Wet-Spun Trojan Horse Cell Constructs for Engineering Muscle.
Engineering of 3D regenerative skeletal muscle tissue constructs (skMTCs) using hydrogels containing muscle precursor cells (MPCs) is of potential benefit for repairing Volumetric Muscle Loss (VML) arising from trauma (e.g., road/industrial accident, war injury) or for restoration of functional muscle mass in disease (e.g., Muscular Dystrophy, muscle atrophy). Additive Biofabrication (AdBiofab) technologies make possible fabrication of 3D regenerative skMTCs that can be tailored to specific delivery requirements of VML or functional muscle restoration. Whilst 3D printing is useful for printing constructs of many tissue types, the necessity of a balanced compromise between cell type, required construct size and material/fabrication process cyto-compatibility can make the choice of 3D printing a secondary alternative to other biofabrication methods such as wet-spinning. Alternatively, wet-spinning is more amenable to formation of fibers rather than (small) layered 3D-Printed constructs. This study describes the fabrication of biosynthetic alginate fibers containing MPCs and their use for delivery of dystrophin-expressing cells to dystrophic muscle in the mdx mouse model of Duchenne Muscular Dystrophy (DMD) compared to poly(DL-lactic-co-glycolic acid) copolymer (PLA:PLGA) topically-seeded with myoblasts. In addition, this study introduces a novel method by which to create 3D layered wet-spun alginate skMTCs for bulk mass delivery of MPCs to VML lesions. As such, this work introduces the concept of "Trojan Horse" Fiber MTCs (TH-fMTCs) and 3d Mesh-MTCs (TH-mMTCs) for delivery of regenerative MPCs to diseased and damaged muscle, respectively.


Antihistamines block radiation-induced taste aversions.
When rats are treated with an antihistamine prior to being given sublethal doses of ionizing radiation, the formation of a conditioned saccharin aversion is completely inhibited. A profound aversion could be conditioned with histamine diphosphate as the aversive stimulus. The increase in histamine production after radiation exposure represents the physiological basis of radiation-induced taste aversions.


Affordability, availability and acceptability barriers to health care for the chronically ill: longitudinal case studies from South Africa.
There is an increasing burden of chronic illness in low and middle income countries, driven by TB/HIV, as well as non-communicable diseases. Few health systems are organized to meet the needs of chronically ill patients, and patients' perspectives on the difficulties of accessing care need to be better understood, particularly in poor resourced settings, to achieve this end. This paper describes the experience of poor households attempting to access chronic care in a rural area of South Africa. A household survey (n = 1446 individuals) was combined with qualitative longitudinal research that followed 30 case study households over 10 months. Illness narratives and diaries provided descriptive textual data of household interactions with the health system. In the survey 74% of reported health problems were 'chronic', 48% of which had no treatment action taken in the previous month. Amongst the case study households, of the 34 cases of chronic illness, only 21 (62%) cases had an allopathic diagnosis and only 12 (35%) were receiving regular treatment. Livelihoods exhausted from previous illness and death, low income, and limited social networks, prevented consultation with monthly expenditure for repeated consultations as high as 60% of income. Interrupted drug supplies, insufficient clinical services at the clinic level necessitating referral, and a lack of ambulances further hampered access to care. Poor provider-patient interaction led to inadequate understanding of illness, inappropriate treatment action, 'healer shopping', and at times a break down in cooperation, with the patient 'giving up' on the public health system. However, productive patient-provider interactions not only facilitated appropriate treatment action but enabled patients to justify their need for financial assistance to family and neighbours, and so access care. In addition, patients and their families with understanding of a disease became a community resource drawn on to assist others. In strengthening the public sector it is important not only to improve drug supply chains, ambulance services, referral systems and clinical capacity at public clinics, and to address the financial constraints faced by the socially disadvantaged, but also to think through how providers can engage with patients in a way that strengthens the therapeutic alliance.


Liver histology as predictor of outcome in patients with acute-on-chronic liver failure (ACLF).
There is paucity of literature on liver histological spectrum of acute-on-chronic liver failure (ACLF). The aims of this study are to (a) to characterize the liver histological features in ACLF, (b) to correlate histological parameters with prognosis, and (c) to investigate whether etiology influences prognosis. We retrospectively studied liver biopsies of patients with ACLF. The histological findings were correlated with the clinical outcome. Fifty cases (median age, 39 years [10-69 years]; M/F, 3:1) were included. Etiology of acute insult was viral or alcohol in majority of the cases. Twenty-five patients survived (good outcome, 50%) and 25 died (poor outcome, 50%). On a univariate analysis, the outcome correlated with fibrosis, ballooning, eosinophilic degeneration, ductular proliferation, pericellular fibrosis, Mallory's hyaline, foci of confluent necrosis and/or bridging necrosis (CN/BN), cholestasis, apoptosis (present), and parenchyma left. However, on a multivariate analysis, only fibrosis, ballooning, ductular proliferation, apoptosis, and parenchyma left were found to be independently associated with outcome. Two distinct patterns of liver histology were observed: pattern I, observed in cases with poor outcome, showing marked ductular proliferation, coarse inspissated ductular bile plugs, eosinophilic degeneration of hepatocytes, foci of CN/BN, higher apoptosis, pericellular fibrosis, Mallory's hyaline, and higher stage of fibrosis. Pattern II is seen in cases with good outcome, show prominent hepatocyte ballooning with lesser parenchymal involvement by fibrosis and necrosis. Histological features of liver biopsy are: extent of fibrosis, ballooning, ductular proliferation, apoptosis, and lesser degree of parenchymal replacement by fibrosis or necrosis which correlates with the outcome in patients with ACLF. Two distinct patterns of liver histology are seen which help in prognostication.


A systematic review on anti-Alzheimer's disease activity of prescription Kangen-karyu.
Traditional Chinese and Japanese medicines have become prime sources of drug discovery and there is a pressing need to investigate the effectiveness of these traditional medicines for modern drug discovery. Recently, among various traditional formulations, studies on Kangen-karyu (Guan-Yuan-Ke-Li), a mixture of six medicinal herbs (Salviae Miltiorrhizae Radix, Cnidii Rhizoma, Paeoniae Radix, Carthami Flos, Aucklandiae Radix, and Cyperi Rhizoma), have been growing to assess its neuroprotective role. This prompted us to undertake a thorough review of various targets of Kangen-karyu regarding its effectiveness against Alzheimer's disease, particularly focusing on cholinesterases, beta-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase 3β. This review provides new insights into Kangen-karyu medication as a prospective anti-Alzheimer's medication and indicates the need for in-depth in vivo investigation in the future.


NMR spectroscopic evidence for the intermediacy of XeF(3)(-) in XeF(2)/F(-) exchange, attempted syntheses and thermochemistry of XeF(3)(-) salts, and theoretical studies of the XeF(3)(-) anion.
The existence of the trifluoroxenate(II) anion, XeF(3)(-), had been postulated in a prior NMR study of the exchange between fluoride ion and XeF(2) in CH(3)CN solution. The enthalpy of activation for this exchange, ΔH(⧧), has now been determined by use of single selective inversion (19)F NMR spectroscopy to be 74.1 ± 5.0 kJ mol(-1) (0.18 M) and 56.9 ± 6.7 kJ mol(-1) (0.36 M) for equimolar amounts of [N(CH(3))(4)][F] and XeF(2) in CH(3)CN solvent. Although the XeF(3)(-) anion has been observed in the gas phase, attempts to prepare the Cs(+) and N(CH(3))(4)(+) salts of XeF(3)(-) have been unsuccessful, and are attributed to the low fluoride ion affinity of XeF(2) and fluoride ion solvation in CH(3)CN solution. The XeF(3)(-) anion would represent the first example of an AX(3)E(3) valence shell electron pair repulsion (VSEPR) arrangement of electron lone pair and bond pair domains. Fluorine-19 exchange between XeF(2) and the F(-) anion has also been probed computationally using coupled-cluster singles and doubles (CCSD) and density functional theory (DFT; PBE1PBE) methods. The energy-minimized geometry of the ground state shows that the F(-) anion is only weakly coordinated to XeF(2) (F(2)Xe---F(-); a distorted Y-shape possessing C(s) symmetry), while the XeF(3)(-) anion exists as a first-order transition state in the fluoride ion exchange mechanism, and is planar and Y-shaped (C(2v) symmetry). The molecular geometry and bonding of the XeF(3)(-) anion has been described and rationalized in terms of electron localization function (ELF) calculations, as well as the VSEPR model of molecular geometry. Quantum-chemical calculations, using the CCSD method and a continuum solvent model for CH(3)CN, accurately reproduced the transition-state enthalpy observed by (19)F NMR spectroscopy, and showed a negative but negligible enthalpy for the formation of the F(2)Xe---F(-) adduct in this medium.


Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction.
Oral phosphodiesterase type 5 inhibitors (PDE5i) have improved treatment options for erectile dysfunction (ED). In case of unresponsiveness to PDE5i, alternative therapies are considered. To evaluate whether combination of vacuum erection device (VED) and PDE5i is effective as salvage therapy in subjects with ED in whom PDE5i alone failed. From September 2007 to May 2008, we evaluated 69 men (aged 36-82 years) in whom PDE5i treatment at the highest recommended dose, with at least 4-6 attempts at intercourse during a 3 months period, had failed. The clinical efficacy of combination therapy was evaluated using the International Index of Erectile Function-5 (IIEF-5) questionnaire, Sexual Encounter Profile (SEP)-2, SEP-3, and Global Patient Assessment Scale (GPAS). Scores on IIEF-5, SEP-2, SEP-3, and GPAS before and after combination therapy were measured. After 4 weeks of combination therapy, the mean IIEF-5 score increased significantly over baseline from 9.0 to 17.6 (P < 0.001). Of the 34 subjects with a SEP-2 response of "no" at baseline, 27 (79%) responded "yes" after combination therapy (P < 0.001). Of the 50 subjects with a SEP-3 response of "no" at baseline, 35 (70%) responded "yes" after combination therapy (P < 0.001). Furthermore, of the 42 subjects with a GPAS response of "not at all" or "slightly" improved at baseline, 31 (74%) responded "moderately" or "greatly" improved after combination therapy (P < 0.001). One subject (1.5%) experienced device-related intermittent penile pain, which resolved after 4 days without any action. Statistically significant improvements over baseline were seen in IIEF-5, SEP-2, SEP-3, and GPAS measures following 4 weeks of combination therapy of PDE5i and VED. This study supports the use of PDE5i with VED in men in whom PDE5i alone failed. This combination therapy may be offered to patients not satisfied with PDE5i alone before being switched to more invasive alternatives.


Maternal and perinatal health research priorities beyond 2015: an international survey and prioritization exercise.
Maternal mortality has declined by nearly half since 1990, but over a quarter million women still die every year of causes related to pregnancy and childbirth. Maternal-health related targets are falling short of the 2015 Millennium Development Goals and a post-2015 Development Agenda is emerging. In connection with this, setting global research priorities for the next decade is now required. We adapted the methods of the Child Health and Nutrition Research Initiative (CHNRI) to identify and set global research priorities for maternal and perinatal health for the period 2015 to 2025. Priority research questions were received from various international stakeholders constituting a large reference group, and consolidated into a final list of research questions by a technical working group. Questions on this list were then scored by the reference working group according to five independent and equally weighted criteria. Normalized research priority scores (NRPS) were calculated, and research priority questions were ranked accordingly. A list of 190 priority research questions for improving maternal and perinatal health was scored by 140 stakeholders. Most priority research questions (89%) were concerned with the evaluation of implementation and delivery of existing interventions, with research subthemes frequently concerned with training and/or awareness interventions (11%), and access to interventions and/or services (14%). Twenty-one questions (11%) involved the discovery of new interventions or technologies. Key research priorities in maternal and perinatal health were identified. The resulting ranked list of research questions provides a valuable resource for health research investors, researchers and other stakeholders. We are hopeful that this exercise will inform the post-2015 Development Agenda and assist donors, research-policy decision makers and researchers to invest in research that will ultimately make the most significant difference in the lives of mothers and babies.


One protein, two chromophores: comparative spectroscopic characterization of 6,7-dimethyl-8-ribityllumazine and riboflavin bound to lumazine protein.
We investigated the lumazine protein from Photobacterium leiognathi in complex with its biologically active cofactor, 6,7-dimethyl-8-ribityllumazine, at different redox states and compared the results with samples containing a riboflavin cofactor. Using anaerobic photoreduction, we were able to record optical absorption kinetics from both cofactors in similar protein environments. It could be demonstrated that the protein is able to stabilize a neutral ribolumazine radical with ∼35% yield. The ribolumazine radical state was further investigated by W-band continuous-wave EPR and X-band pulsed ENDOR spectroscopy. Here, both the principal values of the g-tensor and an almost complete mapping of the proton hyperfine couplings (hfcs) could be obtained. Remarkably, the g-tensor's principal components are similar to those of the respective riboflavin-containing protein; however, the proton hfcs show noticeable differences. Comparing time-resolved optical absorption and fluorescence data from ribolumazine-containing samples, solely fluorescence but no signs of any intermediate radical or a triplet state could be identified. This is in contrast to lumazine protein samples containing the riboflavin cofactor, for which a high yield of the photogenerated triplet state and some excited flavin radical could be detected using time-resolved spectroscopy. These results clearly demonstrate that ribolumazine is a redox-active molecule and could, in principle, be employed as a cofactor in other enzymatic reactions.


Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR.
Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5alpha-androstan-3beta-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches.


Intravenous pentamidine is safe and effective as primary pneumocystis pneumonia prophylaxis in children and adolescents undergoing hematopoietic stem cell transplantation.
Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy. We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected. One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count >1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit. Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.


Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review.
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy. We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT.


Synovial sarcomas of the head and neck: CT and MR findings.
The authors present three cases of histologically proved synovial sarcoma. CT is useful in assessing erosive or destructive changes in bone, and in demonstrating calcifications. MR characteristics are nonspecific; calcifications within these tumors can be missed on MR. MR can help to assess tumor extension, vascular invasion, and hemorrhage within the tumor.


A red-shifted chlorophyll.
Chlorophylls are essential for light-harvesting and energy transduction in photosynthesis. Four chemically distinct varieties have been known for the past 60 years. Here we report isolation of a fifth, which we designate chlorophyll f. Its in vitro absorption (706 nanometers) and fluorescence (722 nanometers) maxima are red-shifted compared to all other chlorophylls from oxygenic phototrophs. On the basis of the optical, mass, and nuclear magnetic resonance spectra, we propose that chlorophyll f is [2-formyl]-chlorophyll a (C55H70O6N4Mg). This finding suggests that oxygenic photosynthesis can be extended further into the infrared region and may open associated bioenergy applications.


Evolutionary dynamics of tumor progression with random fitness values.
Most human tumors result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Mutations that confer a fitness advantage to the cell are known as driver mutations and are causally related to tumorigenesis. Other mutations, however, do not change the phenotype of the cell or even decrease cellular fitness. While much experimental effort is being devoted to the identification of the functional effects of individual mutations, mathematical modeling of tumor progression generally considers constant fitness increments as mutations are accumulated. In this paper we study a mathematical model of tumor progression with random fitness increments. We analyze a multi-type branching process in which cells accumulate mutations whose fitness effects are chosen from a distribution. We determine the effect of the fitness distribution on the growth kinetics of the tumor. This work contributes to a quantitative understanding of the accumulation of mutations leading to cancer.


Simulated Obstructive Sleep Apnea Increases P-Wave Duration and P-Wave Dispersion.
A high P-wave duration and dispersion (Pd) have been reported to be a prognostic factor for the occurrence of paroxysmal atrial fibrillation (PAF), a condition linked to obstructive sleep apnea (OSA). We tested the hypothesis of whether a short-term increase of P-wave duration and Pd can be induced by respiratory manoeuvres simulating OSA in healthy subjects and in patients with PAF. 12-lead-electrocardiography (ECG) was recorded continuously in 24 healthy subjects and 33 patients with PAF, while simulating obstructive apnea (Mueller manoeuvre, MM), obstructive hypopnea (inspiration through a threshold load, ITH), central apnea (AP), and during normal breathing (BL) in randomized order. The P-wave duration and Pd was calculated by using dedicated software for ECG-analysis. P-wave duration and Pd significantly increased during MM and ITH compared to BL in all subjects (+13.1 ms and +13.8 ms during MM; +11.7 ms and +12.9 ms during ITH; p<0.001 for all comparisons). In MM, the increase was larger in healthy subjects when compared to patients with PAF (p<0.05). Intrathoracic pressure swings through simulated obstructive sleep apnea increase P-wave duration and Pd in healthy subjects and in patients with PAF. Our findings imply that intrathoracic pressure swings prolong the intra-atrial and inter-atrial conduction time and therefore may represent an independent trigger factor for the development for PAF.


Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients.
Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been reported. To determine the prevalence of voriconazole-resistant A. fumigatus invasive aspergillosis (IA) and its associated mortality in a large multicentre cohort of haematology patients with culture-positive IA. We performed a multicentre retrospective study, in which outcomes of culture-positive haematology patients with proven/probable IA were analysed. Patients were stratified based on the voriconazole susceptibility of their isolates (EUCAST broth microdilution test). Mycological and clinical data were compared, along with survival at 6 and 12 weeks. We identified 129 A. fumigatus culture-positive proven or probable IA cases; 103 were voriconazole susceptible (79.8%) and 26 were voriconazole resistant (20.2%). All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases). Triazole monotherapy was started in 75.0% (97/129) of patients. Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones. ICU patient mortality at 6 and 12 weeks was very high regardless of triazole susceptibility (75.0% versus 66.7%, P = 0.99; and 75.0% versus 73.3%, P = 0.99). A very high prevalence of voriconazole resistance among culture-positive IA haematology patients was observed. The overall mortality at 12 weeks was significantly higher in non-ICU patients with voriconazole-resistant IA compared with voriconazole-susceptible IA.


Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.
Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects. The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time. This was a new-user cohort study design with propensity score matching. Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4. Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4. Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure. Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change. Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users. Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively. Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness. Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data. This study is registered as EUPAS10029. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.


Climate change on Twitter: topics, communities and conversations about the 2013 IPCC Working Group 1 report.
In September 2013 the Intergovernmental Panel on Climate Change published its Working Group 1 report, the first comprehensive assessment of physical climate science in six years, constituting a critical event in the societal debate about climate change. This paper analyses the nature of this debate in one public forum: Twitter. Using statistical methods, tweets were analyzed to discover the hashtags used when people tweeted about the IPCC report, and how Twitter users formed communities around their conversational connections. In short, the paper presents the topics and tweeters at this particular moment in the climate debate. The most used hashtags related to themes of science, geographical location and social issues connected to climate change. Particularly noteworthy were tweets connected to Australian politics, US politics, geoengineering and fracking. Three communities of Twitter users were identified. Researcher coding of Twitter users showed how these varied according to geographical location and whether users were supportive, unsupportive or neutral in their tweets about the IPCC. Overall, users were most likely to converse with users holding similar views. However, qualitative analysis suggested the emergence of a community of Twitter users, predominantly based in the UK, where greater interaction between contrasting views took place. This analysis also illustrated the presence of a campaign by the non-governmental organization Avaaz, aimed at increasing media coverage of the IPCC report.


Withdrawal, apathy and lack of vigor in late life depression: factorial validity and relationship to diagnosis.
Withdrawal, apathy and lack of vigor (WAV) describe a pattern of lack of vitality and dropping of interests and activities in later life, which may or may not indicate depression. This study examines (a) whether the Geriatric Depression Scale (GDS) contains a measure of this symptom cluster, and if so, (b) whether the presence of WAV leads to more false positive predictions by the GDS. A total of 444 Chinese older persons responded to the GDS and the Mini-Mental State Examination (MMSE), and were independently assessed by psychiatrists for depression and other diagnoses. Confirmatory factor analysis showed that six WAV symptoms formed a distinct cluster on the GDS. WAV was positively correlated with age and MMSE but most other symptom clusters measured on the GDS were not. Nonetheless, the ROC curves were essentially the same, regardless of whether the WAV items were included or not. Further analysis revealed that the optimal cutoff for the GDS without WAV produced fewer false positives, but also missed more true cases, than the full scale. The extent to which false positives become an issue depends on the specific threshold chosen (which entails a tradeoff with sensitivity) rather than the presence of WAV items.


Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats.
Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.


The interfaces between vitamin D, sleep and pain.
The role of vitamin D in osteomineral metabolism is well known. Several studies have suggested its action on different biological mechanisms, such as nociceptive sensitivity and sleep-wake cycle modulation. Sleep is an important biological process regulated by different regions of the central nervous system, mainly the hypothalamus, in combination with several neurotransmitters. Pain, which can be classified as nociceptive, neuropathic and psychological, is regulated by both the central and peripheral nervous systems. In the peripheral nervous system, the immune system participates in the inflammatory process that contributes to hyperalgesia. Sleep deprivation is an important condition related to hyperalgesia, and recently it has also been associated with vitamin D. Poor sleep efficiency and sleep disorders have been shown to have an important role in hyperalgesia, and be associated with different vitamin D values. Vitamin D has been inversely correlated with painful manifestations, such as fibromyalgia and rheumatic diseases. Studies have demonstrated a possible action of vitamin D in the regulatory mechanisms of both sleep and pain. The supplementation of vitamin D associated with good sleep hygiene may have a therapeutic role, not only in sleep disorders but also in the prevention and treatment of chronic pain conditions.


Urinary proteome and potential biomarkers associated with serial pathogenesis steps of focal segmental glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is a chronic nephropathy showing characteristic glomerular sclerosis. So far, the diagnosis and prognosis of FSGS rely mainly on the invasive biopsy. Searching for potential FSGS-associated urinary biomarkers representing pre-sclerotic and serial sclerotic stages of FSGS could be helpful to the non-invasive diagnosis and prognosis of FSGS. In the present study, we used a 2D gel-based proteomic approach to identify urinary proteins at pre-sclerotic and different sclerotic stages of an FSGS mouse model in order to find FSGS-related urinary proteins. The FSGS mouse model was established in Balb/c mice by a single injection of adriamycin, and disease severity was monitored by renal biological parameters and histopathological features. Urine was collected on days 0, 4, 7, 11, 15 and 20, and subjected to two-dimensional electrophoresis (2-DE) analysis. Proteins were identified by matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS) and a protein database search. Some of the identified proteins were confirmed by western blot analysis. We identified 37 urinary proteins showing characteristic patterns of dynamic changes along the disease course of FSGS. Early urinary proteins appearing before glomerular sclerosis were noticed. Importantly, 11 urine proteins are novel to FSGS and have known functions highly associated with different pathogenetic steps of the disease, including haemodynamic disturbance, podocyte apoptosis, ECM-protein deposition and glomerular sclerosis. Some urinary proteins appearing earlier than glomerular sclerosis could serve as potential early diagnostic biomarkers. The proteins with the pathogenic roles could serve as potential non-invasive prognostic markers of FSGS, and give an insight into pathogenic mechanisms of this sclerosis disease.


Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors.
Tightly clustered inositol trisphosphate receptors (IP3Rs) control localized Ca2+ liberation from the endoplasmic reticulum to generate repetitive Ca2+ puffs. Distributions of the interpuff interval (IPI), i.e., the waiting time between successive puffs, are found to be well characterized by a probability density function involving only two parameters, λ and ξ, which represent the basal rate of puff generation and the recovery rate from refractoriness, respectively. However, how the two parameters depend on the kinetic parameters of single IP3Rs in a cluster is still unclear. In this article, using a stochastic puff model and a single-channel data-based IP3R model, we establish the dependencies of λ and ξ on two important IP3R model parameters, IP3 concentration ([IP3]) and the recovery rate from Ca2+ inhibition (rlow). By varying [IP3] and rlow in physiologically plausible ranges, we find that the ξ-λ plane is comprised of only two disjoint regions, a biologically impermissible region and a region where each parameter set (ξ, λ) can be caused by using two different combinations of [IP3] and rlow. The two combinations utilize very different mechanisms to maintain the same IPI distribution, and the mechanistic difference provides a way of identifying IP3R kinetic parameters by observing properties of the IPI.


Isoflurane versus sevoflurane for early brain injury and expression of sphingosine kinase 1 after experimental subarachnoid hemorrhage.
The first step to treat aneurysmal subarachnoid hemorrhage (SAH) is aneurysmal obliteration under general anesthesia but not treat the SAH itself and the secondary effects. However, the identification of anesthetics with properties that help to attenuate post-SAH brain injury can be useful for improving outcomes of SAH patients. We examined whether 2% isoflurane and 3% sevoflurane posttreatment are protective against early brain injury (EBI) after SAH. This study used 87 8-week-old male CD-1 mice. We induced SAH by endovascular perforation in mice. Animals were randomly divided into 4 groups: sham-operated (n = 16), SAH + vehicle-medical air (n = 26), SAH + 2% isoflurane (n = 22), and SAH + 3% sevoflurane (n = 23). Neurobehavioral function, brain water content and Western blotting were evaluated at 24 h. The expression of sphingosine kinase (SphK), cleaved caspase-3 and cyclooxygenase-2 (COX2) was determined by Western blotting. Cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. Both 2% isoflurane and 3% sevoflurane significantly improved neurobehavioral function, and brain edema at 24 h after SAH and attenuated cell death, associated with an increase in SphK1, a decrease in cleaved caspase-3 and COX2. The neuroprotective effects were similar between 2% isoflurane and 3% sevoflurane. These findings suggest that both 2% isoflurane and 3% sevoflurane significantly inhibited EBI by suppressing post-SAH apoptosis and brain inflammation possibly via the SphK1-related pathway.


Rickettsia australis Activates Inflammasome in Human and Murine Macrophages.
Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8-12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.


A model for the optimization of anti-inflammatory treatment with chemerin.
Routine treatment of mild to moderate pain with a combination of non-steroidal anti-inflammatory drugs such as paracetamol in combination with corticoid opioids can lead to severe complications including death from gastrointestinal injury or to drug dependence. There is a need for the development of new safer drugs. Chemerin is a mediator promoting resolution of inflammation and it is then a promising candidate for a new treatment. A pilot experimental work using the zymosan-induced peritonitis model has found that injecting extra chemerin resulted in an approximately 1% reduction in the total number of inflammatory cells recruited. This paper combines and adapts existing mathematical models of inflammation to reproduce these results and to explore the therapeutic potential of chemerin through simulations. Analysis of the model predicts that the injection of chemerin at a concentration of 2000 ng ml-1 within the first 5 min of inflammation onset leads to maximal inflammation inhibition. The degree of inhibition is shown to be sensitive to data used for the fit with a mean inhibition of 22 ± 3.7% for a series of remove-one bootstrap tests, whereas optimal chemerin injection parameters were not. Overall sensitivity analysis identifies parameters of the model that need to be measured more accurately or with increased sampling rate to improve model robustness and confirm chemerin's therapeutic potential.


Modelling the impact of social protection on tuberculosis: the S-PROTECT project.
Tackling the social determinants of Tuberculosis (TB) through social protection is a key element of the post-2015 End TB Strategy. However, evidence informing policies are still scarce. Mathematical modelling has the potential to contribute to fill this knowledge gap, but existing models are inadequate. The S-PROTECT consortium aimed to develop an innovative mathematical modelling approach to better understand the role of social protection to improve TB care, prevention and control. S-PROTECT used a three-steps approach: 1) the development of a conceptual framework; 2) the extraction from this framework of three high-priority mechanistic pathways amenable for modelling; 3) the development of a revised version of a standard TB transmission model able to capture the structure of these pathways. As a test case we used the Bolsa Familia Programme (BFP), the Brazilian conditional cash transfer scheme. Assessing one of these pathways, we estimated that BFP can reduce TB prevalence by 4% by improving households income and thus their nutritional status. When looking at the direct impact via malnutrition (not income mediated) the impact was 33%. This variation was due to limited data availability, uncertainties on data transformation and the pathway approach taken. These results are preliminary and only aim to serve as illustrative example of the methodological challenges encountered in this first modelling attempt, nonetheless they suggest the potential added value of integrating TB standard of care with social protection strategies. Results are to be confirmed with further analysis. However, by developing a generalizable modelling framework, S-PROTECT proved that the modelling of social protection is complex, but doable and allowed to draw the research road map for the future in this field.


Review of transobturator and retropubic tape procedures for stress urinary incontinence.
Recently, various types of tension free vaginal tapes via retropubic and transobturator route (inside-out technique; outside-in technique) have been adopted for treatment of stress urinary incontinence. The aim of this review is to assess the recent evidence on effectiveness and complications of these tapes in stress urinary incontinence. There was no significant difference found between tension free vaginal tapes and colposuspension for the cure of stress urinary incontinence at 5 years in a multicentre randomized controlled trial. Vault and posterior vaginal wall prolapse were commoner after colposuspension. A recent systematic review and meta-analysis reported that subjective cure for inside-out technique (five randomized controlled trials) and outside-in technique (six randomized controlled trials) at 2-12 months was no better when compared with tension free vaginal tapes (odds ratio: 0.85; 95% confidence interval: 0.60-1.21). Bladder injuries (odds ratio: 0.12; 95% confidence interval: 0.05-0.33) and voiding difficulties (odds ratio: 0.55; 95% confidence interval: 0.31-0.98) were less common, whereas groin/thigh pain (odds ratio: 8.28; 95% confidence interval: 2.7-25.4) and vaginal injuries or mesh erosion (odds ratio: 1.96; 95% confidence interval: 0.87-4.39) were more common in transobturator tapes. Sexual function was overall improved; the pain being more with outside-in technique than inside-out technique route. The tension free tapes are effective in treating stress urinary incontinence; evidence for superiority of transobturator over retropubic tapes is currently limited.


Plasma norepinephrine in essential hypertension. A study of the studies.
Of 32 studies comparing plasma norepinephrine concentrations in hypertensive and normotensive groups, 28 (88%) reported higher levels in the hypertensive group. However, only 13 (41%) of the studies reported statistically significant hypertensive-normotensive differences in norepinephrine, leading the present attempt to identify factors differentiating "positive" studies (those reporting significant hypertensive-normotensive differences) from "negative" studies (those reporting nonsignificant differences). Hypertensive norepinephrine levels were similar in positive and negative studies (281 vs 288 pg/ml), but normotensive levels were lower in the positive studies (177 vs 269 pg/ml). When compared with the fluorimetric technique, the radioenzymatic type of assay was associated both with a lower frequency of positive results (25% vs 100%) and greater intrastudy standard deviations (152 vs 72 pg/ml). Hypertensive-normotensive differences varied inversely with age (r = -0.37). Resolution of the persisting controversy about norepinephrine levels in essential hypertension will require more attention to the causes of variability associated with the assay technique, to the sources, characteristics, and treatment of the normotensive controls, and to the age of the patient population.


Variation and genomic localization of genes encoding Drosophila melanogaster male accessory gland proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
Accessory gland proteins from Drosophila melanogaster males have been separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis into nine major bands. When individual males from 175 strains were examined, considerable polymorphism for nearly one-half of the major protein bands was seen, including null alleles for three bands. Variation was observed not only among long-established laboratory strains but also among stocks recently derived from natural populations. There was little difference in the amount of variation between P and M strains, indicating that P element mutagenesis is not a factor producing the variation. Codominant expression of variants for each of five bands was found in heterozygotes, suggesting structural gene variation and not posttranslational modification variation. Stocks carrying electrophoretic variants of four of the major proteins were used to map the presumed structural genes for these proteins; the loci were found to be dispersed on the second chromosome. Since males homozygous for variant proteins were fertile, the polymorphism seems to have little immediate effect on successful sperm transfer. We propose that a high degree of polymorphism can be tolerated because these proteins play a nutritive rather than enzymatic role in Drosophila reproduction.


Polarizable embedding with a multiconfiguration short-range density functional theory linear response method.
We present here the coupling of a polarizable embedding (PE) model to the recently developed multiconfiguration short-range density functional theory method (MC-srDFT), which can treat multiconfigurational systems with a simultaneous account for dynamical and static correlation effects. PE-MC-srDFT is designed to combine efficient treatment of complicated electronic structures with inclusion of effects from the surrounding environment. The environmental effects encompass classical electrostatic interactions as well as polarization of both the quantum region and the environment. Using response theory, molecular properties such as excitation energies and oscillator strengths can be obtained. The PE-MC-srDFT method and the additional terms required for linear response have been implemented in a development version of Dalton. To benchmark the PE-MC-srDFT approach against the literature data, we have investigated the low-lying electronic excitations of acetone and uracil, both immersed in water solution. The PE-MC-srDFT results are consistent and accurate, both in terms of the calculated solvent shift and, unlike regular PE-MCSCF, also with respect to the individual absolute excitation energies. To demonstrate the capabilities of PE-MC-srDFT, we also investigated the retinylidene Schiff base chromophore embedded in the channelrhodopsin protein. While using a much more compact reference wave function in terms of active space, our PE-MC-srDFT approach yields excitation energies comparable in quality to CASSCF/CASPT2 benchmarks.


Immunohistochemical approach to study cylindrospermopsin distribution in tilapia (Oreochromis niloticus) under different exposure conditions.
Cylindrospermopsin (CYN) is a cytotoxic cyanotoxin produced by several species of freshwater cyanobacteria (i.e., Aphanizomenon ovalisporum). CYN is a tricyclic alkaloid combined with a guanidine moiety. It is well known that CYN inhibits both protein and glutathione synthesis, and also induces genotoxicity and the alteration of different oxidative stress biomarkers. Although the liver and kidney appear to be the main target organs for this toxin based on previous studies, CYN also affects other organs. In the present study, we studied the distribution of CYN in fish (Oreochromis niloticus) under two different exposure scenarios using immunohistochemical (IHC) techniques. In the first method, fish were exposed acutely by intraperitoneal injection or by gavage to 200 µg pure CYN/Kg body weight (bw), and euthanized after 24 h or five days of exposure. In the second method, fish were exposed by immersion to lyophilized A. ovalisporum CYN-producing cells using two concentration levels (10 or 100 µg/L) for two different exposure times (7 or 14 days). The IHC was carried out in liver, kidney, intestine, and gills of fish. Results demonstrated a similar pattern of CYN distribution in both experimental methods. The organ that presented the most immunopositive results was the liver, followed by the kidney, intestine, and gills. Moreover, the immunolabeling signal intensified with increasing time in both assays, confirming the delayed toxicity of CYN, and also with the increment of the dose, as it is shown in the sub-chronic assay. Thus, IHC is shown to be a valuable technique to study CYN distribution in these organisms.


Improving the production of AHL lactonase AiiO-AIO6 from Ochrobactrum sp. M231 in intracellular protease-deficient Bacillus subtilis.
Quorum quenching (QQ) blocks bacterial cell-to-cell communication (i.e., quorum sensing), and is a promising antipathogenic strategy to control bacterial infection via inhibition of virulence factor expression and biofilm formation. QQ enzyme AiiO-AIO6 from Ochrobactrum sp. M231 has several excellent properties and shows biotherapeutic potential against important bacterial pathogens of aquatic species. AiiO-AIO6 can be secretory expressed in Bacillus subtilis via a non-classical secretion pathway. To improve AiiO-AIO6 production, four intracellular protease-deletion mutants of B. subtilis 1A751 were constructed by individually knocking out the intracellular protease-encoding genes (tepA, ymfH, yrrN and ywpE). The AiiO-AIO6 expression plasmid pWB-AIO6BS was transformed into the B. subtilis 1A751 and its four intracellular protease-deletion derivatives. Results showed that all recombinant intracellular protease-deletion derivatives (BSΔtepA, BSΔymfH, BSΔyrrN and BSΔywpE) had a positive impact on AiiO-AIO6 production. The highest amount of AiiO-AIO6 extracellular production of BSΔywpE in shake flask reached 1416.47 U/mL/OD600, which was about 121% higher than that of the wild-type strain. Furthermore, LC-MS/MS analysis of the degrading products of 3-oxo-C8-HSL by purification of AiiO-AIO6 indicated that AiiO-AIO6 was an AHL-lactonase which hydrolyzes the lactone ring of AHLs. Phylogenetic analysis showed that AiiO-AIO6 was classified as a member of the α/β hydrolase family with a conserved "nucleophile-acid-histidine" catalytic triad. In summary, this study showed that intracellular proteases were responsible for the reduced yields of heterologous proteins and provided an efficient strategy to enhance the extracellular production of AHL lactonase AiiO-AIO6.


Can child care workers contribute to the early detection of autism spectrum disorders? A comparison between screening instruments with child care workers versus parents as informants.
Several screening instruments for ASD in young children were developed during the last decades. Only few studies compare the discriminative power of these instruments in the same sample. In particular comparisons of instruments that use different informants are scarce in young children. The current study compared the discriminant ability of the Checklist for Early Signs of Developmental Disorders (CESDD) filled out by child care workers with that of frequently used parent questionnaires in a sample of 357 children between 5.57 and 48.13 months old who showed signs of ASD or language delay. The discriminant power of the CESDD was as good as that of parent questionnaires. Therefore, inclusion of child care workers in the early detection of ASD seems promising.


An experimental 'Life' for an experimental life: Richard Waller's biography of Robert Hooke (1705).
Richard Waller's 'Life of Dr Robert Hooke', prefixed to his edition of Hooke's Posthumous Works (1705), is an important source for the life of one of the most eminent members of the early Royal Society. It also has the distinction of being one of the earliest biographies of a man of science to be published in English. I argue that it is in fact the first biography to embrace the subject's natural-philosophical work as the centre of his life, and I investigate Waller's reasons for adopting this strategy and his struggle with the problem of how to represent an early experimental philosopher in print. I suggest that Waller eschews the 'Christian philosopher' tradition of contemporary biography - partly because of the unusually diverse and fragmentary nature of Hooke's intellectual output - and draws instead upon the structure of the Royal Society's archive as a means of organizing and understanding Hooke's life. The most quoted phrase from Waller's biography is that Hooke became 'to a crime close and reserved' in later life; this essay argues that Waller's biographical sketch was fashioned in order to undo the effects of that reserve. In modelling his approach very closely on the structure of the society's records he was principally concerned with making Hooke's work and biography accessible, intelligible and useful to the fellowship in a context familiar to them, a context which had provided the institutional framework for most of Hooke's adult life. I argue that Waller's 'Life' was also intended to make the largest claims for Hooke's intellectual standing that the author dared in the context of the enmity between Hooke and Isaac Newton once the latter became president of the Royal Society. However, I also adduce fresh manuscript evidence that Waller actually compiled, but did not publish, a defence of Hooke's claim to have discovered the inverse square law of gravity, allowing us to glimpse a much more assertive biography of Hooke than the published version.


Genomic Evidence of Local Adaptation to Climate and Diet in Indigenous Siberians.
The indigenous inhabitants of Siberia live in some of the harshest environments on earth, experiencing extended periods of severe cold temperatures, dramatic variation in photoperiod, and limited and highly variable food resources. While the successful long-term settlement of this area by humans required multiple behavioral and cultural innovations, the nature of the underlying genetic changes has generally remained elusive. In this study, we used a three-part approach to identify putative targets of positive natural selection in Siberians. We first performed selection scans on whole exome and genome-wide single nucleotide polymorphism array data from multiple Siberian populations. We then annotated candidates in the tails of the empirical distributions, focusing on candidates with evidence linking them to biological processes and phenotypes previously identified as relevant to adaptation in circumpolar groups. The top candidates were then genotyped in additional populations to determine their spatial allele frequency distributions and associations with climate variables. Our analysis reveals missense mutations in three genes involved in lipid metabolism (PLA2G2A, PLIN1, and ANGPTL8) that exhibit genomic and spatial patterns consistent with selection for cold climate and/or diet. These variants are unified by their connection to brown adipose tissue and may help to explain previously observed physiological differences in Siberians such as low serum lipid levels and increased basal metabolic rate. These results support the hypothesis that indigenous Siberians have genetically adapted to their local environment by selection on multiple genes.


Does apolipoprotein E polymorphism influence susceptibility to malaria?
Outcome of infection varies greatly among people, and in the case of three very different viruses, it is determined by apolipoprotein E (APOE) genotype. APOE might affect outcome of malaria infection also, since apoE protein and the protozoon (like the viruses) share cell entry mediators (heparan sulphate proteoglycans and/or specific apoE receptors). APOE polymorphisms give rise to protein variants that differ in binding strength to these mediators; thus, the extent of competition between apoE and protozoon for cell entry, and hence magnitude of protozoan damage, might depend on apoE isoform. Genotypes of infants infected with malaria were examined. It was found that APOE epsilon 2 homozygotes became infected at an earlier age than those carrying the other genotypes, the difference being statistically significant. Parasite densities, all of which were low, did not differ significantly. This effect, although based on small numbers, suggests that APOE epsilon 2 may be a risk factor for early infection.


Cholera toxin induces synthesis of phospholipase A2-activating protein.
The mechanism of cholera toxin (CT)-stimulated arachidonate metabolism was evaluated. CT caused rapid in vitro synthesis of prostaglandin E2 (PGE2) in murine smooth muscle-like cells (BC3H1), reaching maximal levels within 3 to 4 min. In comparison, cyclic AMP (cAMP) levels were unchanged, and addition of dibutyryl cAMP did not affect PGE2 synthesis. CT-induced PGE2 synthesis was prevented by actinomycin D or cycloheximide, indicating a need for de novo protein synthesis. Northern blot analysis of total RNA from BC3H1 cells revealed that exposure to CT resulted in an increase in abundance of mRNA encoding phospholipase A2 (PLA2)-activating protein (PLAP). PLAP is a regulatory protein that increases the enzymatic activity of cellular PLA(2), which in turn causes increased hydrolysis of arachidonate from membrane phospholipids. Furthermore, CT evoked the accumulation of PLAP mRNA in J774 (murine monocyte/macrophage) and Caco-2 (human intestinal epithelial) cells in vitro, but the responses were more delayed than that of BC3H1 cells. A protein band of approximately 35 kDa, which corresponded to the size of PLAP, was observed in sodium dodecyl sulfate extracts of Caco-2 cells by Western blot (immunoblot) analysis using affinity-purified antibodies to PLAP synthetic peptides. Synthesis of PLAP protein was increased after 2 h of exposure to CT. Exposure of mouse intestinal loops to either CT or live Salmonella typhimurium for 3 h increased mucosal PLAP mRNA levels. The role of PLAP in CT-induced PGE2 synthesis provides an attractive explanation for the reported suppression of CT-induced intestinal secretion by inhibitors of protein synthesis.


Sum of parts is greater than the whole: inference of common genetic history of populations.
Reconstructability of population history, from genetic information of extant individuals, is studied under a simulation setting. We do not address the issue of accuracy of the reconstruction algorithms: we assume the availability of the theoretical best algorithm. On the other hand, we focus on the fraction (1 - f) of the common genetic history that is irreconstructible or impenetrable. Thus the fraction, f, gives an upper bound on the extent of estimability. In other words, there exists no method that can reconstruct a fraction larger than f of the entire common genetic history. For the realization of such a study, we first define a natural measure of the amount of genetic history. Next, we use a population simulator (from literature) that has at least two features. Firstly, it has the capability of providing samples from different demographies, to effectively reflect reality. Secondly, it also provides the underlying relevant genetic history, captured in its entirety, where such a measure is applicable. Finally, to compute f, we use an information content measure of the relevant genetic history. The simulator of choice provided the following demographies: Africans, Europeans, Asians and Afro-Americans. We observe that higher the rate of recombination, lower the value of f, while f is invariant over varying mutation rates, in each of the demographies. The value of f increases with the number of samples, reaching a plateau and suggesting that in all the demographies at least about one-third of the relevant genetic history is impenetrable. The most surprising observation is that the the sum of the reconstructible history of the subsegments is indeed larger than the reconstructible history of the whole segment. In particular, longer the chromosomal segment, smaller the value of f, in all the demographies. We present the very first framework for measuring the fraction of the relevant genetic history of a population that is mathematically elusive. Our observed results on the tested demographies suggest that it may be better to aggregate the analysis of smaller chunks of chromosomal segments than fewer large chunks. Also, no matter the richness of samples in a population, at least one-third of the population genetic history is impenetrable. The framework also opens up possible new lines of investigation along the following. Given the characteristics of a population, possibly derived from observed extant individuals, to estimate the (1) optimal sample size and (2) optimal sequence length for the most informative analysis.


Hemodialysis vascular access options in pediatrics: considerations for patients and practitioners.
Recent data indicate that the incidence of end-stage renal disease (ESRD) in pediatric patients (age 0-19 years) has increased over the past two decades. Similarly, the prevalence of ESRD has increased threefold over the same period. Hemodialysis (HD) continues to be the most frequently utilized modality for renal replacement therapy in incident pediatric ESRD patients. The number of children on HD exceeded the sum total of those on peritoneal dialysis and those undergoing pre-emptive renal transplantation. Choosing the best vascular access option for pediatric HD patients remains challenging. Despite a national initiative for fistula first in the adult hemodialysis population, the pediatric nephrology community in the United States of America utilizes central venous catheters as the primary dialysis access for most patients. Vascular access management requires proper advance planning to assure that the best permanent access is placed, seamless communication involving a multidisciplinary team of nephrologists, nurses, surgeons, and interventional radiologists, and ongoing monitoring to ensure a long life of use. It is imperative that practitioners have a long-term vision to decrease morbidity in this unique patient population. This article reviews the various types of pediatric vascular accesses used worldwide and the benefits and disadvantages of these various forms of access.


Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.


Utilization of Robotic Exoskeleton for Overground Walking in Acute and Chronic Stroke.
Stroke commonly results in gait deficits which impacts functional ambulation and quality of life. Robotic exoskeletons (RE) for overground walking are devices that are programmable to provide high dose and movement-impairment specific assistance thus offering new rehabilitation possibilities for recovery progression in individuals post stroke. The purpose of this investigation is to present preliminary utilization data in individuals with acute and chronic stroke after walking overground with an RE. Secondary analysis on a subset of individuals is presented to understand the mechanistic changes due to RE overground walking. Thirty-eight participants with hemiplegia secondary to stroke were enrolled in a clinical trial conducted at eight rehabilitation centers. Data is presented for four sessions of overground walking in the RE over the course of 2 weeks. Participants continued their standard of care if they had any ongoing therapy at the time of study enrollment. Gait speed during the 10 Meter Walk Test, Gait deviations and the Functional Ambulation Category (FAC) data were collected before (baseline) and after (follow-up) the RE walking sessions. Walking speed significantly increased between baseline and follow-up for participants in the chronic (p <0.01) and acute (p < 0.05) stage of stroke recovery. FAC level significantly improved (p < 0.05) and there were significantly fewer (p < 0.05) gait deviations observed for participants in the acute stages of stroke recovery between baseline and follow-up. Secondary analysis on a subset of eight participants indicated that after four sessions of overground walking with the RE, the participants significantly improved their spatial symmetry. The walk time, step count and ratio of walk time to up time increased from first session to the last session for participants in the chronic and acute stages of stroke. The RE was effectively utilized for overground walking for individuals with acute and chronic stroke with varying severity levels. The results demonstrated an increase in walking speed, improvement in FAC and a decrease in gait deviations (from baseline to follow-up) after four sessions of overground walking in the RE for participants. In addition, preliminary data indicated that spatial symmetry and step length also improved after utilization of an RE for overground walking.


Effective determination of the long-lived nuclide 41Ca in nuclear reactor bioshield concretes: comparison of liquid scintillation counting and accelerator mass spectrometry.
The routine application of liquid scintillation counting to (41)Ca determination has been hindered by the absence of traceable calibration standards of known (41)Ca activity concentrations. The introduction of the new IRMM (41)Ca mass-spectrometric standards with sufficiently high (41)Ca activities for radiometric detection has partly overcome this although accurate measurement of stable Ca concentrations coupled with precise half-life data are still required to correct the certified (41)Ca:(40)Ca ratios to (41)Ca activity concentrations. In this study, (41)Ca efficiency versus quench curves have been produced using the IRMM standard, and their accuracy validated by comparison with theoretical calculations of (41)Ca efficiencies. Further verification of the technique was achieved through the analysis of (41)Ca in a reactor bioshield core that had been previously investigated for other radionuclide variations. Calcium-41 activity concentrations of up to 25 Bq/g were detected. Accelerator mass spectrometry (AMS) measurements of the same suite of samples showed a very good agreement, providing validation of the procedure. Calcium-41 activity concentrations declined exponentially with distance from the core of the nuclear reactor and correlated well with the predicted neutron flux.


Longitudinal measurement invariance of the effort-reward imbalance scales in the Young Finns study.
In order to make valid conclusions about individual change in work-related risk factors it is important to examine whether these factors are measurement invariant over time. We tested the measurement invariance of the effort-reward imbalance (ERI) scales using the ERI Questionnaire (ERI-Q). Additionally, we examined the criterion validity of the ERI scales. The sample used in this study was population-based and comprised 2128 participants (56.6% women) in full-time employment. Data on effort, reward and self-reported general stress were collected in 2007 and 2012. Measurement invariance was assessed separately for the effort and reward scales, with reward treated as a first-order and as a second-order variable. Criterion validity of the ERI scales was also examined using a single-item measure of general stress. Effort and reward were found to be measurement invariant over time, that is, they measured the same latent variable across both time points. Furthermore, ERI and its components showed adequate criterion validity, and effort was additionally found to prospectively predict general stress 5 years later (β=0.072, 95% CI 0.013 to 0.131). Our results indicate that changes in the scores of the ERI scales are more likely caused by changes in perceptions of work characteristics than by changes in the construct of the scales. Additionally, the results support the criterion validity of ERI and its components.


Nicotine receptor partial agonists for smoking cessation.
Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers. We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low-quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80).One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development.We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease-specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline.The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high-quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high-quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate-quality evidence). Four trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high-quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow-up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern. Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research.Future trials of cytisine may test extended regimens and more intensive behavioural support.


In Vivo Imaging Sheds Light on Immune Cell Migration and Function in Cancer.
There is ample evidence for both beneficial and harmful involvement of the immune system in tumor development and spread. Immune cell recruitment to tumors is essential not only for the success of anticancer immune therapies but also for tumor-induced immune suppression. Now that immune-based therapies are playing an increasingly important role in treatment of solid tumors such as metastatic melanomas, precise analysis of the in vivo contributions of different leukocyte subsets in tumor immunity has become an even greater priority. Recently, this goal has been markedly facilitated by the use of intravital microscopy, which has enabled us to visualize the dynamic interactions between cells of the immune system and tumor targets in the context of the tumor microenvironment. For example, intravital imaging techniques have shed new light on T cell infiltration of tumors, the mechanisms of cancer cell killing, and how myeloid cells contribute to tumor tolerance and spread. This mini-review summarizes the recent advances made to our understanding of the roles of innate and adaptive immune cells in cancer based on the use of these in vivo imaging approaches.


Clinical Use of Mood Stabilizers With Antidepressants in Asia: Report From the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) Projects in 2004 and 2013.
As most reports concerning treatment with combinations of mood stabilizer (MS) with antidepressant (AD) drugs are based in the West, we surveyed characteristics of such cotreatment in 42 sites caring for the mentally ill in 10 Asian countries. This cross-sectional, pharmacoepidemiologic study used 2004 and 2013 data from the REAP-AD (Research Study on Asian Psychotropic Prescription Patterns for Antidepressants) to evaluate the rates and doses of MSs given with ADs and associated factors in 4164 psychiatric patients, using standard bivariate methods followed by multivariable logistic regression modeling. Use of MS + AD increased by 104% (5.5% to 11.2%) between 2004 and 2013 and was much more associated with diagnosis of bipolar disorder than major depression or anxiety disorder, as well as with hospitalization > outpatient care, psychiatric > general-medical programs, and young age (all P < 0.001), but not with country, sex, or AD dose. The findings provide a broad picture of contemporary use of MSs with ADs in Asia, support predictions that such treatment increased in recent years, and was associated with diagnosis of bipolar disorder, treatment in inpatient and psychiatric settings, and younger age.


Mechanics regulates fate decisions of human embryonic stem cells.
Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function.


Auricular acupuncture for chronic back pain in adults: a systematic review and metanalysis.
To investigate randomized clinical trials on the action of auricular acupuncture for chronic back pain in adults, and to identify the most commonly used outcomes for assessing this condition, the protocol used for applying the intervention, and the efficacy of the therapy on pain intensity. A systematic review and a metanalysis were carried out between June 2017 and May 2018, based on the PubMed, CINAHL, PEDro, Embase, Scopus, and the Virtual Health Library databases. Reference lists of systematic reviews were also explored. 427 studies were located, 15 included in the qualitative analysis, and seven in the quantitative analysis. Auricular acupuncture led to positive results in 80% of the studies. The most commonly used outcomes were pain intensity and quality, medication consumption, physical disability, and quality of life. There is a lack of protocol standardization for auricular acupuncture for chronic back pain. The metanalysis results showed that auricular acupuncture was effective in reducing pain intensity scores (p=0.038). Auricular acupuncture is a promising practice for the treatment of chronic back pain in adults.


Contribution of the SitABCD, MntH, and FeoB metal transporters to the virulence of avian pathogenic Escherichia coli O78 strain chi7122.
The roles of SitABCD, MntH, and FeoB metal transporters in the virulence of avian pathogenic Escherichia coli (APEC) O78 strain chi7122 were assessed using isogenic mutants in chicken infection models. In a single-strain infection model, compared to chi7122, the Deltasit strain demonstrated reduced colonization of the lungs, liver, and spleen. Complementation of the Deltasit strain restored virulence. In a coinfection model, compared to the virulent APEC strain, the Deltasit strain demonstrated mean 50-fold, 126-fold, and 25-fold decreases in colonization of the lungs, liver, and spleen, respectively. A DeltamntH Deltasit strain was further attenuated, demonstrating reduced persistence in blood and mean 1,400-fold, 954-fold, and 83-fold reduced colonization in the lungs, liver, and spleen, respectively. In coinfections, the DeltafeoB Deltasit strain demonstrated reduced persistence in blood but increased colonization of the liver. The DeltamntH, DeltafeoB, and DeltafeoB DeltamntH strains were as virulent as the wild type in either of the infection models. Strains were also tested for sensitivity to oxidative stress-generating agents. The DeltamntH Deltasit strain was the most sensitive strain and was significantly more sensitive than the other strains to hydrogen peroxide, plumbagin, and paraquat. sit sequences were highly associated with APEC and human extraintestinal pathogenic E. coli compared to commensal isolates and diarrheagenic E. coli. Comparative genomic analyses also demonstrated that sit sequences are carried on conjugative plasmids or associated with phage elements and were likely acquired by distinct genetic events among pathogenic E. coli and Shigella sp. strains. Overall, the results demonstrate that SitABCD contributes to virulence and, together with MntH, to increased resistance to oxidative stress.


Mesopic visual acuity is less crowded.
The decrease in visual acuity under low luminance conditions is well known. Recent laboratory evidence showed that crowding under low luminance (mesopic) light levels is less robust than under photopic conditions. The present study examines whether such differences in crowding influence clinical measurements of mesopic visual acuity, including test-retest repeatability. Twenty adult subjects with normal or corrected to normal visual acuity were recruited for the study. Monocular visual acuity was measured under photopic (228 cd/m2) and mesopic (0.164 cd/m2) luminance conditions using a letter chart, similar in principle to the ETDRS logMAR chart, presented on a computer monitor. Three rows of five letters, each row differing in size by 0.05 logMAR from largest to smallest were displayed at the center of the monitor. The level of crowding was varied by varying the separation between horizontally adjacent letters from 100% optotype size to 50, 20, and 10% optotype size. Inter-row spacing was proportional to optotype size. Observers read the letters on the middle row only. Measurements continued by reducing the size of the letters, until three or more errors on the middle row were made. Each correctly identified letter contributed 0.01 to the recorded logMAR score. All measurements were repeated for each subject on two separate days. Visual acuity (logMAR) was significantly better under photopic than mesopic luminance conditions with a mean difference of 0.48 logMAR. Visual acuity also decreased with decreasing letter separation (i.e. increase in crowding). However, the decrease in visual acuity for the smallest letter separation was less under the mesopic luminance condition, even after accounting for the increased size of threshold acuity letters. Test-retest repeatability for mesopic and photopic conditions was not significantly different. Crowding under mesopic luminance conditions has less impact on visual acuity than under photopic luminance.


The Discovery of a Second Field Methane Brown Dwarf from Sloan Digital Sky Survey Commissioning Data.
We report the discovery of a second field methane brown dwarf from the commissioning data of the Sloan Digital Sky Survey (SDSS). The object, SDSS J134646.45-003150.4 (hereafter SDSS 1346-00), was selected because of its very red color and stellar appearance. Its spectrum between 0.8 and 2.5 µm is dominated by strong absorption bands of H2O and CH4 and closely mimics those of Gliese 229B and SDSS 162414.37+002915.6 (hereafter SDSS 1624+00), two other known methane brown dwarfs. SDSS 1346-00 is approximately 1.5 mag fainter than Gliese 229B, suggesting that it lies about 11 pc from the Sun. The ratio of flux at 2.1 µm to that at 1.27 µm is larger for SDSS 1346-00 than for Gliese 229B and SDSS 1624+00, which suggests that SDSS 1346-00 has a slightly higher effective temperature than the others. Based on a search area of 130 deg2 and a detection limit of z*=19.8, we estimate a space density of 0.05 pc-3 for methane brown dwarfs with Teff approximately 1000 K in the 40 pc3 volume of our search. This estimate is based on small-sample statistics and should be treated with appropriate caution.


Covalently-crosslinked mucin biopolymer hydrogels for sustained drug delivery.
The sustained delivery of both hydrophobic and hydrophilic drugs from hydrogels has remained a challenge requiring the design and scalable production of complex multifunctional synthetic polymers. Here, we demonstrate that mucin glycoproteins, the gel-forming constituents of native mucus, are suitable for assembly into robust hydrogels capable of facilitating the sustained release of hydrophobic and hydrophilic drugs. Covalently-crosslinked mucin hydrogels were generated via exposure of methacrylated mucin to ultraviolet light in the presence of a free radical photoinitiator. The hydrogels exhibited an elastic modulus similar to that of soft mammalian tissue and were sensitive to proteolytic degradation by pronase. Paclitaxel, a hydrophobic anti-cancer drug, and polymyxin B, a positively-charged hydrophilic antibacterial drug, were retained in the hydrogels and released linearly with time over seven days. After four weeks of drug release, the hydrogels continued to release sufficient amounts of active paclitaxel to reduce HeLa cell viability and sufficient amounts of active polymyxin B to prevent bacterial proliferation. Along with previously-established anti-inflammatory, anti-viral, and hydrocarbon-solubilizing properties of mucin, the results of this study establish mucin as a readily-available, chemically-versatile, naturally-biocompatible alternative to complex multifunctional synthetic polymers as building blocks in the design of biomaterials for sustained drug delivery.


Distinguishing Multisystem Inflammatory Syndrome in Children From Kawasaki Disease and Benign Inflammatory Illnesses in the SARS-CoV-2 Pandemic.
The aim of the study was to compare presenting clinical and laboratory features among children meeting the surveillance definition for multisystem inflammatory syndrome in children (MIS-C) across a range of illness severities. This is a retrospective single-center study of patients younger than 21 years presenting between March 1 and May 15, 2020. Included patients met the Centers for Disease Control and Prevention criteria for MIS-C (inflammation, fever, involvement of 2 organ systems, lack of alternative diagnoses). We defined 3 subgroups by clinical outcomes: (1) critical illness requiring intensive care interventions; (2) patients meeting Kawasaki disease (KD) criteria but not requiring critical care; and (3) mild illness not meeting either criteria. A comparator cohort included patients with KD at our institution during the same time frame in 2019. Thirty-three patients were included (5, critical; 8, 2020 KD; 20, mild). The median age for the critical group was 10.9 years (2.7 for 2020 KD; 6.0 for mild, P = 0.033). The critical group had lower median absolute lymphocyte count (850 vs 3005 vs 2940/uL, P = 0.005), platelets (150 vs 361 vs 252 k/uL, P = 0.005), and sodium (129 vs 136 vs 136 mmol/L, P = 0.002), and higher creatinine (0.7 vs 0.2 vs 0.3 mg/dL, P = 0.002). In the critical group, 60% required vasoactive medications, and 40% required mechanical ventilation. Clinical and laboratories features were similar between the 2020 and 2019 KD groups. We describe 3 groups with inflammatory syndromes during the SARS-CoV-2 pandemic. The initial profile of lymphopenia, thrombocytopenia, hyponatremia, and abnormal creatinine may help distinguish critically ill MIS-C patients from classic/atypical KD or more benign acute inflammation.


Valence, arousal, familiarity, concreteness, and imageability ratings for 292 two-character Chinese nouns in Cantonese speakers in Hong Kong.
Words are frequently used as stimuli in cognitive psychology experiments, for example, in recognition memory studies. In these experiments, it is often desirable to control for the words' psycholinguistic properties because differences in such properties across experimental conditions might introduce undesirable confounds. In order to avoid confounds, studies typically check to see if various affective and lexico-semantic properties are matched across experimental conditions, and so databases that contain values for these properties are needed. While word ratings for these variables exist in English and other European languages, ratings for Chinese words are not comprehensive. In particular, while ratings for single characters exist, ratings for two-character words-which often have different meanings than their constituent characters, are scarce. In this study, ratings for 292 two-character Chinese nouns were obtained from Cantonese speakers in Hong Kong. Affective variables, including valence and arousal, and lexico-semantic variables, including familiarity, concreteness, and imageability, were rated in the study. The words were selected from a film subtitle database containing word frequency information that could be extracted and listed alongside the resulting ratings. Overall, the subjective ratings showed good reliability across all rated dimensions, as well as good reliability within and between the different groups of participants who each rated a subset of the words. Moreover, several well-established relationships between the variables found consistently in other languages were also observed in this study, demonstrating that the ratings are valid. The resulting word database can be used in studies where control for the above psycholinguistic variables is critical to the research design.


Increase in observed mental health difficulties one year after acute coronary syndrome: general practitioner survey.
General practitioners (GPs) are often the first to assess mental health difficulties after acute coronary syndrome (ACS). To determine whether GPs observed an increase in mental health difficulties one-year post-hospitalisation for ACS. Postal survey. GPs rated patients (n = 442) as having probable (GP assessed 10%) or definite (formally assessed 7%) mental health difficulties pre-hospitalisation. Post-hospitalisation the prevalence of probable cases increased significantly to 19% (OR = 4.3, 95% CI 2.1-10.2, P < 0.001). In multivariate analysis, only smoking at index hospitalisation was associated with being assessed as a new case of probable/formal mental health difficulties (RR = 2.1, 95% CI 1.3-3.4, P = 0.003). Forty-seven percent of cases were prescribed some medication for this problem. GPs recorded a significant increase in mental health difficulties in ACS patients 12 months after hospitalisation, with smoking used as an indicator of new cases.