality was measured by error rates (logical range errors/inconsistencies, skip errors, missing values, date or time field errors and incorrect data type). Work flow and cost were evaluated in three stages of the survey process: (1) preparation of data collection instrument, (2) data collection and (3) data entry, validation and cleaning. User acceptance was also evaluated in the two groups of participants: (1) data collectors and (2) survey participants. None of the errors presented in 20.8% of the paper questionnaires was found in the data set collected using PDA. Sixty-two percent of the participants perceived that the PDA-based questionnaire took less time to complete. Data entry, validation and cleaning for the PDA-based data collection from 120 participants took a total of 1.5h, a 93.26% reduction of time from 20.5h required using paper and pen. The cost is also significantly reduced with PDA-based protocol. Both data collectors and participants prefer to use PDA instead of paper for data collection. The trial results prove that eSTEPS is a feasible solution for public health surveillance data collection in the field. Several deficiencies of the software were also identified and would be addressed in the next version. eSTEPS offers the potential to meet the need for an effective mobile public health data collection tool for use in the field. The eSTEPS field trial proves that PDA was more efficient than paper for public health survey data collection. It also significantly reduced errors in data entry. The later benefit was derived from the software providing its users with the flexibility of building their own constraints to control the data type, range and logic of data entry.


Hearing and loud music exposure in 14-15 years old adolescents.
Adolescent exposure to loud music has become a social and health problem whose study demands a holistic approach. The aims of the current study are: (1) To detect early noise-induced hearing loss among adolescents and establish its relationship with their participation in musical recreational activities and (2) to determine sound immission levels in nightclubs and personal music players (PMPs). The participants consisted in 172 14-15 years old adolescents from a technical high school. Conventional and extended high frequency audiometry, transient evoked otoacoustic emissions and questionnaire on recreational habits were administered. Hearing threshold levels (HTLs) were classified as: normal (Group 1), slightly shifted (Group 2), and significantly shifted (Group 3). The musical general exposure (MGE), from participation in recreational musical activities, was categorized in low, moderate, and high exposure. The results revealed an increase of HTL in Group 2 compared with Group 1 (P < 0.01), in Group 3 compared with Group 2 (P < 0.05) only in extended high frequency range, in Group 3 compared with Group 1 (P < 0.01). Besides, a decrease in mean global amplitude, reproducibility and in frequencies amplitude in Group 2 compared with Group 1 (P < 0.05) and in Group 3 compared with Group 1 (P < 0.05). A significant difference (P < 0.05) was found in Group 1's HTL between low and high exposure, showing higher HTL in high exposure. The sound immission measured in nightclubs (107.8-112.2) dBA and PMPs (82.9-104.6) dBA revealed sound levels risky for hearing health according to exposure times. It demonstrates the need to implement preventive and hearing health promoting actions in adolescents.


Challenges and future perspective for dengue vector control in the Western Pacific Region.
Dengue remains a significant public health issue in the Western Pacific Region. In the absence of a vaccine, vector control is the mainstay for dengue prevention and control. In this paper we describe vector surveillance and vector control in the Western Pacific countries and areas. Vector surveillance and control strategies used by countries and areas of the Western Pacific Region vary. Vector control strategies include chemical, biological and environmental management that mainly target larval breeding sites. The use of insecticides targeting larvae and adult mosquitoes remains the mainstay of vector control programmes. Existing vector control tools have several limitations in terms of cost, delivery and long-term sustainability. However, there are several new innovative tools in the pipeline. These include Release of Insects Carrying a Dominant Lethal system and Wolbachia, an endosymbiotic bacterium, to inhibit dengue virus in the vector. In addition, the use of biological control such as larvivorous fish in combination with community participation has potential to be scaled up. Any vector control strategy should be selected based on evidence and appropriateness for the entomological and epidemiological setting and carried out in both inter-epidemic and epidemic periods. Community participation and interagency collaboration are required for effective and sustainable dengue prevention and control. Countries and areas are now moving towards integrated vector management.


Teriflunomide Does Not Change Dynamics of Nadph Oxidase Activation and Neuronal Dysfunction During Neuroinflammation.
The multiple sclerosis therapeutic teriflunomide is known to block the de novo synthesis of pyrimidine in mitochondria by inhibiting the enzyme dihydroorotate-dehydrogenase (DHODH). The metabolic processes of oxidative phosphorylation and glycolysis are further possible downstream targets. In healthy adult mice, high levels of dihydroorotate-dehydrogenase (DHODH) activity are measured in the central nervous system (CNS), and DHODH inhibition may cause indirect effects on reactive oxygen species production and NADPH oxidase (NOX) mediated oxidative stress, known to be key aspects of the inflammatory response of the CNS. However, little is known about the effect of teriflunomide on the dynamics of NOX activation in CNS cells and subsequent alterations of neuronal function in vivo. In this study, we employed fluorescence lifetime imaging (FLIM) and phasor analysis of the endogeneous fluorescence of NAD(P)H (nicotinamide adenine dinucleotide phosphate) in the brain stem of mice to visualize the effect of teriflunomide on cellular metabolism. Furthermore, we simultaneously studied neuronal Ca2+ signals in transgenic mice with a FRET-based Troponin C Ca2+ sensor based (CerTN L15) quantified using FRET-FLIM. Hence, we directly correlated neuronal (dys-)function indicated by steadily elevated calcium levels with metabolic activity in neurons and surrounding CNS tissue. Employing our intravital co-registered imaging approach, we could not detect any significant alteration of NOX activation after incubation of the tissue with teriflunomide. Furthermore, we could not detect any changes of the inflammatory induced neuronal dysfunction due to local treatment with teriflunomide. Concerning drug safety, we can confirm that teriflunomide has no metabolic effects on neuronal function in the CNS tissue during neuroinflammation at concentrations expected in orally treated patients. The combined endogenous FLIM and calcium imaging approach developed by us and employed here uniquely meets the need to monitor cellular metabolism as a basic mechanism of tissue functions in vivo.


Detection of vancomycin resistance in enterococcus species isolated from clinical samples and feces of colonized patients by phenotypic and genotypic methods.
The aim of this study was to find out the clinical correlation between the presence of vancomycin-resistant genes (van A and van B) and their expression as detected by phenotypic tests in colonized patients and in clinical isolates. Enterococci were isolated from various clinical samples and also from fecal specimens of colonized patients at the time of admission, after 48 h and after 5 days of admission. Identification to species level was done using standard methods. Vancomycin susceptibility in Enterococci was detected by disc diffusion test. Minimum inhibitory concentration was determined by agar dilution method. Multiplex polymerase chain reaction (PCR) was used to detect the presence of van genes. Out of all the clinical and fecal samples processed, 12.0% isolates were either vancomycin resistant or vancomycin intermediate. Further, these isolates carried van A or van B genes as confirmed by PCR methods. Expression of van A gene was found to be more in Enterococcus faecalis (28.3%) as compared to Enterococcus faecium (25.0%) in both clinical and fecal isolates. 16.6% strains of E. faecium and 15.0% strains each of E. faecalis and Enterococcus gallinarum were found to carry van B genes. The overall prevalence of vancomycin resistant Enterococci (VRE) in colonized patients was about 9.6%. Prior administration of antibiotics had significant effect (P = 0.001) on VRE carriage. Urinary tract infection was the most common infection caused by vancomycin susceptible Enterococci (VSE), 105/214 (49.0%) and VRE, 13/36 (36.1%). There was no significant difference (P = 0.112) in the distribution of VRE and VSE in different infection types. Both clinical and fecal VRE showed maximum resistance to penicillin, ampicillin, and piperacillin. Resistance to linezolid was 2.8% in clinically isolated VRE. VRE in our study were found to be resistant to a number of commonly used antibiotics. The frequency of isolation of vancomycin resistant E. faecalis (VRE.fs), which is highly virulent, and the number of strains harboring van A gene in our hospital setup is high and needs to be addressed.


Comparison of electromagnetically induced transparency between silver, gold, and aluminum metamaterials at visible wavelengths.
Electromagnetically induced transparency (EIT)-like effects in silver, gold, and aluminum metamaterials consisting of dipole resonators and quadrupole resonators were demonstrated at visible wavelengths. Optical characteristics of the metamaterials could be controlled by the gap distance between the two resonators. EIT-like effects were observed at wavelengths between 603 and 789 nm, 654 and 834 nm, and 462 and 693 nm for the silver, gold, and aluminum EIT metamaterials, respectively. At wavelengths longer than around 650 nm, the silver metamaterials had better EIT-like features. At wavelengths shorter than around 650 nm, on the other hand, the aluminum metamaterials showed promising EIT-like results.


Compliance with minimum price and legal age for cigarette purchase laws: evidence from NYC in advance of raising purchase age to 21.
New York City (NYC) raised the minimum purchase age for cigarettes from 18 to 21 on 1 August 2014. The new law is intended to decrease current smoking rates and smoking initiation among the city's youth. Assessment of compliance with existing cigarette sales and tax laws could aid in determining what may be needed for successful implementation of the city's new law. To assess compliance with minimum sales price and purchase age laws in NYC, before change in law. Ten trained field investigators purchased cigarettes from different types of retailers throughout all five NYC boroughs, resulting in 421 purchases. Investigators noted whether they were asked for identification and the price of their purchase. Multivariable logistic and Ordinary Least Squares regression techniques were used to assess predictors of retailer compliance with sales price and minimum purchase age laws. In 29% of purchases, investigators did not have to produce identification (p<0.05) to purchase cigarettes. Only 3.1% of sales were at prices lower than the minimum sales price. City borough was significantly associated with purchase without identification (p<0.001) and mean sales price (p<0.024). Vendor type (independent vs chain) was significantly related to investigators being able to purchase cigarettes without identification (p<0.001). Variation in compliance with existing laws suggests that more active monitoring of compliance with the new minimum legal purchase age will be required in order to realise the new law's public health potential.


Comparative genomics reveals insights into avian genome evolution and adaptation.
Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.


Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.
Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.


Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort.
Data on the frequency of extraintestinal manifestations (EIMs) in Crohn's disease (CD) and ulcerative colitis (UC) and analyses of their risk factors are scarce. We evaluated their prevalence and risk factors in a large nationwide cohort of inflammatory bowel disease (IBD) patients. IBD patients from an adult clinical cohort in Switzerland (Swiss IBD cohort study) were prospectively included. Data from validated physician enrolment questionnaires were analyzed. A total of 950 patients were included, 580 (61%) with CD (mean age 41 years) and 370 (39%) with UC (mean age 42 years). Of these, 249 (43%) of CD and 113 (31%) of UC patients had one to five EIMs. The following EIMs were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), and primary sclerosing cholangitis (CD 1%, UC 4%). Multiple logistic regression identified the following risk factors for ongoing EIM in CD: active disease (odds ratio (OR)=1.95, 95% confidence interval (CI)=1.17-3.23, P=0.01), and positive IBD family history (OR=1.77, 95% CI=1.07-2.92, P=0.025). No risk factors were identified in UC patients. EIMs are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitating their diagnosis and therapeutic management.


Ants (Formicidae): models for social complexity.
The family Formicidae (ants) is composed of more than 12,000 described species that vary greatly in size, morphology, behavior, life history, ecology, and social organization. Ants occur in most terrestrial habitats and are the dominant animals in many of them. They have been used as models to address fundamental questions in ecology, evolution, behavior, and development. The literature on ants is extensive, and the natural history of many species is known in detail. Phylogenetic relationships for the family, as well as within many subfamilies, are known, enabling comparative studies. Their ease of sampling and ecological variation makes them attractive for studying populations and questions relating to communities. Their sociality and variation in social organization have contributed greatly to an understanding of complex systems, division of labor, and chemical communication. Ants occur in colonies composed of tens to millions of individuals that vary greatly in morphology, physiology, and behavior; this variation has been used to address proximate and ultimate mechanisms generating phenotypic plasticity. Relatedness asymmetries within colonies have been fundamental to the formulation and empirical testing of kin and group selection theories. Genomic resources have been developed for some species, and a whole-genome sequence for several species is likely to follow in the near future; comparative genomics in ants should provide new insights into the evolution of complexity and sociogenomics. Future studies using ants should help establish a more comprehensive understanding of social life, from molecules to colonies.


Radiological diagnosis of periapical bone tissue lesions in endodontics: a systematic review.
This systematic review evaluates the diagnostic accuracy of radiographic methods employed to indicate presence/absence and changes over time of periapical bone lesions. Also investigated were the leads radiographic images may give about the nature of the process and the condition of the pulp in nonendodontically treated teeth. Electronic literature search included the databases PubMed, Embase and CENTRAL from January 1950 to June 2011. All languages were accepted provided there was an abstract in English. The MeSH terms were 'Cone beam computed tomography (CBCT)', 'Radiography, panoramic', 'Periapical diseases', 'Dental pulp diseases', 'Sensitivity and specificity', 'receiver operating characteristics (ROC) curve', 'Cadaver', 'Endodontics' and 'Radiography dental'. Two reviewers independently assessed abstracts and full text articles. An article was read in full text if at least one of the two reviewers considered an abstract to be potentially relevant. Altogether, 181 articles were read in full text. The GRADE approach was used to assess the quality of evidence of each radiographic method based on studies of high or moderate quality. Twenty-six studies fulfilled criteria set for inclusion. None was of high quality; 11 were of moderate quality. There is insufficient evidence that the digital intraoral radiographic technique is diagnostically as accurate as the conventional film technique. The same applies to CBCT. No conclusions can be drawn regarding the accuracy of radiological examination in identifying various forms of periapical bone tissue changes or about the pulpal condition.


Psychotropic drug use and alcohol consumption among older adults in Germany: results of the German Health Interview and Examination Survey for Adults 2008-2011.
The use and combined use of psychotropic drugs and alcohol among older adults is a growing public health concern and should be constantly monitored. Relevant studies are scarce in Germany. Using data of the most recent national health survey, we analyse prevalence and correlates of psychotropic drug and alcohol use among this population. Study participants were people aged 60-79 years (N=2508) of the German Health Interview and Examination Survey for Adults 2008-2011. Medicines used during the last 7 days were documented. Psychotropic drugs were defined as medicines acting on the nervous system (ATC code N00) excluding anaesthetics (N01), analgesics/antipyretics (N02B), but including opiate codeines used as antitussives (R05D). Alcohol consumption in the preceding 12 months was measured by frequency (drinking any alcohol-containing beverages at least once a week/a day) and quantity (alcohol consumed in grams/day; cut-offs: 10/20 g/day for women/men defining moderate and risky drinking). SPSS complex sample module was used for analysis. 21.4% of study participants use psychotropic medications, 66.9% consume alcohol moderately and 17.0% riskily, 51.0% drink alcohol at least once a week and 18.4% daily, 2.8% use psychotropic drugs combined with daily alcohol drinking. Among psychotropic drug users, 62.7% consume alcohol moderately, 14.2% riskily. The most frequently used psychotropic medications are antidepressants (7.9%) and antidementia (4.2%). Factors associated with a higher rate of psychotropic drug use are female sex, worse health status, certified disability and polypharmacy. Risky alcohol consumption is positively associated with male sex, smoking, upper social class, better health status, having no disability and not living alone. Despite the high risk of synergetic effects of psychotropic drugs and alcohol, a substantial part of older psychotropic drug users consume alcohol riskily and daily. Health professionals should talk about the additional health risks of alcohol consumption when prescribing psychotropic drugs to older adults.


Decreased exercise muscle lactate release after high altitude acclimatization.
Blood lactate concentration during exercise decreases after acclimatization to high altitude, but it is not clear whether there is decreased lactate release from the exercising muscle or if other mechanisms are involved. We measured iliac venous and femoral arterial lactate concentrations and iliac venous blood flow during cycle exercise before and after acclimatization to 4,300 m. During hypoxia, at a given O2 consumption the venous and arterial lactate concentrations, the venous and arterial concentration differences, and the net lactate release were lower after acclimatization than during acute altitude exposure. While breathing O2-enriched air after acclimatization at a given O2 consumption the venous and arterial lactate concentrations and the venous and arterial concentration differences were significantly lower, and the net lactate release tended to be lower than while breathing ambient air at sea level before acclimatization. We conclude that the lower lactate concentration in venous and arterial blood during exercise after altitude acclimatization reflected less net release of lactate by the exercising muscles, and that this likely resulted from the acclimatization process itself rather than the hypoxia per se.


Systematic Methodological Evaluation of a Multiplex Bead-Based Flow Cytometry Assay for Detection of Extracellular Vesicle Surface Signatures.
Extracellular vesicles (EVs) can be harvested from cell culture supernatants and from all body fluids. EVs can be conceptually classified based on their size and biogenesis as exosomes and microvesicles. Nowadays, it is however commonly accepted in the field that there is a much higher degree of heterogeneity within these two subgroups than previously thought. For instance, the surface marker profile of EVs is likely dependent on the cell source, the cell's activation status, and multiple other parameters. Within recent years, several new methods and assays to study EV heterogeneity in terms of surface markers have been described; most of them are being based on flow cytometry. Unfortunately, such methods generally require dedicated instrumentation, are time-consuming and demand extensive operator expertise for sample preparation, acquisition, and data analysis. In this study, we have systematically evaluated and explored the use of a multiplex bead-based flow cytometric assay which is compatible with most standard flow cytometers and facilitates a robust semi-quantitative detection of 37 different potential EV surface markers in one sample simultaneously. First, assay variability, sample stability over time, and dynamic range were assessed together with the limitations of this assay in terms of EV input quantity required for detection of differently abundant surface markers. Next, the potential effects of EV origin, sample preparation, and quality of the EV sample on the assay were evaluated. The findings indicate that this multiplex bead-based assay is generally suitable to detect, quantify, and compare EV surface signatures in various sample types, including unprocessed cell culture supernatants, cell culture-derived EVs isolated by different methods, and biological fluids. Furthermore, the use and limitations of this assay to assess heterogeneities in EV surface signatures was explored by combining different sets of detection antibodies in EV samples derived from different cell lines and subsets of rare cells. Taken together, this validated multiplex bead-based flow cytometric assay allows robust, sensitive, and reproducible detection of EV surface marker expression in various sample types in a semi-quantitative way and will be highly valuable for many researchers in the EV field in different experimental contexts.


Maternal high fat diet during critical windows of development alters adrenal cortical and medullary enzyme expression in adult male rat offspring.
We previously reported that a maternal high fat (HF) diet resulted in adult offspring with increased adiposity and hyperleptinemia. As leptin has an inhibitory effect on adrenal steroidogenesis and a stimulatory effect on epinephrine synthesis, we hypothesized that key adrenal steroidogenic and catecholaminergic enzymes would be altered in these offspring. Wistar rats were randomized into three groups at weaning: (1) control dams fed a standard control chow diet from weaning and throughout pregnancy and lactation (CON), (2) dams fed a HF diet from weaning and throughout pregnancy and lactation (MHF) and (3) dams fed standard control chow diet throughout life until conception, then fed a HF diet in pregnancy and lactation (PLHF). Dams were mated at day 100 (P100). After birth at P22 (weaning), male offspring were fed a standard control chow (con) or high fat (hf) diet. At P160, plasma samples and adrenal tissues were collected. Postweaning hf diet significantly elevated plasma corticosterone concentrations in PLHF-hf offspring compared to PLHF-con. MHF nutrition increased adrenal adrenocorticotrophic hormone receptor (ACTH-R) mRNA levels compared to CON-con. 3β-hydroxysteroid dehydrogenase (3βHSD) mRNA levels were decreased in MHF compared to PLHF offspring. Phenylethanolamine N-methyltransferase (PNMT) mRNA levels were increased in MHF-hf offspring compared to MHF-con. Plasma homocysteine (HCY) concentrations were significantly elevated in CON-hf and MHF-hf offspring compared to chow-fed offspring, associated with elevated intakes of methionine and reduced intakes of pyridoxine. Immunoreactive leptin receptor (ObRb) and PNMT were colocalized in medullary chromaffin cells. This study suggests that a postweaning HF diet in offspring induced changes in adrenal gene expression levels that are dependent upon the level of maternal nutrition.


Individualized Monitoring of Muscle Recovery in Elite Badminton.
Purpose: Individualized reference ranges for serum creatine kinase (CK) and urea are a promising tool for the assessment of recovery status in high-level endurance athletes. In this study, we investigated the application of this approach in racket sports, specifically for the monitoring of elite badminton players during the preparation for their world championships. Methods: Seventeen elite badminton players were enrolled of which 15 could be included in the final analysis. Repeated measurements of CK and urea at recovered (R) and non-recovered (NR) time points were used for the stepwise individualization of group-based, prior reference ranges as well as for the evaluation of classificatory performance. Specifically, blood samples were collected in the morning following a day off (R) or following four consecutive training days (NR), respectively. Group based reference ranges were derived from the same data. Error rates were compared between the group-based and individualized approaches using the Fisher exact test. Results: Error rates were numerically lower for the individualized as compared to the group-based approach in all cases. Improvements reached statistical significance for urea (test-pass error rate: p = 0.007; test-fail error rate: p = 0.002) but not for CK (p vs. group-based: test-pass error rate: p = 0.275, test-fail error rate: p = 0.291). Regardless of the chosen approach, the use of CK was associated with lower error rates as compared to urea. Conclusion and Practical Applications: Individualized reference ranges seem to offer diagnostic benefits in the monitoring of muscle recovery in elite badminton. The lack of significant improvements in error rates for CK is likely due to the large difference between R and NR for this parameter with error rates that are already low for the group-based approach.


Tyrannobdella rex n. gen. n. sp. and the evolutionary origins of mucosal leech infestations.
Leeches have gained a fearsome reputation by feeding externally on blood, often from human hosts. Orificial hirudiniasis is a condition in which a leech enters a body orifice, most often the nasopharyngeal region, but there are many cases of leeches infesting the eyes, urethra, vagina, or rectum. Several leech species particularly in Africa and Asia are well-known for their propensity to afflict humans. Because there has not previously been any data suggesting a close relationship for such geographically disparate species, this unnerving tendency to be invasive has been regarded only as a loathsome oddity and not a unifying character for a group of related organisms. A new genus and species of leech from Perú was found feeding from the nasopharynx of humans. Unlike any other leech previously described, this new taxon has but a single jaw with very large teeth. Phylogenetic analyses of nuclear and mitochondrial genes using parsimony and Bayesian inference demonstrate that the new species belongs among a larger, global clade of leeches, all of which feed from the mucosal surfaces of mammals. This new species, found feeding from the upper respiratory tract of humans in Perú, clarifies an expansion of the family Praobdellidae to include the new species Tyrannobdella rex n. gen. n. sp., along with others in the genera Dinobdella, Myxobdella, Praobdella and Pintobdella. Moreover, the results clarify a single evolutionary origin of a group of leeches that specializes on mucous membranes, thus, posing a distinct threat to human health.


Adenoviral gene transfer of nitric oxide synthase increases cerebral blood flow in rats.
Depletion of nitric oxide may play a role in the development of vasospasm after aneurysmal subarachnoid hemorrhage. Replenishment of nitric oxide might be a useful treatment for vasospasm. Using rats, we performed intracisternal injections of replication-defective adenovirus containing the endothelial nitric oxide synthase (eNOS) gene and determined the localization of and effect on cerebral blood flow of transgene expression. Rats underwent baseline measurement of cortical cerebral blood flow using laser Doppler flowmetry. Replication-defective adenovirus containing the Escherichia coli LacZ gene (Ad327beta-Gal, n = 2/time point) or the bovine eNOS gene (AdCD8-NOS, n = 4/time point) or physiological saline solution was injected into the cisterna magna. Cerebral blood flow was measured 1, 2, 4, 7, or 14 days later, and the animals were killed. Expression of beta-galactosidase activity from the LacZ gene was examined by histochemical staining and that of eNOS was examined by polymerase chain reaction assays of messenger ribonucleic acid. Brains were histopathologically examined for inflammation. Beta-galactosidase activity was observed throughout the leptomeninges and in some cells in the adventitia of small subarachnoid blood vessels in the Ad327beta-Gal-injected rats. Messenger ribonucleic acid for eNOS was detected in the leptomeninges and brainstem 1 and 2 days after injection of AdCD8-NOS. Rats injected with Ad327beta-Gal or physiological saline solution exhibited decreased cerebral blood flow beginning 2 days after virus injection and lasting up to 14 days after injection. Rats injected with AdCD8-NOS developed significant transient increases in cerebral blood flow 2 days after virus injection, followed by slight decreases in blood flow. There was inflammation in the subarachnoid space of all animals; the inflammation was qualitatively worse in animals injected with Ad327beta-Gal, compared with rats injected with AdCD8-NOS or saline solution. Intracisternal injection of replication-defective adenovirus containing the eNOS gene can transiently increase cerebral blood flow.


Effects of Ramadan intermittent fasting on sports performance and training: a review.
The month-long diurnal Ramadan fast imposes a major challenge to Islamic athletes. Sporting events are programmed throughout the year, with the result that training and competition are often scheduled during Ramadan. The small numbers of well-controlled studies that have examined the effects of Ramadan on athletic performance suggest that few aspects of physical fitness are negatively affected, and only modest decrements are observed. Whereas subjective feelings of fatigue and other mood indicators are often cited as implying additional stress on the athlete throughout Ramadan, most studies show these measures may not be reflected in decreases in performance. The development and early implementation of sensible eating and sleeping strategies can greatly alleviate the disruptions to training and competitiveness, thus allowing the athlete to perform at a high level while undertaking the religious intermittent fast. Nevertheless, further research is required to understand the mechanisms and energy pathways that allow athletes to maintain their performance capacities during Ramadan, and which factors are responsible for the observed decrements in performance of some individuals.


Denaturation and reactivation of dimeric human glutathione reductase--an assay for folding inhibitors.
Human glutathione reductase (GR; which catalyzes the reaction NADPH + GSSG + H+ --> 2 GSH + NADP+) is an obligatory FAD-containing homodimer of known geometry. Native human GR, a potential target of antimalarial and cytostatic agents, cannot be dissociated by dilution or by means of subunit-interface mimetics, similarly to well-studied viral dimeric proteins. However, ab initio folding and/or dimerization of human GR can be inhibited by point mutations or by peptides corresponding to subunit-interface areas, for example synthetic peptide P11, which represents the intersubunit-contact helix H11. The structure of this peptide, which might assist inhibitor design, was solved by high-resolution NMR spectroscopy. Residues 440-453, were found to be alpha helical in the isolated peptide. To quantitate the efficacy of inhibitors such as P11, we developed the following unfolding/reactivation assay. The effects of various guanidine hydrochloride (Gdn/HCl) concentrations were studied by analytical ultracentrifugation. It was shown that human GR denatured by greater than 3 M Gdn/HCl is monomeric and free of FAD. Circular-dichroism experiments at 223 nm indicated a half-life of approximately 20 s at 20 degrees C for the unfolding process. To optimize the reactivation yield, four parameters [protein concentration (x) in the range 0.3-10 microg/ml, cofactor supplementation, temperature (y: 0-32 degrees C), and time (0-72 h)] were varied systematically, and a reactivation score z was given to each constellation of parameters. This type of analysis might be useful to optimize refolding and activation yields for other proteins. For human GR, the highest recovery was found not to occur at one of the corners of the x,y plane, but close to its center. Consequently, the optimal assay conditions for folding and dimerization inhibitors are as follows. The enzyme (at 300 microg/ml) is denatured by 5 M guanidine hydrochloride/5 mM dithiothreitol, then reactivated by dilution to 1 microg/ml at pH 6.9 and 20 degrees C. In the absence of inhibitors, this procedure leads to 70% of the control activity within 8 h. Peptides representing the upper subunit interface (for instance residues 436-478) of human GR were found to inhibit refolding with EC50% values in the micromolar range, whereas fragments from other regions of the protein had no influence on this process. For peptide P11, the EC50% value was 20 microM. In conclusion, hGR, enzyme with a tight intersubunit contact area of 21 nm2, appears to be suitable for studying protein folding, dimerization, and prosthetic-group complexation in the absence and presence of compounds that inhibit these processes. There is a shortage, at least for oligomeric enzymes of eukaryotes, of published systematic studies on protein (re)activation.


Simultaneous EEG/fMRI analysis of the resonance phenomena in steady-state visual evoked responses.
The stability of the steady-state visual evoked potentials (SSVEPs) across trials and subjects makes them a suitable tool for the investigation of the visual system. The reproducible pattern of the frequency characteristics of SSVEPs shows a global amplitude maximum around 10 Hz and additional local maxima around 20 and 40 Hz, which have been argued to represent resonant behavior of damped neuronal oscillators. Simultaneous electroencephalogram/functional magnetic resonance imaging (EEG/fMRI) measurement allows testing of the resonance hypothesis about the frequency-selective increases in SSVEP amplitudes in human subjects, because the total synaptic activity that is represented in the fMRI-Blood Oxygen Level Dependent (fMRI-BOLD) response would not increase but get synchronized at the resonance frequency. For this purpose, 40 healthy volunteers were visually stimulated with flickering light at systematically varying frequencies between 6 and 46 Hz, and the correlations between SSVEP amplitudes and the BOLD responses were computed. The SSVEP frequency characteristics of all subjects showed 3 frequency ranges with an amplitude maximum in each of them, which roughly correspond to alpha, beta and gamma bands of the EEG. The correlation maps between BOLD responses and SSVEP amplitude changes across the different stimulation frequencies within each frequency band showed no significant correlation in the alpha range, while significant correlations were obtained in the primary visual area for the beta and gamma bands. This non-linear relationship between the surface recorded SSVEP amplitudes and the BOLD responses of the visual cortex at stimulation frequencies around the alpha band supports the view that a resonance at the tuning frequency of the thalamo-cortical alpha oscillator in the visual system is responsible for the global amplitude maximum of the SSVEP around 10 Hz. Information gained from the SSVEP/fMRI analyses in the present study might be extrapolated to the EEG/fMRI analysis of the transient event-related potentials (ERPs) in terms of expecting more reliable and consistent correlations between EEG and fMRI responses, when the analyses are carried out on evoked or induced oscillations (spectral perturbations) in separate frequency bands instead of the time-domain ERP peaks.


Tracking the cellulolytic activity of Clostridium thermocellum biofilms.
Microbial cellulose conversion by Clostridium thermocellum 27405 occurs predominantly through the activity of substrate-adherent bacteria organized in thin, primarily single cell-layered biofilms. The importance of cellulosic surface exposure to microbial hydrolysis has received little attention despite its implied impact on conversion kinetics. We showed the spatial heterogeneity of fiber distribution in pure cellulosic sheets, which made direct measurements of biofilm colonization and surface penetration impossible. Therefore, we utilized on-line measurements of carbon dioxide (CO2) production in continuous-flow reactors, in conjunction with confocal imaging, to observe patterns of biofilm invasion and to indirectly estimate microbial accessibility to the substrate's surface and the resulting limitations on conversion kinetics. A strong positive correlation was found between cellulose consumption and CO2 production (R2 = 0.996) and between surface area and maximum biofilm activity (R2 = 0.981). We observed an initial biofilm development rate (0.46 h-1, 0.34 h-1 and 0.33 h-1) on Whatman sheets (#1, #598 and #3, respectively) that stabilized when the accessible surface was maximally colonized. The results suggest that cellulose conversion kinetics is initially subject to a microbial limitation period where the substrate is in excess, followed by a substrate limitation period where cellular mass, in the form of biofilms, is not limiting. Accessible surface area acts as an important determinant of the respective lengths of these two distinct periods. At end-point fermentation, all sheets were digested predominantly under substrate accessibility limitations (e.g., up to 81% of total CO2 production for Whatman #1). Integration of CO2 production rates over time showed Whatman #3 underwent the fastest conversion efficiency under microbial limitation, suggestive of best biofilm penetration, while Whatman #1 exhibited the least recalcitrance and the faster degradation during the substrate limitation period. The results showed that the specific biofilm development rate of cellulolytic bacteria such as C. thermocellum has a notable effect on overall reactor kinetics during the period of microbial limitation, when ca. 20% of cellulose conversion occurs. The study further demonstrated the utility of on-line CO2 measurements as a method to assess biofilm development and substrate digestibility pertaining to microbial solubilization of cellulose, which is relevant when considering feedstock pre-treatment options.


Subnational estimates of factors associated with under-five mortality in Kenya: a spatio-temporal analysis, 1993-2014.
To improve child survival, it is necessary to describe and understand the spatial and temporal variation of factors associated with child survival beyond national aggregates, anchored at decentralised health planning units. Therefore, we aimed to provide subnational estimates of factors associated with child survival while elucidating areas of progress, stagnation and decline in Kenya. Twenty household surveys and three population censuses conducted since 1989 were assembled and spatially aligned to 47 subnational Kenyan county boundaries. Bayesian spatio-temporal Gaussian process regression models accounting for inadequate sample size and spatio-temporal relatedness were fitted for 43 factors at county level between 1993 and 2014. Nationally, the coverage and prevalence were highly variable with 38 factors recording an improvement. The absolute percentage change (1993-2014) was heterogeneous ranging between 1% and 898%. At the county level, the estimates varied across space and over time with a majority showing improvements after 2008 which was preceded by a period of deterioration (late-1990 to early-2000). Counties in Northern Kenya were consistently observed to have lower coverage of interventions and remained disadvantaged in 2014 while areas around Central Kenya had and historically have had higher coverage across all intervention domains. Most factors in Western and South-East Kenya recorded moderate intervention coverage although having a high infection prevalence of both HIV and malaria. The heterogeneous estimates necessitates prioritisation of the marginalised counties to achieve health equity and improve child survival uniformly across the country. Efforts are required to narrow the gap between counties across all the drivers of child survival. The generated estimates will facilitate improved benchmarking and establish a baseline for monitoring child development goals at subnational level.


Mechanisms of RNAi: mRNA cleavage fragments may indicate stalled RISC.
The molecular mechanism of RNA interference (RNAi) is under intense investigation. We previously demonstrated the existence of inactive siRNAs and also of mRNA cleavage in vivo in human cells. Here it is shown that some siRNAs with low activity leave mRNA cleavage fragments while an siRNA with higher activity does not. The pattern is consistent with both short-term (4-24 hours) and long-term (1-4 days) time-series. Analysis of the putative 3' mRNA cleavage product showed high GC content immediately after the cleavage point. The cleavage fragments might indicate a stalled or slowed RNAi cleavage complex - possibly in the RISC enzyme restoration phase - and thus constitute a novel explanation for the existence of inactive siRNAs.


Stand-alone diamond binary phase transmission gratings for the EUV band.
We report on the development of true free-standing phase transmission gratings for the extreme ultraviolet band. An ultra-nanocrystalline, 300 nm thin diamond film on a backside etched silicon wafer is structured by electron-beam lithography to periods of 1 μm. In this way, flat and stable gratings of 400 μm in diameter are fabricated. First-order net efficiencies up to 28% are obtained from measurements at a synchrotron beamline within a wavelength range from 5.0 nm to 8.3 nm, whereas the 0th order is suppressed to 1% near 6.8 nm. Higher diffraction orders up to the 3rd one contribute less than 7% in sum to the far-field pattern.


Evaluation of HA negatively charged membranes in the recovery of human adenoviruses and hepatitis A virus in different water matrices.
Human adenoviruses (HAdV) and hepatitis A virus (HAV) are shed in the faeces and consequently may be present in environmental waters, resulting in an increase in pathogen concentration that can affect water quality and human health. The aim of this study was to evaluate an adsorption-elution method which utilizes negatively charged membrane HA to determine the efficient recovery of HAdV and HAV from different water matrices and to combine this procedure with a qualitative molecular method (nested RT-PCR and nested PCR). The best efficiency recovery was achieved in distilled water and treated wastewater effluent (100%) for both viruses and in recreational lagoon water for HAV (100%). The efficiency recovery was 10% for HAdV and HAV in seawater and 10% for HAdV in lagoon water. The viral detection limit by nested PCR for HAV in water samples ranged between 20-0.2 FFU/mL and 250 and 25 TCID50/mL for HAdV. In conclusion, these results suggest that the HA negatively charged membranes vary their efficiency for recovery of viral concentration depending upon the types of both enteric viruses and water matrices.


Finger force sharing during an adapted power grip task.
This study analyses the finger force sharing using power grip task with adapted experimental conditions. This paradigm limits as much as possible the external constraints when the Index (I), Middle (M), Ring (R) and Little (L) fingers act simultaneously: the thumb did not oppose the other fingers and no secondary moments were applied to the wrist. The motor control of these two parameters was limited in contrary to the previous paradigms of the literature. The results showed that the force sharing, the force deficit and the location of the neutral line were different in this condition compared to a classical finger pressing task. We suggest that the observed behaviour was due to the peripheral architecture (muscle bellies, multi-digit motor units) more than the control of the constraints of the tasks. We propose to use this paradigm in further fundamental studies and also during clinical programmes to evaluate the rehabilitation of peripheral architecture characteristics and also finger control.


The ethics of killing human/great-ape chimeras for their organs: a reply to Shaw et al.
The aim of this paper is to critically examine David Shaw, Wybo Dondorp, and Guido de Wert's arguments in favour of the procurement of human organs from human/nonhuman-primate chimeras, specifically from great-ape/human chimeras. My main claim is that their arguments fail and are in need of substantial revision. To prove this I first introduce the topic, and then reconstruct Shaw et al.'s position and arguments. Next, I show that Shaw et al.: (1) failed to properly apply the subsidiarity and proportionality principles; (2) neglected species overlapping cases in their ethical assessment; (3) ignored the ethics literature on borderline persons; and (4) misunderstood McMahan's two-tiered moral theory. These mistakes render an important part of their conclusions either false or problematic to the point that they would no longer endorse them. Finally I will briefly mention a possible multipolar solution to the human organ shortage problem that would reduce the need for chimeras' organs.


The rationale and design of the national peripartum cardiomyopathy registries in Turkey: The ARTEMIS-I and ARTEMIS-II studies.
Peripartum cardiomyopathy (PPCM) is left ventricular (LV) systolic dysfunction with an ejection fraction of ≤45% occurring in the later stages of pregnancy or soon after delivery. Although various risk factors have been identified, the exact cause of the disease is unknown. Unlike most countries in the European region, Turkey has yet to determine the current PPCM burden. A registry for this purpose does not exist. To close this gap, the A RegisTry of pEripartuM cardIomyopathy in Turkish patientS (ARTEMIS-I and ARTEMIS-II), was planned and endorsed by the Turkish Society of Cardiology. The aim of this manuscript is to describe the rationale and design of the ARTEMIS-I and ARTEMIS-II registries. ARTEMIS was designed to be the nationwide PPCM registry of Turkey, with the goal of identifying problems and opportunities while improving quality and consistency in the medical care of PPCM patients. A second goal is to determine the clinical characteristics pertinent to patients in this region. The ARTEMIS registry will consist of 2 arms. All secondary and tertiary cardiology centers have been electronically invited to participate in ARTEMIS-I, which will be conducted to assess the current standard of care and outcome measures. Centers will be asked to enroll PPCM patients admitted to their clinic in last 5 years retrospectively. Eligibility criteria will consist of pregnant or early postpartum woman without a previous history of heart failure (HF) or known pathology associated with HF, LV ejection fraction ≤45%, and exclusion of other causes of LV systolic dysfunction. ARTEMIS-II will consist of the prospective enrollment of patients. The nationwide PPCM registries, ARTEMIS-I and ARTEMIS-II, are designed to determine the current status of medical care, provide insights into nature of the disease, and suggest solutions on how to improve care and outcomes in these patients.


Test-retest reliability of the PRIME-MD: limitations in diagnosing mental disorders in primary care.
The primary care evaluation of mental disorders (PRIME-MD) can be seen as characteristic for successive refinements of criteria and structured interview techniques for diagnosing psychiatric disorders in primary care. It is one of the most widely used instruments, but there is no evidence to support its test-retest reliability. With 1-week intervals between interviews, a test-retest study of the PRIME-MD was conducted in a general practice population of 100 distressed patients (20- to 60-years old) who were on sick leave. Almost everyone (89%) received one or more diagnoses at both measurements, and there was fair total agreement (kappa = 0.27). The best agreement was found for more severe threshold disorders [major depressive disorder (kappa = 0.58), dysthymia (kappa = 0.57), and generalized anxiety disorder (kappa = 0.59)], while we found indefinite results for the sub-threshold disorders [anxiety disorder not otherwise specified (NOS) (kappa =.30), minor depressive disorder (kappa = -0.03), and somatoform disorder NOS (kappa = 0.11)]. The PRIME-MD is one of the few instruments in primary care that actually diagnoses specific mental disorders according to the DSM criteria. However, there was a failure to adequately classify sub-threshold disorders. Mental disorders, as seen in primary care, encompass important specific symptoms and clinical syndromes that vary in duration and severity over time, but they also encompass an admixture of somatic and psychological symptoms that do not match current diagnostic systems. This most likely resulted in methodological uncertainty about the level of agreement. Diagnostic criteria in psychiatry need to be operationalized for use in primary care and require further evaluation.


Immunogenic assessment of plant-produced human papillomavirus type 16 L1/L2 chimaeras.
Cervical cancer is caused by infection with human papillomaviruses (HPV) and is a global concern, particularly in developing countries, which have ~80% of the burden. HPV L1 virus-like particle (VLP) type-restricted vaccines prevent new infections and associated disease. However, their high cost has limited their application, and cytological screening programmes are still required to detect malignant lesions associated with the nonvaccine types. Thus, there is an urgent need for cheap second-generation HPV vaccines that protect against multiple types. The objective of this study was to express novel HPV-16 L1-based chimaeras, containing cross-protective epitopes from the L2 minor capsid protein, in tobacco plants. These L1/L2 chimaeras contained epitope sequences derived from HPV-16 L2 amino acid 108-120, 56-81 or 17-36 substituted into the C-terminal helix 4 (h4) region of L1 from amino acid 414. All chimaeras were expressed in Nicotiana benthamiana via an Agrobacterium-mediated transient system and targeted to chloroplasts. The chimaeras were highly expressed with yields of ~1.2 g/kg plant tissue; however, they assembled differently, indicating that the length and nature of the L2 epitope affect VLP assembly. The chimaera containing L2 amino acids 108-120 was the most successful candidate vaccine. It assembled into small VLPs and elicited anti-L1 and anti-L2 responses in mice, and antisera neutralized homologous HPV-16 and heterologous HPV-52 pseudovirions. The other chimaeras predominantly assembled into capsomeres and other aggregates and elicited weaker humoral immune responses, demonstrating the importance of VLP assembly for the immunogenicity of candidate vaccines.


Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.
A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.


Improved radiological assessment of neonatal feeding tubes.
In about one-fifth of radiographs performed in neonates, no exact gastric feeding tube position can be defined. To determine whether injection of air via feeding tube before taking radiographs improves radiological assessment of its position. In the study group (n=153), air was injected via gastric feeding tube before taking a radiograph. The tube position on radiographs was compared with a blinded control group (n=381) with no injection of air. The definition of exact gastric tube position was possible in 95% of the study group compared with 78% in the control group (p<0.001). Injection of air before taking a radiograph significantly improves the definition of exact gastric feeding tube position in neonates.


Platelets and Their Interactions with Other Immune Cells.
Platelets are anucleate blood cells, long known to be critically involved in hemostasis and thrombosis. In addition to their role in blood clots, increasing evidence reveals significant roles for platelets in inflammation and immunity. However, the notion that platelets represent immune cells is not broadly recognized in the field of Physiology. This article reviews the role of platelets in inflammation and immune responses, and highlights their interactions with other immune cells, including examples of major functional consequences of these interactions.


Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells.
O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma.


Dissecting the impact of CO2 and pH on the mechanisms of photosynthesis and calcification in the coccolithophore Emiliania huxleyi.
Coccolithophores are important calcifying phytoplankton predicted to be impacted by changes in ocean carbonate chemistry caused by the absorption of anthropogenic CO2 . However, it is difficult to disentangle the effects of the simultaneously changing carbonate system parameters (CO2 , bicarbonate, carbonate and protons) on the physiological responses to elevated CO2 . Here, we adopted a multifactorial approach at constant pH or CO2 whilst varying dissolved inorganic carbon (DIC) to determine physiological and transcriptional responses to individual carbonate system parameters. We show that Emiliania huxleyi is sensitive to low CO2 (growth and photosynthesis) and low bicarbonate (calcification) as well as low pH beyond a limited tolerance range, but is much less sensitive to elevated CO2 and bicarbonate. Multiple up-regulated genes at low DIC bear the hallmarks of a carbon-concentrating mechanism (CCM) that is responsive to CO2 and bicarbonate but not to pH. Emiliania huxleyi appears to have evolved mechanisms to respond to limiting rather than elevated CO2 . Calcification does not function as a CCM, but is inhibited at low DIC to allow the redistribution of DIC from calcification to photosynthesis. The presented data provides a significant step in understanding how E. huxleyi will respond to changing carbonate chemistry at a cellular level.


Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis.
The microbiome can promote or disrupt human health by influencing both adaptive and innate immune functions. We tested whether bacteria that normally reside on human skin participate in host defense by killing Staphylococcus aureus, a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease. High-throughput screening for antimicrobial activity against S. aureus was performed on isolates of coagulase-negative Staphylococcus (CoNS) collected from the skin of healthy and AD subjects. CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects. A low frequency of strains with antimicrobial activity correlated with colonization by S. aureus The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including Staphylococcus epidermidis and Staphylococcus hominis These AMPs were strain-specific, highly potent, selectively killed S. aureus, and synergized with the human AMP LL-37. Application of these CoNS strains to mice confirmed their defense function in vivo relative to application of nonactive strains. Strikingly, reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S. aureus These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.


Vessel caliber--a potential MRI biomarker of tumour response in clinical trials.
Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research.


The SPT10 and SPT21 genes of Saccharomyces cerevisiae.
Mutations in the SPT10 and SPT21 genes were originally isolated as suppressors of Ty and LTR (delta) insertion mutations in Saccharomyces cerevisiae, and the genes were shown to be required for normal transcription at a number of loci in yeast. Now we have cloned, sequenced, mapped and mutagenized SPT10 and SPT21. Since the spt10 mutation used to clone SPT10 resulted in very poor transformation efficiency, a novel method making use of the kar1-1 mutation was used. Neither SPT gene is essential for growth, and constructed null alleles cause phenotypes similar to those caused by spontaneous mutations in the genes. spt10 null alleles are strong suppressor mutations and cause extremely slow growth. Certain spt10 spontaneous alleles are good suppressors but have a normal growth rate, suggesting that the SPT10 protein may have two distinct functions. An amino acid sequence motif that is similar to the Zn-finger motif was found in SPT10. Mutation of the second Cys residue in this motif resulted in loss of complementation of the suppression phenotype but a normal growth rate. Thus, this motif may reside in a part of the SPT10 protein that is important for transcriptional regulation but not for normal growth. Both the SPT10 and SPT21 proteins are relatively tolerant of large deletions; in both cases deletions of the C-terminus resulted in at least partially functional proteins; also, a large internal deletion in SPT21 was phenotypically wild type.


Latitudinal variation in climate-associated genes imperils range edge populations.
The ecological impacts of increasing global temperatures are evident in most ecosystems on Earth, but our understanding of how climatic variation influences natural selection and adaptive resilience across latitudes remains largely unknown. Latitudinal gradients allow testing general ecosystem-level theories relevant to climatic adaptation. We assessed differences in adaptive diversity of populations along a latitudinal region spanning highly variable temperate to subtropical climates. We generated and integrated information from environmental mapping, phenotypic variation and genome-wide data from across the geographical range of the rainbowfish Melanotaenia duboulayi, an emerging aquatic system for studies of climate change. We detected, after controlling for spatial population structure, strong interactions between genotypes and environment associated with variation in stream flow and temperature. Some of these hydroclimate-associated genes were found to interact within functional protein networks that contain genes of adaptive significance for projected future climates in rainbowfish. Hydroclimatic selection was also associated with variation in phenotypic traits, including traits known to affect fitness of rainbowfish exposed to different flow environments. Consistent with predictions from the "climatic variability hypothesis," populations exposed to extremes of important environmental variables showed stronger adaptive divergence and less variation in climate-associated genes compared to populations at the centre of the environmental gradient. Our findings suggest that populations that evolved at environmental range margins and at geographical range edges may be more vulnerable to changing climates, a finding with implications for predicting adaptive resilience and managing biodiversity under climate change.


W+ W- production at hadron colliders in next to next to leading order QCD.
Charged gauge boson pair production at the Large Hadron Collider allows detailed probes of the fundamental structure of electroweak interactions. We present precise theoretical predictions for on-shell W+ W- production that include, for the first time, QCD effects up to next to next to leading order in perturbation theory. As compared to next to leading order, the inclusive W+ W- cross section is enhanced by 9% at 7 TeV and 12% at 14 TeV. The residual perturbative uncertainty is at the 3% level. The severe contamination of the W+ W- cross section due to top-quark resonances is discussed in detail. Comparing different definitions of top-free W+ W- production in the four and five flavor number schemes, we demonstrate that top-quark resonances can be separated from the inclusive W+ W- cross section without a significant loss of theoretical precision.


How Inclusive, User-Centered Design Research Can Improve Psychological Therapies for Psychosis: Development of SlowMo.
Real-world implementation of psychological interventions for psychosis is poor. Barriers include therapy being insufficiently usable and useful for a diverse range of people. User-centered, inclusive design approaches could improve the usability of therapy, which may increase uptake, adherence, and effectiveness. This study aimed to optimize the usability of an existing psychological intervention, Thinking Well, which targets reasoning processes in paranoia using a basic digital interface. We conducted inclusive, user-centered design research characterized by purposive sampling of extreme users from the margins of groups, ethnographic investigation of the problem context, and iterative prototyping of solutions. The UK Design Council's double diamond method was used. This consisted of 4 phases: discover, including a case series of Thinking Well, stakeholder interviews, desk research, user profiling, system mapping, and a mood board; define, consisting of workshops to synthesize findings and generate the design brief; develop, involving concept workshops and prototype testing; and deliver, in which the final minimal viable product was storyboarded and iteratively coded. Consistent with our previous work, the Thinking Well case series showed medium to large effects on paranoia and well-being and small effects on reasoning. These were maintained at follow-up despite some participants reporting difficulties with the therapy interface. Insights from the discover phase confirmed that usability was challenged by information complexity and poor accessibility. Participants were generally positive about the potential of technology to be enjoyable, help manage paranoia, and provide tailored interpersonal support from therapists and peers, although they reported privacy and security concerns. The define phase highlighted that the therapy redesign should support monitoring, simplify information processing, enhance enjoyment and trust, promote personalization and normalization, and offer flexible interpersonal support. During the develop phase over 60 concepts were created, with 2 key concepts of thoughts visualized as bubbles and therapy as a journey selected for storyboarding. The output of the deliver phase was a minimal viable product of an innovative digital therapy, SlowMo. SlowMo works by helping people to notice their worries and fast thinking habits, and encourages them to slow down for a moment to find ways of feeling safer. A Web app supports the delivery of 8 face-to-face sessions, which are synchronized to a native mobile app. SlowMo makes use of personalization, ambient information, and visual metaphors to tailor the appeal, engagement, and memorability of therapy to a diversity of needs. Feasibility testing has been promising, and the efficacy of SlowMo therapy is now being tested in a multicentered randomized controlled trial. The study demonstrates that developments in psychological theory and techniques can be enhanced by improving the usability of the therapy interface to optimize its impact in daily life.


An Aggregate Urine Analysis Tool to Detect Acute Dehydration.
PURPOSE: Urine sampling has previously been evaluated for detecting dehydration in young male athletes. The present study investigated whether urine analysis can serve as a measure of dehydration in men and women of a wide age span. METHODS: Urine sampling and body weight measurement were undertaken before and after recreational physical exercise (median time: 90 minutes) in 57 volunteers aged between 17 and 69 years (mean age: 42). Urine analysis included urine color, osmolality, specific gravity, and creatinine. RESULTS: The volunteers' body weight decreased 1.1% (mean) while they exercised. There were strong correlations between all four urinary markers of dehydration (r = 0.73 to 0.84, P < 0.001). Researchers constructed a composite dehydration index graded from 1 to 6 based on these markers. This index changed from 2.70 before exercising to 3.55 after exercising, which corresponded to dehydration of 1.0% as given by a preliminary reference curve based on seven previous studies in athletes. Men were slightly dehydrated at baseline (mean: 1.9%) compared to women (mean: 0.7%; P < 0.001), while age had no influence on the results. A final reference curve that considered both the present results and the seven previous studies was constructed in which exercise-induced weight loss (x) was predicted by the exponential equation x= 0.20 dehydration index. CONCLUSION: Urine sampling can be used to estimate weight loss due to dehydration in adults up to the age of 70 years. A robust dehydration index based on four indicators reduces the influence of confounders.


Cost analysis of total neoadjuvant therapy with 5 × 5 Gy radiation therapy versus conventional chemoradiotherapy for locally advanced rectal cancer among Peruvians.
Conventional long-course radiotherapy (LCRT) and a new paradigm of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) are used in locally advanced rectal cancer (RC). There are few economic assessment reports available on TNT that focus on cost analysis in a country with limited funding for healthcare systems. The objective of this study was to perform a cost analysis comparing SCRT-TNT versus LCRT. In 2020-2021, a prospective registry was created to document RC patients who received neoadjuvant therapy and the costs of cancer treatments, transportation and the time patients and family members spent in the hospital. This registry outlined the direct and indirect costs of LCRT versus SCRT-TNT. LCRT and SCRT-TNT regimens have direct costs that range from S/.5,993.30 to S/.27,928.36 and from S/.3,409.81 to S/.18,159.42, respectively. FOLFOX regimens are the most expensive. Administering radiotherapy in 28 3D sessions and 5 sessions of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) sessions costs S/.2,603.88, S/.1,277.19 and S/.1,027.77, respectively. The indirect cost of FOLFOX regimens is twice that of the similar modality that combines irradiation and Oxaliplatin IV and Capecitabine VO (CAPOX). SCRT-TNT regimens with CAPOX reduce costs by at least 50%, while SCRT-TNT regimens with FOLFOX reduce costs by 32%. Despite using IMRT/VMAT, SCRT-TNT is a less expensive approach for patients with RC when compared to LCRT. The costs to patients using SCRT-TNT are much lower, but it is also a better option because it saves hospital resources.


Psychophysical scaling with applications in physical work and the perception of exertion.
In studies on work it is important to assess various subjective symptoms, complaints, and annoyances. To measure such symptoms, psychophysical ratio scales may be used, as along with simpler category rating scales. In this paper some of the basic concepts and methods of psychophysics have been described. In the field of heavy physical work and the perception of effort and exertion, one of the most popular methods is the rating of perceived exertion. This scale has been presented together with a new category ratio scale, commonly referred to as the CR-10 scale. Some situations in which it is important to obtain measurements of perceived exertion have also been described in the paper.