Neural correlates of generic versus gender-specific face adaptation.
The perception of facial gender has been found to be adaptively recalibrated: adaptation to male faces causes participants to perceive subsequent faces as more feminine and vice versa [Webster, M. A., Kaping, D., Mizokami, Y., & Duhamel, P. Adaptation to natural facial categories. Nature, 428, 557-561, 2004]. In an event-related brain potential (ERP) study, Kovács et al. [Kovács, G., Zimmer, M., Banko, E., Harza, I., Antal, A., & Vidnyanszky, Z. Electrophysiological correlates of visual adaptation to faces and body parts in humans. Cerebral Cortex, 16, 742-753, 2006] reported reduced N170 amplitudes and increased latencies for test faces following female gender adaptation compared to control stimulus (a phase randomized face) adaptation. We examined whether this N170 attenuation to test faces was related to the adaptor's gender, or to adaptation to face exposure in general. We compared N170 effects after adaptation to either male or androgynous faces. Additionally, we investigated cross-modal adaptation for the same test faces following male or androgynous voice adaptors. Visual adaptation to face gender replicated previously reported aftereffects in classifying androgynous faces, and a similar trend was observed following adaptation to voice gender. Strikingly, N170 amplitudes were dramatically reduced for faces following face adaptors (relative to those following voice adaptors), whereas only minimal gender-specific adaptation effects were seen in the N170. By contrast, strong gender-specific adaptation effects appeared in a centroparietal P3-like component (approximately 400-600 msec), which in the context of adaptation may reflect a neural correlate of the detection of perceptual novelty.


Land Use, Climate, and Water Resources-Global Stages of Interaction.
Land use and climate change can accelerate the depletion of freshwater resources that support humans and ecosystem services on a global scale. Here, we briefly review studies from around the world, and highlight those in this special issue. We identify stages that characterize increasing interaction between land use and climate change. During the first stage, hydrologic modifications and the built environment amplify overland flow via processes associated with runoff-dominated ecosystems (e.g., soil compaction, impervious surface cover, drainage, and channelization). During the second stage, changes in water storage impact the capacity of ecosystems to buffer extremes in water quantity and quality (e.g., either losses in snowpack, wetlands, and groundwater recharge or gains in water and nutrient storage behind dams in reservoirs). During the third stage, extremes in water quantity and quality contribute to losses in ecosystem services and water security (e.g., clean drinking water, flood mitigation, and habitat availability). During the final stage, management and restoration strategies attempt to regain lost ecosystem structure, function, and services but need to adapt to climate change. By anticipating the increasing interaction between land use and climate change, intervention points can be identified, and management strategies can be adjusted to improve outcomes for realistic expectations. Overall, global water security cannot be adequately restored without considering an increasing interaction between land use and climate change across progressive stages and our ever-increasing human domination of the water cycle from degradation to ecosystem restoration.


Ethics of a relaxed antidoping rule accompanied by harm-reduction measures.
Harm-reduction approaches are used to reduce the burden of risky human behaviour without necessarily aiming to stop the behaviour. We discuss what an introduction of harm reduction for doping in sports would mean in parallel with a relaxation of the antidoping rule. We analyse what is ethically at stake in the following five levels: (1) What would it mean for the athlete (the self)? (2) How would it impact other athletes (the other)? (3) How would it affect the phenomenon of sport as a game and its fair play basis (the play)? (4) What would be the consequences for the spectator and the role of sports in society (the display)? and (5) What would it mean for what some consider as essential to being human (humanity)? For each level, we present arguments for and against doping and then discuss what a harm-reduction approach, within a dynamic regime of a partially relaxed antidoping rule, could imply. We find that a harm-reduction approach is morally defensible and potentially provides a viable escape out of the impasse resulting from the impossibility of attaining the eradication of doping. The following question remains to be answered: Would a more relaxed position, when combined with harm-reduction measures, indeed have less negative consequences for society than today's all-out antidoping efforts that aim for abstinence? We provide an outline of an alternative policy, allowing a cautious step-wise change to answer this question and then discuss the ethical aspects of such a policy change.


Circadian Behavioral Responses to Light and Optic Chiasm-Evoked Glutamatergic EPSCs in the Suprachiasmatic Nucleus of ipRGC Conditional vGlut2 Knock-Out Mice.
Intrinsically photosensitive retinal ganglion cells (ipRGCs) innervate the hypothalamic suprachiasmatic nucleus (SCN), a circadian oscillator that functions as a biological clock. ipRGCs use vesicular glutamate transporter 2 (vGlut2) to package glutamate into synaptic vesicles and light-evoked resetting of the SCN circadian clock is widely attributed to ipRGC glutamatergic neurotransmission. Pituitary adenylate cyclase-activating polypeptide (PACAP) is also packaged into vesicles in ipRGCs and PACAP may be coreleased with glutamate in the SCN. vGlut2 has been conditionally deleted in ipRGCs in mice [conditional knock-outs (cKOs)] and their aberrant photoentrainment and residual attenuated light responses have been ascribed to ipRGC PACAP release. However, there is no direct evidence that all ipRGC glutamatergic neurotransmission is eliminated in vGlut2 cKOs. Here, we examined two lines of ipRGC vGlut2 cKO mice for SCN-mediated behavioral responses under several lighting conditions and for ipRGC glutamatergic neurotransmission in the SCN. Circadian behavioral responses varied from a very limited response to light to near normal photoentrainment. After collecting behavioral data, hypothalamic slices were prepared and evoked EPSCs (eEPSCs) were recorded from SCN neurons by stimulating the optic chiasm. In cKOs, glutamatergic eEPSCs were recorded and all eEPSC parameters examined (stimulus threshold, amplitude, rise time or time-to-peak and stimulus strength to evoke a maximal response) were similar to controls. We conclude that a variable number but functionally significant percentage of ipRGCs in two vGlut2 cKO mouse lines continue to release glutamate. Thus, the residual SCN-mediated light responses in these cKO mouse lines cannot be attributed solely to ipRGC PACAP release.


Differential parietal and temporal contributions to music perception in improvising and score-dependent musicians, an fMRI study.
Using fMRI, cerebral activations were studied in 24 classically-trained keyboard performers and 12 musically unskilled control subjects. Two groups of musicians were recruited: improvising (n=12) and score-dependent (non-improvising) musicians (n=12). While listening to both familiar and unfamiliar music, subjects either (covertly) appraised the presented music performance or imagined they were playing the music themselves. We hypothesized that improvising musicians would exhibit enhanced efficiency of audiomotor transformation reflected by stronger ventral premotor activation. Statistical Parametric Mapping revealed that, while virtually 'playing along׳ with the music, improvising musicians exhibited activation of a right-hemisphere distribution of cerebral areas including posterior-superior parietal and dorsal premotor cortex. Involvement of these right-hemisphere dorsal stream areas suggests that improvising musicians recruited an amodal spatial processing system subserving pitch-to-space transformations to facilitate their virtual motor performance. Score-dependent musicians recruited a primarily left-hemisphere pattern of motor areas together with the posterior part of the right superior temporal sulcus, suggesting a relationship between aural discrimination and symbolic representation. Activations in bilateral auditory cortex were significantly larger for improvising musicians than for score-dependent musicians, suggesting enhanced top-down effects on aural perception. Our results suggest that learning to play a music instrument primarily from notation predisposes musicians toward aural identification and discrimination, while learning by improvisation involves audio-spatial-motor transformations, not only during performance, but also perception.


Opioid use in knee or hip osteoarthritis: a region-wide population-based cohort study.
To quantify opioid use in knee and hip osteoarthritis (OA) patients, and to estimate the proportion of opioids in the population attributable to OA patients. Population-based cohort study. We included 751,579 residents in southern Sweden, aged ≥35 years in 2015. Doctor-diagnosed knee or hip OA between 1998 and 2015 was the exposure. Dispensed weak and strong opioids were identified between November 2013 and October 2015 from the Swedish Prescribed Drug Register (SPDR). We determined age- and sex-standardized 12-month period prevalence of opioid use from November 2014 until October 2015 and calculated prevalence ratios and incidence rate ratios adjusted for age, sex, and other socio-demographic variables. We estimated the population attributable fraction (PAF) of incident opioid use attributable to OA patients. The 12-month prevalence of opioid use among OA patients was 23.7% [95% confidence intervals (CI) 23.3-24.2], which was two-fold higher compared to individuals without knee or hip OA: prevalence ratio: 2.1 [95% CI 2.1-2.1]. Similarly, OA patients were more likely to have an incident opioid dispensation, especially for strong opioids (incidence rate ratio: 2.6 [95% CI 2.5-2.7]). Population attributable tractions (PAF) of incident opioid use attributable to OA patients was 12%, 9% for weak and 17% for strong opioids. Every fourth patient with knee or hip OA has opioids dispensed over a 1-year period, and 12% of incident opioid dispensations are attributable to OA and/or its related comorbidities. These results highlight that patients with knee and hip OA constitute a group of patients with an alarmingly high use of opioids.


Quantitation of Single and Combinatorial Histone Modifications by Integrated Chromatography of Bottom-up Peptides and Middle-down Polypeptide Tails.
The analysis of histone post-translational modifications (PTMs) by mass spectrometry (MS) has been critical to the advancement of the field of epigenetics. The most sensitive and accurate workflow is similar to the canonical proteomics analysis workflow (bottom-up MS), where histones are digested into short peptides (4-20 aa) and quantitated in extracted ion chromatograms. However, this limits the ability to detect even very common co-occurrences of modifications on histone proteins, preventing biological interpretation of PTM crosstalk. By digesting with GluC rather than trypsin, it is possible to produce long polypeptides corresponding to intact histone N-terminal tails (50-60 aa), where most modifications reside. This middle-down MS approach is used to study distant PTM co-existence. However, the most sensitive middle-down workflow uses weak cation exchange-hydrophilic interaction chromatography (WCX-HILIC), which is less robust than conventional reversed-phase chromatography. Additionally, since the buffer systems for middle-down and bottom-up proteomics differ substantially, it is cumbersome to toggle back and forth between both experimental setups on the same LC system. Here, we present a new workflow using porous graphitic carbon (PGC) as a stationary phase for histone analysis where bottom-up and middle-down sized histone peptides can be analyzed simultaneously using the same reversed-phase buffer setup. By using this protocol for middle-down sized peptides, we identified 406 uniquely modified intact histone tails and achieved a correlation of 0.85 between PGC and WCX-HILIC LC methods. Together, our method facilitates the analysis of single and combinatorial histone PTMs with much simpler applicability for conventional proteomics labs than the state-of-the-art middle-down MS.


The influence of culture on diabetes self-management: perspectives of Gujarati Muslim men who reside in northwest England.
To present the findings of a study which explored the influence of culture on (type 2) diabetes self-management in Gujarati Muslim men who reside in northwest England. This study was informed by an embodied perspective of culture, in which culture is grounded in the body and self. This contrasts with some contemporary health research and policy which adopts an oversimplified perspective, portraying culture as static and deterministic and being responsible for non-adherent self-management behaviours. A case-study approach was used, which combined interview and participant observation methods. Data were collected from Gujarati Muslim men about their lived experiences of diabetes self-management. These accounts, along with further narrative data from 'significant other' participants, were analysed over several cycles. Two central concepts guide the results: embodied culture and dynamic culture. These concepts reflect the subjective and contextual nature of culture and are illustrated in the themes 'past experiences and socio-economic factors', 'social and gendered roles' and 'personal choice and contextual factors'. The findings highlight that the complexity of life means that culture never exists in isolation, but is one of the many factors that a man negotiates to inform his diabetes self-management. We draw attention to the dissonance between the way culture is presented in some government policy and research, and the way it is understood in an embodied approach. The National Service Framework for Diabetes advocates the provision of individualized culturally appropriate care, and in this paper, we make suggestions as to how an embodied approach can be incorporated within the framework. Nurses have an integral role in implementing the National Service Framework for Diabetes. This paper contributes to the debate about how nurses can best deliver this framework to a diverse patient population.


Role of π-acceptor effects in controlling the lability of novel monofunctional Pt(II) and Pd(II) complexes: crystal structure of [Pt(tripyridinedimethane)Cl]Cl.
The kinetics and mechanism of substitution reactions of novel monofunctional [Pt(tpdm)Cl](+) and [Pd(tpdm)Cl](+) complexes (where tpdm = tripyridinedimethane) and their aqua analogues with thiourea (tu), L-methionine (L-met), glutathione (GSH), and guanosine-5'-monophosphate (5'-GMP) were studied in 0.1 M NaClO(4) at pH = 2.5 (in the presence of 10 mM NaCl for reactions of the chlorido complexes). The reactivity of the investigated nucleophiles follows the order tu > l-met > GSH > 5'-GMP. The reported rate constants showed the higher reactivity of the Pd(II) complexes as well as the higher reactivity of the aqua complex than the corresponding chlorido complex. The negative values reported for the activation entropy as well as the activation volume confirmed an associative substitution mode. In addition, the molecular and crystal structure of [Pt(tpdm)Cl]Cl was determined by X-ray crystallography. The compound crystallizes in a monoclinic space group C2/c with two independent molecules of the complex and unit cell dimensions of a = 38.303(2) Å, b = 9.2555(5) Å, c = 27.586(2) Å, β = 133.573(1)°, and V = 7058.3(8) Å(3). The cationic complex [Pt(tpdm)Cl](+) exhibits square-planar coordination around the Pt(II) center. The lability of the [Pt(tpdm)Cl](+) complex is orders of magnitude lower than that of [Pt(terpyridine)Cl](+). Quantum chemical calculations were performed on the [Pt(tpdm)Cl](+) and [Pt(terpyridine)Cl](+) complexes and their reactions with thiourea. Theoretical computations for the corresponding Ni(II) complexes clearly demonstrated that π-back-bonding properties of the terpyridine chelate can account for acceleration of the nucleophilic substitution process as compared to the tpdm chelate, where introduction of two methylene groups prevents such an effective π-back bonding.


A national mandatory-split liver policy: A report from the Italian experience.
To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50 years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially "splittable" donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P = .009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P = .045]). The pediatric (4.5% vs 2.5% [P = .398]) and adult (9.7% to 5.2% [P < .001]) LT-waiting list mortality reduced; SLT outcomes remained stable. Retransplantation (HR = 2.641, P = .035) and recipient weight >20 kg (HR = 5.113, P = .048) in LLS, and ischemic time >8 hours (HR = 2.475, P = .048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.


Beyond the flesh: some lessons from a mole cricket.
What do linguistic symbols do for minds like ours, and how (if at all) can basic embodied, dynamical, and situated approaches do justice to high-level human thought and reason? These two questions are best addressed together, since our answers to the first may inform the second. The key move in scaling up simple embodied cognitive science is, I argue, to take very seriously the potent role of human-built structures in transforming the spaces of human learning and reason. In particular, in this article I look at a range of cases involving what I dub surrogate situations. Here, we actively create restricted artificial environments that allow us to deploy basic perception-action-reason routines in the absence of their proper objects. Examples include the use of real-world models, diagrams, and other concrete external symbols to support dense looping interactions with a variety of stable external structures that stand in for the absent states of affairs. Language itself, I finally suggest, is the most potent and fundamental form of such surrogacy. Words are both cheap stand-ins for gross behavioral outcomes, and the concrete objects that structure new spaces for basic forms of learning and reason. A good hard look at surrogate situatedness thus turns the standard skeptical challenge on its head. But it raises important questions concerning what really matters about these new approaches, and it helps focus what I see as the major challenge for the future: how, in detail, to conceptualize the role of symbols (both internal and external) in dynamical cognitive processes.


Multiplexed actuation using ultra dielectrophoresis for proteomics applications: a comprehensive electrical and electrothermal design methodology.
In this work, we present a methodological approach to analyze an enhanced dielectrophoresis (DEP) system from both a circuit analysis and electrothermal view points. In our developed model, we have taken into account various phenomena and constraints such as voltage degradation (due to the presence of the protecting oxide layer), oxide breakdown, instrumentation limitations, and thermal effects. The results from this analysis are applicable generally to a wide variety of geometries and high voltage microsystems. Here, these design guidelines were applied to develop a robust electronic actuation system to perform a multiplexed bead-based protein assay. To carry out the multiplexed functionality, along a single microfluidic channel, an array of proteins is patterned, where each element is targeting a specific secondary protein coated on micron-sized beads in the subsequently introduced sample solution. Below each element of the array, we have a pair of addressable interdigitated electrodes. By selectively applying voltage at the terminals of each interdigitated electrode pair, the enhanced DEP, or equivalently 'ultra'-DEP (uDEP) force detaches protein-bound beads from each element of the array, one by one, without disturbing the bound beads in the neighboring regions. The detached beads can be quantified optically or electrically downstream. For proof of concept, we illustrated 16-plex actuation capability of our device to elute micron-sized beads that are bound to the surface through anti-IgG and IgG interaction which is on the same order of magnitude in strength as typical antibody-antigen interactions. In addition to its application in multiplexed protein analysis, our platform can be potentially utilized to statistically characterize the strength profile of biological bonds, since the multiplexed format allows for high throughput force spectroscopy using the array of uDEP devices, under the same buffer and assay preparation conditions.


Integrating advanced practice providers into medical critical care teams.
Because there is increasing demand for critical care providers in the United States, many medical ICUs for adults have begun to integrate nurse practitioners and physician assistants into their medical teams. Studies suggest that such advanced practice providers (APPs), when appropriately trained in acute care, can be highly effective in helping to deliver high-quality medical critical care and can be important elements of teams with multiple providers, including those with medical house staff. One aspect of building an integrated team is a practice model that features appropriate coding and billing of services by all providers. Therefore, it is important to understand an APP's scope of practice, when they are qualified for reimbursement, and how they may appropriately coordinate coding and billing with other team providers. In particular, understanding when and how to appropriately code for critical care services (Current Procedural Terminology [CPT] code 99291, critical care, evaluation and management of the critically ill or critically injured patient, first 30-74 min; CPT code 99292, critical care, each additional 30 min) and procedures is vital for creating a sustainable program. Because APPs will likely play a growing role in medical critical care units in the future, more studies are needed to compare different practice models and to determine the best way to deploy this talent in specific ICU settings.


The 2020 International Alliance for the Control of Scabies Consensus Criteria for the Diagnosis of Scabies.
Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.


Use of a Mobile App to Augment Psychotherapy in a Community Psychiatric Clinic: Feasibility and Fidelity Trial.
Even though 1 in 5 Americans experience some form of mental illness each year, 80% have been shown to discontinue psychotherapy prematurely. The traditional psychotherapy service delivery model, consisting of isolated clinical sessions, lacks the ability to keep patients engaged outside clinical sessions. Newer digital mental health platforms can address the clinical need for a robust tool that tracks mental well-being and improves engagement in patients with depressive symptoms. The primary goals of this feasibility study were to (1) assess compliance among providers and their patients with a digital mental health platform protocol, and (2) examine the usability and fidelity of a mobile app through structured participant feedback. A sample of 30 participants was recruited for a 5-week study from a community-based mental health clinic in Baltimore, Maryland, USA. Inclusion criteria were: aged 18 years or older, having access to a smartphone, and having at least mild-to-moderate depression and/or anxiety as measured by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scales, respectively. Eligible participants were randomized into one of two study arms: (1) the intervention arm or (2) the waitlist control arm. Participants in the intervention arm were asked to download the Rose app and were prompted to complete clinical assessments (PHQ-9 and GAD-7) every other week, daily mood and anxiety Likert scales, and daily journal entries. The participants in the waitlist arm served as controls for the study and completed the clinical assessments only. Both arms engaged in weekly psychotherapy sessions, with participant in-app input informing the psychotherapy process of the intervention arm, while those in the waitlist control arm continued their standard care. Outcomes of interest included adherence to completion of in-app assessments and usability of the Rose mobile app assessed through the modified Mobile Application Rating Scale. Over the study period, a sample of 30 participants used the Rose app 2834 times to complete clinical assessments. On average, 70% (21; 95% CI 61.14%-77.41%) of participants completed mood and anxiety daily check-ins and journal entries 5 days per week. Nearly all participants (29/30, 97%) completed all PHQ-9 and GAD-7 in-app scales during the study. Subjective impressions showed that 73% (22/30) of participants found the mobile app to be engaging and in line with their needs, and approximately 70% (21/30) of participants reported the app functionality and quality of information to be excellent. Additionally, more than two-thirds of the participants felt that their knowledge and awareness of depression and anxiety management improved through using the app. Steady compliance and high app ratings showcase the utility of the Rose mobile mental health app in augmenting the psychotherapy process for patients with mood disorders and improving mental health knowledge. Future studies are needed to further examine the impact of Rose on treatment outcomes. ClinicalTrials.gov NCT04200170; https://clinicaltrials.gov/ct2/show/NCT04200170.


Preliminary evidence of physical activity levels measured by accelerometer in Spanish adolescents: the AFINOS Study.
It is necessary to know the levels of physical activity (PA) for a better understanding of the development of chronic diseases in youth. The aim of this study was to assess levels of total PA and time spent in different PAintensities in Spanish adolescents by accelerometer. A sub-sample of 214 healthy Spanish adolescents (107 females), aged 13-16 years, enrolled in the AFINOS Study was selected for this study. Participants wore the ActiGraph GT1M accelerometer for 7 consecutive days. Total PA and time spent in sedentary, light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) was estimated using the accelerometer. Adiposity was measured in the sample using sum of 6 skinfoldthickness, waist circumference and BMI. Adolescent boys were engaged in higher levels of total PA, moderate PA, vigorous PA and MVPA than adolescent girls, whereas girls were engaged in higher levels of light PA. Differences between age groups showed that the 15-16 years group did more total PA (P = 0.008) than the 13-14 years group. Adolescents with highest levels of body fat were less active and spent less time in vigorous PA and MVPA than adolescents with less body fat. Among the current sample, 71.1% of the adolescents (82.2% adolescent boys and 60.7% adolescent girls) reached the recommendation of > or = 60 min in MVPA. Although these findings suggest that Spanish adolescents have similar PA levels than other European adolescents, further cross-sectional and longitudinal studies must assess PA levels in free-living conditions in Spanish children and adolescents using objective methods such as accelerometers, heart rate monitors and pedometers.


Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study.
Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination of liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study. From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-up, but all the others were followed for at least 4 years or until death. Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months. The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on "radical" surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.


Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.
Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.


Exercise programs for people with dementia.
This is an update of our previous 2013 review. Several recent trials and systematic reviews of the impact of exercise on people with dementia are reporting promising findings. Primary objectiveDo exercise programs for older people with dementia improve their cognition, activities of daily living (ADLs), neuropsychiatric symptoms, depression, and mortality? Secondary objectivesDo exercise programs for older people with dementia have an indirect impact on family caregivers' burden, quality of life, and mortality?Do exercise programs for older people with dementia reduce the use of healthcare services (e.g. visits to the emergency department) by participants and their family caregivers? We identified trials for inclusion in the review by searching ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 4 September 2011, on 13 August 2012, and again on 3 October 2013. In this review, we included randomized controlled trials in which older people, diagnosed with dementia, were allocated either to exercise programs or to control groups (usual care or social contact/activities) with the aim of improving cognition, ADLs, neuropsychiatric symptoms, depression, and mortality. Secondary outcomes related to the family caregiver(s) and included caregiver burden, quality of life, mortality, and use of healthcare services. Independently, at least two authors assessed the retrieved articles for inclusion, assessed methodological quality, and extracted data. We analysed data for summary effects. We calculated mean differences or standardized mean difference (SMD) for continuous data, and synthesized data for each outcome using a fixed-effect model, unless there was substantial heterogeneity between studies, when we used a random-effects model. We planned to explore heterogeneity in relation to severity and type of dementia, and type, frequency, and duration of exercise program. We also evaluated adverse events. Seventeen trials with 1067 participants met the inclusion criteria. However, the required data from three included trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants' dementia, and type, duration, and frequency of exercise. Only two trials included participants living at home.Our meta-analysis revealed that there was no clear evidence of benefit from exercise on cognitive functioning. The estimated standardized mean difference between exercise and control groups was 0.43 (95% CI -0.05 to 0.92, P value 0.08; 9 studies, 409 participants). There was very substantial heterogeneity in this analysis (I² value 80%), most of which we were unable to explain, and we rated the quality of this evidence as very low. We found a benefit of exercise programs on the ability of people with dementia to perform ADLs in six trials with 289 participants. The estimated standardized mean difference between exercise and control groups was 0.68 (95% CI 0.08 to 1.27, P value 0.02). However, again we observed considerable unexplained heterogeneity (I² value 77%) in this meta-analysis, and we rated the quality of this evidence as very low. This means that there is a need for caution in interpreting these findings.In further analyses, in one trial we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program. The mean difference between exercise and control groups was -15.30 (95% CI -24.73 to -5.87; 1 trial, 40 participants; P value 0.001). There was no apparent risk of bias in this study. In addition, there was no clear evidence of benefit from exercise on neuropsychiatric symptoms (MD -0.60, 95% CI -4.22 to 3.02; 1 trial, 110 participants; P value .0.75), or depression (SMD 0.14, 95% CI -0.07 to 0.36; 5 trials, 341 participants; P value 0.16). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. There is promising evidence that exercise programs may improve the ability to perform ADLs in people with dementia, although some caution is advised in interpreting these findings. The review revealed no evidence of benefit from exercise on cognition, neuropsychiatric symptoms, or depression. There was little or no evidence regarding the remaining outcomes of interest (i.e., mortality, caregiver burden, caregiver quality of life, caregiver mortality, and use of healthcare services).


Benzotrithiophene versus Benzo/Naphthodithiophene Building Blocks: The Effect of Star-Shaped versus Linear Conjugation on Their Electronic Structures.
The synthesis, characterization, and optical properties of a novel star-shaped oligothiophene with a central rigid trithienobenzene (BTT) core and diketopyrrolopyrrole (DPP) units are reported and compared with homologous linear systems based on the benzodithiophene (BDT) and the naphthodithiophene (NDT) units end capped with DPPs. This comparison is aimed at elucidating the effect of the star-shaped configuration versus linear conformation on the optical and electrical properties. Electronic and vibrational spectroscopies, together with transient absorption spectroscopy, scanning electronic microscopy, and DFT calculations are used to understand not only the molecular properties of these semiconductors, but also to analyze the supramolecular aggregation in these derivatives. We conclude that although the subject star-shaped derivative is not optimal in terms of π-conjugation, its extended BTT unit significantly favors intermolecular π-stacking interactions, which is interesting for their applications in devices. Field-effect transistors and solar cells were fabricated with these new molecular semiconductors and the performance difference discussed.


The management of benign bone lesions.
The almost bewildering variety of lesions that can affect bone contrasts sharply with the limited potential of bone to differentially respond to those lesions. This paradox can create a challenging problem when a bone lesion is shown on an x-ray film. Although heavily populated with pleuripotential primitive mesenchymal cells, there is seldom a histologic or radiographic change in the involved bone specific enough to allow a comfortable diagnostic autonomy to be enjoyed by surgical pathologists, radiologists or orthopaedic surgeons. Even when diligent and astute clinical evaluation has excluded infectious, parasitic, metabolic and metastatic causes of the change seen on x-ray studies, a physician is often still uncertain as to the exact nature of the lesion. A knowledge of the relative frequency of the common lesions, an acceptance that biopsy studies and treatment must be combined at times, an appreciation of the possibility of malignant change in a given lesion and a tendency to seek early consultation will likely lead to timely and accurate diagnosis. Once the diagnosis is made, optimum management must be selected. The best current opinion categorizes the lesions into treatment groups consisting of observation, curettage and graft, block excision, cryotherapy and radiotherapy.


A novel RT-PCR approach for detection and characterization of citrus viroids.
Citrus plants are natural hosts of five viroid species and a large number of sequence variants. Because of their small size, viroids lend themselves to various RT-PCR approaches for their detection and further characterization. The one-step RT-PCR approach proposed here is based on the synthesis of viroid-cDNA by reverse transcription at 60 degrees C using a viroid specific 27-mer primer followed by standard second strand synthesis plus PCR amplification with various primer pairs. According to the primers used, full or partial length viroid-DNA is obtained. The technique avoids amplicon contamination in routine diagnosis. The suitability of the technique has been demonstrated using several nucleic acid extraction procedures and different viroid infected host species. The homogenization of tissue inside sealed plastic bags followed by nucleic acid extraction using a SDS/potassium acetate method is recommended because of its efficiency, simplicity and low cost. This extraction procedure, when coupled to the one-step RT-PCR approach, can be useful to avoid cross-contamination during routine diagnosis. A PCR strategy capable of discriminating between mild and severe strains of CEVd and identifying cachexia-inducing isolates of HSVd, is also described.


Effects of body weight and alcohol consumption on insulin sensitivity.
Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways. Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes. Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1alpha; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9). We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.


Role of chromatic and luminance contrast in inferring structure from motion.
We measured the ability to infer structure from motion (SFM) in several directions in three-dimensional color space. Only motion cues are useful to subjects in performing this three-dimensional shape-identification task. We report the following results: (1) SFM performance is at chance for equiluminant stimuli that isolate short-wavelength-sensitive cones. Hence the short-wavelength-sensitive-cone input to SFM is negligible. (2) SFM performance increases with the magnitude of delta L - delta M signal when delta L + delta M = 0 (i.e., only chromatic and no luminance contrast is available). We reject the hypothesis that SFM obtains input from a single chromatic mechanism combining the long- and medium-wavelength-sensitive cones linearly. Our data are compatible with SFM that uses the output of two mechanisms, one taking the difference between the long- and medium-wavelength-sensitive-cone signals and the other taking the respective sum. We reject the particular hypothesis that SFM utilizes only the magnitude and not the sign of the long- and medium-wavelength-sensitive-cone signal. (3) We compare SFM performance with threshold performance for velocity and motion discrimination. Stimuli with luminance contrast yield SFM performance that is superior to stimuli without luminance contrast when they are expressed as multiples of velocity discrimination threshold. This superiority is even greater when SFM performance is compared with motion-direction discrimination thresholds.


Sharing of human milk oligosaccharides degradants within bifidobacterial communities in faecal cultures supplemented with Bifidobacterium bifidum.
Gut microbiota of breast-fed infants are generally rich in bifidobacteria. Recent studies show that infant gut-associated bifidobacteria can assimilate human milk oligosaccharides (HMOs) specifically among the gut microbes. Nonetheless, little is known about how bifidobacterial-rich communities are shaped in the gut. Interestingly, HMOs assimilation ability is not related to the dominance of each species. Bifidobacterium longum susbp. longum and Bifidobacterium breve are commonly found as the dominant species in infant stools; however, they show limited HMOs assimilation ability in vitro. In contrast, avid in vitro HMOs consumers, Bifidobacterium bifidum and Bifidobacterium longum subsp. infantis, are less abundant in infant stools. In this study, we observed altruistic behaviour by B. bifidum when incubated in HMOs-containing faecal cultures. Four B. bifidum strains, all of which contained complete sets of HMO-degrading genes, commonly left HMOs degradants unconsumed during in vitro growth. These strains stimulated the growth of other Bifidobacterium species when added to faecal cultures supplemented with HMOs, thereby increasing the prevalence of bifidobacteria in faecal communities. Enhanced HMOs consumption by B. bifidum-supplemented cultures was also observed. We also determined the complete genome sequences of B. bifidum strains JCM7004 and TMC3115. Our results suggest B. bifidum-mediated cross-feeding of HMOs degradants within bifidobacterial communities.


Above-Belowground Herbivore Interactions in Mixed Plant Communities Are Influenced by Altered Precipitation Patterns.
Root- and shoot-feeding herbivores have the capacity to influence one another by modifying the chemistry of the shared host plant. This can alter rates of nutrient mineralization and uptake by neighboring plants and influence plant-plant competition, particularly in mixtures combining grasses and legumes. Root herbivory-induced exudation of nitrogen (N) from legume roots, for example, may increase N acquisition by co-occurring grasses, with knock-on effects on grassland community composition. Little is known about how climate change may affect these interactions, but an important and timely question is how will grass-legume mixtures respond in a future with an increasing reliance on legume N mineralization in terrestrial ecosystems. Using a model grass-legume mixture, this study investigated how simultaneous attack on lucerne (Medicago sativa) by belowground weevils (Sitona discoideus) and aboveground aphids (Acyrthosiphon pisum) affected a neighboring grass (Phalaris aquatica) when subjected to drought, ambient, and elevated precipitation. Feeding on rhizobial nodules by weevil larvae enhanced soil water retention under ambient and elevated precipitation, but only when aphids were absent. While drought decreased nodulation and root N content in lucerne, grass root and shoot chemistry were unaffected by changes in precipitation. However, plant communities containing weevils but not aphids showed increased grass height and N concentrations, most likely associated with the transfer of N from weevil-attacked lucerne plants containing more nodules and higher root N concentrations compared with insect-free plants. Drought decreased aphid abundance by 54% but increased total and some specific amino acid concentrations (glycine, lysine, methionine, tyrosine, cysteine, histidine, arginine, aspartate, and glutamate), suggesting that aphid declines were being driven by other facets of drought (e.g., reduced phloem hydraulics). The presence of weevil larvae belowground decreased aphid numbers by 30%, likely associated with a significant reduction in proline in weevil-treated lucerne plants. This study demonstrates how predicted changes to precipitation patterns and indirect interactions between herbivores can alter the outcome of competition between N-fixing legumes and non-N-fixing grasses, with important implications for plant community structure and productivity.


Aerosol Delivery of a Candidate Universal Influenza Vaccine Reduces Viral Load in Pigs Challenged with Pandemic H1N1 Virus.
Influenza A viruses are a major health threat to livestock and humans, causing considerable mortality, morbidity, and economic loss. Current inactivated influenza vaccines are strain specific and new vaccines need to be produced at frequent intervals to combat newly arising influenza virus strains, so that a universal vaccine is highly desirable. We show that pandemic H1N1 influenza virus in which the hemagglutinin signal sequence has been suppressed (S-FLU), when administered to pigs by aerosol can induce CD4 and CD8 T cell immune responses in blood, bronchoalveolar lavage (BAL), and tracheobronchial lymph nodes. Neutralizing Ab was not produced. Detection of a BAL response correlated with a reduction in viral titer in nasal swabs and lungs, following challenge with H1N1 pandemic virus. Intratracheal immunization with a higher dose of a heterologous H5N1 S-FLU vaccine induced weaker BAL and stronger tracheobronchial lymph node responses and a lesser reduction in viral titer. We conclude that local cellular immune responses are important for protection against influenza A virus infection, that these can be most efficiently induced by aerosol immunization targeting the lower respiratory tract, and that S-FLU is a promising universal influenza vaccine candidate.


Molecular insight into extreme copper resistance in the extremophilic archaeon 'Ferroplasma acidarmanus' Fer1.
'Ferroplasma acidarmanus' strain Fer1 is an extremely acidophilic archaeon involved in the genesis of acid mine drainage, and was isolated from copper-contaminated mine solutions at Iron Mountain, CA, USA. Here, the initial proteomic and molecular investigation of Cu(2+) resistance in this archaeon is presented. Analysis of Cu(2+) toxicity via batch growth experiments and inhibition of oxygen uptake in the presence of ferrous iron demonstrated that Fer1 can grow and respire in the presence of 20 g Cu(2+) l(-1). The Fer1 copper resistance (cop) loci [originally detected by Ettema, T. J. G., Huynen, M. A., de Vos, W. M. & van der Oost, J. Trends Biochem Sci 28, 170-173 (2003)] include genes encoding a putative transcriptional regulator (copY), a putative metal-binding chaperone (copZ) and a putative copper-transporting P-type ATPase (copB). Transcription analyses demonstrated that copZ and copB are co-transcribed, and transcript levels were increased significantly in response to exposure to high levels of Cu(2+), suggesting that the transport system is operating for copper efflux. Proteomic analysis of Fer1 cells exposed to Cu(2+) revealed the induction of stress proteins associated with protein folding and DNA repair (including RadA, thermosome and DnaK homologues), suggesting that 'Ferroplasma acidarmanus' Fer1 uses multiple mechanisms for resistance to high levels of copper.


Complications and outcomes in chronic liver disease.
Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS) and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the last 18 months are reviewed. Predictors of response to lactulose therapy in hepatic encephalopathy have been reported, along with the effect of minimal hepatic encephalopathy on driving. Rifaximin was found to lead to better maintenance of remission and decreased readmission rates in patients with cirrhosis and hepatic encephalopathy. Satavaptan (a vasopressin receptor antagonist) was investigated for treatment of refractory ascites and appeared to be effective, but this compound is not currently approved by the US Food and Drug Administration (FDA). Patients with refractory ascites taking propranolol were found to have poorer outcomes than those not taking propranolol. Terlipressin currently appears to be the best medical therapy available for patients with type 1 HRS; the addition with albumin to terlipressin appeared to decrease mortality in patients with type 1 HRS. In primary prophylaxis of EVH, carvedilol was found to reduce the rate of initial bleeding compared with band ligation. Early transjugular intrahepatic portosystemic shunts placed in highly selected patients with acute EVH and a high risk of endoscopic failure decreased long-term mortality. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared with nonselective beta-blockers. Refinement in clinical management strategies for patients with cirrhosis and its complications appear to continue to contribute to improved patient outcomes.


A randomised feasibility study comparing total hip arthroplasty with and without dual mobility acetabular component in the treatment of displaced intracapsular fractures of the proximal femur : The Warwick Hip Trauma Evaluation Two : WHiTE Two.
The optimal treatment for independent patients with a displaced intracapsular fracture of the hip remains controversial. The recognised alternatives are hemiarthroplasty and total hip arthroplasty. At present there is no established standard of care, with both types of arthroplasty being used in many centres. We conducted a feasibility study comparing the clinical effectiveness of a dual mobility acetabular component compared with standard polyethylene component in total hip arthroplasty for independent patients with a displaced intracapsular fracture of the hip, for a 12-month period beginning in June 2013. The primary outcome was the risk of dislocation one year post-operatively. Secondary outcome measures were EuroQol 5 Dimensions, ICEpop CAPability measure for Older people, Oxford hip score, mortality and re-operation. Only 20 patients were recruited during this time. The baseline demographics were similar in the two groups and no patient suffered a dislocation. Differences in secondary outcomes were not analysed due to the small sample. This feasibility study suggests that any trial investigating the effectiveness of total hip arthroplasty for fracture of the hip might not be deliverable within the constraints of current systems of care in the United Kingdom. Cite this article: Bone Joint J 2016;98-B:1431-5.


Molecular cloning and expression of a cDNA encoding a human thioredoxin-like protein.
This report describes the cloning of a human cDNA that encodes a new protein (Txl, Thioredoxin-like) that belongs to the expanding family of thioredoxins based on sequence comparison of the deduced amino acid sequence. This cDNA, with a total length of 1,278 bp, consists of 205 bp of 5'-untranslated sequence (including an in frame stop codon), an open reading frame of 870 bp and a 203 bp fragment of 3'-untranslated sequence. The coding sequence predicts a protein of 289 amino acids with two distinct domains: an N-terminal domain of 105 residues homologous to the rest of mammalian thioredoxins containing the conserved active site (CGPC) and a C-terminal domain of 184 residues with no homology with any other protein in the database. Northern blot analysis indicates that the txl probe hybridizes to a 1.3 Kb mRNA and is ubiquitously expressed in human tissues with the highest expression in stomach, testis and bone marrow.


High-density lipoprotein metabolism and reverse cholesterol transport: strategies for raising HDL cholesterol.
A key to effective treatment of cardiovascular disease is to understand the body's complex lipoprotein transport system. Reverse cholesterol transport (RCT) is the process of cholesterol movement from the extrahepatic tissues back to the liver. Lipoproteins containing apoA-I [highdensity lipoprotein (HDL)] are key mediators in RCT, whereas non-high-density lipoproteins (non-HDL, lipoproteins containing apoB) are involved in the lipid delivery pathway. HDL particles are heterogeneous; they differ in proportion of proteins and lipids, size, shape, and charge. HDL heterogeneity is the result of the activity of several factors that assemble and remodel HDL particles in plasma: ATP-binding cassette transporter A1 (ABCA1), lecithin cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), hepatic lipase (HL), phospholipid transfer protein (PLTP), endothelial lipase (EL), and scavenger receptor class B type I (SR-BI). The RCT pathway consists of the following steps: 1. Cholesterol efflux from peripheral tissues to plasma, 2. LCAT-mediated esterification of cholesterol and remodeling of HDL particles, 3. direct pathway of HDL cholesterol delivery to the liver, and 4. indirect pathway of HDL cholesterol delivery to the liver via CETP-mediated transfer There are several established strategies for raising HDL cholesterol in humans, such as lifestyle changes; use of drugs including fibrates, statins, and niacin; and new therapeutic approaches. The therapeutic approaches include CETP inhibition, peroxisome proliferator-activated receptor (PPAR) agonists, synthetic farnesoid X receptor agonists, and gene therapy. Results of clinical trials should be awaited before further clinical management of atherosclerotic cardiovascular disease.


Coagulase production by strains of Staphylococcus aureus of differing resistance characters: a comparison of two traditional methods with a latex agglutination system detecting both clumping factor and protein A.
Five groups of strains of Staphylococcus aureus (54 in total) were tested by slide and tube coagulase methods with rabbit and human plasma, and the results were compared with a latex test for both clumping factor and Protein A (Staphaurex, Wellcome Foundation). The five groups comprised: epidemic methicillin resistant S aureus (group 1); other methicillin resistant S aureus (group 2); other resistant S aureus (group 3); other S aureus (group 4); and a group of reference strains, not all true S aureus (group 5). Groups 1, 3, and 4 gave consistently strong positive results with the tube test and the latex test and less strong positive results with the slide test. Group 2 strains sometimes gave weak or negative results in slide and latex tests, but tube tests with both types of plasma were strongly positive. Only within group 5 strains were negative results in the tube test found. Group 1 strains showed no diminution in expression of free coagulase or of clumping factor. The latex test was more sensitive than the slide test but less sensitive than the tube test. Doubtful or negative slide test or latex test results, particularly with strains resistant to methicillin, should be checked by a tube coagulase test.


Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.
Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.


Improved nanoformulation and bio-functionalization of linear-dendritic block copolymers with biocompatible ionic liquids.
Linear-dendritic block copolymers (LDBCs) have emerged as promising materials for drug delivery applications, with their hybrid structure exploiting advantageous properties of both linear and dendritic polymers. LDBCs have promising encapsulation efficiencies that can be used to encapsulate both hydrophobic and hydrophilic dyes for bioimaging, cancer therapeutics, and small biomolecules. Additionally, LDBCS can be readily functionalized with varying terminal groups for more efficient targeted delivery. However, depending on structural composition and surface properties, LDBCs also exhibit high dispersities (Đ), poor shelf-life, and potentially high cytotoxicity to non-target interfacing blood cells during intravenous drug delivery. Here, we show that choline carboxylic acid-based ionic liquids (ILs) electrostatically solvate LDBCs by direct dissolution and form stable and biocompatible IL-integrated LDBC nano-assemblies. These nano-assemblies are endowed with red blood cell-hitchhiking capabilities and show altered cellular uptake behavior ex vivo. When modified with choline and trans-2-hexenoic acid, IL-LDBC dispersity dropped by half compared to bare LDBCs, and showed a significant shift of the cationic surface charge towards neutrality. Proton nuclear magnetic resonance spectroscopy evidenced twice the total amount of IL on the LDBCs relative to an established IL-linear PLGA platform. Transmission electron microscopy suggested the formation of a nanoparticle surface coating, which acted as a protective agent against RBC hemolysis, reducing hemolysis from 73% (LDBC) to 25% (IL-LDBC). However, dramatically different uptake behavior of IL-LDBCs vs. IL-PLGA NPs in RAW 264.7 macrophage cells suggests a different conformational IL-NP surface assembly on the linear versus the linear-dendritic nanoparticles. These results suggest that by controlling the physical chemistry of polymer-IL interactions and assembly on the nanoscale, biological function can be tailored toward the development of more effective and more precisely targeted therapies.


Improved Generation of Induced Pluripotent Stem Cells From Hair Derived Keratinocytes - A Tool to Study Neurodevelopmental Disorders as ADHD.
In the last decade, there is an increasing application of induced pluripotent stem cells (iPSCs) for disease modeling. The iPSC technology enables the study of patient-specific neuronal cell lines in vitro to evaluate dysfunction at the cellular level and identify the responsible genetic factors. This approach might be particularly valuable for filling the gap of knowledge at the cellular and molecular levels underlying the pathophysiology of various neurodevelopmental and/or psychiatric disorders, such as attention-deficit hyperactivity disorder (ADHD). However, the invasiveness of skin biopsy or blood withdrawal might represent a major impediment in such protected population. Using hair derived keratinocytes as starting somatic cells circumvents this problem as sample collections can be performed non-invasively. Here we describe an improved, convenient, standardized and effective method to culture and reprogram hair derived keratinocytes from three healthy controls and one ADHD patient into iPSCs, which in turn will be used to generate differentiated neuronal cells. All the cell types were maintained in highly defined, serum-free conditions and showed expression of the respective key marker genes, assessed by both immunocytochemistry and qRT-PCR. The described in vitro personalized neuronal model has its advantage in modeling neurodevelopmental trajectories since it can recapitulate key processes of brain development at the cellular and molecular level and is intended to be used as for example studying ADHD etiopathology.


Genome-wide annotation and quantitation of translation by ribosome profiling.
Recent studies highlight the importance of translational control in determining protein abundance, underscoring the value of measuring gene expression at the level of translation. A protocol for genome-wide, quantitative analysis of in vivo translation by deep sequencing is presented here. This ribosome-profiling approach maps the exact positions of ribosomes on transcripts by nuclease footprinting. The nuclease-protected mRNA fragments are converted into a DNA library suitable for deep sequencing using a strategy that minimizes bias. The abundance of different footprint fragments in deep sequencing data reports on the amount of translation of a gene. Additionally, footprints reveal the exact regions of the transcriptome that are translated. To better define translated reading frames, an adaptation that reveals the sites of translation initiation by pre-treating cells with harringtonine to immobilize initiating ribosomes is described. The protocol described requires 5 to 7 days to generate a completed ribosome profiling sequencing library. Sequencing and data analysis requires an additional 4 to 5 days.


Limitations in predicting the space radiation health risk for exploration astronauts.
Despite years of research, understanding of the space radiation environment and the risk it poses to long-duration astronauts remains limited. There is a disparity between research results and observed empirical effects seen in human astronaut crews, likely due to the numerous factors that limit terrestrial simulation of the complex space environment and extrapolation of human clinical consequences from varied animal models. Given the intended future of human spaceflight, with efforts now to rapidly expand capabilities for human missions to the moon and Mars, there is a pressing need to improve upon the understanding of the space radiation risk, predict likely clinical outcomes of interplanetary radiation exposure, and develop appropriate and effective mitigation strategies for future missions. To achieve this goal, the space radiation and aerospace community must recognize the historical limitations of radiation research and how such limitations could be addressed in future research endeavors. We have sought to highlight the numerous factors that limit understanding of the risk of space radiation for human crews and to identify ways in which these limitations could be addressed for improved understanding and appropriate risk posture regarding future human spaceflight.


Help-seeking behavior of patients with mental health problems visiting a tertiary care center in north India.
Patients with mental health problems in the nonwestern world seek help from a variety of sources, such as the family physicians, psychiatrists, psychologists, traditional faith-healers, or alternative medicine practitioners. Understanding the help-seeking behavior is important from the public health perspective. Two hundred new patients visiting a psychiatric outpatient service at a tertiary care hospital were interviewed on a semi-structured questionnaire for various services contacted by them for their mental health problems. Psychiatrists were the first choice in 45% of the cases followed by nonpsychiatric physicians and religious faith healers. Important reasons to seek help from different sources included easy accessibility, belief in the system, or particular healer and good reputation. Mean duration of treatment varied from 2.35 months with the alternative system practitioners to 16.63 months with the psychiatrists. The mean expenditure per visit to a service was highest for the nonpsychiatric physician and lowest for alternative system practitioners. Patients with mental health problems seek help from psychiatrists, nonpsychiatric physicians, faith healers, alternative system practitioners, and traditional faith healers for multiple reasons. It is important to sensitize various nonpsychiatric physicians with early identification and optimum management of mental disorders.


Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.
Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 -/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 -/- mouse model. These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.


Relation between primary care physician supply and diabetes care and outcomes: a cross-sectional study.
Higher primary care physician supply is associated with lower mortality due to heart disease, cancer and stroke, but its relation to diabetes care and outcomes is unknown. We examined the association between primary care physician supply and evidence-based testing and hospital visits for people with diabetes in naturally occurring multispecialty physician networks in Ontario, Canada. We conducted a cross-sectional analysis between Apr. 1, 2009, and Mar. 31, 2011, using linked administrative data. We included all Ontario residents over 40 years of age with a diagnosis of diabetes before Apr. 1, 2007, who were alive on Apr. 1, 2009 (N = 712 681). We tested the association between physician supply and outcomes at the network level using separate Poisson regression models for urban and nonurban physician networks. We accounted for clustering at the physician and network level and adjusted for patient characteristics. Patients in physician networks with a high supply of primary care physicians were more likely to receive the optimal number of evidence-based tests for diabetes than patients in networks with low primary care physician supply (urban relative risk [RR] 1.06, 95% confidence interval [CI] 1.04-1.07; nonurban RR 1.17, 95% CI 1.14-1.21) but were no different regarding emergency department visits (urban RR 1.05, 95% CI 0.94-1.17; nonurban RR 0.96, 95% CI 0.85-1.08) or hospital admissions for diabetes complications (urban RR 1.01, 95% CI 0.89-1.14; nonurban RR 0.91, 95% CI 0.77-1.07). Having more primary care physicians per capita is associated with better diabetes care but not with reduced hospital visits in this setting. Further research to understand this relation and how it varies by setting is important for resource planning.


Wideband detection of transient solid-state dynamics using ultrafast fiber lasers and asynchronous optical sampling.
We demonstrate optical time-domain spectroscopy from femtoseconds to nanoseconds using an ultrafast dual-fiber-laser system with kilohertz continuous scanning rates. Utilizing different wavelengths for the pump and probe beams, we exploit this system's broad range of timescales for quantitative studies of thermal transport and the detection of coherent spin and lattice excitations in epitaxial magnetic thin films. The extraordinary temporal dynamic range provides a way to connect the fast and slow timescales in the observation of dissipation and decoherence processes.


Molecular dynamic simulations reveal the structural determinants of Fatty Acid binding to oxy-myoglobin.
The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the protein myoglobin (Mb). Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolites; however, the binding pocket and regulation of the interaction remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of fatty acids (palmitic & oleic acid) binding to Mb. Sequence analysis and docking simulations with a horse (Equus caballus) structural Mb reference reveals a fatty acid-binding site in the hydrophobic cleft near the heme region in Mb. Both palmitic acid and oleic acid attain a "U" shaped structure similar to their conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino group of Lys45, whereas the carboxyl group of oleic acid coordinates with both the amino groups of Lys45 and Lys63. The alkyl tails of both fatty acids are supported by surrounding hydrophobic residues Leu29, Leu32, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. In the saturated palmitic acid, the hydrophobic tail moves freely and occasionally penetrates deeper inside the hydrophobic cleft, making additional contacts with Val28, Leu69, Leu72 and Ile111. Our simulations reveal a dynamic and stable binding pocket in which the oxygen molecule and heme group in Mb are required for additional hydrophobic interactions. Taken together, these findings support a mechanism in which Mb acts as a muscle transporter for fatty acid when it is in the oxygenated state and releases fatty acid when Mb converts to deoxygenated state.


Are users' most recent drug purchases representative?
Various surveys now ask respondents to describe their most recent purchase of illicit drugs, as one mechanism through which market size can be estimated. This raises the question of whether issues surrounding the timing of survey administration might make a sample of most recent purchases differ from a random sample of all purchases. We investigate these issues through a series of questions which ask about the three most recent purchases, and about drug use. Data were drawn from 688 respondents in the Melbourne Injecting Drug User Cohort Study across the period 2008-2013 and 2782 respondents to the Washington Cannabis Consumption Study in 2013. Responses to questions about the most recent purchases were compared to larger subsets of all recent purchases. For heroin, methamphetamine and cannabis no differences were found between the amount spent by participants on their most recent purchase and the average amount spent on three or more recent purchases. There were also no differences concerning the locations and types of deals, and the duration between consecutive cannabis purchases was the same for first and second most recent, and second and third most recent. Asking about the most recent purchase appears to be an economical way to learn about purchases more generally, with little evidence of substantial variation between the most recent purchase and other recent purchases reported by participants. In spite of consistent findings across our two surveys, further replication of the work reported in this paper involving other populations of users is warranted.


Results of the Medications at Transitions and Clinical Handoffs (MATCH) study: an analysis of medication reconciliation errors and risk factors at hospital admission.
This study was designed to determine risk factors and potential harm associated with medication errors at hospital admission. Study pharmacist and hospital-physician medication histories were compared with medication orders to identify unexplained history and order discrepancies in 651 adult medicine service inpatients with 5,701 prescription medications. Discrepancies resulting in order changes were considered errors. Logistic regression was used to analyze the association of patient demographic and clinical characteristics including patients' number of pre-admission prescription medications, pharmacies, prescribing physicians and medication changes; and presentation of medication bottles or lists. These factors were tested after controlling for patient demographics, admitting service and severity of illness. Over one-third of study patients (35.9%) experienced 309 order errors; 85% of patients had errors originate in medication histories, and almost half were omissions. Cardiovascular agents were commonly in error (29.1%). If undetected, 52.4% of order errors were rated as potentially requiring increased monitoring or intervention to preclude harm; 11.7% were rated as potentially harmful. In logistic regression analysis, patient's age > or = 65 [odds ratio (OR), 2.17; 95% confidence interval (CI), 1.09-4.30] and number of prescription medications (OR, 1.21; 95% CI, 1.14-1.29) were significantly associated with errors potentially requiring monitoring or causing harm. Presenting a medication list (OR, 0.35; 95% CI, 0.19-0.63) or bottles (OR, 0.55; 95% CI, 0.27-1.10) at admission was beneficial. Over one-third of the patients in our study had a medication error at admission, and of these patients, 85% had errors originate in their medication histories. Attempts to improve the accuracy of medication histories should focus on older patients with a large number of medications. Primary care physicians and other clinicians should help patients utilize and maintain complete, accurate and understandable medication lists.


Integrins in mechanotransduction.
Mechanical forces are crucial to the regulation of cell and tissue morphology and function. At the cellular level, forces influence cytoskeletal organization, gene expression, proliferation, and survival. Integrin-mediated adhesions are intrinsically mechanosensitive and a large body of data implicates integrins in sensing mechanical forces. We review the relationship between integrins and mechanical forces, the role of integrins in cellular responses to stretch and fluid flow, and propose that some of these events are mechanistically related.


RADIATION DOSE DUE TO RADON AND HEAVY METAL ANALYSIS IN DRINKING WATER SAMPLES OF JAMMU DISTRICT, JAMMU & KASHMIR, INDIA.
In the present investigation, radon concentration and heavy metal analysis were carried out in drinking water samples in Jammu district, Jammu & Kashmir, India. The radon concentration was measured by using RAD-7, portable alpha particle detector. The values of radon concentration in drinking water samples were also compared within the safe limit recommended by different health agencies. The total annual effective dose ranged from 53.04 to 197.29 µSv y-1 The annual effective dose from few locations from the studied area was found to be greater than the safe limit (100 µSv y-1) suggested by World Health Organisation (WHO) and EU Council. Heavy metal concentration was determined by atomic absorption spectrophotometer. A total of eight elements were analysed, viz. arsenic, mercury, zinc, iron, copper, chromium, manganese and cadmium. Heavy metals are considered to be the major pollutants of water sources. The results were compared with the limits of WHO, EU and Indian organisations. The trace metal analysis is not on the exceeding side of the permissible limit in all the samples.


Increased functional connectivity of thalamic subdivisions in patients with Parkinson's disease.
Parkinson's disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.


cycMs3, a novel B-type alfalfa cyclin gene, is induced in the G0-to-G1 transition of the cell cycle.
Cyclins are key regulators of the cell cycle in all eukaryotes. We have previously isolated two B-type cyclin genes, cycMs1 and cycMs2, from alfalfa that are primarily expressed during the G2-to-M phase transition and are most likely mitotic cyclin genes. Here, we report the isolation of a novel alfalfa cyclin gene, termed cycMs3 (for cyclin Medicago sativa), by selecting for mating type alpha-pheromone-induced cell cycle arrest suppression in yeast. The central region of the predicted amino acid sequence of the cycMs3 gene is most similar to the cyclin box of yeast B-type and mammalian A- and B-type cyclins. In situ hybridization showed that cycMs3 mRNA can be detected only in proliferating cells and not in differentiated alfalfa cells. When differentiated G0-arrested cells were induced to reenter the cell cycle in the G1 phase and resume cell division by treatment with plant hormones, cycMs3 transcript levels increased long before the onset of DNA synthesis. In contrast, histone H3-1 mRNA and cycMs2 transcripts were not observed before DNA replication and mitosis, respectively. In addition, cycMs3 mRNA was found in all stages of the cell cycle in synchronously dividing cells, whereas the cycMs2 and histone H3-1 genes showed a G2-to-M phase- or S phase-specific transcription pattern, respectively. These data suggest that the role of cyclin CycMs3 differs from that of CycMs1 and CycMs2. We propose that CycMs3 helps control reentry of quiescent G0-arrested cells into the G1 phase of the cell cycle.


Discounting future health gains: an empirical enquiry into the influence of growing life expectancy.
We tested the influence of the growth in life expectancy over time on social time preferences for health. Growing life expectancy of future generations should raise social discount rates for health because of diminishing marginal utility of additional health gains and equity reasons reflecting the desire for a more equitable distribution of benefits over generations. This influence has, however, been largely ignored in empirical studies. We provide a first comprehensive analysis of how time preferences for health gains vary with projected growth rates, indicating the importance of subjective expectations about the growth in life expectancy in the elicitation of social time preference. Six hundred and fifty-six respondents, representative of the Dutch population, completed one of four questionnaires, differing in the projected growth in life expectancy. Results showed that individuals discount future health gains at different rates, depending on the latency period and on the projected or expected growth in life expectancy. As hypothesized, discount rates increased with higher growth rates. The association between observed discount rates and expectations regarding future life expectancy was confirmed, suggesting that discount rates for health may depend on future life expectancy. In light of our results, specifying life expectancy of future generations in time preference exercises appears appropriate.


H3.3 demarcates GC-rich coding and subtelomeric regions and serves as potential memory mark for virulence gene expression in Plasmodium falciparum.
Histones, by packaging and organizing the DNA into chromatin, serve as essential building blocks for eukaryotic life. The basic structure of the chromatin is established by four canonical histones (H2A, H2B, H3 and H4), while histone variants are more commonly utilized to alter the properties of specific chromatin domains. H3.3, a variant of histone H3, was found to have diverse localization patterns and functions across species but has been rather poorly studied in protists. Here we present the first genome-wide analysis of H3.3 in the malaria-causing, apicomplexan parasite, P. falciparum, which revealed a complex occupancy profile consisting of conserved and parasite-specific features. In contrast to other histone variants, PfH3.3 primarily demarcates euchromatic coding and subtelomeric repetitive sequences. Stable occupancy of PfH3.3 in these regions is largely uncoupled from the transcriptional activity and appears to be primarily dependent on the GC-content of the underlying DNA. Importantly, PfH3.3 specifically marks the promoter region of an active and poised, but not inactive antigenic variation (var) gene, thereby potentially contributing to immune evasion. Collectively, our data suggest that PfH3.3, together with other histone variants, indexes the P. falciparum genome to functionally distinct domains and contribute to a key survival strategy of this deadly pathogen.


Breast imaging reporting and data system standardized mammography lexicon: observer variability in lesion description.
The American College of Radiology has recommended the Breast Imaging Reporting and Data System (BI-RADS) as a standardized scheme for describing mammographic lesions. The objective of this study was to measure inter- and intraobserver variabilities of radiologists' descriptions of mammographic lesions with the BI-RADS standardized lexicon. Sixty mammographic studies with abnormal findings were independently evaluated by five radiologists. Readers described each lesion by selecting a single term from the BI-RADS lexicon for each of eight morphologic categories: calcification distribution, number, and description; mass margin, shape, and density; associated findings; and special cases. Additionally, each reader assessed the significance of each lesion on a five-point scale. One observer read each case twice. Inter- and intraobserver variabilities for each description and interpretation category of the BI-RADS lexicon were determined with Cohen's kappa statistic. Radiologists' specific use of calcification descriptors was evaluated in detail. Substantial agreement was observed between readers for choosing terms to describe masses and calcifications (kappa value range, 0.50 +/- 0.02-0.77 +/- 0.03). Intraobserver agreement for these categories was similar (kappa value range, 0.57 +/- 0.07-0.84 +/- 0.09). Considerable inter- and intraobserver variabilities were noted for the "associated findings" and "special cases" categories (kappa value range, -0.02 +/- 0.14-0.38 +/- 0.12), a result that in part reflected the small number of cases to which these categories were assigned. Moderate interobserver variability and little intraobserver variability in the interpretation of lesion significance were noted when an assessment classification similar to that of BI-RADS was used. Use of terms to describe calcifications did not always conform to BI-RADS-defined levels of suspicion. BI-RADS is moderately successful in providing a standardized language for physicians to describe lesion morphology. Efforts to reevaluate specific terms and the diagnostic significance assigned to calcification descriptors may prove useful in maintaining the promise of improved quality with the BI-RADS standardized mammography lexicon.


Evaluation of ovarian structures using computerized microtomography.
Visualization and clear understanding of the ovarian structures are important in determining the stage of oestrus, helping to diagnose several pathologies and supporting advances in reproductive technologies. In this research, computerized microtomography (microCT) was used to explore and characterize the ovarian structure of seven mammalian species. Ovaries of rats, female dog, queens, cows, mares, sows and a female donkey were used. After microCT scanning, the same samples were prepared for histologic evaluation, used here as a validation criterion. It was possible to distinguish regions of the cortex and medulla, visualize the morphology and distribution of blood vessels, clearly observe corpus luteum and antral follicles, and visualize oocytes inside some antral follicles. This is the first report using microCT to explore and compare ovarian structures in several domestic mammals. MicroCT revealed great potential for the evaluation of ovarian structures. This research open prospects for the use of computerized tomography (CT) as a non-invasive approach to studying ovarian structures in live animals, which may be especially attractive for scientific study of development of ovarian structures and/or ovarian pathologies in small animals' models.


Influence of vasopressin and amiloride on shunt pathways of frog skin.
Studies were done to determine the influence of vasopressin and amiloride on the sodium backflux of nonedge-damaged frog skin. As before, the bidirectional fluxes of sodium appeared to be limited primarily to the active transport pathways of control skins. When the skins were treated with vasopressin, the sodium backflux was increased selectively (over that of sucrose) and more so than was expected for the active transportpathway alone. In control skins, amiloride had no effect on the flux of the shunt pathway. However, with vasopressin-treated skins, amiloride at 10(-6) M decreased the sodium backflux of the shunt pathway to levels observed previously for the control skins. These observations are compatible with the idea that the shunt pathway may in part be cellular and in part extracellular. When the changes in open-circuit voltage and shunt resistance caused by vasopressin and amiloride (as determined from the I-V relationships) were examined, the data were also found to be compatible with the idea that vasopressin exerted an influence on the shunt pathway of the frog skin, and this effect of vasopressin could be reversed by amiloride.


"Striving for a good life" - the management of rheumatoid arthritis as experienced by patients.
To generate a theoretical model how patients experience their management of rheumatoid arthritis (RA) in everyday life. An explorative design with the grounded theory approach was used by interviewing 16 informants with RA. The generated theoretical model emerged in a core category- Striving for a good life with two categories; making use of personal resources and grasping for support from others, which formed the base of managing RA. When relating these categories together, four dimensions emerged which characterised patients' different ways of managing RA: mastering, relying, struggling and being resigned. The management of RA incorporated the use of personal resources and the grasping for support from others. Both self-management strategies and patients' need of support were highlighted as aspects that were of importance when managing RA. Patients' experiences of their need of support to manage RA give extended knowledge that is of importance for nurses and other healthcare providers. The relationship between patients and healthcare providers is always the key to a good encounter. Interventions to increase self-management in RA have to incorporate this knowledge when trying to increase patients' self-efficacy and with their experience of support.


Inertial-ordering-assisted droplet microfluidics for high-throughput single-cell RNA-sequencing.
Single-cell RNA-seq reveals the cellular heterogeneity inherent in the population of cells, which is very important in many clinical and research applications. Recent advances in droplet microfluidics have achieved the automatic isolation, lysis, and labeling of single cells in droplet compartments without complex instrumentation. However, barcoding errors occurring in the cell encapsulation process because of the multiple-beads-in-droplet and insufficient throughput because of the low concentration of beads for avoiding multiple-beads-in-a-droplet remain important challenges for precise and efficient expression profiling of single cells. In this study, we developed a new droplet-based microfluidic platform that significantly improved the throughput while reducing barcoding errors through deterministic encapsulation of inertially ordered beads. Highly concentrated beads containing oligonucleotide barcodes were spontaneously ordered in a spiral channel by an inertial effect, which were in turn encapsulated in droplets one-by-one, while cells were simultaneously encapsulated in the droplets. The deterministic encapsulation of beads resulted in a high fraction of single-bead-in-a-droplet and rare multiple-beads-in-a-droplet although the bead concentration increased to 1000 μl-1, which diminished barcoding errors and enabled accurate high-throughput barcoding. We successfully validated our device with single-cell RNA-seq. In addition, we found that multiple-beads-in-a-droplet, generated using a normal Drop-Seq device with a high concentration of beads, underestimated transcript numbers and overestimated cell numbers. This accurate high-throughput platform can expand the capability and practicality of Drop-Seq in single-cell analysis.