Laser-induced plasma peculiarity at low pressures from the elemental lifetime perspective.
The Laser-Induced Breakdown Spectroscopy (LIBS) plasma characteristics are known to strongly dependent on the surrounding pressure. Six different samples (C, Ni, Cu, Sn, Al, Zn) are used to support the existence of a `soft spot' in the vicinity of 1 torr where the maxima in plasma lifetime is observed. With pressure decrease, the elemental lifetimes of samples except for carbon increased until 1 torr and started to decline with continued pressure drop. The boiling point and electronegativity of the samples are amongst the physicochemical properties that are used to explain this peculiarity.


Randomised controlled trial of computer assisted management of hypertension in primary care.
The hypothesis that general practitioners would obtain better outcomes for patients with hypertension using a computer than doctors not using a computer was tested. Sixty family physicians were randomised to two treatment strategies. "Test" physicians completed a data collection form after each visit from a patient with hypertension and mailed the forms to the test centre for processing. Computer feedback on management was mailed to the doctors. This encouraged doctors to apply the "stepped care" protocol, supplied charts of diastolic blood pressure v time, and ranked patients' diastolic blood pressures by percentile. Letters were mailed to patients to remind them of appointments. "Control" doctors filled out the same data collection forms as test physicians, but neither doctors nor patients received computer feedback. Physicians who used the computer saw more patients per practice than control doctors (test 50 patients, control 40). For all patients the length of follow up was significantly longer in test practices (test 199 days, control 167), and a smaller percentage dropped out of active treatment in test practices (test 37.5%, control 42.1%). For patients with "moderate" hypertension of a baseline diastolic pressure of greater than 104 mm Hg the mean score of the last recorded pressure was below the goal of 90 mm Hg in test practices (88.5 mm Hg), but it failed to reach this goal in control practices (93.3 mm Hg). A greater average reduction of diastolic pressure was achieved in test practices (test 21.7 mm Hg, control 16.7 mm Hg). Though patients with "moderate" hypertension were better controlled in test practices than in control practices, the patients in test practices visited their doctors less often (test 13.3 visits per patient-year, control 17.4 visits). Among patients with newly detected hypertension test practices achieved a greater reduction in diastolic pressure than control practices (test 15.1 mm Hg v control 11.3 mm Hg) and more sustained control of hypertension (test 323 days per patient-year with a diastolic pressure of 90 mm Hg or less v control 259 days).


Sensitivity to tumor microvasculature without contrast agents in high spectral and spatial resolution MR images.
Contrast-enhanced (CE)-MRI is sensitive to cancers but can produce adverse reactions and suffers from insufficient specificity and morphological detail. This research investigated whether high spectral and spatial resolution (HiSS) MRI detects tumor vasculature without contrast agents, based on the sensitivity of the water resonance line shape to tumor blood vessels. HiSS data from AT6.1 tumors inoculated in the hind legs of rats (N = 8) were collected pre- and post-blood pool contrast agent (iron-oxide particles) injection. The waterline in small voxels was significantly more asymmetric at the tumor rim compared to the tumor center and normal muscle (P < 0.003). Composite images were synthesized, with the intensity in each voxel determined by the Fourier component (FC) of the water resonance having the greatest relative image contrast at that position. We tested whether regions with high contrast in FC images (FCIs) contain vasculature by comparing FCIs with CE-MRI as the "gold standard" of vascular density. The FCIs had 75% +/- 13% sensitivity, 74% +/- 10% specificity, and 91% +/- 4% positive predictive value (PPV) for vasculature detection at the tumor rim. These results suggest that tumor microvasculature can be detected using HiSS imaging without the use of contrast agents.


Tobacco use in the Dominican Republic: understanding the culture first.
To conduct formative research on the landscape of tobacco use to guide survey and subsequent intervention development in the Dominican Republic (DR). Rapid Assessment Procedures, systematic qualitative methods (participant-observations, in-depth interviewing, focus groups) using bilingual mixed age and gendered teams from the United States and DR. Over 160 adults (men and women), ages 18 to 90 years, current, former and never smokers, community members and leaders from six underserved, economically disadvantaged DR communities. Key domains: tobacco use patterns and attitudes; factors affecting smoking initiation, continuation, quitting; perceived risks/benefits/effects of smoking; and awareness/effects of advertising/regulations. Perceptions of prevalence varied widely. While "everybody" smokes, smokers or ex-smokers were sometimes difficult to find. Knowledge of health risks was limited to the newly mandated statement "Fumar es prejudicial para la salud" [Smoking is harmful to your health]. Smokers started due to parents, peers, learned lifestyle, fashion or as something to do. Smoking served as an escape, relaxation or diversion. Quit attempts relied on personal will, primarily for religious or medical reasons. Social smoking (custom or habit) (< 10 cigarettes per day) was viewed as a lifestyle choice rather than a vice or addiction. Out of respect, smokers selected where they smoked and around whom. Health care providers typically were reactive relative to tobacco cessation, focusing on individuals with smoking related conditions. Tobacco advertising was virtually ubiquitous. Anti-tobacco messages were effectively absent. Cultures of smoking and not smoking coexisted absent a culture of quitting. Systematic qualitative methods provided pertinent information about tobacco attitudes and use to guide subsequent project steps. Integrating qualitative then quantitative research can be replicated in similar countries that lack empirical data on the cultural dimensions of tobacco use.


Who should receive life support during a public health emergency? Using ethical principles to improve allocation decisions.
A public health emergency, such as an influenza pandemic, will lead to shortages of mechanical ventilators, critical care beds, and other potentially life-saving treatments. Difficult decisions about who will and will not receive these scarce resources will have to be made. Existing recommendations reflect a narrow utilitarian perspective, in which allocation decisions are based primarily on patients' chances of survival to hospital discharge. Certain patient groups, such as the elderly and those with functional impairment, are denied access to potentially life-saving treatments on the basis of additional allocation criteria. We analyze the ethical principles that could guide allocation and propose an allocation strategy that incorporates and balances multiple morally relevant considerations, including saving the most lives, maximizing the number of "life-years" saved, and prioritizing patients who have had the least chance to live through life's stages. We also argue that these principles are relevant to all patients and therefore should be applied to all patients, rather than selectively to the elderly, those with functional impairment, and those with certain chronic conditions. We discuss strategies to engage the public in setting the priorities that will guide allocation of scarce life-sustaining treatments during a public health emergency.


Breath-to-breath relationships between respiratory cycle variables in humans at fixed end-tidal PCO2 and PO2.
This study examined the statistical properties of breath-to-breath variations in the inspiratory and expiratory volumes and times during rest and light exercise. Sixty data sets were analyzed. Initial data and residuals after fitting time-series models were examined for 1) sustained periodicities with use of spectral analysis, 2) temporal changes in signal power with use of evolutionary spectral analysis, and 3) auto- and cross correlations with use of a portmanteau test. The major findings were as follows: 1) no sustained periodic components were detected; 2) temporal changes in signal power were normally present, but these did not affect significantly the results from time-series modeling; 3) for all variables, a simple autoregressive moving average (ARMA) AR1MA1 model generally described the autocorrelation; 4) considerable cross correlation remained between residuals from the AR1MA1 model; 5) relationships between variables could be described by using a multivariate time-series model; 6) residual fluctuations in end-tidal PCO2 had little influence; and 7) responses were broadly similar between rest and exercise, although some quantitative differences were found. The multivariate model provides a description of the structure of the interrelationships between cycle variables in a quantitative and a qualitative form.


[The design and implementation of effective epidemiological surveillance programmes in Sub-Saharan Africa].
Livestock is one of the main sources of wealth in developing countries. The improvement of national herds and of their productivity through controlling the main diseases and preventing epizootics is a major objective in these countries. The organisation of surveillance systems is indispensable to proper animal health management, both nationally and internationally. Therefore, thanks to foreign assistance, developing countries have gradually established epidemiological surveillance networks, despite unfavourable contexts (poverty, lack of resources or infrastructure...). To date, many networks are operating in satisfactory manner and produce tangible results. However, further efforts must be made to improve the quality of sanitary information produced, its performance and sustainability. This article discusses the context and motivations for the establishment of epidemiological surveillance networks in developing countries, especially in Africa, by describing some of their operational specificities and some results. Finally, it presents the example of a Mauritanian animal disease epidemiological surveillance network and its role in managing a health crisis.


A universal scale of aromaticity for pi-organic compounds.
Aromaticity is an essential concept in chemistry, invented to account for the stability, reactivity, molecular structure, and properties of many organic and inorganic compounds. In recent years, numerous methods to quantify aromaticity based on the energetic, magnetic, structural, and electronic properties of molecules have been proposed but none of them is universal. The inability of establishing a universal scale of aromaticity based on a single parameter is due to the multidimensional character of this phenomenon. Consequently, aromaticity analyses should be carried out by employing a set of aromaticity descriptors on the basis of different physical manifestations of aromaticity. Here, we report a universal scale of aromaticity for pi-organic compounds based on the Euclidean distance between neurons in a self-organizing map. The most widely used aromaticity indicators have been used as molecular descriptors, and so our approach provides the first scale of aromaticity which contains the energetic, magnetic, and structural aspects of this property. The method is applicable to a wide variety of unsaturated organic compounds and allows quantification of both aromaticity and antiaromaticity. Additionally, the position of a compound on the bidimensional map determinates immediately the following: (a) the group (aromatic, nonaromatic, or antiaromatic) to which the system belongs, (b) their degree of pi-electronic delocalization, and (c) the similarity in aromaticity/antiaromaticity between different compounds. This new scale of aromaticity is able to indicate the expected order of aromaticity of analogues of fulvene and heptafulvene, heteroaromatic species, substituted benzenes, and functionalized cyclopentadienyl compounds.


Are empathic abilities impaired in posttraumatic stress disorder?
Trauma survivors with PTSD show social interaction and relationship impairments. It is hypothesized that traumatic experiences lead to known PTSD symptoms, empathic ability impairment, and difficulties in sharing affective, emotional, or cognitive states. A PTSD group (N=16) and a nontraumatized Control group (N=16) were compared on empathic abilities, namely the Empathic Resonance Test, Reading the Mind in the Eyes Test, and Faux Pas Test. The Interpersonal Reactivity Index as a self-report measure of empathy and measures of non-social cognitive functions, namely the Verbal Fluency Test, the Five-Point Test, and the Stroop Test, were also administered. The PTSD group showed lower empathic resonance. No clear indications of other impairments in social cognitive functions were found. The PTSD group had significantly higher personal distress. Empathic resonance impairments did not correlate with subjective severity of PTSD symptomatology. This article discusses whether impaired empathic resonance in PTSD trauma survivors is a consequence of trauma itself or a protective coping strategy.


COVID-19 infection with asymptomatic or mild disease severity in young patients: Clinical course and association between prevalence of pneumonia and viral load.
Few studies have focused on clinical courses or viral loads in young asymptomatic or mild patients with COVID-19 infection. We sought to better understand the clinical course and association between viral load and prevalence of pneumonia in young COVID-19 patients with asymptomatic or mild disease severity. In this retrospective study, 106 COVID-19 young patients with asymptomatic or mild disease severity were analyzed for clinical characteristics, clinical course, prevalence of radiologically proven pneumonia and viral load. The cut-off value of viral load for presence of pneumonia was also investigated. The mean age was 28.0±9.3 years. Eleven patients (10.4%) experienced viral remission within one week of diagnosis, but one (0.9%) transferred to the hospital due to aggravation of pneumonia. Patients with pneumonia had significantly higher viral load than those without, and the cut-off value of the Ct value for presence of pneumonia were 31.38. The patients with pneumonia had significantly slower recovery times than those without. Diarrhea was significantly more common in patients with pneumonia than patients without pneumonia. In conclusion, most young asymptomatic and mildly symptomatic patients showed stable clinical course. There were significant differences in viral load and recovery times between patients with and without pneumonia.


Electrical conductivity and oxygen diffusion behaviour of the (La0.8Sr0.2)0.95CrxFe1-xO3-δ (x = 0.3, 0.5 and 0.7) A-site deficient perovskites.
Lanthanum strontium chromite ferrite ((La0.8Sr0.2)0.95CrxFe1-xO3-δ, LSCrF) pellets with 5% A-site deficiency were fabricated and the electrical conductivity and oxygen diffusion behaviour with different Cr substitution levels (x = 0.3, 0.5 and 0.7) were investigated. As the Cr content increased, the electrical conductivity increased and then a maximum value was achieved at x = 0.7. In the oxygen diffusion studies, all the measured materials present good surface exchange rates (>9 × 10-8 cm s-1 at 900 °C) while the bulk diffusivity of the investigated materials decreased as the Cr substitution level increased: at 900 °C the oxygen diffusion coefficients of the LSCrF materials (x = 0.3, 0.5 and 0.7) are 1.1 × 10-10 cm2 s-1, 3.7 × 10-12 cm2 s-1 and 8.6 × 10-13 cm2 s-1, respectively. Oxygen diffusion in the perovskite materials (LSCrF) is shown to be bulk diffusion limited and it was found that analysis on this type of material using the line scan mode in Time-of-Flight Secondary Ion Mass Spectrometry may result in significant underestimation of the surface exchange coefficient due to the oxygen saturation, while the depth profile mode provides more reliable results but the obtained surface exchange coefficients may also only reach a lower limit. Moreover, fast grain boundary diffusion behaviour was observed in the LSCrF (x = 0.7) material and the Le Claire, and Chung and Wuensch approximations were applied to analyse the oxygen diffusion profiles. For this material, the two approximations provided similar results for the grain boundary product (Dgbδ) and under the assumption that the width of a grain boundary is on the nanometre scale, the oxygen diffusion coefficient of the grain boundaries was about 3-4 orders of magnitude higher than that of the bulk at temperatures ≤900 °C.


Novel immunotherapeutic approaches for allergy and asthma.
The immune response is a tightly regulated process, which normally results in protection from infection and tolerance of innocuous environmental antigens. However, in allergic disease, the activated immune response results in a chronic pro-inflammatory state characterized by antibody secretion (IgE) and T cell activation to normally well-tolerated antigens. Currently, the treatment of allergic disease is focused on the suppression of key inflammatory mediators or inflammatory cell populations and include anti-histamines, anti-leukotrienes, β2 adrenergic receptor agonists and corticosteroids. However, these approaches only provide a temporary suppression of disease symptoms. Successful long-term treatment can only be provided by allergen-specific immunotherapy (allergen-SIT), which restores normal immunity against allergens. This review will discuss novel approaches to the management of allergy and asthma by targeting the T regulatory cell via modulation of the commensal microbiota and allergen-SIT.


The incorporation of 5-fluorouracil into RNA affects the ribonucleolytic activity of the exosome subunit Rrp6.
5-Fluorouracil (5FU) is a fluoropyrimidine used for the treatment of solid tumors. 5FU is a precursor of dTTP and UTP during biogenesis, and it interferes with both DNA and RNA metabolism. The RNA exosome, a multisubunit complex with ribonucleolytic activity, has been identified as one of the targets of 5FU in yeast. Studies in human cells have shown that the catalytic subunit of the nuclear exosome, Rrp6, is specifically targeted. Here, we have investigated the direct effect of 5FU on the activity of Rrp6 in Drosophila S2 cells, and we have identified two aspects of Rrp6 function that are altered by 5FU. First, gel filtration analysis revealed that the repertoire of multimolecular complexes that contain Rrp6 is modified by exposure to 5FU, which is consistent with the proposal that incorporation of 5FU into RNA leads to the sequestration of Rrp6 in ribonucleoprotein complexes. Second, the incorporation of 5FU into RNA renders the RNA less susceptible to degradation by Rrp6, as shown by Rrp6 activity assays in vitro. Our results imply that aberrant transcripts synthesized in 5FU-treated cells cannot be turned over efficiently by the surveillance machinery. Together with previous results on the mechanisms of action of 5FU, our findings suggest that the cytotoxicity of 5FU at the RNA level is the result of at least three different effects: the increased levels of retroviral transcripts with mutagenic potential, the reduced synthesis of ribosomes, and the inhibition of the nuclear RNA surveillance pathways. Drugs that reinforce any of these effects may boost the cytotoxicity of 5FU.


Enzymatic characterization of a trypsin-like serine protease encoded by the genome of cell fusing agent virus.
Cell fusing agent virus (CFAV) is a positive strand RNA insect virus first isolated from a mosquito cell line. Based on viral morphology, phenotypic and phylogenetic studies, CFAV had been tentatively assigned to the genus Flavivirus (family Flaviviridae). The determination of the CFAV polyprotein complete sequence showed a putative serine protease domain analogue to the flaviviral NS2B/NS3 complex. This complex had been extensively studied, because it represented one of the main targets for antiflavivirus therapy development. We report herein the biochemical characterization of CFAV DeltaNS2B-NS3pro protease complex. CFAV polyprotein sequence was computationally analysed to identify the amino-acid regions involved in protease activity. We designed, expressed and purified a catalytically active protease whose enzymatic properties were determined using fluorogenic substrates. Our results showed that, despite the low level of conservation of its amino-acid sequence, CFAV protease exhibited physico-chemical properties of other flaviviruses (high pH value requirement for optimal activity, inhibition by salt and preference for substrates featuring a basic residue at P(1) position).


Avian genomics lends insights into endocrine function in birds.
The genomics era has brought along the completed sequencing of a large number of bird genomes that cover a broad range of the avian phylogenetic tree (>30 orders), leading to major novel insights into avian biology and evolution. Among recent findings, the discovery that birds lack a large number of protein coding genes that are organized in highly conserved syntenic clusters in other vertebrates is very intriguing, given the physiological importance of many of these genes. A considerable number of them play prominent endocrine roles, suggesting that birds evolved compensatory genetic or physiological mechanisms that allowed them to survive and thrive in spite of these losses. While further studies are needed to establish the exact extent of avian gene losses, these findings point to birds as potentially highly relevant model organisms for exploring the genetic basis and possible therapeutic approaches for a wide range of endocrine functions and disorders.


Phosphorylation of AKT and abdominal aortic aneurysm formation.
It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.


A global analysis of CNVs in swine using whole genome sequence data and association analysis with fatty acid composition and growth traits.
Copy number variations (CNVs) are important genetic variants complementary to SNPs, and can be considered as biomarkers for some economically important traits in domestic animals. In the present study, a genomic analysis of porcine CNVs based on next-generation sequencing data was carried out to identify CNVs segregating in an Iberian x Landrace backcross population and study their association with fatty acid composition and growth-related traits. A total of 1,279 CNVs, including duplications and deletions, were detected, ranging from 106 to 235 CNVs across samples, with an average of 183 CNVs per sample. Moreover, we detected 540 CNV regions (CNVRs) containing 245 genes. Functional annotation suggested that these genes possess a great variety of molecular functions and may play a role in production traits in commercial breeds. Some of the identified CNVRs contained relevant functional genes (e.g., CLCA4, CYP4X1, GPAT2, MOGAT2, PLA2G2A and PRKG1, among others). The variation in copy number of four of them (CLCA4, GPAT2, MOGAT2 and PRKG1) was validated in 150 BC1_LD (25% Iberian and 75% Landrace) animals by qPCR. Additionally, their contribution regarding backfat and intramuscular fatty acid composition and growth-related traits was analyzed. Statistically significant associations were obtained for CNVR112 (GPAT2) for the C18:2(n-6)/C18:3(n-3) ratio in backfat and carcass length, among others. Notably, GPATs are enzymes that catalyze the first step in the biosynthesis of both triglycerides and glycerophospholipids, suggesting that this CNVR may contribute to genetic variation in fatty acid composition and growth traits. These findings provide useful genomic information to facilitate the further identification of trait-related CNVRs affecting economically important traits in pigs.


Chaos in neuronal networks with balanced excitatory and inhibitory activity.
Neurons in the cortex of behaving animals show temporally irregular spiking patterns. The origin of this irregularity and its implications for neural processing are unknown. The hypothesis that the temporal variability in the firing of a neuron results from an approximate balance between its excitatory and inhibitory inputs was investigated theoretically. Such a balance emerges naturally in large networks of excitatory and inhibitory neuronal populations that are sparsely connected by relatively strong synapses. The resulting state is characterized by strongly chaotic dynamics, even when the external inputs to the network are constant in time. Such a network exhibits a linear response, despite the highly nonlinear dynamics of single neurons, and reacts to changing external stimuli on time scales much smaller than the integration time constant of a single neuron.


Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs.
Block of human ether-a-go-go related gene (hERG) K(+) channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to potentially fatal arrhythmias. This undesirable long QT side effect has been a major reason for the withdrawal of medications from the pharmaceutical market. Understanding the molecular basis of hERG block is therefore essential to facilitate the design of safe drugs. Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625). We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions. Although changing the basic nitrogen from quaternary to tertiary accelerated the onset of block, the IC(50) and kinetics for recovery from block were similar. In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block. The highest potency was achieved with polar or electronegative para-substituents, whereas neutral para-substituents had potencies more than 100-fold lower. Results from mutagenesis and molecular modeling studies suggest that phenyl ring para-substituents influence drug interactions with Thr-623, Ser-624, and Tyr-652 and strongly affect binding affinity. Together, these findings suggest that modifying the para-substituent could be a useful strategy for reducing hERG potency and increasing the safety margin of compounds in development.


Dysfunctional effort-based decision-making underlies apathy in genetic cerebral small vessel disease.
Apathy is a syndrome of reduced motivation that commonly occurs in patients with cerebral small vessel disease, including those with the early onset form, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The cognitive mechanisms underlying apathy are poorly understood and treatment options are limited. We hypothesized that disrupted effort-based decision-making, the cognitive process by which potential rewards and the effort cost required to obtain them is integrated to drive behaviour, might underlie the apathetic syndrome. Nineteen patients with a genetic diagnosis of CADASIL, as a model of 'pure' vascular cognitive impairment, and 19 matched controls were assessed using two different behavioural paradigms and MRI. On a decision-making task, participants decided whether to accept or reject sequential offers of monetary reward in return for exerting physical effort via handheld dynamometers. Six levels of reward and six levels of effort were manipulated independently so offers spanned the full range of possible combinations. Choice, decision time and force metrics were recorded. Each participant's effort and reward sensitivity was estimated using a computational model of choice. On a separate eye movement paradigm, physiological reward sensitivity was indexed by measuring pupillary dilatation to increasing monetary incentives. This metric was related to apathy status and compared to the behavioural metric of reward sensitivity on the decision-making task. Finally, high quality diffusion imaging and tract-based spatial statistics were used to determine whether tracts linking brain regions implicated in effort-based decision-making were disrupted in apathetic patients. Overall, apathetic patients with CADASIL rejected significantly more offers on the decision-making task, due to reduced reward sensitivity rather than effort hypersensitivity. Apathy was also associated with blunted pupillary responses to incentives. Furthermore, these independent behavioural and physiological markers of reward sensitivity were significantly correlated. Non-apathetic patients with CADASIL did not differ from controls on either task, whilst actual motor performance of apathetic patients in both tasks was also normal. Apathy was specifically associated with reduced fractional anisotropy within tracts connecting regions previously associated with effort-based decision-making. These findings demonstrate behavioural, physiological and anatomical evidence that dysfunctional effort-based decision-making underlies apathy in patients with CADASIL, a model disorder for sporadic small vessel disease. Reduced incentivization by rewards rather than hypersensitivity to effort costs drives this altered pattern of behaviour. The study provides empirical evidence of a cognitive mechanism for apathy in cerebral small vessel disease, and identifies a promising therapeutic target for interventions to improve this debilitating condition.


Temporal summation phenomena at threshold: their relation to visual mechanisms.
Threshold energies were determined for brief flashes as a function of their duration in order to determine the maximum duration for which the flash intensity and duration could be varied reciprocally without affecting detectability (the Bunsen-Roscoe effect). A pair of threshold-level flashes for which reciprocity obtained in the determination of threshold were shown to be discriminable from each other at several imperfectly detectable energy levels. Thus equal detectability of flashes of equal energy does not imply identical neural responses to such stimuli. It is suggested that the summation reflects primarily the operation of the detection mechanism rather than of the peripheral visual mechanism. Some general implications for the interpretation of threshold measures are also discussed.


Towards Robot Scientists for autonomous scientific discovery.
We review the main components of autonomous scientific discovery, and how they lead to the concept of a Robot Scientist. This is a system which uses techniques from artificial intelligence to automate all aspects of the scientific discovery process: it generates hypotheses from a computer model of the domain, designs experiments to test these hypotheses, runs the physical experiments using robotic systems, analyses and interprets the resulting data, and repeats the cycle. We describe our two prototype Robot Scientists: Adam and Eve. Adam has recently proven the potential of such systems by identifying twelve genes responsible for catalysing specific reactions in the metabolic pathways of the yeast Saccharomyces cerevisiae. This work has been formally recorded in great detail using logic. We argue that the reporting of science needs to become fully formalised and that Robot Scientists can help achieve this. This will make scientific information more reproducible and reusable, and promote the integration of computers in scientific reasoning. We believe the greater automation of both the physical and intellectual aspects of scientific investigations to be essential to the future of science. Greater automation improves the accuracy and reliability of experiments, increases the pace of discovery and, in common with conventional laboratory automation, removes tedious and repetitive tasks from the human scientist.


Human peripheral blood derived mesenchymal stem cells demonstrate similar characteristics and chondrogenic differentiation potential to bone marrow derived mesenchymal stem cells.
The use of mesenchymal stem cells (MSCs) for cartilage repair has generated much interest owing to their multipotentiality. However, their significant presence in peripheral blood (PB) has been a matter of much debate. The objectives of this study are to isolate and characterize MSCs derived from PB and, compare their chondrogenic potential to MSC derived from bone marrow (BM). PB and BM derived MSCs from 20 patients were isolated and characterized. From 2 ml of PB and BM, 5.4 ± 0.6 million and 10.5 ± 0.8 million adherent cells, respectively, were obtained by cell cultures at passage 2. Both PB and BM derived MSCs were able to undergo tri-lineage differentiation and showed negative expression of CD34 and CD45, but positively expressed CD105, CD166, and CD29. Qualitative and quantitative examinations on the chondrogenic potential of PB and BM derived MSCs expressed similar cartilage specific gene (COMP) and proteoglycan levels, respectively. Furthermore, the s-GAG levels expressed by chondrogenic MSCs in cultures were similar to that of native chondrocytes. In conclusion, this study demonstrates that MSCs from PB maintain similar characteristics and have similar chondrogenic differentiation potential to those derived from BM, while producing comparable s-GAG expressions to chondrocytes.


Palatal pyogenic granuloma: An unusual complication following mucogingival surgery for alveolar socket preservation.
We report a case of palatal pyogenic granuloma following mucogingival surgery for alveolar socket preservation. A 24-year-old systemically healthy female underwent a pediculated palatal pedicle graft procedure to achieve soft tissue augmentation over a grafted maxillary anterior extraction site. After 1 month, a 15 mm × 20 mm exophytic growth extending from the palatal donor site to distance of 3-4 mm from the extraction socket was observed. After obtaining the subject's consent, local anesthesia was administered and the growth was excised from the base. On histopathological examination, the findings suggestive of pyogenic granuloma were seen. Palatal pyogenic granuloma occurs rarely and the authors were unable to find the reports of pyogenic granuloma originating in the vicinity of a surgical wound after a pediculated connective tissue mucogingival procedure. Healing plays a vital role in mucogingival procedures, and thus, it is very important to know about the complications affecting this important cascade of events. Failing to consider potential sources of irritation or trauma at the surgical site may lead to considerable morbidity even in sites that may heal without any untoward complications.


The Smads.
The large transforming growth factor-beta (TGFbeta) superfamily of secreted proteins regulate the growth, development and differentiation of cells in diverse organisms, including nematode worms, flies, mice and humans. Signals are initiated upon binding of TGFbeta superfamily members to cell-surface serine/threonine kinase receptors and are then propagated by the intracellular mediators known as Smads. Activation of Smads results in their translocation from the cytoplasm into the nucleus, where they activate or repress transcription together with transcription factors so as to regulate target gene expression. Most Smads consist of two conserved domains. Mad homology (MH) domains I and 2, which are separated by a non-conserved linker region. These domains lack enzymatic activity and, instead, Smads mediate their effects through protein-protein and protein-DNA interactions. Targeted disruption of Smad genes in mice has revealed their importance in embryonic development, and a tumor-suppressor role for Smads in human cancers has been described. Smads therefore play an essential role in mediating TGFbeta-superfamily signals in development and disease.


The association between recreational parks, facilities and childhood obesity: a cross-sectional study of the 2007 National Survey of Children's Health.
Despite the rising childhood obesity rates, few studies have examined the association between access to recreational parks and facilities and obesity. A cross-sectional study was performed among 42 278 US children who participated in the 2007 National Survey of Children's Health. Access to parks and recreational facilities was self-reported by parents, and body mass index was calculated from parents' self-report of the child's height and weight. Logistic regression was used to obtain ORs and 95% CIs. Since obesity was not a rare occurrence, an OR correction method was used to provide a more reliable estimate of the prevalence ratio (PR). Children with access to parks and facilities had decreased prevalence of obesity as compared to children without access (PR=0.79, 95% CI 0.69 to 0.91). After adjustment for covariates, the magnitude of the association remained unchanged; however, results were no longer statistically significant (PR=0.77, 95% CI 0.55 to 1.07). Race/ethnicity was an effect modifier of the access-obesity relationship (p<0.0001). Among Non-Hispanic White children, there was no strong association (PR=0.89, 95% CI 0.64 to 1.23). However, among Non-Hispanic Black children, those who had access to recreational parks and facilities had 0.40 times the prevalence of obesity as compared to those without access, and this result was statistically significant (95% CI 0.17 to 0.90). This research highlights potential health disparities in childhood obesity due to limited access to recreational parks and facilities. Additional studies are needed to further investigate this association. If confirmed, providing safe, accessible parks and facilities may be one way to combat childhood obesity, particularly among minority children.


Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.


Two distinct antigen-specific suppressor factors induced by the oral administration of antigen.
The feeding of sheep erythrocytes (SRBC) to mice leads to the production of two distinct T cell-derived suppressor factors by spleen cells. Each has been characterized for specificity, genetic restrictions, and cellular interactions. Fraction I has a 60,000-75,000 mol wt, is specific for antigen, and is suppressive of primary in vitro anti-SRBC responses at all times. It is not restricted by major histocompabitility complex (MHC)- or Igh-linked genes, but it fails to suppress spleen cells derived from any strain of mouse with a B10 background. It acts on an Lyt-2+ T cell to increase suppressive activity. An antiserum has been prepared against this factor that reacts with other, unrelated T cell suppressor factors. Fraction II has an approximately 30,000-40,000 mol wt, is specific for antigen, and has a dual effect on in vitro anti-SRBC responses. On day 3 of culture, it leads to augmentation of the response, whereas at day 5 it suppresses the response. It is not restricted by MHC genes, but it is restricted by Igh-linked genets. It acts by activating an Ly-1 t cell to both help and induce feedback suppression. These factors, and the antisera prepared against them, should allow more precise dissection of the molecular pathways by which immunoregulatory cells communicate with one another.


Investigation of HMG-CoA reductase inhibitory and antioxidant effects of various hydroxycoumarin derivatives.
Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low-density lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG-CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum-chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG-CoA reductase inhibitory activity (IC50 = 42.0 µM) in vitro. Cupric-reducing antioxidant capacity and ferric-reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.


Epidemiology of Musculoskeletal Injuries Among Naval Special Warfare Personnel.
Musculoskeletal injuries (MSIs) are an important cause of morbidity in the military, especially among Special Forces. The aim of this analysis was to describe MSIs among two groups of Naval Special Warfare (NSW) personnel-Special Warfare Combatant-Craft Crewman (SWCC) Operators and Crewman Qualification Training (CQT) students. In this cross-sectional study, we describe self-reported MSIs that occurred during a one-year period and the calculated financial costs of MSIs. Group comparisons were conducted using Fisher's exact tests and independent samples t tests. Data were available for 142 SWCC Operators (26.9 ± 5.9 years, 1.8 ± 0.1 meters, 85.4 ± 10.4 kilograms) and 187 CQT students (22.8 ± 3.2 years, 1.8 ± 0.2 meters, 81.4 ± 8.9 kilograms). The one-year cumulative MSI incidence was significantly lower among SWCC Operators (21.1%) compared to CQT students (37.4%, p = 0.002). The most common anatomic location for MSIs was the lower extremity (SWCC: 50.0% of MSIs, CQT: 66.3%). Physical training was the predominant activity when MSIs occurred (SWCC: 31.6%, CQT: 77.6%). The lifetime cost of all the MSIs included in the analysis was approximately $580,000 among 142 SWCC Operators and $1.2 million among 187 CQT students. MSIs, especially those affecting the lower extremity and occurring during physical training, cause considerable morbidity and financial burden among NSW personnel. Many of the musculoskeletal injuries are to musculotendinous tissue, which typically results from tissue overload or inadequate recovery. Further investigation of the preventable causes of these MSIs and development of a customized, evidence-based MSI prevention program is required to reduce the burden of these MSIs.


Loss-of-function of SHARPIN causes an osteopenic phenotype in mice.
SHARPIN is a novel protein thought to interact with SHANK family and is widely expressed in multiple tissues/cells, including osteoblasts and osteoclasts. Loss-of-function of Sharpin develops the chronic proliferative dermatitis mutation (CPDM) in mice as well as a severe inflammation in other organs. The actual function of SHARPIN is poorly understood. Our aim was to determine the functional roles of SHARPIN in bone metabolism by using CPDM mice. The skeletal phenotypes were determined by peripheral quantitative computed tomography, micro-computed tomography, and quantitative real-time RT-PCR, the cellular functions of osteoblasts and osteoclasts were investigated by ex vivo cell culture. Compared to wild-type controls, CPDM mice demonstrated significantly lower total and cortical bone mineral content and bone mineral density, trabecular and cortical bone volume, and trabecular number. The mRNA expression of Runx2, osterix, type I collagen, and osteocalcin was significantly lower in the bone from CPDM mice. Osteoclasts and osteoblasts from CPDM mice were functionally defective. Our result suggests that SHARPIN plays important regulating roles in bone metabolism. These functional roles may either come from systemic chronic inflammatory or directly signaling pathway within bone cells.


Molecular characterization of Giardia isolates from calves and humans in a region in which dairy farming has recently intensified.
Giardiasis is a notifiable disease of high prevalence in New Zealand, but there is limited knowledge about the sources of Giardia duodenalis genotypes that can potentially cause human infections. Dairy calves are one environmental source of Giardia isolates, but it is unknown whether they harbor genotypes that are potentially capable of causing infections in humans. To address these questions, 40 Giardia isolates from calves and 30 from humans, living in the same region and collected over a similar period, were genotyped using the beta-giardin gene. The G. duodenalis genetic assemblages A and B were identified from both calves and humans, and genotype comparisons revealed a substantial overlap of identical genotypes from the two hosts for both assemblages. Significantly, no assemblage E (the genotype commonly found in cattle elsewhere in the world) has been detected in New Zealand livestock to date. Given recent and rapid land use conversions to dairy farming in many South Island regions of New Zealand, an increasingly large concentration of domestic cattle harboring genotypes potentially capable of causing infections in humans is particularly concerning.


Recognition by the thyroid hormone receptor of canonical DNA response elements.
To shed more light on the molecular requirements for recognition of thyroid response elements (TREs) by thyroid receptors (TRs), we compared the specific aspects of DNA TRE recognition by different TR constructs. Using fluorescence anisotropy, we performed a detailed and hierarchical study of TR-TRE binding. This was done by comparing the binding affinities of three different TR constructs for four different TRE DNA elements, including palindromic sequences and direct repeats (F2, PAL, DR-1, and DR-4) as well as their interactions with nonspecific DNA sequences. The effect of MgCl(2) on suppressing of nonselective DNA binding to TR was also investigated. Furthermore, we determined the dissociation constants of the hTRbeta DBD (DNA binding domain) and hTRbeta DBD-LBD (DNA binding and ligand binding domains) for specific TREs. We found that a minimum DNA recognition peptide derived from DBD (H1TR) is sufficient for recognition and interaction with TREs, whereas scrambled DNA sequences were unrecognized. Additionally, we determined that the TR DBD binds to F2, PAL, and DR-4 with high affinity and similar K(d) values. The TR DBD-LBD recognizes all the tested TREs but binds preferentially to F2, with even higher affinity. Finally, our results demonstrate the important role played by LBDs in modulating TR-DNA binding.


Modeling the impact of formal and informal supports for young children with disabilities and their families.
The purpose of this work was to examine factors related to perceived impact of early intervention on children with disabilities and their families. A nationally representative sample of approximately 2100 parents completed a 40-minute telephone interview near their child's third birthday. Structural equation modeling examined the relationships between 3 support variables (quality of child services, quality of family services, and family/community support) and 2 outcomes at 36 months (impact on child and impact on family) and determined whether these relationships were mediated by 2 perceptual variables (optimism and confidence in parenting) or moderated by 5 demographic variables (poverty, maternal education, ethnicity, age of initial Individual Family Service Plan, and health at 36 months). Perceived impact of early intervention on both child and family were significantly related to each other. The quality of child services was related to impact on the child but not on the family. The quality of family services was related to both child and family impact. Informal support was not related to perceived impact on children or families but was strongly related to confidence in parenting and optimism. Neither optimism nor confidence in parenting mediated the relationships between services or supports and perceived impact. Minority families and families of children with poor health reported lower quality of services, but these characteristics did not moderate the relationships between services and perceived impact on the child. However, both poverty status and minority status were associated with perceptions of impact on the family. Findings reinforce the role of high-quality services in maximizing perceived impact. They also highlight the important role of informal support in promoting optimism and confidence in parenting. Poverty status, minority status, and poor health of the child are salient factors in predicting lower perceived quality of and benefit from services.


Paraneoplastic ataxia and dystonia secondary to a malignant fibrous histiocytoma.
Paraneoplastic movement disorders are part of the spectrum of paraneoplastic syndromes caused by the production of onconeural antibodies such as anti-Hu by underlying tumours. These attack specific neurons depending on receptor aetiology. We report the case of a 53-year-old man who presented 8 years previously with symptoms of upper limb weakness, light headedness, dizziness and falls. His condition followed a progressive course. Two years after onset he had right-sided weakness, diplopia and generalised dystonia. Initial investigations identified a positive anti-Hu antibody, but an extensive search for a primary tumour was negative. A malignant fibrous histiocytoma in his right gluteal fold was subsequently identified. At this stage he was bed bound with severe ataxia, dystonia and spasticity. Following surgical excision and treatment with high dose steroids and pulse immunoglobulin, further progression was arrested and minor improvements occurred. He can now ambulate with bilateral assistance but remains severely disabled.


Quantitative proton magnetic resonance imaging in focal cerebral ischemia in rat brain.
Proton magnetic resonance (MR) imaging has been recommended as a diagnostic tool for the detection of focal cerebral ischemia. We compared microscopic MR images of rat brains after focal cerebral ischemia with evidence of histological damage found on corresponding silver-impregnated or cresyl violet-stained brain sections. Ten male Wistar rats were subjected to permanent unilateral occlusions of the right middle cerebral and common carotid arteries under halothane anesthesia. Twenty-four hours later the area of injury on MR images amounted to 26% of the total slice area, whereas only 9% of the total slice area was necrotic on histological sections from the same animals. The infarcted areas on tissue sections were surrounded by regions of selective neuronal injury in the cerebral cortex and occasionally in the hippocampus. The area of injury on MR images was larger than the combined areas of infarction and selective neuronal injury on histological sections. Areas of increased T2 values on MR images extended medially into noninfarcted striatum and laterally and dorsally into noninfarcted cortex. The lateral and dorsal areas on MR images frequently coincided with cortical areas in which considerable selective neuronal injury was present in the upper cortical layers. We hypothesize that the abnormal areas on MR images above histologically normal brain tissue represent the ischemic penumbra. If true, this is the first demonstration of the ischemic penumbra by MR imaging and may reflect our use of Wistar rats, a new image analysis technique, and ultra-high resolution MR imaging.


Resveratrol prevents acute renal injury in a model of ruptured abdominal aortic aneurysm.
To examine the biochemical and histopathological effects of ischemia/reperfusion (I/R) injury in a ruptured abdominal aortic aneurysm (RAAA) model in rats, and to investigate the potential protective role of resveratrol. Thirty-two male Sprague-Dawley rats were randomly assigned into four groups-control, I/R, sham (I/R + solvent/dimethyl sulfoxide), and I/R + resveratrol. The control group underwent midline laparotomy only. In the other groups, infrarenal vascular clamps were attached following 60-min shock to the abdominal aorta. Ischemia was applied for 60 min followed by reperfusion for 120 min. In the I/R + resveratrol group, intraperitoneal 10 mg/kg resveratrol was administered 15 min prior to ischemia and immediately before reperfusion. The I/R + dimethyl sulfoxide group received dimethyl sulfoxide, and the I/R group was given saline solution. All animals were sacrificed by exsanguination from the carotid artery at the end of the experiment. In addition to histopathological examination of the rat kidney tissues, malondialdehyde, glutathione, catalase, and nitric oxide levels were also investigated. A decrease in glutathione, catalase and nitric oxide levels, together with increases in malondialdehyde levels, numbers of apoptotic renal tubular cells, caspase-3 levels, and tubular necrosis scores, were observed in the IR and I/R + dimethyl sulfoxide groups. In contrast, resveratrol increased glutathione, catalase and nitric oxide levels in renal tissues exposed to I/R, while reducing malondialdehyde levels, apoptotic renal tubular cell numbers, caspase-3 levels, and tubular necrosis scores. Our findings suggest that resveratrol can be effective against I/R-related acute kidney damage developing during RAAA surgery by reducing oxidative stress and apoptosis.


The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells.
Src-protein tyrosine kinases are intimately involved in TCR-initiated signaling in T lymphocytes. One member of this family, Lck, is also involved in CD28-mediated costimulation in Th1 cells. In Th2 lymphocytes, the costimulatory signal can also be provided by the interaction of IL-1 with type I IL-1R (IL-1RI), culminating in the activation of NF-kappaB transcription factors. Proximal steps in the IL-1R pathway, however, remain poorly understood, and there is conflicting evidence as to the importance of tyrosine phosphorylation in IL-1R signaling. We have addressed this issue by examining the ability of IL-1 to costimulate the activation of Lck-deficient Th2 cells. Our data demonstrate that, in the absence of Lck, the IL-1 costimulatory pathway is blocked despite the expression of normal levels of IL-1RI. Moreover, the block is associated with a defective degradation of IkappaB-alpha and an incomplete activation of NF-kappaB heterodimeric complexes. Protein expression of NF-kappaB monomers, including p50, p65, and c-Rel, is equivalent in both wild-type and Lck-deficient Th2 cell clones. Finally, we demonstrate that, in normal Th2 cells, stimulation with IL-1 leads to a rapid induction in tyrosine phosphorylation of several substrates including Lck itself. These findings strongly suggest that Lck is required for signaling in the IL-1 costimulatory pathway in Th2 lymphocytes.


Value of preoperative investigations in diagnosing prosthetic joint infection: retrospective cohort study and literature review.
The diagnosis of a prosthetic joint infection is difficult, but crucial for appropriate treatment. Scintigraphy with specific markers for infection (labelled white cells or immunoglobulin-G) has been reported as a more reliable diagnostic tool than clinical assessment (fever, fistula), laboratory studies (polynuclear neutrophil count, erythrocyte rate sedimentation, and C-reactive protein), and preoperative aspiration. In the first part of this study, we retrospectively reviewed 230 patients admitted with a suspected prosthetic joint infection, and examined the validity of the different diagnostic tools for the group as a whole and for subgroups according to the Coventry classification. In the second part, we reviewed 35 articles about preoperative evaluation of infection in prosthetic joints and compared them to our findings. Our study indicates that C-reactive protein and joint aspiration are the most useful tools to diagnose prosthetic joint infection even in situations of chronic infection (Coventry type II).


Effects of space allocation and housing density on measures of wellbeing in laboratory mice: a review.
In the majority of countries where there are legislative requirements pertaining to the use of animals in research, figures are quoted for minimum cage sizes or space allocation to be provided per animal. These figures are generally based on professional judgement and are in common usage. However, there is a growing trend and expectation that welfare science should inform regulatory decision-making. Given the importance of the potential welfare influences of cage size on the animals themselves, this paper presents the latest scientific knowledge on this topic in one of the most commonly used animals in research, the mouse. A comprehensive review of studies in laboratory mice was undertaken, examining the effects of space allocation per animal and animal density on established welfare indicators. To date, animal density studies have predominated, and the effects of space allocation per se are still relatively unclear. This information will guide those involved in facility management or legislative review, and provide a more solid foundation for further studies into the effects of routine husbandry practices on animal welfare.


Multiple sexual partners and condom use among 10 - 19 year-olds in four districts in Tanzania: what do we learn?
Although some studies in Tanzania have addressed the question of sexuality and STIs among adolescents, mostly those aged 15 - 19 years, evidence on how multiple sexual partners influence condom use among 10 - 19 year-olds is limited. This study attempts to bridge this gap by testing a hypothesis that sexual relationships with multiple partners in the age group 10 - 19 years spurs condom use during sex in four districts in Tanzania. Secondary analysis was performed using data from the Adolescents Module of the cross-sectional household survey on Maternal, Newborn and Child Health (MNCH) that was done in Kigoma, Kilombero, Rufiji and Ulanga districts, Tanzania in 2008. A total of 612 adolescents resulting from a random sample of 1200 households participated in this study. Pearson Chi-Square was used as a test of association between multiple sexual partners and condom use. Multivariate logistic regression model was fitted to the data to assess the effect of multiple sexual partners on condom use, having adjusted for potential confounding variables. STATA (10) statistical software was used to carry out this process at 5% two-sided significance level. Of the 612 adolescents interviewed, 23.4% reported being sexually active and 42.0% of these reported having had multiple (> 1) sexual partners in the last 12 months. The overall prevalence of condom use among them was 39.2%. The proportion using a condom at the last sexual intercourse was higher among those who knew that they can get a condom if they want than those who did not. No evidence of association was found between multiple sexual partners and condom use (OR = 0.77, 95% CI = 0.35 - 1.67, P = 0.504). With younger adolescents (10 - 14 years) being a reference, condom use was associated with age group (15 - 19: OR = 3.69, 95% CI = 1.21 - 11.25, P = 0.022) and district of residence (Kigoma: OR = 7.45, 95% CI = 1.79 - 31.06, P = 0.006; Kilombero: OR = 8.89, 95% CI = 2.91 - 27.21, P < 0.001; Ulanga: OR = 5.88, 95% CI = 2.00 - 17.31, P = 0.001), Rufiji being a reference category. No evidence of association was found between multiple sexual partners and condom use among adolescents in the study area. The large proportion of adolescents who engage in sexual activity without using condoms, even those with multiple partners, perpetuates the risk of transmission of HIV infections in the community. Strategies such as sex education and easing access to and making a friendly environment for condom availability are important to address the risky sexual behaviour among adolescents.


An Exploratory Framework for Cyclone Identification and Tracking.
Analyzing depressions plays an important role in meteorology, especially in the study of cyclones. In particular, the study of the temporal evolution of cyclones requires a robust depression tracking framework. To cope with this demand we propose a pipeline for the exploration of cyclones and their temporal evolution. This entails a generic framework for their identification and tracking. The fact that depressions and cyclones are not well-defined objects and their shape and size characteristics change over time makes this task especially challenging. Our method combines the robustness of topological approaches and the detailed tracking information from optical flow analysis. At first cyclones are identified within each time step based on well-established topological concepts. Then candidate tracks are computed from an optical flow field. These tracks are clustered within a moving time window to distill dominant coherent cyclone movements, which are then forwarded to a final tracking step. In contrast to previous methods our method requires only a few intuitive parameters. An integration into an exploratory framework helps in the study of cyclone movement by identifying smooth, representative tracks. Multiple case studies demonstrate the effectiveness of the method in tracking cyclones, both in the northern and southern hemisphere.


Improving the process of pain care in nursing homes: a literature synthesis.
Regulatory agencies, researchers, and clinicians have identified improving pain assessment and management in nursing homes as a high priority, but there is no consensus regarding the best strategies to change pain management practices in nursing homes. The goal of this article is to present a synthesis of published literature of process-level pain management improvement projects in nursing homes and identify and describe the role and necessary skills of various clinicians and nursing leaders in successful interventions. This literature synthesis is limited to research in nursing homes. Reports of research or reports of evaluation of quality improvement programs and descriptions of process interventions that targeted pain assessment and management were reviewed. Studies that focused primarily on the efficacy of pain treatment (e.g., analgesic trials or nonpharmacological therapies) were excluded. Of the original 472 articles, 53 were kept for a full text review. Of these, 10 were included in the final synthesis. Findings from this synthesis suggest that pain management practices may improve with the adoption of systematic implementation models, clinical decision-making algorithms, an interdisciplinary approach, continuous evaluation of outcomes, and use of on-site resource consultants. Clinician leaders in nursing homes require adept pain assessment and management skills and working knowledge of organizational change practices, including quality improvement processes, team building, collaborative decision-making, and assessing and solving system-level problems.


Identification of the binding roles of terminal and internal glycan epitopes using enzymatically synthesized N-glycans containing tandem epitopes.
Glycans play diverse roles in a wide range of biological processes. Research on glycan-binding events is essential for learning their biological and pathological functions. However, the functions of terminal and internal glycan epitopes exhibited during binding with glycan-binding proteins (GBPs) and/or viruses need to be further identified. Therefore, a focused library of 36 biantennary asparagine (Asn)-linked glycans with some presenting tandem glycan epitopes was synthesized via a combined Core Isolation/Enzymatic Extension (CIEE) and one-pot multienzyme (OPME) synthetic strategy. These N-glycans include those containing a terminal sialyl N-acetyllactosamine (LacNAc), sialyl Lewis x (sLex) and Siaα2-8-Siaα2-3/6-R structures with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc) sialic acid form, LacNAc, Lewis x (Lex), α-Gal, and Galα1-3-Lex; and tandem epitopes including α-Gal, Lex, Galα1-3-Lex, LacNAc, and sialyl LacNAc, presented with an internal sialyl LacNAc or 1-2 repeats of an internal LacNAc or Lex component. They were synthesized in milligram-scale, purified to over 98% purity, and used to prepare a glycan microarray. Binding studies using selected plant lectins, antibodies, and viruses demonstrated, for the first time, that when interpreting the binding between glycans and GBPs/viruses, not only the structure of the terminal glycan epitopes, but also the internal epitopes and/or modifications of terminal epitopes needs to be taken into account.


Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment.
Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K-AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells.


The Association Between Men's Concern About Demonstrating Masculine Characteristics and Their Sexual Risk Behaviors: Findings from the Dominican Republic.
Quantitative analyses exploring the relationship between masculinities and men's sexual risk behaviors have most commonly used one dimension of masculinities: men's gender ideology. Examining other dimensions may enhance our understanding of and ability to intervene upon this relationship. In this article, we examined the association between gender role conflict/stress (GRC/S)-men's concern about demonstrating masculine characteristics-and three different sexual risk behaviors (having two or more sex partners in the last 30 days; never/inconsistent condom use with non-steady partners; and drinking alcohol at last sex) among a sample of heterosexual men in the Dominican Republic who were participating in an HIV prevention intervention (n = 293). The GRC/S Scale we used was adapted for this specific cultural context and has 17 items (α = 0.75). We used logistic regression to assess the relationship between GRC/S and each sexual behavior, controlling for sociodemographic characteristics. In adjusted models, a higher GRC/S score was significantly associated with increased odds of having two or more sex partners in the past 30 days (AOR 1.33, 95 % CI 1.01-1.74), never/inconsistent condom use with non-steady partners (AOR 1.45, 95 % CI 1.04-2.01), and drinking alcohol at last sex (AOR 1.56, 95 % CI 1.13-2.17). These results highlight the importance of expanding beyond gender ideology to understanding the influence of GRC/S on men's sexual risk behaviors. Interventions should address men's concern about demonstrating masculine characteristics to reduce the social and internalized pressure men feel to engage in sexual risk behaviors.


One-way optical transmission in silicon grating-photonic crystal structures.
One-way optical transmission through a composite structure of grating-photonic crystal (PC) is presented. This unidirectional transportation property originates from the diffraction of grating to change the direction of light incident into the PC from pseudobandgaps to passbands of the PC. Numerical simulation shows that a light beam in a certain range of frequencies can transmit the composite structure when it is incident from the grating interface but is completely reflected by the structure when it is incident from the PC interface, which is further verified experimentally. The present structure may provide another more compact way for designing on-chip optical diode-like integrated devices.


Electron beam-induced immobilization of laccase on porous supports for waste water treatment applications.
The versatile oxidase enzyme laccase was immobilized on porous supports such as polymer membranes and cryogels with a view of using such biocatalysts in bioreactors aiming at the degradation of environmental pollutants in wastewater. Besides a large surface area for supporting the biocatalyst, the aforementioned porous systems also offer the possibility for simultaneous filtration applications in wastewater treatment. Herein a "green" water-based, initiator-free, and straightforward route to highly reactive membrane and cryogel-based bioreactors is presented, where laccase was immobilized onto the porous polymer supports using a water-based electron beam-initiated grafting reaction. In a second approach, the laccase redox mediators 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and syringaldehyde were cross-linked instead of the enzyme via electron irradiation in a frozen aqueous poly(acrylate) mixture in a one pot set-up, yielding a mechanical stable macroporous cryogel with interconnected pores ranging from 10 to 50 µm in size. The membranes as well as the cryogels were characterized regarding their morphology, chemical composition, and catalytic activity. The reactivity towards waste- water pollutants was demonstrated by the degradation of the model compound bisphenol A (BPA). Both membrane- and cryogel-immobilized laccase remained highly active after electron beam irradiation. Apparent specific BPA removal rates were higher for cryogel- than for membrane-immobilized and free laccase, whereas membrane-immobilized laccase was more stable with respect to maintenance of enzymatic activity and prevention of enzyme leakage from the carrier than cryogel-immobilized laccase. Cryogel-immobilized redox mediators remained functional in accelerating the laccase-catalyzed BPA degradation, and especially ABTS was found to act more efficiently in immobilized than in freely dissolved state.


Temporal and spatial dynamics of competitive parapatry in chewing lice.
We synthesize observations from 1979 to 2016 of a contact zone involving two subspecies of pocket gophers (Thomomys bottae connectens and T. b. opulentus) and their respective chewing lice (Geomydoecus aurei and G. centralis) along the Río Grande Valley in New Mexico, U.S.A., to test predictions about the dynamics of the zone. Historically, the natural flood cycle of the Rio Grande prevented contact between the two subspecies of pocket gophers. Flood control measures completed in the 1930s permitted contact, thus establishing the hybrid zone between the pocket gophers and the contact zone between their lice (without hybridization). Since that time, the pocket gopher hybrid zone has stabilized, whereas the northern chewing louse species has replaced the southern louse species at a consistent rate of ~150 m/year. The 0.2-0.8 width of the replacement zone has remained constant, reflecting the constant rate of chewing louse species turnover on a single gopher and within a local pocket gopher population. In contrast, the full width of the replacement zone (northernmost G. centralis to southernmost G. aurei) has increased annually. By employing a variety of metrics of the species replacement zone, we are better able to understand the dynamics of interactions between and among the chewing lice and their pocket gopher hosts. This research provides an opportunity to observe active species replacement and resulting distributional shifts in a parasitic organism in its natural setting.


Transcriptome characterization and differentially expressed genes under flooding and drought stress in the biomass grasses Phalaris arundinacea and Dactylis glomerata.
Perennial grasses are a global resource as forage, and for alternative uses in bioenergy and as raw materials for the processing industry. Marginal lands can be valuable for perennial biomass grass production, if perennial biomass grasses can cope with adverse abiotic environmental stresses such as drought and waterlogging. In this study, two perennial grass species, reed canary grass (Phalaris arundinacea) and cocksfoot (Dactylis glomerata) were subjected to drought and waterlogging stress to study their responses for insights to improving environmental stress tolerance. Physiological responses were recorded, reference transcriptomes established and differential gene expression investigated between control and stress conditions. We applied a robust non-parametric method, RoDEO, based on rank ordering of transcripts to investigate differential gene expression. Furthermore, we extended and validated vRoDEO for comparing samples with varying sequencing depths. This allowed us to identify expressed genes under drought and waterlogging whilst using only a limited number of RNA sequencing experiments. Validating the methodology, several differentially expressed candidate genes involved in the stage 3 step-wise scheme in detoxification and degradation of xenobiotics were recovered, while several novel stress-related genes classified as of unknown function were discovered. Reed canary grass is a species coping particularly well with flooding conditions, but this study adds novel information on how its transcriptome reacts under drought stress. We built extensive transcriptomes for the two investigated C3 species cocksfoot and reed canary grass under both extremes of water stress to provide a clear comparison amongst the two species to broaden our horizon for comparative studies, but further confirmation of the data would be ideal to obtain a more detailed picture.


21st-century hazards of smoking and benefits of cessation in the United States.
Extrapolation from studies in the 1980s suggests that smoking causes 25% of deaths among women and men 35 to 69 years of age in the United States. Nationally representative measurements of the current risks of smoking and the benefits of cessation at various ages are unavailable. We obtained smoking and smoking-cessation histories from 113,752 women and 88,496 men 25 years of age or older who were interviewed between 1997 and 2004 in the U.S. National Health Interview Survey and related these data to the causes of deaths that occurred by December 31, 2006 (8236 deaths in women and 7479 in men). Hazard ratios for death among current smokers, as compared with those who had never smoked, were adjusted for age, educational level, adiposity, and alcohol consumption. For participants who were 25 to 79 years of age, the rate of death from any cause among current smokers was about three times that among those who had never smoked (hazard ratio for women, 3.0; 99% confidence interval [CI], 2.7 to 3.3; hazard ratio for men, 2.8; 99% CI, 2.4 to 3.1). Most of the excess mortality among smokers was due to neoplastic, vascular, respiratory, and other diseases that can be caused by smoking. The probability of surviving from 25 to 79 years of age was about twice as great in those who had never smoked as in current smokers (70% vs. 38% among women and 61% vs. 26% among men). Life expectancy was shortened by more than 10 years among the current smokers, as compared with those who had never smoked. Adults who had quit smoking at 25 to 34, 35 to 44, or 45 to 54 years of age gained about 10, 9, and 6 years of life, respectively, as compared with those who continued to smoke. Smokers lose at least one decade of life expectancy, as compared with those who have never smoked. Cessation before the age of 40 years reduces the risk of death associated with continued smoking by about 90%.


Does the immune reaction cause malignant transformation by disrupting cell-to-cell or cell-to-matrix communications?
TUMOR PROGRESSION: In many (perhaps in all) tumor systems, a malignant cancer is preceded by a benign lesion. Most benign lesions do not transform to malignancy and many regress. The final transformative step to malignancy differs from the preceding steps in, among other things, that it often occurs in the absence of the original carcinogenic stimulus. Relatively low titers of specific immune reactants are known to stimulate, but cell-to-cell or cell-to-matrix interactions appear to be major inhibitors of tumor-growth. Therefore, it seems reasonable to hypothesize that the mechanism of immunostimulation may be an interference with cell-to-cell or cell-to-matrix communication by a sub-lethal immune-reaction. While the above hypothesis remains unproven, some evidence suggests that immunity may have a major facilitating effect on tumor growth especially at the time of malignant transformation. There is even some evidence suggesting that transformation in vivo may seldom occur in the absence of immunostimulation of the premalignant lesion. Positive selection by the immune reaction may be the reason that tumors are immunogenic.


Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue.
Pulmonary fibrosis results from an altered deposition of collagen within the lung parenchyma. This alteration is likely the result of both increased fibroblast proliferation and abnormalities in fibroblast collagen metabolism. Although the development of pulmonary fibrosis is preceded by inflammatory events in the lung, it is unclear whether altered fibroblast behavior requires continuous exposure to inflammatory mediators or alternatively results from the emergence in the lung of fibroblast populations possessing characteristics such as to explain the abnormalities seen in pulmonary fibrosis. To examine the latter hypothesis, we have established a number of fibroblast cell lines from control (C) lung tissue as well as from tissue from patients with active pulmonary fibrosis (PF), and have examined their in vitro proliferative characteristics. Our data show that PF fibroblasts proliferate significantly faster compared to C fibroblasts under standard culture conditions. We have also examined the in vitro proliferative characteristics of a substantial number of clonally derived fibroblasts. We report that a marked heterogeneity exists in terms of proliferation and also that a small but significant number of fast-growing clones are present in panels of clones derived from fibrotic tissue. These data suggest that there exists in fibrotic tissue, clones of fibroblasts with intrinsic growth characteristics which could in itself explain the increased fibroblast proliferation seen in pulmonary fibrosis. The fibrotic clones may emerge as dominant in the fibrotic lung under conditions of injury and repair likely to favor the expansion of this phenotype.


Nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study: Design and methods.
Acute kidney injury (AKI) carries an increasing incidence rate worldwide and increases the risk of developing end-stage renal disease (ESRD) as well as the medical expenses during the post-AKI course. The Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKs) has thus launched a nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study, which prospectively enrols critically ill patients with AKI. Through thoroughly evaluating the risk and prognostic factors of AKI, we hope to lower the incidence of AKI and ESRD from the perspective of AKI-ESRD interaction. The CAKs includes 30 hospitals which distribute widely through the four geographical regions (north, middle, south, and east) of Taiwan, and have a 1:1 ratio of medical centres to regional hospitals in each region. The NEP-AKI-D study enrols intensive care unit-based AKI patients who receive dialysis in the four seasonal sampled months (October 2014, along with January, April, and July 2015) in the included hospitals. The collected data include demographic information, pertaining laboratory results, dialysis settings and patient outcomes. The data are uploaded in a centre website and will be audited by on-site principal investigators, computer logic gates, and the CAKs staffs. The outcomes of interest are in-hospital mortality, dialysis-dependency and readmission rate within 90 days after discharge. The NEP-AKI-D study enrols a large number of representative AKI patients throughout Taiwan. The results of the current study are expected to provide more insight into the risk and prognostic factors of AKI and further attenuated further chronic kidney disease transition.


Medicare physician payment systems: impact of 2011 schedule on interventional pain management.
Physicians in the United States have been affected by significant changes in the patterns of medical practice evolving over the last several decades. The recently passed affordable health care law, termed the Patient Protection and Affordable Care Act of 2010 (the ACA, for short) affects physicians more than any other law. Physician services are an integral part of health care. Physicians are paid in the United States for their personal services. This payment also includes the overhead expenses for maintaining an office and providing services. The payment system is highly variable in the private insurance market; however, governmental systems have a formula-based payment, mostly based on the Medicare payment system. Physician services are billed under Part B. Since the inception of the Medicare program in 1965, several methods have been used to determine the amounts paid to physicians for each covered service. Initially, the payment systems compensated physicians on the basis of their charges. In 1975, just over 10 years after the inception of the Medicare program, payments changed so as not to exceed the increase in the Medical Economic Index (MEI). Nevertheless, the policy failed to curb increases in costs, leading to the determination of a yearly change in fees by legislation from 1984 to 1991. In 1992, the fee schedule essentially replaced the prior payment system that was based on the physician's charges, which also failed to live up to expectations for operational success. Then, in 1998, the sustainable growth rate (SGR) system was introduced. In 2009, multiple attempts were made by Congress to repeal the formula - rather unsuccessfully. Consequently, the SGR formula continues to hamper physician payments. The mechanism of the SGR includes 3 components that are incorporated into a statutory formula: expenditure targets, growth rate period, and annual adjustments of payment rates for physician services. Further, the relative value of a physician fee schedule is based on 3 components: physician work, practice expense (PE), and malpractice expense that are used to determine a value ranking for each service to which it is applied. On average, the work component represents 53.5% of a service's relative value, the fee component represents 43.6%, and the malpractice component represents 3.9%. The final schedule for physician payment was issued on November 24, 2010. This was based on a total cut of 30.8% with 24.9% of the cut attributed to SGR. However, as usual, with patchwork efficiency, Congress passed a one-year extension of the 0% update, effective through December 2011. Consequently, CMS issued an emergency update of the 2011 Medicare fee schedule, with multiple revisions, resulting in a reduction of the conversion factor of $36.8729 from December 2010 to $33.9764 for 2011.


Quantifying interhospital patient sharing as a mechanism for infectious disease spread.
Assessments of infectious disease spread in hospitals seldom account for interfacility patient sharing. This is particularly important for pathogens with prolonged incubation periods or carrier states. We quantified patient sharing among all 32 hospitals in Orange County (OC), California, using hospital discharge data. Same-day transfers between hospitals were considered "direct" transfers, and events in which patients were shared between hospitals after an intervening stay at home or elsewhere were considered "indirect" patient-sharing events. We assessed the frequency of readmissions to another OC hospital within various time points from discharge and examined interhospital sharing of patients with Clostridium difficile infection. In 2005, OC hospitals had 319,918 admissions. Twenty-nine percent of patients were admitted at least twice, with a median interval between discharge and readmission of 53 days. Of the patients with 2 or more admissions, 75% were admitted to more than 1 hospital. Ninety-four percent of interhospital patient sharing occurred indirectly. When we used 10 shared patients as a measure of potential interhospital exposure, 6 (19%) of 32 hospitals "exposed" more than 50% of all OC hospitals within 6 months, and 17 (53%) exposed more than 50% within 12 months. Hospitals shared 1 or more patient with a median of 28 other hospitals. When we evaluated patients with C. difficile infection, 25% were readmitted within 12 weeks; 41% were readmitted to different hospitals, and less than 30% of these readmissions were direct transfers. In a large metropolitan county, interhospital patient sharing was a potential avenue for transmission of infectious agents. Indirect sharing with an intervening stay at home or elsewhere composed the bulk of potential exposures and occurred unbeknownst to hospitals.


Diagnosis and exploration of massively univariate neuroimaging models.
The goal of this work is to establish the validity of neuroimaging models and inferences through diagnosis and exploratory data analysis. While model diagnosis and exploration are integral parts of any statistical modeling enterprise, these aspects have been mostly neglected in functional neuroimaging. We present methods that make diagnosis and exploration of neuroimaging data feasible. We use three- and one-dimensional summaries that characterize the model fit and the four-dimensional residuals. The statistical tools are diagnostic summary statistics with tractable null distributions and the dynamic graphical tools which allow the exploration of multiple summaries in both spatial and temporal/interscan aspects, with the ability to quickly jump to spatiotemporal detail. We apply our methods to a fMRI data set, demonstrating their ability to localize subtle artifacts and to discover systematic experimental variation not captured by the model.


Digital contact tracing technologies in epidemics: a rapid review.
Reducing the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global priority. Contact tracing identifies people who were recently in contact with an infected individual, in order to isolate them and reduce further transmission. Digital technology could be implemented to augment and accelerate manual contact tracing. Digital tools for contact tracing may be grouped into three areas: 1) outbreak response; 2) proximity tracing; and 3) symptom tracking. We conducted a rapid review on the effectiveness of digital solutions to contact tracing during infectious disease outbreaks. To assess the benefits, harms, and acceptability of personal digital contact tracing solutions for identifying contacts of an identified positive case of an infectious disease. An information specialist searched the literature from 1 January 2000 to 5 May 2020 in CENTRAL, MEDLINE, and Embase. Additionally, we screened the Cochrane COVID-19 Study Register. We included randomised controlled trials (RCTs), cluster-RCTs, quasi-RCTs, cohort studies, cross-sectional studies and modelling studies, in general populations. We preferentially included studies of contact tracing during infectious disease outbreaks (including COVID-19, Ebola, tuberculosis, severe acute respiratory syndrome virus, and Middle East respiratory syndrome) as direct evidence, but considered comparative studies of contact tracing outside an outbreak as indirect evidence. The digital solutions varied but typically included software (or firmware) for users to install on their devices or to be uploaded to devices provided by governments or third parties. Control measures included traditional or manual contact tracing, self-reported diaries and surveys, interviews, other standard methods for determining close contacts, and other technologies compared to digital solutions (e.g. electronic medical records). Two review authors independently screened records and all potentially relevant full-text publications. One review author extracted data for 50% of the included studies, another extracted data for the remaining 50%; the second review author checked all the extracted data. One review author assessed quality of included studies and a second checked the assessments. Our outcomes were identification of secondary cases and close contacts, time to complete contact tracing, acceptability and accessibility issues, privacy and safety concerns, and any other ethical issue identified. Though modelling studies will predict estimates of the effects of different contact tracing solutions on outcomes of interest, cohort studies provide empirically measured estimates of the effects of different contact tracing solutions on outcomes of interest. We used GRADE-CERQual to describe certainty of evidence from qualitative data and GRADE for modelling and cohort studies. We identified six cohort studies reporting quantitative data and six modelling studies reporting simulations of digital solutions for contact tracing. Two cohort studies also provided qualitative data. Three cohort studies looked at contact tracing during an outbreak, whilst three emulated an outbreak in non-outbreak settings (schools). Of the six modelling studies, four evaluated digital solutions for contact tracing in simulated COVID-19 scenarios, while two simulated close contacts in non-specific outbreak settings. Modelling studies Two modelling studies provided low-certainty evidence of a reduction in secondary cases using digital contact tracing (measured as average number of secondary cases per index case - effective reproductive number (R eff)). One study estimated an 18% reduction in R eff with digital contact tracing compared to self-isolation alone, and a 35% reduction with manual contact-tracing. Another found a reduction in R eff for digital contact tracing compared to self-isolation alone (26% reduction) and a reduction in R eff for manual contact tracing compared to self-isolation alone (53% reduction). However, the certainty of evidence was reduced by unclear specifications of their models, and assumptions about the effectiveness of manual contact tracing (assumed 95% to 100% of contacts traced), and the proportion of the population who would have the app (53%). Cohort studies Two cohort studies provided very low-certainty evidence of a benefit of digital over manual contact tracing. During an Ebola outbreak, contact tracers using an app found twice as many close contacts per case on average than those using paper forms. Similarly, after a pertussis outbreak in a US hospital, researchers found that radio-frequency identification identified 45 close contacts but searches of electronic medical records found 13. The certainty of evidence was reduced by concerns about imprecision, and serious risk of bias due to the inability of contact tracing study designs to identify the true number of close contacts. One cohort study provided very low-certainty evidence that an app could reduce the time to complete a set of close contacts. The certainty of evidence for this outcome was affected by imprecision and serious risk of bias. Contact tracing teams reported that digital data entry and management systems were faster to use than paper systems and possibly less prone to data loss. Two studies from lower- or middle-income countries, reported that contact tracing teams found digital systems simpler to use and generally preferred them over paper systems; they saved personnel time, reportedly improved accuracy with large data sets, and were easier to transport compared with paper forms. However, personnel faced increased costs and internet access problems with digital compared to paper systems. Devices in the cohort studies appeared to have privacy from contacts regarding the exposed or diagnosed users. However, there were risks of privacy breaches from snoopers if linkage attacks occurred, particularly for wearable devices. The effectiveness of digital solutions is largely unproven as there are very few published data in real-world outbreak settings. Modelling studies provide low-certainty evidence of a reduction in secondary cases if digital contact tracing is used together with other public health measures such as self-isolation. Cohort studies provide very low-certainty evidence that digital contact tracing may produce more reliable counts of contacts and reduce time to complete contact tracing. Digital solutions may have equity implications for at-risk populations with poor internet access and poor access to digital technology. Stronger primary research on the effectiveness of contact tracing technologies is needed, including research into use of digital solutions in conjunction with manual systems, as digital solutions are unlikely to be used alone in real-world settings. Future studies should consider access to and acceptability of digital solutions, and the resultant impact on equity. Studies should also make acceptability and uptake a primary research question, as privacy concerns can prevent uptake and effectiveness of these technologies.